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Rivas-Salazar v. Immigration and Naturalization Service | Ninth Circuit | 04-03-1996 | www.anylaw.com
Research the case of Rivas-Salazar v. Immigration and Naturalization Service, from the Ninth Circuit, 04-03-1996. AnyLaw is the FREE and Friendly legal research service that gives you unlimited access to massive amounts of valuable legal data.
Rivas-Salazar v. Immigration and Naturalization Service
MEMORANDUM*fn*
I.
David Peter Rivas-Salazar petitions for review of the Board of Immigration Appeals' ("BIA") dismissal of his appeal from the immigration Judge's ("IJ") denial of asylum and withholding of deportation. He challenges the BIA's finding that he failed to demonstrate eligibility for asylum or withholding of deportation as prescribed by Immigration and Nationality Act sections 208(a) and 243(h).
II.
The burden of proof is on the petitioner to establish eligibility for asylum. INS v. Stevic, 467 U.S. 407, n.16, 81 L. Ed. 2d 321, 104 S. Ct. 2489 (1984). We uphold the BIA's denial of asylum if it is supported by reasonable, substantial, and probative evidence in the record. INS v. Elias-Zacarias, 502 U.S. 478, 481, 117 L. Ed. 2d 38, 112 S. Ct. 812 (1992).
Rivas-Salazar contends that he is eligible for asylum because he established that he was persecuted on account of his political activity as a student at Federico Villareal University. The BIA found that Rivas-Salazar failed to establish eligibility for asylum. First, it found that the petitioner failed to establish a reasonable belief that the men who attacked him were members of the guerrilla movement Sendero Luminoso. Second, the BIA found that the petitioner failed to indicate that he expressed a political opinion in refusing to attend the university. Third, the BIA found that at most, Rivas-Salazar had shown that like others at the university, he was a victim of random attacks by members of the Sendero Luminoso.
Rivas-Salazar testified that Federico Villareal University is supported by the political party APRA. Rivas-Salazar would also have us believe that the Sendero Luminoso imputed to him a particular political ideology on account of his attendance at an APRA-supported university. While it is the case that one's affiliation with a politically oppressed group may raise an inference of political persecution, see C.F.R. § 208.13(b)(2)(i), Rivas-Salazar has not presented evidence sufficient to support such a claim. Like a majority of the students at the university, he participated in political rallies and put up posters as an implicit condition of his attendance at the university. His activity could be labeled as political. On the other hand, his activity could be labeled as non-political since it was an implicit condition of his attendance at the university. Rivas-Salazar presented no evidence to indicate that his activities were based on his political opinion. In fact, the BIA noted that the petitioner did not attend the university for political reasons, but rather for a purely economic reasons.
"The ordinary meaning of the phrase 'persecution on account of . . . political opinion' in § 101(a)(42) is persecution on account of the victim's political opinion, not the persecutor's." Elias-Zacarias, 502 U.S. at 482. Although the Sendero Luminoso guerillas may have targeted Rivas-Salazar because he was a student at the university sponsored by a political party that opposed their political ideology, this evidence alone is not sufficient to establish persecution on account of political opinion. Rivas-Salazar presented no evidence of his political opinion.
The petitioner also contends that he left Peru because he was fearful that the Sendero Luminoso would forcibly recruit him. The refusal to join a guerilla organization, alone, does not establish a well-founded fear of persecution because of a political opinion. Id. at 483. Since petitioner has not established what, if any, political opinion he held, he has failed to demonstrate the necessity to reverse the BIA finding to the contrary. Pursuant to Elias-Zacarias, we uphold the BIA's denial of asylum because it is supported by reasonable, substantial, and probative evidence in the record.
III.
Rivas-Salazar argues that he deserves a new evidentiary hearing in order for him to attempt to satisfy the requirements of Elias-Zacarias. He contends that during the pendency of his appeal of the IJ's decision to the BIA, the Supreme Court issued its opinion in Elias-Zacarias. He cites to Fisher v. INS, 37 F.3d 1371, 1377 (9th Cir. 1994) as authority. Fisher has been amended and superseded. Fisher v. INS, 61 F.3d 1366 (9th Cir. 1994), reh'ing en banc granted. He cites no other authority to support his proposition that he should get a second bite at the apple. This argument is meritless and, in any event, his "new" evidence would not change the result.
IV.
The well-founded fear standard for asylum requires less of an evidentiary showing than the clear probability standard for withholding of deportation. INS v. Cardoza-Fonseca, 480 U.S. 421, 428, 94 L. Ed. 2d 434, 107 S. Ct. 1207 (1987). Since Rivas-Salazar failed to provide sufficient evidence to support his eligibility for asylum, he also fails to show his eligibility for withholding of deportation.
The petition for review is DENIED.
Disposition
The petition for review is DENIED.
| https://www.anylaw.com/case/rivas-salazar-v-immigration-and-naturalization-service/ninth-circuit/04-03-1996/mYgQQGYBTlTomsSBy9dS |
Exploring the experiences of the sibling of a child with an intellectual disability
ENGLISH ABSTRACT: This study is aimed at gaining insight into the experiences of siblings of an individual with an intellectual and physical disability. Attaining greater insight into their lived reality, their feelings and concerns could make it possible to provide appropriate support. The review of selected literature provides information on many aspects of the these siblings' experience. Although many studies are quantitative in their approach, the literature review provides relevant and useful findings and inferences which were used to support and substantiate findings. During this qualitative study, which is situated within an interpretive phenomenological paradigm, four participants between the ages of eight and sixteen years were interviewed using semi-structured interviews. This format of interview allowed participants to use their own words to express their personal experiences. The results showed that siblings have both positive and negative experiences when another sibling has an intellectual disability. Other common difficulties include embarrassment, guilt, and the experience of differential treatment. Positive experiences and competencies include love and acceptance, personal growth, maturity, pride in siblings accomplishments, and appreciation for one's sibling. Several experiences were congruent with those mentioned in the literature. The insights into the experiences this study provides has implications for the development and provision of sibling support programmes and interventions. At present, state group support programmes for siblings are not provided within the Western Cape area. The interventions and assistance that do exist seem to be provided by the private sector only. Support can prove very costly, which means that it is not accessible to many who require it. Sibling workshop groups could provide a valuable support alternative to a currently " unsupported" group, the siblings.
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Exploring the experiences of the sibling of a child with an intellectual disability
Exploring the experiences of the sibling of a child with an intellectual disability
Files
jervis_exploring_2008.pdf(867.34 KB)
Date
2008-03
Authors
Jervis, Sarah Jenny
Journal Title
Journal ISSN
Volume Title
Publisher
Stellenbosch : Stellenbosch University
Abstract
ENGLISH ABSTRACT: This study is aimed at gaining insight into the experiences of siblings of an individual with an intellectual and physical disability. Attaining greater insight into their lived reality, their feelings and concerns could make it possible to provide appropriate support. The review of selected literature provides information on many aspects of the these siblings' experience. Although many studies are quantitative in their approach, the literature review provides relevant and useful findings and inferences which were used to support and substantiate findings. During this qualitative study, which is situated within an interpretive phenomenological paradigm, four participants between the ages of eight and sixteen years were interviewed using semi-structured interviews. This format of interview allowed participants to use their own words to express their personal experiences. The results showed that siblings have both positive and negative experiences when another sibling has an intellectual disability. Other common difficulties include embarrassment, guilt, and the experience of differential treatment. Positive experiences and competencies include love and acceptance, personal growth, maturity, pride in siblings accomplishments, and appreciation for one's sibling. Several experiences were congruent with those mentioned in the literature. The insights into the experiences this study provides has implications for the development and provision of sibling support programmes and interventions. At present, state group support programmes for siblings are not provided within the Western Cape area. The interventions and assistance that do exist seem to be provided by the private sector only. Support can prove very costly, which means that it is not accessible to many who require it. Sibling workshop groups could provide a valuable support alternative to a currently "unsupported" group, the siblings.
AFRIKAANSE OPSOMMING: Hierdie studie poog om insig te verkry in die ondervindings van die broers en susters van 'n kind met intellektuele en fisiese gestremdhede. Beter insig in die realiteit van hul leefwyse, hulle gevoelens en bekommernisse kan beter ondersteuning aan hulle moontlik te maak. Die ondersoek van geselekteerde literatuur voorsien inligting rakende vele aspekte van die ondervindings van hierdie kinders. Alhoewel baie van die studies kwantitatief in hul benadering is, het die bestaande literatuur tog relevante en bruikbare bydraes en gevolgtrekkings verskaf wat gebruik kon word om bevindings te bevestig en te staaf. Hierdie kwantitatiewe studie het plaasgevind in 'n verklarende fenomenologiese paradigma en vier semi-gestruktureerde onderhoude is gevoer met deelnemers tussen die ouderomme van 8 jaar en 16 jaar. Hierdie formaat van onderhoudvoering dra by dat deelnemers hulle gevoelens in hul eie woorde uitdruk. Die bevindings het gewys dat broers/susters beide positiewe en negatiewe ondervindings van kinders met 'n intellektuele gestremdheid het. Ander algemene probleme sluit in skaamte, skuldgevoelens en die gevoel van gedifferensieerde behandeling. Positiewe ondervindings en vaardighede van broers en susters sluit liefde en aanvaarding, persoonlike groei, volwassenheid, trots op die broers/suster se bekwaamheid en die waardering van so 'n broer/suster in. Verskeie van die ondervindings het ooreengestem met bevindings wat in die literatuur gevind is. Die insigte in hierdie ondervindings wat deur hierdie studie voorsien word het implikasies vir programme en intervensies wat ondersteuning aan hierdie kinders bied. Tans is daar nie sodanige staatsgefinansierde ondersteuningsprogramme in die Wes-Kaap area nie. Die intervensies en ondersteuning wat wel beskikbaar is word slegs in die privaatsektor aangebied. Ondersteuning kan baie duur wees, wat beteken dat dit vir baie kinders wat dit nodig het, ontoeganklik is. Ondersteuningsgroepwerkswinkels kan 'n waardevolle alternatief bied vir die "nieondersteunde" groep, die kinders.
Description
Thesis (MEdPsych)--Stellenbosch University, 2008.
Keywords
Children with mental disabilities -- Family relationships -- Case studies,Brothers and sisters -- Attitudes -- Case studies,Theses -- Education,Dissertations -- Education
Citation
URI
http://hdl.handle.net/10019.1/21630
Collections
Masters Degrees (Educational Psychology)
Full item page
| https://scholar.sun.ac.za/handle/10019.1/21630 |
\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 2.\u003C\/span\u003E \u003Cp id=\u0022p-97\u0022 class=\u0022first-child\u0022\u003EDedicated scoring panel for AutoRayValid-RBknee in ANOVI (Reference Expert\u2019s view).\u003C\/p\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cdiv id=\u0022F3\u0022 class=\u0022fig pos-float type-figure odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022https:\/\/www.medrxiv.org\/content\/medrxiv\/early\/2022\/08\/30\/2022.08.29.22279328\/F3.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Paired reader trial, without and with decision support. Readings of the studies are done twice, in two separate sessions. For each study, RBknee will be available in one of the sessions and the order of which RBknee will be available is randomised between the sessions.\u0022 class=\u0022highwire-fragment fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-1467531140\u0022 data-figure-caption=\u0022\u0026lt;div class=\u0026quot;highwire-markup\u0026quot;\u0026gt;Paired reader trial, without and with decision support. Readings of the studies are done twice, in two separate sessions. For each study, RBknee will be available in one of the sessions and the order of which RBknee will be available is randomised between the sessions.\u0026lt;\/div\u0026gt;\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cspan class=\u0022hw-responsive-img\u0022\u003E\u003Cimg class=\u0022highwire-fragment fragment-image lazyload\u0022 alt=\u0022Figure 3.\u0022 src=\u0022data:image\/gif;base64,R0lGODlhAQABAIAAAAAAAP\/\/\/yH5BAEAAAAALAAAAAABAAEAAAIBRAA7\u0022 data-src=\u0022https:\/\/www.medrxiv.org\/content\/medrxiv\/early\/2022\/08\/30\/2022.08.29.22279328\/F3.medium.gif\u0022 width=\u0022440\u0022 height=\u0022154\u0022\/\u003E\u003Cnoscript\u003E\u003Cimg class=\u0022highwire-fragment fragment-image\u0022 alt=\u0022Figure 3.\u0022 src=\u0022https:\/\/www.medrxiv.org\/content\/medrxiv\/early\/2022\/08\/30\/2022.08.29.22279328\/F3.medium.gif\u0022 width=\u0022440\u0022 height=\u0022154\u0022\/\u003E\u003C\/noscript\u003E\u003C\/span\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u0022download-fig first\u0022\u003E\u003Ca href=\u0022https:\/\/www.medrxiv.org\/content\/medrxiv\/early\/2022\/08\/30\/2022.08.29.22279328\/F3.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 3.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u0022new-tab last\u0022\u003E\u003Ca href=\u0022https:\/\/www.medrxiv.org\/content\/medrxiv\/early\/2022\/08\/30\/2022.08.29.22279328\/F3.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 3.\u003C\/span\u003E \u003Cp id=\u0022p-98\u0022 class=\u0022first-child\u0022\u003EPaired reader trial, without and with decision support. Readings of the studies are done twice, in two separate sessions. For each study, RBknee will be available in one of the sessions and the order of which RBknee will be available is randomised between the sessions.\u003C\/p\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cdiv id=\u0022F4\u0022 class=\u0022fig pos-float type-figure odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022https:\/\/www.medrxiv.org\/content\/medrxiv\/early\/2022\/08\/30\/2022.08.29.22279328\/F4.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Illustration of output from RBknee.\u0022 class=\u0022highwire-fragment fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-1467531140\u0022 data-figure-caption=\u0022\u0026lt;div class=\u0026quot;highwire-markup\u0026quot;\u0026gt;Illustration of output from RBknee.\u0026lt;\/div\u0026gt;\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cspan class=\u0022hw-responsive-img\u0022\u003E\u003Cimg class=\u0022highwire-fragment fragment-image lazyload\u0022 alt=\u0022Figure 4.\u0022 src=\u0022data:image\/gif;base64,R0lGODlhAQABAIAAAAAAAP\/\/\/yH5BAEAAAAALAAAAAABAAEAAAIBRAA7\u0022 data-src=\u0022https:\/\/www.medrxiv.org\/content\/medrxiv\/early\/2022\/08\/30\/2022.08.29.22279328\/F4.medium.gif\u0022 width=\u0022373\u0022 height=\u0022440\u0022\/\u003E\u003Cnoscript\u003E\u003Cimg class=\u0022highwire-fragment fragment-image\u0022 alt=\u0022Figure 4.\u0022 src=\u0022https:\/\/www.medrxiv.org\/content\/medrxiv\/early\/2022\/08\/30\/2022.08.29.22279328\/F4.medium.gif\u0022 width=\u0022373\u0022 height=\u0022440\u0022\/\u003E\u003C\/noscript\u003E\u003C\/span\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u0022download-fig first\u0022\u003E\u003Ca href=\u0022https:\/\/www.medrxiv.org\/content\/medrxiv\/early\/2022\/08\/30\/2022.08.29.22279328\/F4.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 4.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u0022new-tab last\u0022\u003E\u003Ca href=\u0022https:\/\/www.medrxiv.org\/content\/medrxiv\/early\/2022\/08\/30\/2022.08.29.22279328\/F4.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 4.\u003C\/span\u003E \u003Cp id=\u0022p-99\u0022 class=\u0022first-child\u0022\u003EIllustration of output from RBknee.\u003C\/p\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cdiv id=\u0022F5\u0022 class=\u0022fig pos-float type-figure odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022https:\/\/www.medrxiv.org\/content\/medrxiv\/early\/2022\/08\/30\/2022.08.29.22279328\/F5.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Data Collection Pipeline\u0022 class=\u0022highwire-fragment fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-1467531140\u0022 data-figure-caption=\u0022\u0026lt;div class=\u0026quot;highwire-markup\u0026quot;\u0026gt;Data Collection Pipeline\u0026lt;\/div\u0026gt;\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cspan class=\u0022hw-responsive-img\u0022\u003E\u003Cimg class=\u0022highwire-fragment fragment-image lazyload\u0022 alt=\u0022Figure 5.\u0022 src=\u0022data:image\/gif;base64,R0lGODlhAQABAIAAAAAAAP\/\/\/yH5BAEAAAAALAAAAAABAAEAAAIBRAA7\u0022 data-src=\u0022https:\/\/www.medrxiv.org\/content\/medrxiv\/early\/2022\/08\/30\/2022.08.29.22279328\/F5.medium.gif\u0022 width=\u0022269\u0022 height=\u0022440\u0022\/\u003E\u003Cnoscript\u003E\u003Cimg class=\u0022highwire-fragment fragment-image\u0022 alt=\u0022Figure 5.\u0022 src=\u0022https:\/\/www.medrxiv.org\/content\/medrxiv\/early\/2022\/08\/30\/2022.08.29.22279328\/F5.medium.gif\u0022 width=\u0022269\u0022 height=\u0022440\u0022\/\u003E\u003C\/noscript\u003E\u003C\/span\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u0022download-fig first\u0022\u003E\u003Ca href=\u0022https:\/\/www.medrxiv.org\/content\/medrxiv\/early\/2022\/08\/30\/2022.08.29.22279328\/F5.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 5.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u0022new-tab last\u0022\u003E\u003Ca href=\u0022https:\/\/www.medrxiv.org\/content\/medrxiv\/early\/2022\/08\/30\/2022.08.29.22279328\/F5.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 5.\u003C\/span\u003E \u003Cp id=\u0022p-100\u0022 class=\u0022first-child\u0022\u003EData Collection Pipeline\u003C\/p\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cdiv id=\u0022sec-38\u0022 class=\u0022subsection\u0022\u003E\u003Ch3\u003EReference test: Reference Experts\u003C\/h3\u003E\u003Cp id=\u0022p-101\u0022\u003EEach of the three clinical Sites will recruit one KOA Expert that will be used to construct a Reference Atlas (see later) and establish the Reference Standard. The KOA Experts are defined as individuals with extensive (\u0026gt;10 years) experience with clinical KOA reporting and research experience with KL and OARSI grading. Before the grading of trial studies begin the Reference Experts will convene in three separate Alignment Sessions. During these Sessions the Reference Experts will thoroughly discuss how they evaluate each separate feature mentioned below. Furthermore, the Reference Experts will create a Reference Atlas during these sessions (using a separate dataset from BFH) which will be made available to the Index Readers during trial readings.\u003C\/p\u003E\u003Cp id=\u0022p-102\u0022\u003EThe three Reference Experts will grade all of the 225 studies \u003Cstrong\u003Eonce\u003C\/strong\u003E without any decision aid.\u003C\/p\u003E\u003Cdiv id=\u0022sec-39\u0022 class=\u0022subsection\u0022\u003E\u003Ch4\u003EFeatures\u003C\/h4\u003E\u003Cp id=\u0022p-103\u0022\u003EFor each knee on the PA\/AP projection, the Reference Experts will assign one KL-grade (0-4) as well as OARSI grades for medial and lateral joint space narrowing (0-3), osteophytes (0-3) and rate subchondral sclerosis (no\/yes) on the medial and lateral distal femur and proximal tibia. In addition, the Reference Experts will rate osteophytes on the tibial eminence (no\/yes). They will comment on any additional findings using a free-text field.\u003C\/p\u003E\u003Cp id=\u0022p-104\u0022\u003EFor the lateral projection, the Reference Experts will rate osteophytes (no\/yes) on the proximal and distal patella. They will comment on any additional findings using a free-text field.\u003C\/p\u003E\u003C\/div\u003E\u003Cdiv id=\u0022sec-40\u0022 class=\u0022subsection\u0022\u003E\u003Ch4\u003EAssignment of final reference grade\u003C\/h4\u003E\u003Cp id=\u0022p-105\u0022\u003EThe reference standard will be based on majority voting. For cases where majority voting would leave an invalid result, the three Reference Experts will convene and, based on discussion, will adjudicate a final grade. The Reference Experts are blinded to the output of RBknee and the other Index Readers.\u003C\/p\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cdiv id=\u0022sec-41\u0022 class=\u0022subsection\u0022\u003E\u003Ch3\u003EIndex test: Index Readers\u003C\/h3\u003E\u003Cp id=\u0022p-106\u0022\u003EIt is expected that readers are accustomed to reading and grading radiographic KOA in clinical practice. However, prior experience with KL-grading or the OARSI atlas is not a prerequisite. Prior to the Index Reader Sessions, an atlas of radiographic KOA will be developed by the three Reference Experts which will be available to all Index Readers during all their readings. No images from this atlas are present in the Trial Sample. Index Readers will be instructed that their assigned KL-grades should correspond to the Allocation to Clinical Relevance section as described above.\u003C\/p\u003E\u003Cdiv id=\u0022sec-42\u0022 class=\u0022subsection\u0022\u003E\u003Ch4\u003EInterventions\u003C\/h4\u003E\u003Cp id=\u0022p-107\u0022\u003EThe trial uses retrospective data; hence no patient will undergo a supplementary examination or radiation exposure, nor will it influence their treatment.\u003C\/p\u003E\u003Cp id=\u0022p-108\u0022\u003ERBknee (v2.1) will be the diagnostic intervention.\u003C\/p\u003E\u003Cp id=\u0022p-109\u0022\u003ERandomisation to the intervention will be applied using a random number generator (via the random core package in Python v. 3.9.5) so that for half of the patient studies, the aid will be present at the first read and vice versa. Randomisation will be performed by a suitably trained person, performing the data management.\u003C\/p\u003E\u003C\/div\u003E\u003Cdiv id=\u0022sec-43\u0022 class=\u0022subsection\u0022\u003E\u003Ch4\u003EFirst reading session\u003C\/h4\u003E\u003Cp id=\u0022p-110\u0022\u003EReadings will be done in the imaging trial platform; \u003Cem\u003EANOVI\u003C\/em\u003E (\u003Cstrong\u003EDICOM-viewer with dedicated scoring panel\u003C\/strong\u003E). For half of the patient studies, only the original radiographs will be available to the reader. For the other half of the patients, the original radiographs will be available together with the output from RBknee. Readers are blinded to the study indication, original study report, results of the reference test, and the results of all other index tests.\u003C\/p\u003E\u003C\/div\u003E\u003Cdiv id=\u0022sec-44\u0022 class=\u0022subsection\u0022\u003E\u003Ch4\u003ESecond reading session\u003C\/h4\u003E\u003Cp id=\u0022p-111\u0022\u003EThe second reading session will be similar to the first reading session, except that the intervention is reversed, i.e. patient studies that were read without aid in the first session will be read with aid in the second session and vice versa.\u003C\/p\u003E\u003Cp id=\u0022p-112\u0022\u003EThe second session will be separated in time by a wash-out period of at least four weeks. The readers will be blinded to the results of the first reading session.\u003C\/p\u003E\u003C\/div\u003E\u003Cdiv id=\u0022sec-45\u0022 class=\u0022subsection\u0022\u003E\u003Ch4\u003EFeatures\u003C\/h4\u003E\u003Cp id=\u0022p-113\u0022\u003EThe Index Readers will grade the studies independently on the following features:\u003C\/p\u003E\u003Cul class=\u0022list-unord \u0022 id=\u0022list-16\u0022\u003E\u003Cli id=\u0022list-item-32\u0022\u003E\u003Cp id=\u0022p-114\u0022\u003EFor the PA\/AP projection they will assign a KL-grade (0-4). They are instructed that their assigned KL-grade should represent Allocation to Clinical Relevance as described in that section\u003C\/p\u003E\u003C\/li\u003E\u003Cli id=\u0022list-item-33\u0022\u003E\u003Cp id=\u0022p-115\u0022\u003EFor the lateral projection they will rate osteophytes (no\/yes) on the proximal and distal patella.\u003C\/p\u003E\u003C\/li\u003E\u003Cli id=\u0022list-item-34\u0022\u003E\u003Cp id=\u0022p-116\u0022\u003EFor both images, they can assign the image as of inadequate quality. They are instructed that the heuristic should be that they would send the patient back for a new radiograph if encountered in daily clinical practice.\u003C\/p\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cdiv id=\u0022sec-46\u0022 class=\u0022subsection\u0022\u003E\u003Ch3\u003EIndex test: RBknee\u003C\/h3\u003E\u003Cp id=\u0022p-117\u0022\u003ERBknee v2.1 will analyse all studies in the Trial Sample. RBknee takes as input DICOM files encapsulating radiographs of knees in binary format. Output is probabilities of various KL, OARSI grades and tibial eminence osteophytes for PA\/AP radiographs and probabilities for presence\/absence of proximal and distal osteophytes for lateral radiographs.\u003C\/p\u003E\u003C\/div\u003E\u003Cdiv id=\u0022sec-47\u0022 class=\u0022subsection\u0022\u003E\u003Ch3\u003EReader election\u003C\/h3\u003E\u003Cp id=\u0022p-118\u0022\u003EOne Reference Expert and four Index Readers of different levels of experience and specialty \u003Cstrong\u003Efrom each site\u003C\/strong\u003E will participate in the trial;\u003C\/p\u003E\u003Cul class=\u0022list-unord \u0022 id=\u0022list-17\u0022\u003E\u003Cli id=\u0022list-item-35\u0022\u003E\u003Cp id=\u0022p-119\u0022\u003Eone knee OA expert (Reference Expert, defined above)\u003C\/p\u003E\u003C\/li\u003E\u003Cli id=\u0022list-item-36\u0022\u003E\u003Cp id=\u0022p-120\u0022\u003Eone radiologist in training (Index Reader)\u003C\/p\u003E\u003C\/li\u003E\u003Cli id=\u0022list-item-37\u0022\u003E\u003Cp id=\u0022p-121\u0022\u003Eone radiologist regularly reporting on KOA (Index Reader)\u003C\/p\u003E\u003C\/li\u003E\u003Cli id=\u0022list-item-38\u0022\u003E\u003Cp id=\u0022p-122\u0022\u003Eone knee-specialised orthopaedic surgeon (Index Reader)\u003C\/p\u003E\u003C\/li\u003E\u003Cli id=\u0022list-item-39\u0022\u003E\u003Cp id=\u0022p-123\u0022\u003Eone orthopaedic surgeon in training (Index Reader)\u003C\/p\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003Cp id=\u0022p-124\u0022\u003EThe following information will be collected from both the Reference Experts and the Index Readers:\u003C\/p\u003E\u003Cdiv id=\u0022T3\u0022 class=\u0022table pos-float\u0022\u003E\u003Cdiv class=\u0022table-inline table-callout-links\u0022\u003E\u003Cdiv class=\u0022callout\u0022\u003E\u003Cspan\u003EView this table:\u003C\/span\u003E\u003Cul class=\u0022callout-links\u0022\u003E\u003Cli class=\u0022view-inline first\u0022\u003E\u003Ca href=\u0022##\u0022 class=\u0022table-expand-inline\u0022 data-table-url=\u0022\/highwire\/markup\/554840\/expansion?postprocessors=highwire_tables%2Chighwire_reclass%2Chighwire_figures%2Chighwire_math%2Chighwire_inline_linked_media%2Chighwire_embed\u0026amp;table-expand-inline=1\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView inline\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u0022view-popup\u0022\u003E\u003Ca href=\u0022\/highwire\/markup\/554840\/expansion?width=1000\u0026amp;height=500\u0026amp;iframe=true\u0026amp;postprocessors=highwire_tables%2Chighwire_reclass%2Chighwire_figures%2Chighwire_math%2Chighwire_inline_linked_media%2Chighwire_embed\u0022 class=\u0022colorbox colorbox-load table-expand-popup\u0022 rel=\u0022gallery-fragment-tables\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView popup\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u0022download-ppt last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/554840\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-48\u0022\u003E\u003Ch2 class=\u0022\u0022\u003EMethods: Data Collection and Management\u003C\/h2\u003E\u003Cdiv id=\u0022sec-49\u0022 class=\u0022subsection\u0022\u003E\u003Ch3\u003EData Collection\u003C\/h3\u003E\u003Cp id=\u0022p-125\u0022\u003EImaging data will be extracted in the DICOM-format from the hospital\u2019s PACS and anonymised using local procedures. Clinical data (age, sex, symptomatic side, radiographic projection, and date of study) will be collected before anonymisation.\u003C\/p\u003E\u003Cp id=\u0022p-126\u0022\u003EThe anonymised imaging studies will be uploaded to the online imaging trial platform, ANOVI, to be used for data collection throughout the study. The platform works in the cloud and is compliant to handle pseudonymised (or fully anonymised) imaging data.\u003C\/p\u003E\u003C\/div\u003E\u003Cdiv id=\u0022sec-50\u0022 class=\u0022subsection\u0022\u003E\u003Ch3\u003EData management\u003C\/h3\u003E\u003Cp id=\u0022p-127\u0022\u003EEach patient will be assigned a unique study ID, e.g., BFH001, EMC001, CUH001, BFH002, EMC002, CUH002 etc. Measurements will be reported in a designated \u003Cstrong\u003Edatabase\u003C\/strong\u003E. The clinical data will be manually entered into the database. The feature gradings from ANOVI will automatically be stored and later merged in the \u003Cstrong\u003Edatabase\u003C\/strong\u003E.\u003C\/p\u003E\u003Cp id=\u0022p-128\u0022\u003EThe measurements that will be collected are:\u003C\/p\u003E\u003Cdiv id=\u0022T4\u0022 class=\u0022table pos-float\u0022\u003E\u003Cdiv class=\u0022table-inline table-callout-links\u0022\u003E\u003Cdiv class=\u0022callout\u0022\u003E\u003Cspan\u003EView this table:\u003C\/span\u003E\u003Cul class=\u0022callout-links\u0022\u003E\u003Cli class=\u0022view-inline first\u0022\u003E\u003Ca href=\u0022##\u0022 class=\u0022table-expand-inline\u0022 data-table-url=\u0022\/highwire\/markup\/554831\/expansion?postprocessors=highwire_tables%2Chighwire_reclass%2Chighwire_figures%2Chighwire_math%2Chighwire_inline_linked_media%2Chighwire_embed\u0026amp;table-expand-inline=1\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView inline\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u0022view-popup last\u0022\u003E\u003Ca href=\u0022\/highwire\/markup\/554831\/expansion?width=1000\u0026amp;height=500\u0026amp;iframe=true\u0026amp;postprocessors=highwire_tables%2Chighwire_reclass%2Chighwire_figures%2Chighwire_math%2Chighwire_inline_linked_media%2Chighwire_embed\u0022 class=\u0022colorbox colorbox-load table-expand-popup\u0022 rel=\u0022gallery-fragment-tables\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView popup\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cdiv id=\u0022sec-51\u0022 class=\u0022subsection\u0022\u003E\u003Ch3\u003EStatistical methods\u003C\/h3\u003E\u003Cdiv id=\u0022sec-52\u0022 class=\u0022subsection\u0022\u003E\u003Ch4\u003EIndex test: Evaluation of Index Readers\u003C\/h4\u003E\u003Cp id=\u0022p-129\u0022\u003EOrdinal weighted accuracy for KL-grading will be calculated for all Index Readers without and with decision support from RBknee \u003Csup\u003E\u003Ca id=\u0022xref-ref-18-2\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-18\u0022\u003E18\u003C\/a\u003E\u003C\/sup\u003E.\u003C\/p\u003E\u003Cp id=\u0022p-130\u0022\u003EBalanced accuracy for grading presence\/absence of patellar osteophytes on lateral projection images will be calculated for all Index Readers without and with decision support from RBknee.\u003C\/p\u003E\u003Cp id=\u0022p-131\u0022\u003EQuadratic weighted Light\u2019s kappa will be calculated among all Index Readers for KL-grading for the without and the with decision support readings.\u003C\/p\u003E\u003Cp id=\u0022p-132\u0022\u003EFor the metrics above, hypothesis testing will be done using permutation tests. In addition, per specialty and per experience level subgroup analyses will also be performed.\u003C\/p\u003E\u003C\/div\u003E\u003Cdiv id=\u0022sec-53\u0022 class=\u0022subsection\u0022\u003E\u003Ch4\u003EIndex test: Stand alone evaluation of RBknee\u003C\/h4\u003E\u003Cp id=\u0022p-133\u0022\u003EOrdinal weighted accuracy will be calculated for RBknee for KL-grading, OARSI-JSN grading, and OARSI-osteophyte grading. Balanced accuracy will be calculated for RBknee for OARSI subchondral sclerosis grading. Hypothesis testing will be done using permutation tests.\u003C\/p\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cdiv class=\u0022section data-availability\u0022 id=\u0022sec-55\u0022\u003E\u003Ch2 class=\u0022\u0022\u003EData Availability\u003C\/h2\u003E\u003Cp id=\u0022p-134\u0022\u003EAll data produced in the present study are available upon reasonable request to the authors\u003C\/p\u003E\u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-56\u0022\u003E\u003Ch2 class=\u0022\u0022\u003EEthics and Dissemination\u003C\/h2\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-57\u0022\u003E\u003Ch3\u003ERegulatory and ethical considerations\u003C\/h3\u003E\u003Cp id=\u0022p-146\u0022\u003EThe trial is conducted in accordance with the Declaration of Helsinki \u003Csup\u003E\u003Ca id=\u0022xref-ref-19-2\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-19\u0022\u003E19\u003C\/a\u003E\u003C\/sup\u003E and the General Data Protection Regulation (GDPR) \u003Csup\u003E\u003Ca id=\u0022xref-ref-20-2\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-20\u0022\u003E20\u003C\/a\u003E\u003C\/sup\u003E. Prior to the start of any study activities at each of the sites, local ethics committee opinion and approval from national competent authorities will be collected and, unless the requirement is waived, informed consent will be collected prior to inclusion of patients.\u003C\/p\u003E\u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-58\u0022\u003E\u003Ch3\u003EProtocol amendments\u003C\/h3\u003E\u003Cp id=\u0022p-147\u0022\u003EAny significant protocol modifications (e.g. changes in eligibility criteria, outcomes, analysis) must be approved by all investigators and, if necessary, communicated to the respective national ethical authorities.\u003C\/p\u003E\u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-59\u0022\u003E\u003Ch3\u003EConfidentiality\u003C\/h3\u003E\u003Cp id=\u0022p-148\u0022\u003EAnonymized data will be entered into the database which allows sharing among the investigators.\u003C\/p\u003E\u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-60\u0022\u003E\u003Ch3\u003EAccess to data\u003C\/h3\u003E\u003Cp id=\u0022p-149\u0022\u003EAll investigators and the sponsor will have access to the final, anonymised trial dataset as recorded in the database.\u003C\/p\u003E\u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-61\u0022\u003E\u003Ch3\u003EDissemination policy\u003C\/h3\u003E\u003Cp id=\u0022p-150\u0022\u003EFindings from this trial are intended for publication in scientific peer-reviewed journals. Furthermore, results will be presented at national and international conferences. All forthcoming studies based on collected data are agreed upon by the trial group. The first author assumes responsibility for all practical issues and the first drafts of all articles. Articles are written and authorship decided according to guidelines by the International Committee of Medical Journal Editors.\u003C\/p\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cdiv class=\u0022section glossary\u0022\u003E\u003Ch2 class=\u0022\u0022\u003EAbbreviations\u003C\/h2\u003E\u003Cdl id=\u0022def-list-1\u0022\u003E\u003Cdt id=\u0022def-item-1\u0022\u003EAP\u003Cspan class=\u0022def-item-dt-sep\u0022\u003E\u003C\/span\u003E\u003C\/dt\u003E\u003Cdd\u003EAnterior-posterior\u003Cspan class=\u0022def-item-dd-sep\u0022\u003E\u003C\/span\u003E\u003C\/dd\u003E\u003Cdt id=\u0022def-item-2\u0022\u003EBFH\u003Cspan class=\u0022def-item-dt-sep\u0022\u003E\u003C\/span\u003E\u003C\/dt\u003E\u003Cdd\u003EBispebjerg and Frederiksberg Hospital\u003Cspan class=\u0022def-item-dd-sep\u0022\u003E\u003C\/span\u003E\u003C\/dd\u003E\u003Cdt id=\u0022def-item-3\u0022\u003ECUB\u003Cspan class=\u0022def-item-dt-sep\u0022\u003E\u003C\/span\u003E\u003C\/dt\u003E\u003Cdd\u003ECharit\u00e9 Universit\u00e4tsmedizin Berlin\u003Cspan class=\u0022def-item-dd-sep\u0022\u003E\u003C\/span\u003E\u003C\/dd\u003E\u003Cdt id=\u0022def-item-4\u0022\u003EEMC\u003Cspan class=\u0022def-item-dt-sep\u0022\u003E\u003C\/span\u003E\u003C\/dt\u003E\u003Cdd\u003EErasmus Medical Center\u003Cspan class=\u0022def-item-dd-sep\u0022\u003E\u003C\/span\u003E\u003C\/dd\u003E\u003Cdt id=\u0022def-item-5\u0022\u003EEULAR\u003Cspan class=\u0022def-item-dt-sep\u0022\u003E\u003C\/span\u003E\u003C\/dt\u003E\u003Cdd\u003EEuropean League Against Rheumatism\u003Cspan class=\u0022def-item-dd-sep\u0022\u003E\u003C\/span\u003E\u003C\/dd\u003E\u003Cdt id=\u0022def-item-6\u0022\u003EJSN\u003Cspan class=\u0022def-item-dt-sep\u0022\u003E\u003C\/span\u003E\u003C\/dt\u003E\u003Cdd\u003EJoint-Space Narrowing\u003Cspan class=\u0022def-item-dd-sep\u0022\u003E\u003C\/span\u003E\u003C\/dd\u003E\u003Cdt id=\u0022def-item-7\u0022\u003EKOA\u003Cspan class=\u0022def-item-dt-sep\u0022\u003E\u003C\/span\u003E\u003C\/dt\u003E\u003Cdd\u003EKnee Osteoarthritis\u003Cspan class=\u0022def-item-dd-sep\u0022\u003E\u003C\/span\u003E\u003C\/dd\u003E\u003Cdt id=\u0022def-item-8\u0022\u003EMRMC\u003Cspan class=\u0022def-item-dt-sep\u0022\u003E\u003C\/span\u003E\u003C\/dt\u003E\u003Cdd\u003EMulti-reader, multi-case\u003Cspan class=\u0022def-item-dd-sep\u0022\u003E\u003C\/span\u003E\u003C\/dd\u003E\u003Cdt id=\u0022def-item-9\u0022\u003EOA\u003Cspan class=\u0022def-item-dt-sep\u0022\u003E\u003C\/span\u003E\u003C\/dt\u003E\u003Cdd\u003EOsteoarthritis\u003Cspan class=\u0022def-item-dd-sep\u0022\u003E\u003C\/span\u003E\u003C\/dd\u003E\u003Cdt id=\u0022def-item-10\u0022\u003EOARSI\u003Cspan class=\u0022def-item-dt-sep\u0022\u003E\u003C\/span\u003E\u003C\/dt\u003E\u003Cdd\u003EOsteoarthritis Research Society International\u003Cspan class=\u0022def-item-dd-sep\u0022\u003E\u003C\/span\u003E\u003C\/dd\u003E\u003Cdt id=\u0022def-item-11\u0022\u003EPA\u003Cspan class=\u0022def-item-dt-sep\u0022\u003E\u003C\/span\u003E\u003C\/dt\u003E\u003Cdd\u003EPosterior-anterior\u003C\/dd\u003E\u003C\/dl\u003E\u003C\/div\u003E\u003Cdiv class=\u0022section ref-list\u0022 id=\u0022ref-list-1\u0022\u003E\u003Ch2 class=\u0022\u0022\u003EReferences\u003C\/h2\u003E\u003Col class=\u0022cit-list ref-use-labels\u0022\u003E\u003Cli\u003E\u003Cspan class=\u0022ref-label\u0022\u003E1.\u003C\/span\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-1-1\u0022 title=\u0022View reference 1. in text\u0022 id=\u0022ref-1\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-journal\u0022 id=\u0022cit-2022.08.29.22279328v1.1\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003E\u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003ECui\u003C\/span\u003E, \u003Cspan class=\u0022cit-name-given-names\u0022\u003EA.\u003C\/span\u003E\u003C\/span\u003E \u003Cspan class=\u0022cit-etal\u0022\u003Eet al.\u003C\/span\u003E \u003Cspan class=\u0022cit-article-title\u0022\u003EGlobal, regional prevalence, incidence and risk factors of knee osteoarthritis in population-based studies\u003C\/span\u003E. \u003Cabbr class=\u0022cit-jnl-abbrev\u0022\u003EEClinicalMedicine\u003C\/abbr\u003E \u003Cspan class=\u0022cit-vol\u0022\u003E29-30\u003C\/span\u003E, \u003Cspan class=\u0022cit-fpage\u0022\u003E100587\u003C\/span\u003E (\u003Cspan class=\u0022cit-pub-date\u0022\u003E2020\u003C\/span\u003E).\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003Ca href=\u0022{openurl}?query=rft.jtitle%253DEClinicalMedicine%26rft.volume%253D2930%26rft.spage%253D100587%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url\u0022\u003E\u003Cspan\u003EOpenUrl\u003C\/span\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Cspan class=\u0022ref-label\u0022\u003E2.\u003C\/span\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-2-1\u0022 title=\u0022View reference 2. in text\u0022 id=\u0022ref-2\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-journal\u0022 id=\u0022cit-2022.08.29.22279328v1.2\u0022 data-doi=\u002210.1136\/ard.2009.113100\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003E\u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EZhang\u003C\/span\u003E, \u003Cspan class=\u0022cit-name-given-names\u0022\u003EW.\u003C\/span\u003E\u003C\/span\u003E \u003Cspan class=\u0022cit-etal\u0022\u003Eet al.\u003C\/span\u003E \u003Cspan class=\u0022cit-article-title\u0022\u003EEULAR
evidence-based recommendations for the diagnosis of knee osteoarthritis\u003C\/span\u003E. \u003Cabbr class=\u0022cit-jnl-abbrev\u0022\u003EAnn. Rheum. Dis\u003C\/abbr\u003E. \u003Cspan class=\u0022cit-vol\u0022\u003E69\u003C\/span\u003E, \u003Cspan class=\u0022cit-fpage\u0022\u003E483\u003C\/span\u003E\u2013\u003Cspan class=\u0022cit-lpage\u0022\u003E489\u003C\/span\u003E (\u003Cspan class=\u0022cit-pub-date\u0022\u003E2010\u003C\/span\u003E).\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003Ca href=\u0022{openurl}?query=rft.jtitle%253DAnn.%2BRheum.%2BDis%26rft_id%253Dinfo%253Adoi%252F10.1136%252Fard.2009.113100%26rft_id%253Dinfo%253Apmid%252F19762361%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url\u0022\u003E\u003Cspan\u003EOpenUrl\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/ijlink\/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6MTE6ImFubnJoZXVtZGlzIjtzOjU6InJlc2lkIjtzOjg6IjY5LzMvNDgzIjtzOjQ6ImF0b20iO3M6NTA6Ii9tZWRyeGl2L2Vhcmx5LzIwMjIvMDgvMzAvMjAyMi4wOC4yOS4yMjI3OTMyOC5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30=\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-ijlink\u0022\u003E\u003Cspan\u003E\u003Cspan class=\u0022cit-reflinks-abstract\u0022\u003EAbstract\u003C\/span\u003E\u003Cspan class=\u0022cit-sep cit-reflinks-variant-name-sep\u0022\u003E\/\u003C\/span\u003E\u003Cspan class=\u0022cit-reflinks-full-text\u0022\u003E\u003Cspan class=\u0022free-full-text\u0022\u003EFREE \u003C\/span\u003EFull Text\u003C\/span\u003E\u003C\/span\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Cspan class=\u0022ref-label\u0022\u003E3.\u003C\/span\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-3-1\u0022 title=\u0022View reference 3. in text\u0022 id=\u0022ref-3\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-journal\u0022 id=\u0022cit-2022.08.29.22279328v1.3\u0022 data-doi=\u002210.1136\/ard.16.4.494\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003E\u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EKellgren\u003C\/span\u003E, \u003Cspan class=\u0022cit-name-given-names\u0022\u003EJ. H.\u003C\/span\u003E\u003C\/span\u003E \u0026amp; \u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003ELawrence\u003C\/span\u003E, \u003Cspan class=\u0022cit-name-given-names\u0022\u003EJ. S.\u003C\/span\u003E\u003C\/span\u003E \u003Cspan class=\u0022cit-article-title\u0022\u003ERadiological assessment of osteo-arthrosis\u003C\/span\u003E. \u003Cabbr class=\u0022cit-jnl-abbrev\u0022\u003EAnn. Rheum. Dis\u003C\/abbr\u003E. \u003Cspan class=\u0022cit-vol\u0022\u003E16\u003C\/span\u003E, \u003Cspan class=\u0022cit-fpage\u0022\u003E494\u003C\/span\u003E\u2013\u003Cspan class=\u0022cit-lpage\u0022\u003E502\u003C\/span\u003E (\u003Cspan class=\u0022cit-pub-date\u0022\u003E1957\u003C\/span\u003E).\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003Ca href=\u0022{openurl}?query=rft.jtitle%253DAnnals%2Bof%2Bthe%2BRheumatic%2BDiseases%26rft.stitle%253DAnn%2BRheum%2BDis%26rft.aulast%253DKellgren%26rft.auinit1%253DJ.%2BH.%26rft.volume%253D16%26rft.issue%253D4%26rft.spage%253D494%26rft.epage%253D502%26rft.atitle%253DRadiological%2BAssessment%2Bof%2BOsteo-Arthrosis%26rft_id%253Dinfo%253Adoi%252F10.1136%252Fard.16.4.494%26rft_id%253Dinfo%253Apmid%252F13498604%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url\u0022\u003E\u003Cspan\u003EOpenUrl\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/ijlink\/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6MzoiUERGIjtzOjExOiJqb3VybmFsQ29kZSI7czoxMToiYW5ucmhldW1kaXMiO3M6NToicmVzaWQiO3M6ODoiMTYvNC80OTQiO3M6NDoiYXRvbSI7czo1MDoiL21lZHJ4aXYvZWFybHkvMjAyMi8wOC8zMC8yMDIyLjA4LjI5LjIyMjc5MzI4LmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-ijlink\u0022\u003E\u003Cspan\u003E\u003Cspan class=\u0022cit-reflinks-full-text\u0022\u003E\u003Cspan class=\u0022free-full-text\u0022\u003EFREE \u003C\/span\u003EFull Text\u003C\/span\u003E\u003C\/span\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Cspan class=\u0022ref-label\u0022\u003E4.\u003C\/span\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-4-1\u0022 title=\u0022View reference 4. in text\u0022 id=\u0022ref-4\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-journal\u0022 id=\u0022cit-2022.08.29.22279328v1.4\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003E\u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003ESheehy\u003C\/span\u003E, \u003Cspan class=\u0022cit-name-given-names\u0022\u003EL.\u003C\/span\u003E\u003C\/span\u003E \u0026amp; \u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003ECooke\u003C\/span\u003E, \u003Cspan class=\u0022cit-name-given-names\u0022\u003ET. D. V.\u003C\/span\u003E\u003C\/span\u003E \u003Cspan class=\u0022cit-article-title\u0022\u003ERadiographic assessment of leg alignment and grading of knee osteoarthritis: A critical review\u003C\/span\u003E. \u003Cabbr class=\u0022cit-jnl-abbrev\u0022\u003EWORLD\u003C\/abbr\u003E \u003Cspan class=\u0022cit-vol\u0022\u003E2\u003C\/span\u003E, (\u003Cspan class=\u0022cit-pub-date\u0022\u003E2015\u003C\/span\u003E).\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Cspan class=\u0022ref-label\u0022\u003E5.\u003C\/span\u003E\u003Cdiv class=\u0022cit ref-cit ref-journal no-rev-xref\u0022 id=\u0022cit-2022.08.29.22279328v1.5\u0022 data-doi=\u002210.1007\/s00167-014-3205-0\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003E\u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003ECulvenor\u003C\/span\u003E, \u003Cspan class=\u0022cit-name-given-names\u0022\u003EA. G.\u003C\/span\u003E\u003C\/span\u003E, \u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EEngen\u003C\/span\u003E, \u003Cspan class=\u0022cit-name-given-names\u0022\u003EC. N.\u003C\/span\u003E\u003C\/span\u003E, \u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003E\u00d8iestad\u003C\/span\u003E, \u003Cspan class=\u0022cit-name-given-names\u0022\u003EB. E.\u003C\/span\u003E\u003C\/span\u003E, \u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EEngebretsen\u003C\/span\u003E, \u003Cspan class=\u0022cit-name-given-names\u0022\u003EL.\u003C\/span\u003E\u003C\/span\u003E \u0026amp; \u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003ERisberg\u003C\/span\u003E, \u003Cspan class=\u0022cit-name-given-names\u0022\u003EM. A.\u003C\/span\u003E\u003C\/span\u003E \u003Cspan class=\u0022cit-article-title\u0022\u003EDefining the presence of radiographic knee osteoarthritis: a comparison between the Kellgren and Lawrence system and OARSI atlas criteria\u003C\/span\u003E. \u003Cabbr class=\u0022cit-jnl-abbrev\u0022\u003EKnee Surg. Sports Traumatol. Arthrosc\u003C\/abbr\u003E. \u003Cspan class=\u0022cit-vol\u0022\u003E23\u003C\/span\u003E, \u003Cspan class=\u0022cit-fpage\u0022\u003E3532\u003C\/span\u003E\u2013\u003Cspan class=\u0022cit-lpage\u0022\u003E3539\u003C\/span\u003E (\u003Cspan class=\u0022cit-pub-date\u0022\u003E2015\u003C\/span\u003E).\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003Ca href=\u0022{openurl}?query=rft.jtitle%253DKnee%2BSurg.%2BSports%2BTraumatol.%2BArthrosc%26rft.volume%253D23%26rft.spage%253D3532%26rft_id%253Dinfo%253Adoi%252F10.1007%252Fs00167-014-3205-0%26rft_id%253Dinfo%253Apmid%252F25079135%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url\u0022\u003E\u003Cspan\u003EOpenUrl\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=10.1007\/s00167-014-3205-0\u0026amp;link_type=DOI\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-doi cit-ref-sprinkles-crossref\u0022\u003E\u003Cspan\u003ECrossRef\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=25079135\u0026amp;link_type=MED\u0026amp;atom=%2Fmedrxiv%2Fearly%2F2022%2F08%2F30%2F2022.08.29.22279328.atom\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-medline\u0022\u003E\u003Cspan\u003EPubMed\u003C\/span\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Cspan class=\u0022ref-label\u0022\u003E6.\u003C\/span\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-6-1\u0022 title=\u0022View reference 6. in text\u0022 id=\u0022ref-6\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-journal\u0022 id=\u0022cit-2022.08.29.22279328v1.6\u0022 data-doi=\u002210.3928\/01477447-20121217-14\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003E\u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003ERiddle\u003C\/span\u003E, \u003Cspan class=\u0022cit-name-given-names\u0022\u003ED. L.\u003C\/span\u003E\u003C\/span\u003E, \u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EJiranek\u003C\/span\u003E, \u003Cspan class=\u0022cit-name-given-names\u0022\u003EW. A.\u003C\/span\u003E\u003C\/span\u003E \u0026amp; \u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EHull\u003C\/span\u003E, \u003Cspan class=\u0022cit-name-given-names\u0022\u003EJ. R.\u003C\/span\u003E\u003C\/span\u003E \u003Cspan class=\u0022cit-article-title\u0022\u003EValidity and reliability of radiographic knee osteoarthritis measures by arthroplasty surgeons\u003C\/span\u003E. \u003Cabbr class=\u0022cit-jnl-abbrev\u0022\u003EOrthopedics\u003C\/abbr\u003E \u003Cspan class=\u0022cit-vol\u0022\u003E36\u003C\/span\u003E, \u003Cspan class=\u0022cit-fpage\u0022\u003Ee25\u003C\/span\u003E\u2013\u003Cspan class=\u0022cit-lpage\u0022\u003E32\u003C\/span\u003E (\u003Cspan class=\u0022cit-pub-date\u0022\u003E2013\u003C\/span\u003E).\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003Ca href=\u0022{openurl}?query=rft.jtitle%253DOrthopedics%26rft.volume%253D36%26rft.spage%253De25%26rft_id%253Dinfo%253Adoi%252F10.3928%252F01477447-20121217-14%26rft_id%253Dinfo%253Apmid%252F23276348%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url\u0022\u003E\u003Cspan\u003EOpenUrl\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=10.3928\/01477447-20121217-14\u0026amp;link_type=DOI\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-doi cit-ref-sprinkles-crossref\u0022\u003E\u003Cspan\u003ECrossRef\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=23276348\u0026amp;link_type=MED\u0026amp;atom=%2Fmedrxiv%2Fearly%2F2022%2F08%2F30%2F2022.08.29.22279328.atom\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-medline\u0022\u003E\u003Cspan\u003EPubMed\u003C\/span\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Cspan class=\u0022ref-label\u0022\u003E7.\u003C\/span\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-7-1\u0022 title=\u0022View reference 7. in text\u0022 id=\u0022ref-7\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-journal\u0022 id=\u0022cit-2022.08.29.22279328v1.7\u0022 data-doi=\u002210.1016\/j.joca.2006.06.017\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003E\u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EAltman\u003C\/span\u003E, \u003Cspan class=\u0022cit-name-given-names\u0022\u003ER. D.\u003C\/span\u003E\u003C\/span\u003E \u0026amp; \u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EGold\u003C\/span\u003E, \u003Cspan class=\u0022cit-name-given-names\u0022\u003EG. E.\u003C\/span\u003E\u003C\/span\u003E \u003Cspan class=\u0022cit-article-title\u0022\u003EAtlas of individual radiographic features in osteoarthritis, revised\u003C\/span\u003E. \u003Cabbr class=\u0022cit-jnl-abbrev\u0022\u003EOsteoarthritis Cartilage\u003C\/abbr\u003E \u003Cspan class=\u0022cit-vol\u0022\u003E15\u003C\/span\u003E, \u003Cspan class=\u0022cit-fpage\u0022\u003E1\u003C\/span\u003E\u2013\u003Cspan class=\u0022cit-lpage\u0022\u003E56\u003C\/span\u003E (\u003Cspan class=\u0022cit-pub-date\u0022\u003E2007\u003C\/span\u003E).\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003Ca href=\u0022{openurl}?query=rft.jtitle%253DOsteoarthritis%2Band%2Bcartilage%2B%252F%2BOARS%252C%2BOsteoarthritis%2BResearch%2BSociety%26rft.stitle%253DOsteoarthritis%2BCartilage%26rft.aulast%253DMobasheri%26rft.auinit1%253DA.%26rft.volume%253D15%26rft.issue%253D1%26rft.spage%253D1%26rft.epage%253D8%26rft.atitle%253DEvidence%2Bfor%2Bfunctional%2BATP-sensitive%2B%2528K%2528ATP%2529%2529%2Bpotassium%2Bchannels%2Bin%2Bhuman%2Band%2Bequine%2Barticular%2Bchondrocytes.%26rft_id%253Dinfo%253Adoi%252F10.1016%252Fj.joca.2006.06.017%26rft_id%253Dinfo%253Apmid%252F16891130%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url\u0022\u003E\u003Cspan\u003EOpenUrl\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=10.1016\/j.joca.2006.06.017\u0026amp;link_type=DOI\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-doi cit-ref-sprinkles-crossref\u0022\u003E\u003Cspan\u003ECrossRef\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=16891130\u0026amp;link_type=MED\u0026amp;atom=%2Fmedrxiv%2Fearly%2F2022%2F08%2F30%2F2022.08.29.22279328.atom\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-medline\u0022\u003E\u003Cspan\u003EPubMed\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=000244182900001\u0026amp;link_type=ISI\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-newisilink cit-ref-sprinkles-webofscience\u0022\u003E\u003Cspan\u003EWeb of Science\u003C\/span\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Cspan class=\u0022ref-label\u0022\u003E8.\u003C\/span\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-8-1\u0022 title=\u0022View reference 8. in text\u0022 id=\u0022ref-8\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-journal\u0022 id=\u0022cit-2022.08.29.22279328v1.8\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003E\u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EThomas\u003C\/span\u003E, \u003Cspan class=\u0022cit-name-given-names\u0022\u003EK. A.\u003C\/span\u003E\u003C\/span\u003E \u003Cspan class=\u0022cit-etal\u0022\u003Eet al.\u003C\/span\u003E \u003Cspan class=\u0022cit-article-title\u0022\u003EAutomated Classification of Radiographic Knee Osteoarthritis Severity Using Deep Neural Networks\u003C\/span\u003E. \u003Cabbr class=\u0022cit-jnl-abbrev\u0022\u003ERadiology: Artificial Intelligence\u003C\/abbr\u003E \u003Cspan class=\u0022cit-vol\u0022\u003E2\u003C\/span\u003E, \u003Cspan class=\u0022cit-fpage\u0022\u003Ee190065\u003C\/span\u003E (\u003Cspan class=\u0022cit-pub-date\u0022\u003E2020\u003C\/span\u003E).\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003Ca href=\u0022{openurl}?query=rft.jtitle%253DRadiology%253A%2BArtificial%2BIntelligence%26rft.volume%253D2%26rft.spage%253D190065e%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url\u0022\u003E\u003Cspan\u003EOpenUrl\u003C\/span\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Cspan class=\u0022ref-label\u0022\u003E9.\u003C\/span\u003E\u003Cdiv class=\u0022cit ref-cit ref-journal no-rev-xref\u0022 id=\u0022cit-2022.08.29.22279328v1.9\u0022 data-doi=\u002210.1038\/s41598-019-56527-3\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003E\u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003ETiulpin\u003C\/span\u003E, \u003Cspan class=\u0022cit-name-given-names\u0022\u003EA.\u003C\/span\u003E\u003C\/span\u003E \u003Cspan class=\u0022cit-etal\u0022\u003Eet al.\u003C\/span\u003E \u003Cspan class=\u0022cit-article-title\u0022\u003EMultimodal Machine Learning-based Knee Osteoarthritis Progression Prediction from Plain Radiographs and Clinical Data\u003C\/span\u003E. \u003Cabbr class=\u0022cit-jnl-abbrev\u0022\u003ESci. Rep\u003C\/abbr\u003E. \u003Cspan class=\u0022cit-vol\u0022\u003E9\u003C\/span\u003E, \u003Cspan class=\u0022cit-fpage\u0022\u003E20038\u003C\/span\u003E (\u003Cspan class=\u0022cit-pub-date\u0022\u003E2019\u003C\/span\u003E).\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003Ca href=\u0022{openurl}?query=rft.jtitle%253DSci.%2BRep%26rft.volume%253D9%26rft.spage%253D20038%26rft_id%253Dinfo%253Adoi%252F10.1038%252Fs41598-019-56527-3%26rft_id%253Dinfo%253Apmid%252Fhttp%253A%252F%252Fwww.n%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url\u0022\u003E\u003Cspan\u003EOpenUrl\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=10.1038\/s41598-019-56527-3\u0026amp;link_type=DOI\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-doi cit-ref-sprinkles-crossref\u0022\u003E\u003Cspan\u003ECrossRef\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=http:\/\/www.n\u0026amp;link_type=MED\u0026amp;atom=%2Fmedrxiv%2Fearly%2F2022%2F08%2F30%2F2022.08.29.22279328.atom\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-medline\u0022\u003E\u003Cspan\u003EPubMed\u003C\/span\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Cspan class=\u0022ref-label\u0022\u003E10.\u003C\/span\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-10-1\u0022 title=\u0022View reference 10. in text\u0022 id=\u0022ref-10\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-journal\u0022 id=\u0022cit-2022.08.29.22279328v1.10\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003E\u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003ETiulpin\u003C\/span\u003E, \u003Cspan class=\u0022cit-name-given-names\u0022\u003EA.\u003C\/span\u003E\u003C\/span\u003E \u0026amp; \u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003ESaarakkala\u003C\/span\u003E, \u003Cspan class=\u0022cit-name-given-names\u0022\u003ES.\u003C\/span\u003E\u003C\/span\u003E \u003Cspan class=\u0022cit-article-title\u0022\u003EAutomatic Grading of Individual Knee Osteoarthritis Features in Plain Radiographs Using Deep Convolutional Neural Networks\u003C\/span\u003E. \u003Cabbr class=\u0022cit-jnl-abbrev\u0022\u003EDiagnostics (Basel)\u003C\/abbr\u003E \u003Cspan class=\u0022cit-vol\u0022\u003E10\u003C\/span\u003E, (\u003Cspan class=\u0022cit-pub-date\u0022\u003E2020\u003C\/span\u003E).\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Cspan class=\u0022ref-label\u0022\u003E11.\u003C\/span\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-11-1\u0022 title=\u0022View reference 11. in text\u0022 id=\u0022ref-11\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-journal\u0022 id=\u0022cit-2022.08.29.22279328v1.11\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003E\u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003ENehrer\u003C\/span\u003E, \u003Cspan class=\u0022cit-name-given-names\u0022\u003ES.\u003C\/span\u003E\u003C\/span\u003E \u003Cspan class=\u0022cit-etal\u0022\u003Eet al.\u003C\/span\u003E \u003Cspan class=\u0022cit-article-title\u0022\u003EAutomated Knee Osteoarthritis Assessment Increases Physicians\u2019 Agreement Rate and Accuracy: Data from the Osteoarthritis Initiative\u003C\/span\u003E. \u003Cabbr class=\u0022cit-jnl-abbrev\u0022\u003ECartilage 1947603519888793\u003C\/abbr\u003E (\u003Cspan class=\u0022cit-pub-date\u0022\u003E2019\u003C\/span\u003E).\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Cspan class=\u0022ref-label\u0022\u003E12.\u003C\/span\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-12-1\u0022 title=\u0022View reference 12. in text\u0022 id=\u0022ref-12\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-journal\u0022 id=\u0022cit-2022.08.29.22279328v1.12\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003E\u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EEgnell\u003C\/span\u003E, \u003Cspan class=\u0022cit-name-given-names\u0022\u003EL.\u003C\/span\u003E\u003C\/span\u003E \u003Cspan class=\u0022cit-etal\u0022\u003Eet al.\u003C\/span\u003E \u003Cspan class=\u0022cit-article-title\u0022\u003EEvaluation of an AI system for knee ostearthritis\u003C\/span\u003E. \u003Cabbr class=\u0022cit-jnl-abbrev\u0022\u003Ein 15th International Workshop o n Osteoarthritis Imaging Rotterdam, Netherlands June 30 July 2, 2021 17 (International Society of Osteoarthritis Imaging (ISOAI)\u003C\/abbr\u003E, \u003Cspan class=\u0022cit-pub-date\u0022\u003E2021\u003C\/span\u003E).\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Cspan class=\u0022ref-label\u0022\u003E13.\u003C\/span\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-13-1\u0022 title=\u0022View reference 13. in text\u0022 id=\u0022ref-13\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-journal\u0022 id=\u0022cit-2022.08.29.22279328v1.13\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003E\u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EBrejneb\u00f8l\u003C\/span\u003E, \u003Cspan class=\u0022cit-name-given-names\u0022\u003EM. W.\u003C\/span\u003E\u003C\/span\u003E \u003Cspan class=\u0022cit-etal\u0022\u003Eet al.\u003C\/span\u003E \u003Cspan class=\u0022cit-article-title\u0022\u003EExternal validation of an artificial intelligence tool for radiographic knee osteoarthritis severity classification\u003C\/span\u003E. \u003Cabbr class=\u0022cit-jnl-abbrev\u0022\u003EEur. J. Radiol\u003C\/abbr\u003E. \u003Cspan class=\u0022cit-vol\u0022\u003E150\u003C\/span\u003E, \u003Cspan class=\u0022cit-fpage\u0022\u003E110249\u003C\/span\u003E (\u003Cspan class=\u0022cit-pub-date\u0022\u003E2022\u003C\/span\u003E).\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003Ca href=\u0022{openurl}?query=rft.jtitle%253DEur.%2BJ.%2BRadiol%26rft.volume%253D150%26rft.spage%253D110249%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url\u0022\u003E\u003Cspan\u003EOpenUrl\u003C\/span\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Cspan class=\u0022ref-label\u0022\u003E14.\u003C\/span\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-14-1\u0022 title=\u0022View reference 14. in text\u0022 id=\u0022ref-14\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-journal\u0022 id=\u0022cit-2022.08.29.22279328v1.14\u0022 data-doi=\u002210.1136\/bmj.m3210\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003E\u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003ERivera\u003C\/span\u003E, \u003Cspan class=\u0022cit-name-given-names\u0022\u003ES. C.\u003C\/span\u003E\u003C\/span\u003E \u003Cspan class=\u0022cit-etal\u0022\u003Eet al.\u003C\/span\u003E \u003Cspan class=\u0022cit-article-title\u0022\u003EGuidelines for clinical trial protocols for interventions involving artificial intelligence: the SPIRIT-AI Extension\u003C\/span\u003E. \u003Cabbr class=\u0022cit-jnl-abbrev\u0022\u003EBMJ\u003C\/abbr\u003E \u003Cspan class=\u0022cit-vol\u0022\u003E370\u003C\/span\u003E, \u003Cspan class=\u0022cit-fpage\u0022\u003Em3210\u003C\/span\u003E (\u003Cspan class=\u0022cit-pub-date\u0022\u003E2020\u003C\/span\u003E).\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003Ca href=\u0022{openurl}?query=rft.jtitle%253DBMJ%26rft_id%253Dinfo%253Adoi%252F10.1136%252Fbmj.m3210%26rft_id%253Dinfo%253Apmid%252F32907797%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url\u0022\u003E\u003Cspan\u003EOpenUrl\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/ijlink\/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6MzoiYm1qIjtzOjU6InJlc2lkIjtzOjE4OiIzNzAvc2VwMDhfMTYvbTMyMTAiO3M6NDoiYXRvbSI7czo1MDoiL21lZHJ4aXYvZWFybHkvMjAyMi8wOC8zMC8yMDIyLjA4LjI5LjIyMjc5MzI4LmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-ijlink\u0022\u003E\u003Cspan\u003E\u003Cspan class=\u0022cit-reflinks-abstract\u0022\u003EAbstract\u003C\/span\u003E\u003Cspan class=\u0022cit-sep cit-reflinks-variant-name-sep\u0022\u003E\/\u003C\/span\u003E\u003Cspan class=\u0022cit-reflinks-full-text\u0022\u003E\u003Cspan class=\u0022free-full-text\u0022\u003EFREE \u003C\/span\u003EFull Text\u003C\/span\u003E\u003C\/span\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Cspan class=\u0022ref-label\u0022\u003E15.\u003C\/span\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-15-1\u0022 title=\u0022View reference 15. in text\u0022 id=\u0022ref-15\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-journal\u0022 id=\u0022cit-2022.08.29.22279328v1.15\u0022 data-doi=\u002210.1136\/bmjopen-2016-012799\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003E\u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003ECohen\u003C\/span\u003E, \u003Cspan class=\u0022cit-name-given-names\u0022\u003EJ. F.\u003C\/span\u003E\u003C\/span\u003E \u003Cspan class=\u0022cit-etal\u0022\u003Eet al.\u003C\/span\u003E \u003Cspan class=\u0022cit-article-title\u0022\u003ESTARD 2015 guidelines for reporting diagnostic accuracy studies: explanation and elaboration\u003C\/span\u003E. \u003Cabbr class=\u0022cit-jnl-abbrev\u0022\u003EBMJ Open\u003C\/abbr\u003E \u003Cspan class=\u0022cit-vol\u0022\u003E6\u003C\/span\u003E, \u003Cspan class=\u0022cit-fpage\u0022\u003Ee012799\u003C\/span\u003E (\u003Cspan class=\u0022cit-pub-date\u0022\u003E2016\u003C\/span\u003E).\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003Ca href=\u0022{openurl}?query=rft.jtitle%253DBMJ%2BOpen%26rft_id%253Dinfo%253Adoi%252F10.1136%252Fbmjopen-2016-012799%26rft_id%253Dinfo%253Apmid%252F28137831%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url\u0022\u003E\u003Cspan\u003EOpenUrl\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/ijlink\/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NzoiYm1qb3BlbiI7czo1OiJyZXNpZCI7czoxMjoiNi8xMS9lMDEyNzk5IjtzOjQ6ImF0b20iO3M6NTA6Ii9tZWRyeGl2L2Vhcmx5LzIwMjIvMDgvMzAvMjAyMi4wOC4yOS4yMjI3OTMyOC5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30=\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-ijlink\u0022\u003E\u003Cspan\u003E\u003Cspan class=\u0022cit-reflinks-abstract\u0022\u003EAbstract\u003C\/span\u003E\u003Cspan class=\u0022cit-sep cit-reflinks-variant-name-sep\u0022\u003E\/\u003C\/span\u003E\u003Cspan class=\u0022cit-reflinks-full-text\u0022\u003E\u003Cspan class=\u0022free-full-text\u0022\u003EFREE \u003C\/span\u003EFull Text\u003C\/span\u003E\u003C\/span\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Cspan class=\u0022ref-label\u0022\u003E16.\u003C\/span\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-16-1\u0022 title=\u0022View reference 16. in text\u0022 id=\u0022ref-16\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-journal\u0022 id=\u0022cit-2022.08.29.22279328v1.16\u0022 data-doi=\u002210.1016\/j.jclinepi.2010.03.002\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003E\u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EKottner\u003C\/span\u003E, \u003Cspan class=\u0022cit-name-given-names\u0022\u003EJ.\u003C\/span\u003E\u003C\/span\u003E \u003Cspan class=\u0022cit-etal\u0022\u003Eet al.\u003C\/span\u003E \u003Cspan class=\u0022cit-article-title\u0022\u003EGuidelines for Reporting Reliability and Agreement Studies (GRRAS) were proposed\u003C\/span\u003E. \u003Cabbr class=\u0022cit-jnl-abbrev\u0022\u003EJ. Clin. Epidemiol\u003C\/abbr\u003E. \u003Cspan class=\u0022cit-vol\u0022\u003E64\u003C\/span\u003E, \u003Cspan class=\u0022cit-fpage\u0022\u003E96\u003C\/span\u003E\u2013\u003Cspan class=\u0022cit-lpage\u0022\u003E106\u003C\/span\u003E (\u003Cspan class=\u0022cit-pub-date\u0022\u003E2011\u003C\/span\u003E).\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003Ca href=\u0022{openurl}?query=rft.jtitle%253DJournal%2Bof%2Bclinical%2Bepidemiology%26rft.stitle%253DJ%2BClin%2BEpidemiol%26rft.aulast%253DKottner%26rft.auinit1%253DJ.%26rft.volume%253D64%26rft.issue%253D1%26rft.spage%253D96%26rft.epage%253D106%26rft.atitle%253DGuidelines%2Bfor%2BReporting%2BReliability%2Band%2BAgreement%2BStudies%2B%2528GRRAS%2529%2Bwere%2Bproposed.%26rft_id%253Dinfo%253Adoi%252F10.1016%252Fj.jclinepi.2010.03.002%26rft_id%253Dinfo%253Apmid%252F21130355%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url\u0022\u003E\u003Cspan\u003EOpenUrl\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=10.1016\/j.jclinepi.2010.03.002\u0026amp;link_type=DOI\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-doi cit-ref-sprinkles-crossref\u0022\u003E\u003Cspan\u003ECrossRef\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=21130355\u0026amp;link_type=MED\u0026amp;atom=%2Fmedrxiv%2Fearly%2F2022%2F08%2F30%2F2022.08.29.22279328.atom\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-medline\u0022\u003E\u003Cspan\u003EPubMed\u003C\/span\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Cspan class=\u0022ref-label\u0022\u003E17.\u003C\/span\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-17-1\u0022 title=\u0022View reference 17. in text\u0022 id=\u0022ref-17\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-journal\u0022 id=\u0022cit-2022.08.29.22279328v1.17\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003E\u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EObuchowski\u003C\/span\u003E, \u003Cspan class=\u0022cit-name-given-names\u0022\u003EN. A.\u003C\/span\u003E\u003C\/span\u003E \u0026amp; \u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EBullen\u003C\/span\u003E, \u003Cspan class=\u0022cit-name-given-names\u0022\u003EJ.\u003C\/span\u003E\u003C\/span\u003E \u003Cspan class=\u0022cit-article-title\u0022\u003EMultireader Diagnostic Accuracy Imaging Studies: Fundamentals of Design and Analysis\u003C\/span\u003E. \u003Cabbr class=\u0022cit-jnl-abbrev\u0022\u003ERadiology\u003C\/abbr\u003E \u003Cspan class=\u0022cit-fpage\u0022\u003E211593\u003C\/span\u003E (\u003Cspan class=\u0022cit-pub-date\u0022\u003E2022\u003C\/span\u003E).\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Cspan class=\u0022ref-label\u0022\u003E18.\u003C\/span\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-18-1\u0022 title=\u0022View reference 18. in text\u0022 id=\u0022ref-18\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-journal\u0022 id=\u0022cit-2022.08.29.22279328v1.18\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003E\u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EObuchowski\u003C\/span\u003E, \u003Cspan class=\u0022cit-name-given-names\u0022\u003EN. A.\u003C\/span\u003E\u003C\/span\u003E \u003Cspan class=\u0022cit-article-title\u0022\u003EEstimating and comparing diagnostic tests\u2019 accuracy when the gold standard is not binary\u003C\/span\u003E. \u003Cabbr class=\u0022cit-jnl-abbrev\u0022\u003Ein Academic Radiology\u003C\/abbr\u003E vol. \u003Cspan class=\u0022cit-vol\u0022\u003E12\u003C\/span\u003E \u003Cspan class=\u0022cit-fpage\u0022\u003E1198\u003C\/span\u003E\u2013\u003Cspan class=\u0022cit-lpage\u0022\u003E1204\u003C\/span\u003E (\u003Cspan class=\u0022cit-pub-date\u0022\u003E2005\u003C\/span\u003E).\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003Ca href=\u0022{openurl}?query=rft.jtitle%253Din%2BAcademic%2BRadiology%26rft.volume%253D12%26rft.spage%253D1198%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url\u0022\u003E\u003Cspan\u003EOpenUrl\u003C\/span\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Cspan class=\u0022ref-label\u0022\u003E19.\u003C\/span\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-19-1\u0022 title=\u0022View reference 19. in text\u0022 id=\u0022ref-19\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-journal\u0022 id=\u0022cit-2022.08.29.22279328v1.19\u0022 data-doi=\u002210.1001\/jama.2013.281053\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003E\u003Cspan class=\u0022cit-auth cit-collab\u0022\u003EWorld Medical Association\u003C\/span\u003E. \u003Cspan class=\u0022cit-article-title\u0022\u003EWorld Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects\u003C\/span\u003E. \u003Cabbr class=\u0022cit-jnl-abbrev\u0022\u003EJAMA\u003C\/abbr\u003E \u003Cspan class=\u0022cit-vol\u0022\u003E310\u003C\/span\u003E, \u003Cspan class=\u0022cit-fpage\u0022\u003E2191\u003C\/span\u003E\u2013\u003Cspan class=\u0022cit-lpage\u0022\u003E2194\u003C\/span\u003E (\u003Cspan class=\u0022cit-pub-date\u0022\u003E2013\u003C\/span\u003E).\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003Ca href=\u0022{openurl}?query=rft.jtitle%253DJAMA%26rft.volume%253D310%26rft.spage%253D2191%26rft_id%253Dinfo%253Adoi%252F10.1001%252Fjama.2013.281053%26rft_id%253Dinfo%253Apmid%252F24141714%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url\u0022\u003E\u003Cspan\u003EOpenUrl\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=10.1001\/jama.2013.281053\u0026amp;link_type=DOI\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-doi cit-ref-sprinkles-crossref\u0022\u003E\u003Cspan\u003ECrossRef\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=24141714\u0026amp;link_type=MED\u0026amp;atom=%2Fmedrxiv%2Fearly%2F2022%2F08%2F30%2F2022.08.29.22279328.atom\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-medline\u0022\u003E\u003Cspan\u003EPubMed\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=000327404400028\u0026amp;link_type=ISI\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-newisilink cit-ref-sprinkles-webofscience\u0022\u003E\u003Cspan\u003EWeb of Science\u003C\/span\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Cspan class=\u0022ref-label\u0022\u003E20.\u003C\/span\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-20-1\u0022 title=\u0022View reference 20. in text\u0022 id=\u0022ref-20\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-journal\u0022 id=\u0022cit-2022.08.29.22279328v1.20\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003E\u003Cspan class=\u0022cit-auth cit-collab\u0022\u003ERegulation (EU) 2016\/679 of the European Parliament and of the Council of 27 April 2016\u003C\/span\u003E (\u003Cabbr class=\u0022cit-jnl-abbrev\u0022\u003EGeneral Data Protection Regulation)\u003C\/abbr\u003E.\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003C\/ol\u003E\u003C\/div\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan class=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003C\/div\u003E \u003C\/div\u003E\n\n \n \u003C\/div\u003E\n\u003C\/div\u003E\n \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022https:\/\/www.medrxiv.org\/sites\/default\/files\/js\/js_zP7WWIfzbyzvaM63L39cNV2juU_1XVH7wduFK9gcMNI.js\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}
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Directive 2007/46/EC of the European Parliament and of the Council of 5 September 2007 establishing a framework for the approval of motor vehicles and their trailers, and of systems, components and separate technical units intended for such vehicles (Framework Directive) (Text with EEA relevance) (repealed)
Directive 2007/46/EC of the European Parliament and of the Council of 5 September 2007 establishing a framework for the approval of motor vehicles and their trailers, and of systems, components and separate technical units intended for such vehicles (Framework Directive) (Text with EEA relevance) (repealed)
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EU Official Journal Version Revised version PDFs Expand PDFs from EUR-Lex Revised 02/09/2020 0.44 MB Revised 01/09/2020 5.54 MB Revised 01/09/2019 5.43 MB Revised 24/04/2019 5.41 MB Revised 01/01/2019 5.36 MB Revised 31/03/2018 4.33 MB Revised 18/01/2018 4.19 MB Revised 01/11/2017 4.19 MB Revised 27/07/2017 4.40 MB Revised 01/07/2016 4.08 MB Revised 01/01/2016 3.50 MB Revised 24/02/2015 3.46 MB Revised 04/02/2015 4.21 MB Revised 01/11/2014 4.21 MB Revised 01/07/2014 4.30 MB Revised 01/01/2014 1.55 MB Revised 01/07/2013 1.54 MB Revised 19/03/2013 1.54 MB Revised 10/01/2013 1.52 MB Revised 31/12/2012 1.43 MB Revised 26/02/2012 1.37 MB Revised 04/08/2011 1.24 MB Revised 24/02/2011 1.10 MB Revised 29/04/2010 0.72 MB Revised 09/04/2010 0.69 MB Revised 24/11/2009 0.68 MB Revised 29/04/2009 0.68 MB
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[ F1 SIDE 2 VEHICLE CATEGORIES O 3 AND O 4
U.K.
(complete and completed vehicles)
U.K.
Side 2
U.K.
General construction characteristics
U.K.
1. Number of axles: … and wheels: …
U.K.
1.1. Number and position of axles with twin wheels: …
2. Steered axles (number, position): …
U.K.
Main dimensions
U.K.
4. Wheelbase ( e ): … mm
U.K.
4.1. Axle spacing:
1-2: … mm
2-3: … mm
3-4: … mm
5. Length: … mm
U.K.
6. Width: … mm
U.K.
7. Height: … mm
U.K.
10. Distance between the centre of the coupling device and the rear end of the vehicle: … mm
U.K.
11. Length of the loading area: … mm
U.K.
12. Rear overhang: … mm
U.K.
Masses
U.K.
13. Mass of the vehicle in running order: … kg ( f )
U.K.
13.1. Distribution of this mass amongst the axles:
1. … kg
2. … kg
3. … kg
16. Technically permissible maximum masses
U.K.
16.1. Technically permissible maximum laden mass: … kg
16.2. Technically permissible mass on each axle:
1. … kg
2. … kg
3. … kg etc.
16.3. Technically permissible mass on each axle group:
1. … kg
2. … kg
3. … kg etc.
17. Intended registration/in service maximum permissible masses in national/international traffic ( 1 )( o )
U.K.
17.1. Intended registration/in service maximum permissible laden mass: … kg
17.2. Intended registration/in service maximum permissible laden mass on each axle:
1. … kg
2. … kg
3. … kg
17.3. Intended registration/in service maximum permissible laden mass on each axle group:
1. … kg
2. … kg
3. … kg
19. Technically permissible maximum static mass on the coupling point of a semi-trailer or centre-axle trailer: … kg
U.K.
Maximum speed
U.K.
29. Maximum speed: … km/h
U.K.
Axles and suspension
U.K.
31. Position of retractable axle(s): …
U.K.
32. Position of loadable axle(s): …
U.K.
34. Axle(s) fitted with air suspension or equivalent: yes/no ( 1 )
U.K.
35. Tyre/wheel combination ( h ): …
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Brakes
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36. Trailer brake connections mechanical/electric/pneumatic/hydraulic ( 1 )
U.K.
Bodywork
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38. Code for bodywork ( i ): …
U.K.
Coupling device
U.K.
44. Approval number or approval mark of coupling device (if fitted): …
U.K.
45.1. Characteristics values ( 1 ): D: …/ V: …/ S: …/ U: …
U.K.
Miscellaneous
U.K.
50. Type-approved according to the design requirements for transporting dangerous goods: yes/class(es): …/no ( l ):
U.K.
51. For special purpose vehicles: designation in accordance with Annex II Section 5: …
U.K.
52. Remarks ( n ): … ]
U.K.
Textual Amendments
F1 Substituted by Commission Regulation (EC) No 385/2009 of 7 May 2009 replacing Annex IX to Directive 2007/46/EC of the European Parliament and of the Council establishing a framework for the approval of motor vehicles and their trailers, and of systems, components and separate technical units intended for such vehicles (Framework Directive) (Text with EEA relevance) .
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Sensors | Free Full-Text | A New Application of Internet of Things and Cloud Services in Analytical Chemistry: Determination of Bicarbonate in Water
In a constantly evolving world, new technologies such as Internet of Things (IoT) and cloud-based services offer great opportunities in many fields. In this paper we propose a new approach to the development of smart sensors using IoT and cloud computing, which open new interesting possibilities in analytical chemistry. According to IoT philosophy, these new sensors are able to integrate the generated data on the existing IoT platforms, so that information may be used whenever needed. Furthermore, the utilization of these technologies permits one to obtain sensors with significantly enhanced features using the information available in the cloud. To validate our new approach, a bicarbonate IoT-based smart sensor has been developed. A classical CO2 ion selective electrode (ISE) utilizes the pH information retrieved from the cloud and then provides an indirect measurement of bicarbonate concentration, which is offered to the cloud. The experimental data obtained are compared to those yielded by three other classical ISEs, with satisfactory results being achieved in most instances. Additionally, this methodology leads to lower-consumption, low-cost bicarbonate sensors capable of being employed within an IoT application, for instance in the continuous monitoring of HCO3& minus; in rivers. Most importantly, this innovative application field of IoT and cloud approaches can be clearly perceived as an indicator for future developments over the short-term.
A New Application of Internet of Things and Cloud Services in Analytical Chemistry: Determination of Bicarbonate in Water
by J. V. Capella 1 , Alberto Bonastre 1,* , Rafael Ors 1 and Miguel Peris 2,*
Sensors 2019 , 19 (24), 5528; https://doi.org/10.3390/s19245528
Received: 10 October 2019 / Revised: 22 November 2019 / Accepted: 12 December 2019 / Published: 14 December 2019
(This article belongs to the Special Issue State-of-the-Art Sensors Technology in Spain 2019-2020 )
Abstract
:
In a constantly evolving world, new technologies such as Internet of Things (IoT) and cloud-based services offer great opportunities in many fields. In this paper we propose a new approach to the development of smart sensors using IoT and cloud computing, which open new interesting possibilities in analytical chemistry. According to IoT philosophy, these new sensors are able to integrate the generated data on the existing IoT platforms, so that information may be used whenever needed. Furthermore, the utilization of these technologies permits one to obtain sensors with significantly enhanced features using the information available in the cloud. To validate our new approach, a bicarbonate IoT-based smart sensor has been developed. A classical CO
2
ion selective electrode (ISE) utilizes the pH information retrieved from the cloud and then provides an indirect measurement of bicarbonate concentration, which is offered to the cloud. The experimental data obtained are compared to those yielded by three other classical ISEs, with satisfactory results being achieved in most instances. Additionally, this methodology leads to lower-consumption, low-cost bicarbonate sensors capable of being employed within an IoT application, for instance in the continuous monitoring of HCO
3
−
in rivers. Most importantly, this innovative application field of IoT and cloud approaches can be clearly perceived as an indicator for future developments over the short-term.
Keywords:
smart sensors
;
cloud services
;
Internet of Things
;
water analysis
Graphical Abstract
1. Introduction
Carbon dioxide (CO
2
) emissions, mainly due to fossil fuel combustion, land use change, and other sources, have dramatically increased over the past one hundred years. In this sense, natural waters, including oceans, lakes, and streams, serve as the major sinks for increasing levels of CO
2
in the atmosphere. The net flux of this gas into these water reservoirs is primarily driven by solubilization of carbon dioxide. Its dissociation mainly generates bicarbonate (HCO
3
−
) and carbonate (CO
3
2−
) ions, which together constitute the total carbonates present. They represent a major source of alkalinity and buffering in natural aqueous environments [
1
]. Bicarbonate constitutes a principal component of the total inorganic carbonates under natural conditions (pH 6–9) [
2
]. Their solution chemistry, along with that of alkali and alkaline earth metals, is of paramount importance for aquatic life and also influences the distribution of flora and fauna [
3
].
Therefore, a fast, accurate, and reliable means of monitoring HCO
3
−
in such media will provide a key tool to ensure the proper functioning and understanding of carbonate equilibria. Moreover, it will serve as a safeguard against drastic changes in alkalinity as a consequence of different metal complexation processes [
4
]. Bearing that in mind, various instrumental methods have been developed so far [
5
]. However, it is important to remark that many of these approaches solely depend upon laboratory-based analysis due to a lack of techniques that can be utilized on-site, the use of ion selective electrodes (ISEs) [
6
] being one of the most important exceptions. Therefore, and owing to the vital impact of water soluble HCO
3
−
and the ever-better performance of these portable analytical means for “in situ” analyses, this potentiometric technique has become the cornerstone in the present research work.
As widely shown in the literature [
7
], the equilibrium concentrations of the different species (H
2
CO
3
/CO
2
, HCO
3
−
, CO
3
2−
) in an aqueous solution of bicarbonate ions depend on the pH value of the medium, in such a way that they can be calculated as a function of said value as well as the two dissociation constants of carbonic acid (K
1
= 10
−6.4
and K
2
= 10
−10.3
). This is the procedure on which several ISEs are based to determine the bicarbonate concentration in all types of waters and aqueous solutions; it can be carried out (a) directly or (b) by measuring CO
2
or carbonate [HCO
3
−
], being then automatically calculated using the pH of the solution. In order to obtain this last value, the aforementioned ISE is equipped with a glass electrode that simultaneously determines the pH value.
Our research work aims at achieving the design and development of smart sensors for the upcoming Internet of Things (IoT). For example, the future in IoT describes a scenario where a set of environmental sensors will upload their measurements in a cloud service; in this way, it will be possible to know the concentrations of different species occurring in water, since they are recorded on a common IoT platform. For such an application, the aforementioned sensors must be provided with the ability to integrate themselves on IoT platforms [ 8 ].
In this paper, we propose a methodology for this integration, based on the so-called distributed rational agents (DRAs); they allow for achieving this goal, i.e., the design of sensors that benefit from cloud services offered by IoT. Examples include interference from polluting agents, influence of temperature and/or pressure, or other existing open data.
The utilization of this methodology will provide a bicarbonate smart sensor with the ability to integrate into IoT platforms, thus improving its performance, since it will be able to determine [HCO
3
−
] without needing to include a pH sensor (pH data will be retrieved from the cloud). This leads to greater simplicity of the sensor, as well as lower cost and energy consumption.
On the other hand, a wider objective will be achieved. There is no doubt that this is a future trend in many fields, including electroanalytical chemistry. In this sense, these sensors will provide the cloud with suitable information, on the assumption that they are connected to the Internet [ 9 ]. At any rate, this is an initial approach to this issue, although it can be clearly perceived as an indicator for future developments over the short-term.
2. IoT and Cloud-Based Services in Analytical Chemistry
The evolution of computer systems, as well as the miniaturization of electronic devices and the improvement of communications, have allowed for the emergence of wireless sensor networks (WSNs), which measure and transmit data. WSNs are now a well-established technology [ 10 ].
Smart and distributed sensing systems are one of the technological cornerstones of the Internet of Things (IoT) [
11
], applicable to many fields, such as wearable sensors, industrial smart metering, and environmental monitoring. Today, one of the major challenges of using smart wireless sensors in real deployments is related to energy consumption, cost, and guaranteeing adequate lifetime. The support for the remote management (reception, storage, processing, and sharing) of these data is provided by so-called cloud computing technologies. They consists of the presence of Internet servers—clusters—which offer data carrier services through the Internet, including:
-
SAAS (Software as a Service): it provides the end user with final applications of Internet-accessible data.
-
PAAS (Platform as a Service): it allows for the development of applications that take advantage of the environment (ubiquity, high availability).
-
IAAS (Infrastructure as a Service): it permits one to obtain computer resources in the form of virtual machines, which gives rise to seemingly endless scalability.
Figure 1
shows the different elements that are combined in a cloud-based IoT platform. Through the communication infrastructures, all sensors and actuators are able to exchange information with the cloud; sensors provide the information, whereas actuators carry out actions on the environment. This information can be stored on distributed databases that are utilized by several applications (running in the cloud) in order to provide an added value. In this sense, the data carrier provided by the cloud also includes their processing, i.e., the combination of different data to produce a new knowledge. Sometimes this is an easy process (for example, the search for conventional statistical information or basic operations), but it is not always so; in other cases, the great amount of data to be stored on these cloud systems require the application of Big Data techniques (the processing of a large volume of information in order to achieve added value). In this sense, Big Data allows for predictive analysis, trend searches, and data correctness assessment.
Given the increasing complexity of these systems, it is necessary to resort to some abstractions for an easier implementation in an intuitive, systematic, and structured way. For this purpose, the use of the so-called ‘intelligent agents’ is proposed as one of the most suitable paradigms. An agent (A) is anything that can be viewed as perceiving its environment through sensors and acting upon that environment through actuators. For each possible percept sequence, a rational agent (RA, also known as an intelligent agent) should select an action that maximizes its performance measure (in expectation) given the evidence provided by the percept sequence and whatever built in knowledge the agent has. Finally, a distributed rational agent (DRA) is an RA composed of different functionalities (consisting of hardware/software modules), which can be located in different network nodes, and all of them are connected by means of a communication network through which information is exchanged.
Figure 2
summarizes the integration of a DRA into a cloud-based IoT environment. This DRA has been added to the scheme shown in
Figure 1
, in such a way that the different functionalities, according to specific optimization criteria, can be placed either in the sensors/actuators side or in the cloud side, or even in both of them. For example, if the calculation part requires a great amount of CPU resources, then it can be carried out in the cloud; in doing so, the consumption of the node is reduced, its lifetime being longer. Among the different options, two of them are noted: At one end, there can be very simple nodes that only transmit raw data to the cloud, all other processes being performed in the cloud to get the expected data. On the other side, very powerful nodes may be available so that all functionalities can be located in the node itself, expected data being sent to the cloud following the open-data philosophy.
The DRA indicated in Figure 2 does not show all possible functionalities, nor is it necessary that each sensor/actuator implements all of them. Depending on the application, the designer will select which ones are to be implemented and where.
The interaction of a huge number of objects, as well as their diversity, and the processing of all the available information opens up new prospects for society. An intelligent object will be able to process the self-generated data using additional information that can be obtained from other objects.
It is very significant, as shown in Figure 2 , that IoT can integrate data from multiple sources and object categories. For instance, data required by a particular application may come from either private agents (firms and users who voluntarily upload this information) or public institutions (administrations, universities, research centers). In spite of data heterogeneity, the task of integration of all this information and the use of suitable IoT platforms permit their easier interoperability (although it is not guaranteed).
In the near future, trends show the possibility of obtaining nearly any measured data (regardless of the agent) on a common platform, and accessible for any application—be it public or private—that needs them. Initiatives such as open data from New York City or Valencia (our hometown in Spain) already offer a great amount of data, both from the public domain or provided by private agents.
One of the most promising features of IoT is the ability of the objects to integrate information processing routines, thus providing a faster local service; alternatively, it can resort to a more traditional cloud computing approach, according to which the computation is located in the cloud, like in the WSN.
Figure 3 shows how the node implements both sensorization and basic communications functionalities, whereas the access to the open database is remotely provided for obtaining and publishing information. There is an intermediate step between the two functionalities: the processing of the acquired information to get a processed measurement (shown in Figure 3 as a DRA).
Its main feature is the fact that it can be run on different hardware environments, depending on its requirements. In this environment, information processing may be carried out in two ways:
(a)
Processing in the node: In this case, the smart sensor can directly access the public database in order to obtain the values it needs, and thereafter it is able to generate the final output. This mode has the advantage that the node offers greater intelligence, thus directly providing the processed information; this means that there is no need to transmit the obtained measurements (very abundant in some cases). They are also straightforward with data privacy and confidentiality, since both raw data and their processed values remain in the node itself. On the other hand, this mechanism needs a higher processing capacity in the node, and therefore, greater energy requirements.
(b)
Processing in the Cloud: On a reciprocal basis, the node transmits the obtained measurements for their further processing in the cloud infrastructure. This means that the node does not directly interact with the public database, but there is an intermediate layer that is able to collect the corresponding data, as well as to receive the measured values and to process them in order to get the final result. Its most significant advantage consists of the reduction in both computing power and node consumption, even though a final transmission of the result is required if the node has to manage the processed information. The opposite case is a sensor network.
One aspect that should be underlined is the vast range of existing cloud services, which guarantees the service quality as well as the confidentiality and integrity of data and processes. In fact, they are straightforward with enhanced performances in terms of availability, with lower costs, since they take advantage of the benefits of economies of scale.
The application of IoT technologies leads to some troublesome issues, such as information storage and management, and ubiquitous access (while ensuring security and privacy). On the other hand, cloud computing environments provide storage and computation ubiquitous services that may address these needs. Therefore, the symbiosis between both ecosystems is highly profitable. An interesting example, in this case related to health issues, is shown in [ 12 ].
There is scarcely any doubt that analytical chemistry (as well as many other disciplines) will soon benefit from the important aforementioned advantages of cloud computing and IoT. Nevertheless, to date a detailed search in the literature has resulted in only a few relevant contributions [ 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 ], hence the importance of the present work as a somewhat pioneering contribution in this application field.
3. Application to the Determination of Bicarbonate in Water
The first step consisted of the incorporation of this paradigm into an application for the determination of bicarbonate concentration using carbon dioxide sensors. For this purpose, we needed to know the pH value, which was obtained from the cloud.
The determination of HCO 3 − concentration can be carried out using an appropriate ISE [ 25 ]. Nevertheless, this is unusual, since the optimum pH working range is 7–8 and real sample values are generally lower, ISE response then being then unsatisfactory. Instead, in most cases carbon dioxide is measured by means of either a carbon dioxide ISE or a carbonate ISE (coupled with a glass electrode), and the concentration obtained is converted into [HCO 3 – ] using the pH value provided by the glass electrode [ 26 ].
However, in some cases there are pH meters that are able to continuously monitor the pH values of an aqueous solution, the obtained measurements being gathered on open-access free public IoT platforms. In this regard, since the sensors must be equipped with communication mechanisms to provide the database with this information, it could be considered that glass electrodes in the ISEs are not essential; in fact, they raise the overall costs as well as energy consumption (and the information provided would be redundant). Furthermore, we subscribe to the pH information, so that [CO
2
] is measured when the provider updates the pH values. Nevertheless, if the sensor detects that there has been no updating in the last 12 h, [CO
2
] is measured using the latest available pH value despite of the low reliability. Our proposal in this paper takes into account the ever-increasing number of data providers (existing WSN, user contributions, results from other IoT processes) and the appearance of IoT-based integration platforms (they provide access to large open databases). On that basis, this new approach consists of the design and development of a simplified bicarbonate sensor based on a carbon dioxide ISE with IoT abilities. The main goal is to get pH values from open databases for the calculation of bicarbonate concentration.
The starting point of the methodology proposed is the sensor described by our research group [
10
], which consists of a microprocessor-based system equipped with a power supply that is recharged by means of a small solar panel. The core of the system consists of a low-consumption, low-cost microcontroller; its capacity is nevertheless more than sufficient to carry out all the operations required to apply the developed techniques. This microcontroller is a small integrated circuit that contains all the computer components (CPU, memory, and necessary I/O subsystems) and therefore offers the possibility to implement complete applications using only one chip. The device chosen (ARM Cortex M0) is a 32-bit microcontroller with high energy efficiency (12.5 μW/MHz) and performance; it has 2 KB RAM memory and 8 KB flash memory, as well as three timers (16 and 32 bits) and an A/D converter (10-bit resolution and 8 channels). Incoming signals from ISEs are adapted/amplified by means of an AD524 Instrumentation Amplifier (Analog Devices). Furthermore, it includes a CC1110 controller, which allows for its connection with a gateway to the Internet using the 868 MHz band. This node design was used again, it being fitted with the ISEs described in
Section 4
.
The following DRA functionalities were then incorporated into the sensor node shown in Figure 3 :
-
Processing Module: It is in charge of processing the data provided by the sensing functionalities. It also transmits the obtained measurement to the data storage module (located in the cloud).
-
Sensor Modules: Two sensor modules were utilized in this application: The first one receives the data from the ISE, whereas the second one is a virtual pH transducer sensing functionality that gets the data from the data collection functionality (also situated in the cloud). Said module can be considered as a virtual transducer, since it does not obtain the data from a physical sensor (in the node) but from other agents that obviously have the corresponding physical transducers located in the cloud.
On the other hand, other DRA functionalities can also be found in the cloud. They include:
-
Data Storage: This module receives the correct values measured by the smart sensor and stores them on the distributed database system, more specifically on the selected IoT platforms. These data become available to the rest of agents in the cloud; they may use them in the same way as the existing pH data.
-
Data Collection: This module is in charge of getting the requested information from the cloud (pH in our case) by interacting with the other agents (platforms). This information is then transmitted to the sensor functionality, which interprets it and passes it on to the processing module.
4. Experimental
4.1. FiWare Infrastructure
FiWare [
27
] is an open architecture that allows one to build a sustainable ecosystem around public software platform standards, free of rights and based on implementation in order to facilitate the development of new smart applications in many sectors. This open source platform was selected owing to its robustness and reliability, as well as its great number of users. The implementation cost may therefore be considered as very low in comparison with other options. FiWare manages the concept of generic enabler (GE), which is related to a library of general purpose services that cover common functionalities in fields such as security, storage, cloud, data context, and Internet of Things. These services are available through usable application programming interfaces (APIs) so that developers can use those functionalities when implementing their own applications. Each GE can be considered a block that contains a set of APIs for the construction of smart applications. These GE are divided into seven technical chapters, which cover cloud hosting, data and context management, interfaces to networks and devices, advanced web-based user interfaces, security, Internet of Things, and finally applications/services and data delivery.
FiWare infrastructure was utilized for the implementation of the experiments that were carried out. Two applications were implemented with JavaScript on the FiLab platform. One of them captures the current pH value using a pH-meter connected to a Raspberry Pi, the value being periodically uploaded by means of message queue telemetry transport (MQTT, an open standard network protocol for publish–subscribe services between devices) messages. The other one, implemented on the aforementioned microcontrollers, is subscribed to this information by means of the context broker (Orion), so as to obtain the bicarbonate concentration from [CO
2
]. This information was accessed by the proposed smart sensor in order to calculate [HCO
3
−
].
The ISEs described in Section 4.2 , Section 4.3 , Section 4.4 , Section 4.5 and Section 4.6 were utilized.
4.2. ISE 1: Bicarbonate ISE (Direct Determination)
A homemade electrode was fabricated following to some extent the process outlined in [
26
]. This ISE consisted of a polyvinyl chloride tube covered with a thin (10–25 µm) HCO
3
−
selective membrane made from a mixture containing polyvinyl chloride, di-(2-ethylhexyl) sebacate, trioctyl tin chloride and an H
+
interference-removing trifluroacetophenone (trifluoroacetyldecyl-benzene), a liquid solution containing 50 mM phosphate buffer and 0.01 M sodium chloride in the tube, and a lead wire connected to a Ag/AgCl reference electrode positioned in the tube. This electrode had the following features: a Nernstian slope of 55 ± 5 mV per decade change in activity (an expected Nernstian monovalent response), a limit of detection of 1.4 mg L
−1
of bicarbonate, and a response time of less than 20 s. On the other hand, the drift of the electrode contacting a 10 mM bicarbonate solution was less than 0.5 mV·h
−1
, measured at constant temperature and with the electrodes continually immersed in the solution.
The electrode was conditioned in 0.1 M NaHCO
3
for 24 h after one week of measurements. Sodium bicarbonate standard solutions were also utilized for calibrating the ISE.
4.3. ISE 2: Commercial Carbon Dioxide ISE (Classical Version)
The carbon dioxide ion selective electrode (9502BNWP) was purchased from Thermo Fisher Scientific (Waltham, MA, USA). CO 2 measured was related to bicarbonate concentration using the pH values provided by the glass electrode.
This ISE had the following specifications: a Nernstian slope of 28 ± 5 mV per decade change in activity (an expected Nernstian divalent response), a limit of detection of 6.4 mg·L −1 of bicarbonate, and a response time of less than 15 s. On the other hand, the drift of the electrode contacting the 10 mM bicarbonate solution was less than 0.5 mV·h −1 , measured at constant temperature and with the electrodes continually immersed in the solution.
4.4. ISE 3: Non-Severinghaus Carbon Dioxide ISE (Most Recent Version)
The electrode was prepared and assembled following the procedure described in [ 28 ], with only some small modifications. The presence of a glass pH electrode with combined Ag/AgCl reference (Ecotrode Plus) and a double junction Ag/AgCl reference electrode allowed for the conversion of the CO 2 measured into bicarbonate concentration electrode.
This electrode then had the following characteristics: a Nernstian slope of 27 ± 5 mV per decade change in activity (an expected Nernstian divalent response), a limit of detection of 5.3 mg·L
−1
of bicarbonate, and a response time of 5 s. On the other hand, the drift of the electrode contacting the 10 mM bicarbonate solution was less than 0.5 mV·h
−1
, measured at constant temperature and with the electrodes continually immersed in the solution.
ISE 2 and ISE 3 are considered to be very similar, since ISE 3 is really an enhanced version of ISE 2. Owing to its improved performance, we believe that there is no need to further compare ISE 2 with the other devices, since ISE 3 better represents the classical determination of CO
2
.
4.5. ISE 4: Proposed Sensor
A homemade conventional CO 2 -ISE was modified accordingly, and later connected to the node described in Section 3 . Then, this ‘virtual’ ISE provided [CO 2 ] data and [HCO 3 − ] values were calculated therefrom using the corresponding equations and pH data retrieved from the cloud. As mentioned above, these calculations could be carried out either in the node or in the cloud, the former being what was done in our case; pH was obtained from the FiWare server (located in the cloud), the final result was then displayed in the node, and [HCO 3 − ] was finally sent to the cloud for its storage.
This electrode had then the following features: a Nernstian slope of 27 ± 5 mV per decade change in activity (an expected Nernstian divalent response), a limit of detection of 6.0 mg·L
−1
of bicarbonate, and a response time of less than 20 s. On the other hand, the drift of the electrode contacting the 10 mM bicarbonate solution was less than 0.5 mV·h
−1
, measured at constant temperature and with the electrodes continually immersed in the solution.
4.6. Experimental Details
All solutions were maintained, using a thermostat, at 25 °C. This temperature was chosen because the values of acid–base dissociation constants listed in most of the tables are referred to at 25 °C.
All solvents and reagents used were analytically pure. Sets of 10 aqueous bicarbonate solutions (concentrations ranging between 30 and 300 mg·L
−1
) were prepared by dissolving the appropriate amounts of NaHCO
3
in Milli-Q purified water. The pH values of these solutions were adjusted in a range between 4.5 and 7.0 using the corresponding buffers. ISE 1 directly measured bicarbonate concentration, whereas ISE 2 and ISE 3 evaluated the levels of CO
2
and converted them into bicarbonate concentrations using the pH measured. Finally, ISE 4 also measured CO
2
, but the values obtained were transformed into bicarbonate concentrations from pH data contained in the cloud.
The pH values were monitored potentiometrically every six hours and simultaneously entered into the cloud database. They were obtained at the same time as the bicarbonate measurements, all of them being the mean value of
n
replicates (see the end of this section).
All four sensors were deployed nonstop for 24 h, calibration checks being performed twice a day; they showed a negligible drift during that period of time.
In order to obtain reliable results, n replications were performed for each measurement, n being calculated as follows:
The results for each measurement were considered as random variables (
X 1 , X 2 , …, X n
) with a μ mean value;
n
measurements were repeated until an estimation of μ was obtained with a 90% confidence interval according to the expression:
X
¯
(
n
)
±
t
n
−
1
,
0.95
S
2
(
n
)
n
where
t n –
1, 0.95
represents the upper limit of the Student’s t-distribution on
n
– 1 degrees of freedom, and
X
(
n
) and
S
2
(
n
) are the mean and the variance of the results obtained in the different experiments. In general, 5–15 replications were carried out for each measurement.
5. Results and Discussion
The experimental results obtained are shown in the following graphs ( Figure 4 ).
As stated in Section 4.4 , the comparison between ISE 2 and ISE 3 does not seem relevant to us, and therefore ISE 3 is considered to be representative of commercial CO 2 ISEs. That is why no comparison between ISE 2 and ISE 3 was carried out.
In order to compare the results obtained from ISE 1 (direct measurements; assumed to be the most accurate value) with those from ISE 4, relative errors (RE) were calculated using the following expression:
RE = (value ISE 4 – value ISE 1)/value ISE 1.
The same procedure was utilized in the case of ISE 3:
RE = (value ISE 3 – value ISE 1)/value ISE 1.
The results obtained in both comparisons are summarized in Figure 5 a,b.
As shown in Figure 5 a (ISE 1 vs. ISE 4), the error was lower than 2% in most cases, and did not exceed 3% in 90% of cases. As expected, Figure 5 a shows that the maximum relative error took place when both pH and the magnitude measured were very low. This case corresponded to a 6.9% relative error. Root Mean Square Error (RMSE) was also calculated, a value of 0.021 being obtained.
When the comparison was made with regard to ISE 3 (
Figure 5
b), accuracy was not so high, but it could be observed that more than half of all data showed an error under 2%, two-thirds of them being lower than 3%. In this case, the errors in pH and [CO
2
] measurements were accumulated, the highest relative error being then 20% (unacceptable, but corresponding to a very uncommon situation). On the other hand, for common pH values of water (5.5–6.5), the maximum error was lower than 4%. Even in the rare instance of pH = 7, the error was still low for bicarbonate concentrations between 120 and 240 mg·L
−1
. As in the previous comparison, RMSE was also calculated, a value of 0.049 being obtained.
As regards response times, those of the ISEs studied were in the range between 5 and 20 s. On the other hand, access time for cloud data was estimated to be 1−2 s, whereas by calculation it turned out to be negligible (a few milliseconds), which means that the response time of ISE 4 was limited by the acquisition capabilities of the CO
2
ISE. Furthermore, while the ISEs utilized in these experiments had a response time of less than 20 s, state-of-the-art technologies (such as those used in ISE 3) could reduce it to 5 s, with a lower energy consumption (no pH electrode).
When dealing with energy consumption, ISE 4 operation was monitored in order to evaluate its behavior. It was found that ISE 4 required about half the energy of ISE 3 for correct operation.
6. Conclusions
A new approach was presented for the development of sensors based on cloud services and the Internet of Things. Following this methodology, and as an example, a new smart sensor was designed and tested; it is a bicarbonate smart sensor (cheaper, simpler, and more efficient) based on a combination of a real CO
2
ISE with a virtual pH-meter transducer, which obtains its values from a cloud service that supports the IoT platform used.
The starting point was a study that clearly shows the existing symbiosis between analytical chemistry and the new technologies such as IoT and cloud-based services. In this way, the former can benefit from the advances provided by the latter; conversely, these state-of-the-art technologies need new sensors with special features that should be offered by new developments in analytical chemistry.
With a view to facilitating the design of these new sensors, the present work proposes a new approach based on the application of intelligent agents (DRA, distributed rational agents), whose functionalities may be implemented either in the cloud or in the sensor and actuator nodes themselves. According to the application and the sensor type, it is necessary to define the functionalities to be implemented as well as their location.
As an example of application of the proposed methodology, a new sensor for the potentiometric determination of bicarbonate in water is described. A carbon dioxide ISE is utilized for this purpose, but with an important novelty: The ISE measures the concentration of CO
2
and, using the pH data available in the cloud, is able to provide the values of bicarbonate concentrations. Moreover, the overall energy consumption is substantially lower, since no additional electrode is required for measuring pH. This also leads to a decrease in both cost and size. When it comes to the implementation of this sensor, DRA functionalities are distributed between the cloud and the sensor node in such a way that sensing and processing attributions are located in the sensor node, whereas data collection and data storage remain in the cloud. Communication modules between both blocks are also provided.
From a chemical point of view, the results obtained are quite encouraging. Taking into account the most common pH values of water (in the range of 5.5 to 6.5), satisfactory accuracy and precision were obtained (as shown in the experiments of comparison with the other sensors). On the other hand, no significant operation errors were detected and there were only a few data transmission errors, recovered by the communication functionalities using common retransmission protocols. However, in any case, it must be remarked that this is an initial investigation, and therefore some work still needs to be carried out to achieve the ultimate goal of developing a truly smart sensor using IoT and cloud services.
Additionally, with this proposal it is possible to infer indirect determinations based on easier and inexpensive measurements, along with the information available on existing databases, both public and private. As shown in the previous sections, the information of these IoT platforms can be utilized for specific applications, thanks to the disconnection between sources and consumers. In this way, it is possible to develop sensors that can ‘virtually’ determine (and upload to the IoT platform) some chemical parameters without physical transducers. Finally, a virtuous cycle takes place in this environment: The more public information available, the greater the number of benefitted applications, which also means more available data.
In conclusion, the most relevant contribution of this work consists of the application of IoT and cloud-based services in analytical chemistry environments, such as the potentiometric determinations of ionic species in aqueous solutions. This new ecosystem is based on the confluence —on a single exchange platform—of data from multiple sources (sensor networks, industrial systems, personal contributions, and so on) that can be employed by any user. Following this line of thinking, the amount of information of this kind available in the cloud is growing exponentially. Therefore, it is necessary to implement the integration of analytical chemistry into the new IoT applications (as proposed in this paper). Undoubtedly, further advances in this line will open up a whole new and exciting world of IoT applications.
Author Contributions
All authors have read and agree to the published version of the manuscript. Conceptualization, M.P., J.V.C., R.O. and A.B.; methodology, M.P. and A.B.; software, J.V.C.; validation, A.B., J.V.C. and R.O.; formal analysis, M.P.; investigation, M.P., A.B and J.V.C; resources, R.O.; data curation, A.B.; writing—original draft preparation, M.P. and R.O.; writing—review and editing, A.B and J.V.C.; supervision, R.O.; project administration, R.O.; funding acquisition, R.O.
Funding
This research was funded by the Spanish Ministerio de Economía y Competitividad, grant number DPI2016-80303-C2-1-P.
Conflicts of Interest
The authors declare no conflict of interest.
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Figure 1. Different elements combined within an Internet of Things (IoT) cloud-based platform.
Figure 2. Integration of the distributed rational agents (DRAs) in an IoT cloud-based application.
Figure 2. Integration of the distributed rational agents (DRAs) in an IoT cloud-based application.
Figure 3. DRA distribution scheme in the proposed application.
Figure 3. DRA distribution scheme in the proposed application.
Figure 4. Comparison of the results obtained with the four ion selective electrodes (ISEs).
Figure 4. Comparison of the results obtained with the four ion selective electrodes (ISEs).
Figure 5. Errors in the results obtained: ( a ) ISE 1 vs. ISE 4, ( b ) ISE 3 vs. ISE 4.
Figure 5. Errors in the results obtained: ( a ) ISE 1 vs. ISE 4, ( b ) ISE 3 vs. ISE 4.
© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/ ).
MDPI and ACS Style
Capella, J.V.; Bonastre, A.; Ors, R.; Peris, M. A New Application of Internet of Things and Cloud Services in Analytical Chemistry: Determination of Bicarbonate in Water. Sensors 2019, 19, 5528.
https://doi.org/10.3390/s19245528
AMA Style
Capella JV, Bonastre A, Ors R, Peris M. A New Application of Internet of Things and Cloud Services in Analytical Chemistry: Determination of Bicarbonate in Water. Sensors. 2019; 19(24):5528.
https://doi.org/10.3390/s19245528
Chicago/Turabian Style
Capella, J. V., Alberto Bonastre, Rafael Ors, and Miguel Peris. 2019. "A New Application of Internet of Things and Cloud Services in Analytical Chemistry: Determination of Bicarbonate in Water" Sensors19, no. 24: 5528.
https://doi.org/10.3390/s19245528
| https://www.mdpi.com/1424-8220/19/24/5528/htm |
The Effects of 4%Fe on the Performance of Pure Zinc as Biodegradable Implant Material | Request PDF
Request PDF | The Effects of 4%Fe on the Performance of Pure Zinc as Biodegradable Implant Material | The efforts to develop structural materials for biodegradable metal implants have lately shifted their focus from Magnesium and Iron base alloys... | Find, read and cite all the research you need on ResearchGate
The Effects of 4%Fe on the Performance of Pure Zinc as Biodegradable Implant Material
March 2019
Annals of Biomedical Engineering47(10)
DOI: 10.1007/s10439-019-02245-w
Authors:
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe>
Alon Kafri
Ben-Gurion University of the Negev
<here is a image 02863946c90fbbb9-20cf74b49837677f>
Shira Ovadia
Ben-Gurion University of the Negev
<here is a image f2f62089ad6ff61c-d19572ff1996375a>
Galit Yosafovich-Doitch
Galit Yosafovich-Doitch
<here is a image bb0e872c47185af2-378cbcc27aa018e0>
Eli Aghion
Ben-Gurion University of the Negev
Abstract
The efforts to develop structural materials for biodegradable metal implants have lately shifted their focus from Magnesium and Iron base alloys towards Zinc. This was mainly due to the accelerated corrosion rate of Mg that is accompanied by hydrogen gas evolution, formation of voluminous iron oxide products with reduced degradation rate in the case of Iron implants and the crucial role of Zn in many physiological processes. However the mechanical properties and degradation capabilities of pure zinc in physiological environment are limited and do not comply with the requirements of biodegradable implants. The present study aims at evaluating the effect of 4%Fe on the in-vitro and in-vivo behavior of pure Zinc. This was carried out in order to address the inherent disadvantages of pure zinc in terms of mechanical properties and biodegradability. The results obtained clearly indicate that the biocompatibility and mechanical properties of the new material system was in accord with the prospective requirements of biodegradable implants. However the corrosion degradation of the new alloy in in-vivo conditions was quite similar to that of pure zinc in spite of the significant micro-galvanic effect created by Delta phase Zn11Fe.
<here is a image 175d1bd4b7439d95-754927124da715c1>
... The development of innovative biodegradable metal implants is mainly focused on using Fe-, Mg-and Zn-based alloys due to their acceptable biocompatibility performance. However, Fe-based alloys tend to generate insufficient degradation rates and, consequently, produce voluminous oxide that can encourage inflammation and repulse neighboring biological matrices [4,[14][15][16][17][18][19][20]
[21]
. As for Mg-based alloys, these mainly suffer from accelerated corrosion degradation [22] that is accompanied by hydrogen gas evolution, which can lead to the danger of gas embolism [7,[23][24][25][26][27][28][29][30][31][32][33][34]. ...
... In addition, Zn plays several crucial physiological roles in the human body, such as being a functional element in more than 300 enzymes and its involvement in nucleic acid metabolism. It is also believed to act as an antibacterial and antiviral constituent [27,[38][39][40][41]. Nevertheless, the disadvantage of pure zinc is the danger of relatively high levels of anemia, unsatisfactory mechanical properties and the risk of fibrous encapsulation due to its relatively high potential (−0.762 V) [2,
21]
. The alloy-based matrix (Zn-2%Fe) selected for this study has already been developed and studied by the authors of this paper [21,30] and was found to be a possible solution to overcome the danger of fibrous encapsulation. ...
... It is also believed to act as an antibacterial and antiviral constituent [27,[38][39][40][41]. Nevertheless, the disadvantage of pure zinc is the danger of relatively high levels of anemia, unsatisfactory mechanical properties and the risk of fibrous encapsulation due to its relatively high potential (−0.762 V) [2,21]. The alloy-based matrix (Zn-2%Fe) selected for this study has already been developed and studied by the authors of this paper
[21,
30] and was found to be a possible solution to overcome the danger of fibrous encapsulation. Apparently, the addition of Fe to pure Zn created a microgalvanic effect between the Delta phase (Zn 11 Fe) and the Zn-matrix, which consequently doubled the degradation rate of the alloy in both in vitro and in vivo conditions [21,30]. ...
The Effect of Mn on the Mechanical Properties and In Vitro Behavior of Biodegradable Zn-2%Fe Alloy
Article
Full-text available
Jul 2022
Lital Ben Tzion-Mottye
<here is a image bdc93ead6b6e9f25-cb18379f78bbe6be> Dan Eliezer
<here is a image 257681a091ad93df-2464bfba60ca2a78> Tomer Ron
Eli Aghion
The attractiveness of Zn-based alloys as structural materials for biodegradable implants mainly relates to their excellent biocompatibility, critical physiological roles in the human body and excellent antibacterial properties. Furthermore, in in vivo conditions, they do not tend to produce hydrogen gas (as occurs in the case of Mg-based alloys) or voluminous oxide (as occurs in Fe-based alloys). However, the main disadvantages of Zn-based alloys are their reduced mechanical properties and their tendency to provoke undesirable fibrous encapsulation due to their relatively high standard reduction potential. The issue of fibrous encapsulation was previously addressed by the authors via the development of the Zn-2%Fe alloy that was selected as the base alloy for this study. This development assumed that the addition of Fe to pure Zn can create a microgalvanic effect between the Delta phase (Zn11Fe) and the Zn-matrix that significantly increases the biodegradation rate of the alloy. The aim of the present study is to examine the effect of up to 0.8% Mn on the mechanical properties of biodegradable Zn-2%Fe alloy and to evaluate the corrosion behavior and cytotoxicity performance in in vitro conditions. The selection of Mn as an alloying element is related to its vital role in the synthesis of proteins and the activation of enzyme systems, as well as the fact that Mn is not considered to be a toxic element. Microstructure characterization was carried out by optical microscopy and scanning electron microscopy (SEM), while phase analysis was obtained by X-ray diffraction (XRD). Mechanical properties were examined in terms of hardness and tensile strength, while corrosion performance and electrochemical behavior were assessed by immersion tests, open circuit potential examination, potentiodynamic polarization analysis and impedance spectroscopy. All the in vitro corrosion testing was performed in a simulated physiological environment in the form of a phosphate-buffered saline (PBS) solution. The cytotoxicity performance was evaluated by indirect cell viability analysis, carried out according to the ISO 10993-5/12 standard using Mus musculus 4T1 cells. The obtained results clearly demonstrate the strengthening effect of the biodegradable Zn-2%Fe alloy due to Mn addition. The effect of Mn on in vitro corrosion degradation was insignificant, while in parallel Mn had a favorable effect on indirect cell viability.
... Biodegradable Fe-containing Zn alloys are in their primary developmental stage. A few have been reported previously, including Zn-Fe, Zn-Mn-Fe(-RE) and Zn-Cu-Fe alloy systems [7][8][9]14,
22,
23]. Controlling volume fraction and size of FeZn 13 particles is a common basic issue faced by all of them and future designed alloys. ...
... When v ζ = 50 vol%, x is about 2.6 wt%, i.e., Fe contents in biodegradable Zn alloys should be controlled lower than 2.6 wt%. As a counterexample, Zn-4Fe alloy
[22]
is likely to be largely non-degradable with v ζ as high as 76.5%. Guided by Fig. 8b, seemingly abnormal corrosion behaviors of Zn-Fe alloys can be well explained. ...
... Guided by Fig. 8b, seemingly abnormal corrosion behaviors of Zn-Fe alloys can be well explained. It is reported that corrosion rates of pure Zn, Zn-1.3Fe and Zn-4Fe are 296 μm/y, 509 μm/y and 225 μm/y respectively, measured through static immersion tests in phosphate-buffered saline (PBS) at 37°C for 20 days [7,
22]
. Compared with pure Zn, Zn-1.3Fe ...
Enhancement in mechanical and corrosion resistance properties of a biodegradable Zn Fe alloy through second phase refinement
Article
Jun 2020
MAT SCI ENG C-BIO S
<here is a image 7747d088ad0536e3-a4296cc8eef7bc34> Chen hong-ting
<here is a image 130ed85cac4f4bb9-112c92bcefb1a855> Zhang-Zhi Shi
Xi-Xian Gao
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Luning Wang
Biodegradable Zn alloys containing Fe suffer from a common problem that FeZn13 second phase particles are coarse. This problem roots thermodynamically from the negligible solid solubility of Fe in Zn and priority of FeZn13 solidification over Zn. In this paper, bottom circulating water-cooled casting method is successfully developed to significantly refine FeZn13 particles in Zn-0.3Fe alloy, owing to its cooling speed about 8 times of that of conventional casting. The second phase refinement alleviates brittleness of the alloy, increases the ultimate tensile strength by about 62%, and decreases electrochemical corrosion rate (CR) by about 19%, but immersion CR by only about 4% due to barrier effect of corrosion products. Viability of human umbilical vein endothelial cells maintains at a high level over 95% in 25– 100% extracts. A great potential is shown for improving comprehensive properties of biodegradable Zn alloys without changing its chemical compositions through such a physical method.
... γ = 90°) similar to MnZn 13 is a main second phase in Zn alloys containing Fe [19,41]. However, the coarse Fe-rich phase in Zn-1.3Fe and Zn-4Fe alloys (in wt.%) is claimed to be FeZn 11 [42,
43]
. This is doubtful since there is no such phase in Zn-Fe phase diagram [44]. ...
... C = 10%, t = 5 days) have almost the same ICFs of 203-204, their EA.hy926 cell viabilities are about 43% [5,18,22,24,27,28,[32][33][34]38,[41][42]
[43]
45,48,49,51,52,[58][59][60][61][62][63][64][65][66]. (b) Yield strength (in red), Vickers hardness (in blue), and content of alloying elements. ...
... (b) Yield strength (in red), Vickers hardness (in blue), and content of alloying elements. Data are collected from literatures [5,16,18,19,22,24,27,28,[32][33][34]38,39,[41][42]
[43]
45,46,[48][49][50][51][52][58][59][60][61][62][63][64][65][66][67][68]. X in (a) and (b) refers to an alloying element. ...
Design biodegradable Zn alloys: Second phases and their significant influences on alloy properties
Article
Full-text available
Feb 2020
<here is a image 130ed85cac4f4bb9-112c92bcefb1a855> Zhang-Zhi Shi
Xi-Xian Gao
Hai-Jun Zhang
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Luning Wang
Alloying combined with plastic deformation processing is widely used to improve mechanical properties of pure Zn. As-cast Zn and its alloys are brittle. Beside plastic deformation processing, no effective method has yet been found to eliminate the brittleness and even endow room temperature super-ductility. Second phase, induced by alloying, not only largely determines the ability of plastic deformation, but also influences strength, corrosion rate and cytotoxicity. Controlling second phase is important for designing biodegradable Zn alloys. In this review, knowledge related to second phases in biodegradable Zn alloys has been analyzed and summarized, including characteristics of binary phase diagrams, volume fraction of second phase in function of atomic percentage of an alloying element, and so on. Controversies about second phases in Zn–Li, Zn–Cu and Zn–Fe systems have been settled down, which benefits future studies. The effects of alloying elements and second phases on microstructure, strength, ductility, corrosion rate and cytotoxicity have been neatly summarized. Mg, Mn, Li, Cu and Ag are recommended as the major alloying elements, owing to their prominent beneficial effects on at least one of the above properties. In future, synergistic effects of these elements should be more thoroughly investigated. For other nutritional elements, such as Fe and Ca, refining second phase is a matter of vital concern.
... However, research carried out by Guillory et al. [33] indicated that pure Zn may suffer from insufficient corrosion degradation rates in in vivo conditions that consequently can provoke fibrous encapsulation and limit the proper dissolution of the implant. To prevent this phenomenon, Fe and other alloying elements were added to pure Zinc in order to accelerate the corrosion rate by a micro-galvanic effect
[34]
. The present study aims to evaluate the prospects of a Ti-6Al-4V lattice infiltrated with biodegradable Zn-2%Fe alloy as a structural material system for osseointegrated implants in in vitro conditions. ...
... All the AM lattices were manufactured in the Z-direction and in accordance with ASTM standard 52921-13. The selection of Zn-2%Fe as the biodegradable alloy mainly relates to the relative advantage of this alloy composition in terms of corrosion degradation [18,
34]
. This selection aims to avoid the danger of insufficient corrosion degradation rates, which can promote fibrous encapsulation and limit the dissolution of the infiltrated alloy [33]. ...
Evaluating the Prospects of Ti-Base Lattice Infiltrated with Biodegradable Zn–2%Fe Alloy as a Structural Material for Osseointegrated Implants—In Vitro Study
Article
Full-text available
Aug 2021
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Noa Gabay
<here is a image 5d64036a1bb250b7-5191395526d33d4c> Razi Vago
<here is a image 257681a091ad93df-2464bfba60ca2a78> Tomer Ron
Eli Aghion
The term “osseointegrated implants” mainly relates to structural systems that contain open spaces, which enable osteoblasts and connecting tissue to migrate during natural bone growth. Consequently, the coherency and bonding strength between the implant and natural bone can be significantly increased, for example in operations related to dental and orthopedic applications. The present study aims to evaluate the prospects of a Ti–6Al–4V lattice, produced by selective laser melting (SLM) and infiltrated with biodegradable Zn2%Fe alloy, as an OI–TiZn system implant in in vitro conditions. This combined material structure is designated by this study as an osseointegrated implant (OI–TiZn) system. The microstructure of the tested alloys was examined both optically and using scanning electron microscopy (SEM) and X-ray diffraction (XRD) analysis. The mechanical properties were assessed in terms of compression strength, as is commonly acceptable in cases of lattice-based structures. The corrosion performance was evaluated by immersion tests and electrochemical analysis in terms of potentiodynamic polarization and electrochemical impedance spectroscopy (EIS), all in simulated physiological environments in the form of phosphate buffered saline (PBS) solution. The cytotoxicity was evaluated in terms of indirect cell viability. The results obtained demonstrate the adequate performance of the OI–TiZn system as a non-cytotoxic structural material that can maintain its mechanical integrity under compression, while presenting acceptable corrosion rate degradation.
... Further, metals like titanium (Ti), magnesium (Mg), and zinc (Zn) are being widely explored for designing dental implants due to their excellent osseointegration efficacies in integrating joints to bones via extracellular matrices. 33,
51
For instance, Azizabadi et al. 8 designed Ti-MOF loaded PVA based EMs, as dental nanocoatings with a high surface area of~3204 m 2 /g, the thermal stability of~368°C, and compressive strength of~559 Pa. Similarly, Toledano-Osorio et al. 115 reported the osteogenic gene expression potential of silicon dioxide nanoparticles loaded (methyl methacrylate) 1 -co-(hydroxyethyl methacrylate) 1 / (methyl acrylate) 3 -co-(hydroxyethyl acrylate) 2 (50/50 w/w) FIGURE 2. Representative schematic of different manufacturing processes for designing 3D constructs for various dental applications. ...
... Further, innovative biodegradable and biocompatible metallic implant materials with excellent mechanical properties are being explored. 33,
51
Such implant materials when used in conjugation with soft biomimetic frameworks, may potentially, enhance the cellular compatibility and conformability of the resultant hybrid constructs. Thus, as the choice of materials for designing desired 3D constructs, remains limited, therefore, modern research should proactively focus more on designing hybrid constructs, comprising of acceptable physicomechanical performance and bioactivity. ...
Biodegradable and Biocompatible 3D Constructs for Dental Applications: Manufacturing Options and Perspectives
Article
Jul 2021
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Deepika Sharma
<here is a image e0806f58ba8051c9-7af21cc08980891e> Vijay Prakash Mathur
Bhabani K. Satapathy
Designing 3D constructs with appropriate materials and structural frameworks for complex dental restorative/regenerative procedures has always remained a multi-criteria optimization challenge. In this regard, 3D printing has long been known to be a potent tool for various tissue regenerative applications, however, the preparation of biocompatible, biodegradable, and stable inks is yet to be explored and revolutionized for overall performance improvisation. The review reports the currently employed manufacturing processes for the development of engineered self-supporting, easily processable, and cost-effective 3D constructs with target-specific tuneable mechanics, bioactivity, and degradability aspects in the oral cavity for their potential use in numerous dental applications ranging from soft pulp tissues to hard alveolar bone tissues. A hybrid synergistic approach, comprising of development of multi-layered, structurally stable, composite building blocks with desired physicomechanical performance and bioactivity presents an optimal solution to circumvent the major limitations and develop new-age advanced dental restorations and implants. Further, the review summarizes some manufacturing perspectives which may inspire the readers to design appropriate structures for clinical trials so as to pave the way for their routine applications in dentistry in the near future.
... Furthermore, pure Zn tends to provoke encapsulation processes in in vivo conditions [33], which can isolate the implant from the physiological environment and hence limits its capability to act as a suitable biodegradable material. This encapsulation problem was partly addressed in previous studies of the authors [34][35]
[36]
by developing innovative Zn-Fe based alloys that have relatively increased corrosion rates compared to pure Zn. The present study aims to evaluate the effect of 0.3-1.6% ...
... The encapsulation event can practically isolate the implant from the surrounding physiological environment, and subsequently limits its capability to perform as a biodegradable material [44,45]. In order to address this problem, previous research activities carried out by the authors [34,
36,
46] paved the way for the development of Zn-Fe based alloys that have a relatively increased corrosion rate compared to pure Zn. The additions of various amounts of Ca with a relatively lower potential (−2.87 V) to Zn-Fe based alloys aim to further increase the degradation rate of those alloys in order to overcome the problem of encapsulation. ...
The Effect of Ca on In Vitro Behavior of Biodegradable Zn-Fe Alloy in Simulated Physiological Environments
Article
Full-text available
Dec 2020
Orit Avior
Noa Ben Ghedalia-Peled
<here is a image 257681a091ad93df-2464bfba60ca2a78> Tomer Ron
Eli Aghion
The growing interest in Zn based alloys as structural materials for biodegradable implants is mainly attributed to the excellent biocompatibility of Zn and its important role in many physiological reactions. In addition, Zn based implants do not tend to produce hydrogen gas in in vivo conditions and hence do not promote the danger of gas embolism. However, Zn based implants can provoke encapsulation processes that, practically, may isolate the implant from its surrounding media, which limits its capability of performing as an acceptable biodegradable material. To overcome this problem, previous research carried out by the authors has paved the way for the development of Zn-Fe based alloys that have a relatively increased corrosion rate compared to pure Zn. The present study aims to evaluate the effect of 0.3–1.6% Ca on the in vitro behavior of Zn-Fe alloys and thus to further address the encapsulation problem. The in vitro assessment included immersion tests and electrochemical analysis in terms of open circuit potential, potentiodynamic polarization, and impedance spectroscopy in phosphate buffered saline (PBS) solution at 37 °C. The mechanical properties of the examined alloys were evaluated by tension and hardness tests while cytotoxicity properties were examined using indirect cell metabolic activity analysis. The obtained results indicated that Ca additions increased the corrosion rate of Zn-Fe alloys and in parallel increased their strength and hardness. This was mainly attributed to the formation of a Ca-rich phase in the form CaZn13. Cytotoxicity assessment showed that the cells’ metabolic activity on the tested alloys was adequate at over 90%, which was comparable to the cells’ metabolic activity on an inert reference alloy Ti-6Al-4V.
... The acquired values of V corr , I corr and CR of Zn-1.3Fe alloy was found to be increased notably compared to pure Zn for immersion period of 20 days (Table 6). However, in another study, they reported a reduction of CR in Zn-4Fe alloy with respect to pure Zn in the same corrosion medium owing to the passivation effect of corrosion products
[272]
. Addition of Mn was noted to shrink the CR of pure Zn, such as, addition of 4 and 24 wt% Mn in pure Zn dropped the CR of Zn more than 3 and 100 times, respectively, which was ascribed to finer microstructure and the formation of a fewer intermetallic compound [139]. ...
... Various animal models such as those using Sprague-Dawley (SD) rats [78,282,283], Wistar rats [230,
272,
284], C57BL/6 mice [147], beagle dogs [87], white pigs [285], and rabbits [90,148] have been used in previous studies for in vivo degradation assessment of metallic biomaterials. The implantation sites in these animals are generally application-driven. ...
Recent research and progress of biodegradable zinc alloys and composites for biomedical applications: Biomechanical and biocorrosion perspectives
Article
Sep 2020
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Humayun Kabir
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Khurram Munir
<here is a image 4513b8899aeaa00f-74907b74e397ae2c> Cuie Wen
<here is a image f778fb86bb6153bc-19c15db08ea10b5f> Yuncang Li
Biodegradable metals (BMs) gradually degrade in vivo by releasing corrosion products once exposed to the physiological environment in the body. Complete dissolution of biodegradable implants assists tissue healing, with no implant residues in the surrounding tissues. In recent years, three classes of BMs have been extensively investigated, including magnesium (Mg)-based, iron (Fe)-based, and zinc (Zn)-based BMs. Among these three BMs, Mg-based materials have undergone the most clinical trials. However, Mg-based BMs generally exhibit faster degradation rates, which may not match the healing periods for bone tissue, whereas Fe-based BMs exhibit slower and less complete in vivo degradation. Zn-based BMs are now considered a new class of BMs due to their intermediate degradation rates, which fall between those of Mg-based BMs and Fe-based BMs, thus requiring extensive research to validate their suitability for biomedical applications. In the present study, recent research and development on Zn-based BMs are reviewed in conjunction with discussion of their advantages and limitations in relation to existing BMs. The underlying roles of alloy composition, microstructure, and processing technique on the mechanical and corrosion properties of Zn-based BMs are also discussed.
... However, because the rate of disintegration is excessively slow, the retention of the breakdown product is damaging the body. Recently, material scientists and medical professionals have paid close attention to the potential medical applications of biodegradable metallic materials [13][14]
[15]
. ...
Surface Modification of Biodegradable Zinc Alloy for Biomedical Applications
Article
Full-text available
Jun 2023
<here is a image 4c57a948a1a5379f-e3957aa437c974e4> Pralhad Pesode
<here is a image 9fdafa7207dfb6ac-41ddec69a1346977> Dr. Shivprakash Bhagwatrao Barve
In recent years, zinc, and its alloys, along with biodegradable metals made of Mg and Fe, have been projected as potential replacements for biodegradable metals due to their better corrosion rate and high biocompatibility in gastrointestinal, bone,
and cardiovascular contexts. Clinical application of Zn-related biodegradable metals with a reasonable rate of membrane degradation and outstanding mechanical properties for guided bone regeneration membranes is very promising. Nevertheless, in order to properly control their biodegradation behavior, Zn-based biodegradable metals do require surface treatment. First off, certain Zn-based biodegradable metals that were implanted in a cardiovascular background showed signs of intimal activation and moderate inflammation. Second, Zn-based biodegradable metals for orthopaedic applications biodegrade at relatively moderate rates, resulting in long-term retention after completing their task. The development of next-generation orthopaedic implants made on Zn related biodegradable alloys or composites has the capacity to eliminate revision surgeries
and biocompatibility problems. In the meantime, increased Zn2+
release during breakdown will result in delayed osseointegration
and in vitro cytotoxicity. Surface modification Zn-based biomaterials can solve above problems. In this review, we first provide a summary of the available Zn-based alloy’s surface modification techniques for biomedical applications
such as chemical conversion coatings, different types of chemical conversion coating, and organic coatings. Advantages and challenges of Zn-based biomaterials are also discussed at the last.
... In contrast, the Vanadium (V), Chromium (Cr), manganese (Mn), copper (Cu), Zirconium (Zr), and silver (Ag) have been blended into the metallic biomaterials [20]. Among them, Mn [21], Ag [22], Fe
[23]
, and Cu [24][25][26] have been explored previously in Zn alloys. In surveying more alloying possibilities, three transition metallic elements, Cr, Zr, V, have been targeted in the present study because of their similar metallurgy properties to Zn. ...
Blending with transition metals improves bioresorbable zinc as better medical implants
Article
Full-text available
Feb 2023
<here is a image 0b280c7b30afeb8a-48a3dc701f10e75f> Juncen Zhou
<here is a image 081d2d06c6c262ba-6701d705363addc3> Yingchao Su
Jiayin Fu
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Donghui Zhu
Zinc (Zn) is a new class of bioresorbable metal that has potential for cardiovascular stent material, orthopedic implants, wound closure devices, etc. However, pure Zn is not ideal for these applications due to its low mechanical strength and localized degradation behavior. Alloying is the most common/effective way to overcome this limitation. Still, the choice of alloying element is crucial to ensure the resulting alloy possesses sufficient mechanical strength, suitable degradation rate, and acceptable biocompatibility. Hereby, we proposed to blend selective transition metals (i.e., vanadium-V, chromium-Cr, and zirconium-Zr) to improve Zn's properties. These selected transition metals have similar properties to Zn and thus are beneficial for the metallurgy process and mechanical property. Furthermore, the biosafety of these elements is of less concern as they all have been used as regulatory approved medical implants or a component of an implant such as Ti6Al4V, CoCr, or Zr-based dental implants. Our study showed the first evidence that blending with transition metals V, Cr, or Zr can improve Zn's properties as bioresorbable medical implants. In addition, three in vivo implantation models were explored in rats: subcutaneous, aorta, and femoral implantations, to target the potential clinical applications of bioresorbable Zn implants.
... Several different methods used to accelerate the degradation of pure iron were introduced. Alloying with different biocompatible elements such as magnesium (Mg) or zinc (Zn) 17,[21][22][23]
[24]
, or controllable changes in material porosity were already studied 22,25,26 . The desired acceleration of corrosion can be achieved by using these methods, however, the use of elements that are non-toxic and choosing a degree of porosity that does not negatively affect the resulting mechanical properties of the material is still challenging. ...
Interaction of thin polyethyleneimine layer with the iron surface and its effect on the electrochemical behavior
Article
Full-text available
Mar 2022
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Natália Podrojková
<here is a image 700c9f9892498e01-1209cad4e57ed328> Katarína Sisáková
<here is a image 7743ea705c8c92ab-ec3800f0a8da36fe> Radka Gorejová
<here is a image e79a86ffeb94df07-54ecce529feee99d> Renáta Oriňáková
Polymer-coated metals may act as biodegradable orthopedic implants with adjustable corrosion rates. Metallic surfaces represent a dynamic system with specific interactions occurring after the material is implanted into the human body. An additional layer, in the form of polymeric thin film, changes the nature of this metal-body fluids interface. Moreover, the interaction between polymer and metal itself can differ for various systems. Iron-based material modified with a thin layer of polyethyleneimine (PEI) coating was prepared and studied as potential absorbable implant. Computational methods were employed to study the interaction between the metallic surface and polymer functional monomer units at atomic levels. Various spectroscopical and optical methods (SEM, AFM, Confocal, and Raman spectroscopy) were also used to characterize prepared material. Electrochemical measurements have been chosen to study the polymer adsorption process onto the iron surface and corrosion behavior which is greatly influenced by the PEI presence. The adsorption mechanism of PEI onto iron was proposed alongside the evaluation of Fe and Fe-PEI degradation behavior studied using the impedance method. Bonding via amino -NH2 group of PEI onto Fe and enhanced corrosion rate of coated samples were observed and confirmed.
... Not surprisingly, many studies have been performed to improve the strength of pure Zn through conventional metallurgical approaches, including alloying. Among these alloys include Zn-Mg [14], Zn-Ca and Zn-Sr [15], Zn-Fe-Mg [16], Zn-Mg-Sr [17], Zn-Mg-Mn [18], Zn-Fe
[19]
. These alloys exhibit increased strength, although the degradation rates are still too low or, in some cases, too high to serve as biodegradable implants. ...
Stress Corrosion Analysis and Direct Cell Viability of Biodegradable Zn-Fe-Ca Alloy in In-Vitro Conditions
Article
Full-text available
Jan 2022
Orit Avior
Noa Ben Ghedalia-Peled
<here is a image 257681a091ad93df-2464bfba60ca2a78> Tomer Ron
Eli Aghion
Due to the excellent biocompatibility of Zn and Zn-based alloys, researchers have shown great interest in developing biodegradable implants based on zinc. Furthermore, zinc is an essential component of many enzymes and proteins. The human body requires ~15 mg of Zn per day, and there is minimal concern for systemic toxicity from a small zinc-based cardiovascular implant, such as an arterial stent. However, biodegradable Zn-based implants have been shown to provoke local fibrous encapsulation reactions that may isolate the implant from its surrounding environment and interfere with implant function. The development of biodegradable implants made from Zn-Fe-Ca alloy was designed to overcome the problem of fibrous encapsulation. In a previous study made by the authors, the Zn-Fe-Ca system demonstrated a suitable corrosion rate that was higher than that of pure Zn and Zn-Fe alloy. The Zn-Fe-Ca system also showed adequate mechanical properties and a unique microstructure that contained a secondary Ca-reach phase. This has raised the promise that the tested alloy could serve as a biodegradable implant metal. The present study was conducted to further evaluate this promising Zn alloy. Here, we assessed the material’s corrosion performance in terms of cyclic potentiodynamic polarization analysis and stress corrosion behavior in terms of slow strain rate testing (SSRT). We also assessed the ability of cells to survive on the alloy surface by direct cell culture test. The results indicate that the alloy develops pitting corrosion, but not stress corrosion under phosphate-buffered saline (PBS) and air environment. The direct cell viability test demonstrates the successful adherence and growth of cells on the alloy surface.
... Alloying and plastic deformation treatments are the top two methods used to modify the microstructures and thus improve the mechanical and corrosion properties of metallic materials [2,7]. Many alloying elements have been used in Zn alloys, including Mg [8][9][10][11][12], calcium (Ca) [11,13], lithium (Li) [14], manganese (Mn) [15], silver (Ag) [16], Fe
[17]
, copper (Cu) [18][19][20], and germanium [21]. Strontium (Sr) plays critical roles in the bone resorption and formation process and mainly exist in bone tissue [22]. ...
Biodegradable Zn–Sr alloys with enhanced mechanical and biocompatibility for biomedical applications
Article
Dec 2021
<here is a image 081d2d06c6c262ba-6701d705363addc3> Yingchao Su
Jiayin Fu
Shaokang Du
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Donghui Zhu
Zinc (Zn) is a new generation of biodegradable metal as temporary biomedical implants with a promising degradation rate. However, its clinical applications have been limited because of the insufficient mechanical properties. Considering the degradation property and biocompatibility, we proposed Zn–Sr alloys after extrusion treatments to simultaneously improve the mechanical strength and ductility. The in vitro and in vivo degradation and biocompatibility were also evaluated using electrochemical and immersion corrosion tests, various cell and bacterial models, together with subcutaneous and femoral implantations in rats. Results showed that the extruded Zn-0.7Sr alloys exhibited two times higher mechanical strengths (∼120 MPa) and better ductility (∼10%) than the pure Zn counterparts. The Zn–Sr alloys provided enhanced in vitro and in vivo biocompatibility along with promising antibacterial properties.
... Several papers studied iron composite materials or alloys with the addition of manganese, tungsten, palladium, silver or carbon nanotubes (CNT), for example [22][23][24]. However, only several papers deal with the absorbable Fe-Zn materials [25][26]
[27]
[28] even though both these elements are biocompatible and have a great potential in the field of biodegradable metals. ...
Corrosion Behavior of Zn, Fe and Fe-Zn Powder Materials Prepared via Uniaxial Compression
Article
Full-text available
Aug 2021
<here is a image 8aa6d04408b4991f-bc5b178add7ee36e> Ivana Šišoláková
Pavol Cipa
<here is a image 7743ea705c8c92ab-ec3800f0a8da36fe> Radka Gorejová
<here is a image e79a86ffeb94df07-54ecce529feee99d> Renáta Oriňáková
Powder metallurgy is one of the most prevalent ways for metallic degradable materials preparation. Knowledge of the properties of initial powders used during this procedure is therefore of great importance. Two different metals, iron and zinc, were selected and studied in this paper due to their promising properties in the field of biodegradable implants. Raw powders were studied using scanning electron microscopy (SEM) coupled with energy dispersive spectrometry (EDX). Powders (Fe, Zn and Fe-Zn in a weight ratio of 1:1) were then compressed at the pressure of 545 MPa to the form of pellets with a diameter of 1.7 cm. Surface morphology and degradation behavior in the Hanks´ solution were studied and evaluated. Electrochemical polarization tests along with the static immersion tests carried out for 21 days were employed for corrosion behavior characterization. The highest corrosion rate was observed for pure Zn powder followed by the Fe-Zn and Fe, respectively. A mixed Fe-Zn sample showed similar properties as pure zinc with no signs of iron degradation after 21 days due to the effect of galvanic protection secured by the zinc acting as a sacrificial anode.
... This ratio corresponds to the delta (δ) Zn phase (Zn 11 Fe). Kafri et al. describe the same formation of the intermetallic phase for samples with an iron content of 4 wt %
[35]
. In addition to the (δ) phase, more other phases were present in the Zn-Fe alloys. ...
Biodegradable zinc-iron alloys: Complex study of corrosion behavior, mechanical properties and hemocompatibility
Article
Full-text available
Jan 2021
<here is a image 8d360dfeddb3b8f9-372bf6584cc10b4e> Zuzana Orsagova Kralova
<here is a image 7743ea705c8c92ab-ec3800f0a8da36fe> Radka Gorejová
<here is a image e79a86ffeb94df07-54ecce529feee99d> Renáta Oriňáková
Karol Kovaľ
Zn-Fe alloys have been extensively investigated in this study with a view to their application as biodegradable bone implants. Biogenic element zinc is a very appropriate metal because of the ideal degradation rate compared to those of Mg and Fe. Studied alloys were made by compressing metallic powders in a content ratio of 100% Zn, Zn-1% Fe, Zn-2% Fe, Zn-5% Fe and Zn-10% Fe and sintering at 350 °C for 1 h. Prepared samples were examined by optical microscopy, SEM and XRD. Corrosion behavior, mechanical testing and hemocompatibility were observed subsequently. The electrochemical performance of such materials was studied in the simulated body fluids. The enhanced corrosion rate was observed for all samples after iron addition due to the micro-galvanic effect between the pure Zn and Zn11Fe intermetallic phase. The corrosion rate of the Zn-5% Fe alloyed sample was more than 20-times higher (2.89 mmpy) compared to the pure Zn. However, alloying with more than 5 wt % of iron diminished the mechanical performance of the material. Therefore, the performed mechanical and hemocompatibility tests showed acceptable biocompatibility of zinc and Zn-1% Fe and Zn-2% Fe samples.
... This similarity was also maintained by the Bode magnitude diagram (Figure 9b) that introduces the solution resistance. The related electrical equivalent circuit and corresponding fitting parameters (R1solution resistance, R2 and Q1-capacitor) [39,
40]
are introduced in Figure 10 and Table 5, respectively. Altogether, the EIS analysis clearly indicates that the corrosion resistance of printed and counterpart alloys was quite similar. ...
Effect of Phase Transformation on Stress Corrosion Behavior of Additively Manufactured Austenitic Stainless Steel Produced by Directed Energy Deposition
Article
Full-text available
Dec 2020
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Ohad Dolev
<here is a image 257681a091ad93df-2464bfba60ca2a78> Tomer Ron
<here is a image 03232e42af7cfc10-2d321dcbb9fa73ce> Avi Leon
Eli Aghion
The present study aims to evaluate the stress corrosion behavior of additively manufactured austenitic stainless steel produced by the wire arc additive manufacturing (WAAM) process. This was examined in comparison with its counterpart, wrought alloy, by electrochemical analysis in terms of potentiodynamic polarization and impedance spectroscopy and by slow strain rate testing (SSRT) in a corrosive environment. The microstructure assessment was performed using optical and scanning electron microscopy along with X-ray diffraction analysis. The obtained results indicated that in spite of the inherent differences in microstructure and mechanical properties between the additively manufactured austenitic stainless steel and its counterpart wrought alloy, their electrochemical performance and stress corrosion susceptibility were similar. The corrosion attack in the additively manufactured alloy was mainly concentrated at the interface between the austenitic matrix and the secondary ferritic phase. In the case of the counterpart wrought alloy with a single austenitic phase, the corrosion attack was manifested by uniform pitting evenly scattered at the external surface. Both alloys showed ductile failure in the form of “cap and cone” fractures in post-SSRT experiments in corrosive environment.
Microstructures, mechanical properties and in vitro corrosion behavior of biodegradable Zn alloys microalloyed with Al, Mn, Cu, Ag and Li elements
In this work, Zn microalloyed with Al, Mn, Cu, Ag and Li was cast, annealed and extruded. The results showed that addition of multiple trace elements causes significant change in the microstructures, mechanical properties and corrosion behavior of Zn-0.1Al-0.1Mn-0.1Cu-0.1Ag (¹ZM), Zn-0.1Al-0.1Mn-0.1Cu-0.1Ag- 0.1Li (²ZM-0.1Li) and Zn-0.1Al-0.1Mn-0.1Cu-0.1Ag-0.35Li (³ZM-0.35Li) alloys. Two ternary phases with the approximate compositions of Al13Mn3Zn34 and Al10MnZn89 phases are formed in the casting and annealing processes of these alloys, respectively. Wavy β-LiZn4 lamellae that have not been extensively reported are precipitated from the primary Zn dendrites in the casting process of ZM-0.35Li alloy. Also, Zn laths are precipitated from the eutectic β-LiZn4 phase in the annealing process of ZM-0.35Li alloy. The above-mentioned phases are crushed or elongated in the as-extruded alloys, which play an important role in improving the strength of the alloys. All the as-extruded alloys have typical (0001) basal texture, accompanied with relatively low {0001}<112¯0> slip and high {101¯2}<101¯1¯> twinning Schmid factors, which are advantageous and disadvantageous to the strength enhancement of the alloys, respectively. All the as-cast alloys exhibit poor mechanical properties, especially low ductility. The as-extruded ZM alloy exhibits ultrahigh ductility, with an elongation of up to 82.2%±2.94%. The as-extruded ZM-0.35Li alloy shows the best comprehensive mechanical properties, with yield strength, ultimate tensile strength, elongation and hardness of 380±1.6 MPa, 449±7.4 MPa, 62.3%±4.63% and 98±1.4 HV, respectively. Electrochemical corrosion rates of the ZM, ZM-0.1Li and ZM-0.35Li alloys are 0.241±0.004, 0.206±0.006 and 0.189±0.008 mm/year, respectively. In vitro immersion corrosion rates (after 26 d in SBF solution) of them are 0.134±0.005, 0.125±0.004 and 0.121±0.003 mm/year, respectively. The as-extruded ZM-0.35Li alloy exhibits the best corrosion resistance.
Biodegradable Mg alloys for orthopedic implants – A review
The last decade has seen a significant growth in the market for alloys used for implants, especially for those intended for orthopedic implants. Research into biodegradable magnesium-based alloys has made great strides in this period, so huge progress has been made in their use in the medical industry. The important factors that led to the intensification of research in this regard, were social but also economic, wanting to improve the quality of life, by reducing the use of conventionally permanent metallic implants (stainless steel, cobalt-based alloys, and titanium alloys) which involve the second implant removal surgery and other undesirable effects (stress shielding and metal ion releases), with a negative impact on the emotional and physical condition of patients, and by significantly reducing the costs for both the patient and the health system in the field of orthopedics. This paper refers to the impact and importance of biodegradable Mg alloys, reviewing the beginning of their development, the significant characteristics that make them so desirable for such applications (orthopedic implants) but also the characteristics that must be modulated (corrosion rate and mechanical properties) to arrive at the ideal product for the targeted application. It highlights, in detail, the mechanism and aspects related to the corrosion behaviour of Mg alloys, electrochemical characterization techniques / methods, as well as strategies to improve the corrosion behaviour and mechanical properties of these types of biodegradable alloys. The means of optimization, the category and the effect of the alloying elements, the design criteria, the requirements that the implants of biodegradable alloys Mg-based must meet and the aspects related to their efficiency are also presented. Finally, the potential applications in the specialized clinics, as well as the final products currently used and made by important prestigious companies in the world are approached.
Development of a high-strength Zn-Mn-Mg alloy for ligament reconstruction fixation
Although various biodegradable materials have been investigated for ligament reconstruction fixation in the past decades, only few of them possess a combination of high mechanical properties, appropriate degradation rate, good biocompatibility, and osteogenic effect, thus limiting their clinical applications. A high-strength Zn-0.8Mn-0.4Mg alloy (i.e., Zn08Mn04Mg) with yield strength of 317 MPa was developed to address this issue. The alloy showed good biocompatibility and promising osteogenic effect in vitro. The degradation effects of Zn08Mn04Mg interference screws on the interface between soft tissue and bone were investigated in anterior cruciate ligament (ACL) reconstruction in rabbits. Compared to Ti6Al4V, the Zn alloy screws significantly accelerated the formation of new bone and further induced partial tendon mineralization, which promoted tendon-bone integration. The newly developed screws are believed to facilitate early joint function recovery and rehabilitation training and also avoid screw breakage during insertion, thereby contributing to an extensive clinical prospect.
Alloy Materials for Biomedical Applications
Metals and alloys have widespread use as biomedical materials for replacing dysfunctional hard tissues. The demand for development of alloy materials that fulfill all the requirements of biomedical alloys regarding mechanical, chemical, and biological characteristics is getting higher fast with increasing elderly population. Representative employed metallic materials are 316L stainless steel, cobalt (Co)‐based alloys, and titanium (Ti) alloys. New nickel‐free low modulus Ti alloys, zirconium alloys, biodegradable alloys, and niobium and tantalum alloys are proving very interesting to biomedical applications and are still under development nowadays. This chapter describes the commonly used biomedical alloys as well as the new metallic materials and the essential factors affecting their performance for clinical applications.
In vitro and in vivo studies of Zn-Mn biodegradable metals designed for orthopedic applications
In recent years, Zn-based materials provide a new option as biodegradable metals for orthopedic applications. To improve the low strength and brittle nature of pure Zn, small amounts of alloying element Mn (0.1, 0.4 and 0.8 wt. %) were added into Zn to fabricate binary Zn-Mn alloys. An extremely high elongation (83.96 ± 2.36%) was achieved in the resulting Zn-0.8wt.%Mn alloy. Moreover, Zn-Mn alloys displayed significantly improved cytocompatibility as compared to pure Zn, according to cell proliferation and morphology analyses. More importantly, a significantly improved osteogenic activity was verified after adding Mn regarding ALP activity and osteogenic expression. Furthermore, Zn-0.8wt.%Mn alloy scaffolds were implanted into the rat femoral condyle for repairing bone defects with pure Ti as control. Enhanced osteogenic activities were confirmed for Zn-0.8Mn alloy in contrast to pure Ti based on Micro-CT and histological results, and favorable in vivo biosafety of Zn-0.8Mn alloy was verified by H&E staining and blood tests. The exceptional mechanical performance and favorable osteogenic capability render Zn-Mn alloy a promising candidate material in the treatment of bone defects or fracture repair.
Statements of significance
The element Mn, on the one hand, as an essential trace element in the human body, promotes cell proliferation, adhesion, spreading, and regulates bone metabolism; on the other hand, it could significantly improve the ductility of Zn alloys. Here, we systematically reported the biocompatibility and biofunctionality of binary biodegradable Zn-Mn alloys in the bone environment. The Zn-Mn alloys promoted MC3T3-E1 cell proliferation, adhesion, spreading, and osteogenic differentiation in vitro. Furthermore, a rat femoral condyle defect model was established; porous Zn-Mn alloy scaffolds were manufactured to repair the bone defects. Significant bone regenerations, considerable bone ingrowth, and desirable biosafety were confirmed in vivo. Therefore, biodegradable Zn-Mn with promising osteogenic properties may become new options for orthopedic implant materials.
The effect of hot isostatic pressure on the corrosion performance of Ti-6Al-4V produced by an electron-beam melting additive manufacturing process
Additive manufacturing (AM) is a rapidly growing technology that enables the fast production of complex and near-net-shaped (NNS) components. Among the many applicable AM methods (particularly powder bed technologies), electron-beam melting (EBM) is gaining increased interest mainly in aerospace and medical industries, due to its inherent advantages for the printing of Ti-6Al-4V alloy. Although major strides have been made towards understanding the effect of hot isostatic pressure (HIP) on the mechanical properties of Ti-6Al-4V produced by AM, its effect on corrosion performance remains relatively unexplored. To date, the reported corrosion studies remain essentially limited to the selective laser melting (SLM) process, while the corrosion behavior of EBM Ti-6Al-4V and particularly HIPed EBM Ti-6Al-4V have not been fully realized. This paper provides a detailed analysis of this corrosion performance, including the stress-corrosion susceptibility of EBM Ti-6Al-4V in as-build condition and after HIP heat treatment. Microstructure and phase identifications were examined by scanning electron microscopy (SEM) and X-ray diffraction analysis. Corrosion performance was evaluated by electrochemical measurements, including open-circuit potential (OCP), potentiodynamic polarization analysis and impedance spectroscopy (EIS), as well as stress-corrosion examination in terms of slow strain-rate testing (SSRT). All of the corrosion tests were carried out in a 3.5 wt.% NaCl solution at ambient temperature. Owing to the natural excellent corrosion resistance of Ti-6Al-4V, the obtained results revealed that the HIP process has only a slight positive effect on the corrosion resistance of Ti-6Al-4V produced by EBM. This minor improvement may be related to the improved efficiency of the passivation layer that was attributed to the increased β-phase content and the reduction of α/β interfaces. In terms of stress corrosion sensitivity, the HIPed specimens exhibited extended time-to-failure (TTF) at the low strain rate at 2.5•10⁻⁷ 1/sec, where the effect of the corrosive environment was more dominant.
| https://www.researchgate.net/publication/331624459_The_Effects_of_4Fe_on_the_Performance_of_Pure_Zinc_as_Biodegradable_Implant_Material |
License to Kill - POZ
Gore guns for Third World countries trying to make cheap AIDS drugs
License to Kill
Gore guns for Third World countries trying to make cheap AIDS drugs
While Bill Clinton and Al Gore spend billions to blast the Serbs into submission, ostensibly to save lives, their international AIDS policy is politically smart—bombing Third World countries to save profits, not people with HIV. The administration, in cahoots with the pharmaceutical industry, is using economic and political blackmail to stop developing countries from making inexpensive copies of patented AIDS drugs.Take Thailand, with nearly a million infected with HIV. The United States has been applying immense pressure to block Thai companies from producing generic versions of ddI, a nucleoside analog created by our government’s own researchers and marketed worldwide exclusively by Bristol-Myers Squibb. Also targeted are Thai generic versions of Bristol-Myers and Pfizer drugs used to treat cryptococcal meningitis, an often-fatal fungal brain infection affecting some 200,000 HIV positive Thais.At issue is an obscure portion of international trade law known as compulsory licensing, designed to expand access to patented or copyrighted products considered essential goods and services. Under rules of the World Trade Organization—of which the United States is a charter member—countries with a public health crisis can use compulsory licensing to manufacture drugs more cheaply, as long as they reasonably compensate the patent holders.Yet the Clinton-Gore administration is adamantly opposed to compulsory licensing by other countries, even though U.S. law permits it. Gore—currently raising money for his presidential campaign—has been the administration’s point man in defending these companies’ monopolies. This may come as news to the gay fatcats whom Gore is courting so assiduously, but it doesn’t come out of the blue: Gore’s chief domestic policy advisor, David Beier, was the main lobbyist for Genentech, a biotech behemoth. Co-chair of the U.S.–South Africa Binational Commission, Gore is pummeling South Africa—which has the world’s fastest-growing infection rate—to abrogate its recent law allowing compulsory licensing of pharmaceuticals. As the Watergate saying goes, “Follow the money.”Most drugs, including antiretrovirals, are relatively inexpensive to produce. As David Scondras, an activist campaigning for lower drug pricing, wrote recently in AIDS Treatment News: “For example, AZT in bulk can be purchased for 42 cents for 300 mg from the worldwide suppliers; this price reflects profits not only to the manufacturer but also to the middleman bulk buyer. The same drug retails at my local pharmacy for $5.82 per pill. This ridiculous price bears no real relation to the cost of production.”The primary reason the pharmaceutical giants are fighting so hard against compulsory licensing of AIDS drugs abroad is not because of the potential to lose profits there—Third World people and governments can’t afford to pay U.S. prices anyway. Instead, they fear that if other countries make those drugs available to their PWAs at a tiny fraction of the retail cost, it would set off a major price-gouging scandal here, in the United States, when the true size of drug companies’ markups are revealed.Rep. Jesse Jackson Jr.’s HOPE for Africa bill (see “Keep HOPE Alive”) would prohibit the use of U.S. funds to undermine African intellectual property and competition policies designed to increase the availability of vital medicines. But as Richard Laing, MD, a Boston University public health expert, points out, even the Jackson bill is no panacea for the continent’s epidemic, since in most of sub-Saharan Africa, “where a dollar a year per person is spent on health care, the vast majority struggle to have access just to simple antibiotics, and the AIDS numbers are too big for compulsory licensing to make a difference.”The Clinton-Gore administration has engaged in a series of grotesque and secretive maneuverings to avoid having to consult with or debate public health leaders on these issues. But a March conference in Geneva, organized by Ralph Nader’s Consumer Project on Technology, Doctors Without Borders and Health Action International, brought together 60 nongovernmental organizations from around the world to mobilize opposition to U.S. policy, and activists in the United States are now forging a coalition. The president’s Advisory Commission on AIDS has finally consented to take up the issue this summer. Still, since Clinton has so often ignored his own commission’s recommendations, it will take a major public outcry to alter U.S. policy—especially given the puissant lobbying of the multinational monopolies.
| https://www.poz.com/article/License-to-Kill-10386-7757 |
In re Succession of Pittman, 2019-CA-0683 - Louisiana - Case Law - VLEX 891379245
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In re Succession of Pittman, 2019-CA-0683
<table><tbody><tr><td> Court</td><td> Court of Appeal of Louisiana (US)</td></tr><tr><td> Writing for the Court</td><td> JUDGE SANDRA CABRINA JENKINS</td></tr><tr><td> Parties</td><td> SUCCESSION OF ALBERT E. PITTMAN</td></tr><tr><td> Docket Number</td><td> NO. 2019-CA-0683,2019-CA-0683</td></tr><tr><td> Decision Date</td><td> 01 July 2020</td></tr></tbody></table>
SUCCESSION OF ALBERT E. PITTMAN
NO. 2019-CA-0683
COURT OF APPEAL FOURTH CIRCUIT STATE OF LOUISIANA
JULY 1, 2020
APPEAL FROM CIVIL DISTRICT COURT, ORLEANS PARISH
NO. 2000-11819, DIVISION "D"
Honorable Nakisha Ervin-Knott, Judge
JUDGE SANDRA CABRINA JENKINS
(Court composed of Judge Edwin A. Lombard, Judge Joy Cossich Lobrano, Judge Rosemary Ledet, Judge Sandra Cabrina Jenkins, Judge Dale N. Atkins)
LOBRANO, J., CONCURS IN THE RESULT
LEDET, J., DISSENTS WITH REASONS
ATKINS, J., DISSENTS FOR THE REASONS ASSIGNED BY J. LEDET
Brett M. Dupuy
Rebecca S. Miller
MIDDLEBERG RIDDLE GROUP
909 Poydras Street, Suite 1400
New Orleans, LA 70112
COUNSEL FOR PLAINTIFF/APPELLANT
Michael R.C. Riess
Christy R. Bergeron
RIESS LEMIEUX, LLC
1100 Poydras Street, Suite 1100
New Orleans, LA 70163
COUNSEL FOR DEFENDANT/APPELLEE
AFFIRMED
Page 2
SCJ
EAL
This appeal arises from a dispute over the management of a testamentary trust ("the Trust"), created upon the death of Albert E. Pittman in 2000. In the Trust, Mr. Pittman designated his wife, Gloria, as Trustee and income beneficiary, and named his four children as equal principal beneficiaries. In 2017, a representative of one of four principal beneficiaries, Lisa Montgomery ("Montgomery"), filed a Rule to Remove Trustee and for Restitution of Funds. In response, Gloria, as Trustee, filed a motion for summary judgment seeking the dismissal of the Rule to Remove. Montgomery now appeals the trial court's judgment granting the motion for summary judgment filed by Gloria and dismissing the Rule to Remove. Based on our de novoreview of the motion for summary judgment, we affirm the trial court's judgment.
FACTUAL AND PROCEDURAL BACKGROUND
In 1974, Albert Pittman and Gloria Pittman were married. At that time, they each had two children from prior marriages—Albert's children were Sandra
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(Sandy) Pittman and Chris Pittman; Gloria's children were Donna Pittman Velez and Cynthia Pittman Rodriguez.
In July 2000, Albert died testate, with his will providing for specific bequests of assets to Gloria and his children and creating the Trust with the remaining assets. Albert designated Gloria the Trustee and income beneficiary of the Trust, which was divided into Portions A and B for federal tax purposes, 1and named his four children as equal principal beneficiaries of the Trust. As the income beneficiary, Gloria was entitled to the income interest upon the entire corpus of the Trust for her lifetime. Upon Gloria's death, the Trust terminates and the children receive equal distributions of the corpus of the Trust. As to the administration of the Trust during Gloria's lifetime, the will states as follows:
(13) I suggest Gloria, as trustee, to make monthly payments, first out of income from the invested funds, then, if necessary, out of the principal of these invested funds, and finally, from my interest in the corporation named in paragraph 10, as follows: (a) $4,000.00 to Gloria until her death.
Gloria shall have the right to invade the corpus balance if
,
when and to the extent necessary to maintain her present standard of living and well-being
,
and maintenance of her home.
Upon and after Gloria's death, I suggest my co-trustees to make monthly payments in the same order of such funds of $4,000.00 each to Chris, Sandy, Cindy, and Donna, until their deaths or total depletion of all property and funds in my estate.
Shortly after Albert's death, in August 2000, the co-executrixes of his succession—Gloria and his daughter, Sandra—filed a "Petition to Probate Will and Qualify Co-Executrixes" in Orleans Parish Civil District Court, opening the Succession. In September 2002, the co-executrixes obtained a judgment of
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possession. Among the assets included in the estate were two notes payable to the testator, Albert, by his daughter, Sandy.
In April 2003, Sandy executed a promissory note in the amount of $193,160.23, payable to Albert's estate and Gloria, representing and replacing the two pre-death notes. In 2008, Gloria, individually and on behalf of the estate, filed suit against Sandra to collect on the promissory note. Following multiple years of litigation, including a judgment in favor of the estate and Gloria, 2a settlement was reached. As part of the settlement, in June 2015, Sandy renounced her interest in her father's estate.
In 2006, Albert's son, Chris, died testate, leaving a surviving spouse, Montgomery, and four adult children—Jonathan, Rachel, Christopher, and Jaime—from previous marriages. In his will, Chris named Montgomery as the executrix of his estate.
From December 2008 to February 2013, Montgomery, a licensed Louisiana attorney, was employed as an associate at the law firm of Kingsmill Riess, L.L.C., now know as Riess LeMieux, L.L.C. (the "Riess Firm"). During Montgomery's tenure there, Gloria retained the Reiss Firm to represent Albert's estate and herself in the lawsuit filed against Sandy. However, Montgomery was not a named attorney representing the estate or the Trustee in the litigation against Sandra.
In 2016, the instant dispute arose between Montgomery and Gloria, who began to withdraw $7,000 per month from the Trust to make $1000 monthly gifts
Page 5
to Donna, Cynthia, Montgomery, and each of Chris's four children. Gloria made the same withdrawal and distributions for thirteen months, totally $91,000.00 in distributions.
In February 2017, Montgomery, as the executrix and representative of Chris's estate, filed a "Rule to Show Cause for Accounting of Trusts and Other Relief" in this (Albert's) succession case. Montgomery asserted that she had requested accountings and additional information regarding the trust assets and administration of the Trust, but that the responses to her requests were "generally delayed" and the accounting information was "unclear" and "incomplete." In response to Montgomery's rule to show cause, Gloria filed an opposition asserting that she has complied with all requests for accounting, having Greg Rodriguez, Albert and Gloria's son-in-law and a certified public accountant, provide the responses to Montgomery's requests for accountings through Montgomery's attorneys, who sent the written requests. Following a hearing on the rule for accounting, the trial court's May 3, 2017 judgement ordered Gloria to submit the annual accounting for 2016 to all beneficiaries of the Trust, including Montgomery; to provide electronic copies of the monthly statements for the Trust for 2013 through 2016 to Montgomery; and, going forward, to provide electronic copies of the monthly statements for the Trust to Montgomery.
In November 2017, Montgomery, on behalf of Chris's estate, filed the Rule to Remove Trustee and for Restitution of Funds in this succession case. Montgomery asserted that Gloria had disregarded the plain language of the Trust
Page 6
by invading the corpus of the Trust and breached her fiduciary duties as Trustee to a principal beneficiary of the Trust, Chris's succession. 3Montgomery sought an order declaring that Gloria had breached her fiduciary duties to Chris's succession, that Gloria be removed as Trustee and replaced with a third party trustee, and that Gloria be required to pay restitution for sums paid out of the Trust and to pay other damages.
In August 2018, Gloria filed a motion for summary judgment seeking dismissal of the Rule to Remove filed by Montgomery. Gloria argued summary judgment was warranted on three grounds: (1) the clear wording of Albert's will allows for Gloria to expend the Trust fund as she desires; (2) Montgomery is equitably estopped from challenging whether the clear wording of the will allows Gloria to expend the Trust funds; and (3) Montgomery is judicially estopped from making the challenge.
On November 2, 2018, the trial court held a hearing, at the conclusion of which the trial court granted the motion for summary judgment in favor of Gloria. The trial court's December 3, 2018 judgment granted Gloria's motion for summary judgment, and dismissed Montgomery's Rule to Remove Trustee and for Restitution of Funds. Montgomery then filed a timely motion for new trial, which the trial court denied after a hearing.
Page 7
Montgomery now appeals the trial court's December 3, 2018 judgment granting the motion for summary judgment in favor of Gloria and dismissing the Rule to Remove Trustee and for Restitution of Funds.
DISCUSSION
Standard of Review
Appellate courts review a trial court's ruling on a motion for summary judgment under a de novostandard of review, using the same criteria applied by the trial court in determining whether summary judgment is appropriate. Smith v. State, 18-0197, p. 3 (La.App. 4 Cir. 1/19/19),262 So.3d 977, 980. Thus, the appellate court applies the summary judgment standard for granting summary judgment set forth in La. C.C.P. art. 966(A)(3), as follows: " [a]fter an opportunity for adequate discovery, a motion for summary judgment shall be granted if the motion, memorandum, and supporting documentation show that there is no genuine issue as to material fact and that the mover is entitled to judgment as a matter of law." The appellate court is not required to analyze the facts and evidence with deference to the judgment of the trial court or its reasons for judgment but looks at the record anew to make an independent determination regarding whether there are genuine issues of material fact that would preclude granting summary judgment. Smith, 18-0197, p. 3, 262 So.3d at 980.
Burden of Proof
" [I]n reviewing summary judgments, we remain mindful of which party bears the burden of proof." Orleans Parish Sch. Bd. v. Lexington Ins. Co., 12-
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0095, p. 6 (La. App. 4 Cir. 8/28/13),123 So.3d 787, 790. "Although the burden of proof on a motion for summary judgment remains with the moving party, the mover's burden changes depending upon whether he or she will bear the burden of proof at trial on the matter that is the subject of the motion for summary judgment." Id. As set forth in La. C.C.P. art. 966(D)(1), when...
| https://case-law.vlex.com/vid/in-re-succession-of-891379245 |
United States v. Costello | Second Circuit | 05-20-1958 | www.anylaw.com
Research the case of United States v. Costello, from the Second Circuit, 05-20-1958. AnyLaw is the FREE and Friendly legal research service that gives you unlimited access to massive amounts of valuable legal data.
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United States v. Costello
255 F.2d 876 (1958) | Cited 119 times
| Second Circuit | May 20, 1958
HINCKS, Circuit Judge.
This is an appeal from an order of the District Court which denied appellant's motion for a new trial under Rule 33 of the Federal Rules of Criminal Procedure. 1The motion initially was based only upon a claim of newly discovered evidence allegedly showing that the fruits of illegal wire tapping had been used at the trial. In the course of hearings on the motion, the appellant was permitted by amendment to enlarge his motion to include two further grounds, viz., an allegedly illegal mail watch and an allegedly improper inspection of the tax returns of veniremen on the trial panel on the orders of the United States Attorney prior to the trial.
Appellant was indicted in 1953 for income tax evasion, in violation of Section 145(b) of the 1939 Internal Revenue Code, 26 U.S.C.A. § 145(b), covering the years 1946 through 1949. After trial upon a prosecution based on the net worth theory he was acquitted on the 1946 count but was convicted on the other three counts. He was sentenced to concurrent five year sentences and was fined $10,000 on each of these three counts. 2On appeal, this court affirmed the convictions for 1948 and 1949 but reversed as to 1947. 2 Cir., 221 F.2d 668. The Supreme Court, having granted certiorari limited to the question of the sufficiency of the evidence presented to the grand jury, affirmed. 350 U.S. 359, 76 S. Ct. 406, 100 L. Ed. 397.
In May, 1956, pursuant to 28 U.S.C.A. § 2255, the appellant filed a motion for correction of sentence, and the District Court denied the motion. We affirmed. 2 Cir., 239 F.2d 177. The Supreme Court granted certiorari and affirmed. 353 U.S. 978, 77 S. Ct. 1281, 1 L. Ed. 2d 1140.
In November, 1956, the motion now before us on appeal was filed below. The District Court, after allowing the amendments referred to above and after an extended hearing of appellant's case, upon a comprehensive and carefully reasoned opinion denied the motion. 157 F.Supp. 461.
Wiretap Evidence
The district judge concluded that there was no proof that evidence which the Government had introduced at the trial was the fruit of wiretaps and that at any rate there was enough untainted evidence to support the convictions on the counts for 1948 and 1949. We need consider only his further holding that the appellant has not shown that the use of wiretap evidence was not known or could not, with due diligence, have been discovered prior to the trial.
The federal courts in varying circumstances have used either of two recognized tests or standards to determine when new trials should be permitted. One of these tests was originally laid down in the case of Berry v. State, 10 Ga. 511, 527, where the court listed the following six requirements:
"1st. That the evidence has come to his knowledge since the trial. 2d. That it was not owing to the want of due diligence that it did not come sooner. 3d. That it is so material that it would probably produce a different verdict, if the new trial were granted. 4th. That it is not cumulative only - viz.: speaking to facts, in relation to which there was evidence on the trial. 5th. That the affidavit of the witness himself should be produced, or its absence accounted for. And 6th, a new trial will not be granted, if the only object of the testimony is to impeach the character or credit of a witness."
The other test was developed in the case of Larrison v. United States, 7 Cir., 24 F.2d 82, wherein the following three requirements were specified:
"(a) The court is reasonably well satisfied that the testimony given by a material witness is false.
"(b) That without it the jury might have reached a different conclusion.
"(c) That the party seeking the new trial was taken by surprise when the false testimony was given and was unable to meet it or did not know of its falsity until after the trial." 24 F.2d at pages 87-88.
The Government contends that the appellant's motion should be determined by application of the Berry rule, while the appellant urges that the Larrison rule is the appropriate test.
It has been stated that the Larrison rule is limited to cases of "recantation or where it has been proved that false testimony was given at the trial." United States v. Hiss, D.C.S.D.N.Y., 107 F.Supp. 128, 136, affirmed 2 Cir., 201 F.2d 372, certiorari denied 345 U.S. 942, 73 S. Ct. 830, 97 L. Ed. 1368. But we need not decide whether appellant's claim comes within the Berry rule or the Larrison rule, or perhaps fits into a category of its own, because the same result is reached no matter which rule is applied. It is well settled that motions for new trials are not favored and should be granted only with great caution. United States v. Johnson, 327 U.S. 106, 66 S. Ct. 464, 90 L. Ed. 562; Weiss v. United States, 5 Cir., 122 F.2d 675, certiorari denied 314 U.S. 687, 62 S. Ct. 300, 86 L. Ed. 550. We think it fundamental that a defendant seeking a new trial under any theory must satisfy the district court that the material asserted to be newly discovered is in fact such and could not with due diligence have been discovered before or, at the latest, at the trial. Nardone v. United States, 308 U.S. 338, 342, 60 S. Ct. 266, 84 L. Ed. 307. See also United States v. Flynn, D.C., 131 F.Supp. 742, 743, where Judge Dimock reached the conclusion that the Larrison rule "like so many of the other rules in our law, requires due diligence of him who invokes it."
Did the appellant or his counsel exercise due diligence at the trial to ascertain and exclude evidence obtained by wiretaps? In this connection the record shows that in 1943 the appellant admittedly had been made aware of the fact that the District Attorney for New York County had placed wiretaps upon his phone. This was again brought to his attention in 1951 in the course of the much-publicized hearings of the Senate's Special Committee to Investigate Organized Crime in Interstate Commerce - the so-called Kefauver Committee. As a witness in the proceedings below, the appellant testified that this 1943 use of wiretaps by the state authorities had been known to him, in 1954, at the time of trial. And also in the proceedings below lawyers who had represented the appellant at his trial testified that they too had known of these earlier 1943 taps. They also must have known the rule of the second Nardone case, supra. But the appellant and these lawyers all denied that prior to the trial they had known that federal Internal Revenue agents had access to the wiretap information in the possession of the New York County District Attorney. And these denials seem not to have been expressly contradicted on the record.
However, in spite of knowledge of earlier wiretaps there is nothing whatever in the record now before us to show that the appellant or his counsel, in defending against the criminal charge of tax evasion, before or at the trial made any effort to discover whether evidence which the prosecution proposed to offer and did offer at the trial had been obtained through the use of wiretaps or to exclude evidence obtained therefrom. Such inaction, in our opinion, constituted a lack of diligence which warranted denial of the motion in so far as it sought a new trial on the ground that some of the evidence received at the trial had been obtained by wiretaps.Especially is this so since, as Judge McGohey remarked below [151 F.Supp. 467]: "[there] is no rational basis for believing he [the appellant] is so naive as to have supposed that the practice which then [in 1943] proved so fruitful for the State investigation was discontinued." In any event, Judge McGohey after painstaking hearing and meticulous consideration of the appellant's motion found a lack of diligence. There was certainly ample evidence to support that finding. And as the Supreme Court said in United States v. Johnson, supra, 327 U.S. at page 111, 66 S. Ct. at page 466, "* * * it is not the province of this Court or the Circuit Court of Appeals to review orders granting or denying motions for a new trial when such review is sought on the alleged ground that the trial court made erroneous findings of fact." The Court further said that an appellate court should never intervene "where it does not clearly appear that the findings are not supported by any evidence." 327 U.S. at page 112, 66 S. Ct. at page 466.
The appellant argues that until the recent decision in Benanti v. United States, 355 U.S. 96, 78 S. Ct. 155, 2 L. Ed. 2d 126, the use made by federal agents of the taps by State authorities was generally believed not to be illegal and that consequently his absence of effort to discover and exploit such evidence in advance of trial involved no lack of diligence. Essentially the same argument was made in Sunal v. Large, 332 U.S. 174, 67 S. Ct. 1588, 1590, 91 L. Ed. 1982: there, as here, the argument was "that since the state of the law made the appeals seem futile, it would be unfair to those registrants [i. e., convicted defendants] to conclude them by their failure to appeal." In Sunal, the Court answered this argument by pointing out that "the question of law had not been decided by the Court, * * *. The case, therefore, is not one where the law was changed after the time for appeal had expired. * * * It is rather a situation where at the time of the convictions the definitive ruling on the question of law had not crystallized. Of course, if [the defendants] had pursued the appellate course and failed, their cases would be quite different. But since they chose not to pursue the remedy which they had, we do not think they should now be allowed to justify their failure by saying they deemed any appeal futile."
The answer is equally applicable to the argument now made for Costello. He too, like the defendant Benanti, might have raised the point now pressed, on trial and by appeal. And because he now, belatedly, seeks to press the point by a motion for a new trial, he is entitled to no more favorable treatment than the defendants in Sunal who unsuccessfully sought to raise their claim by habeas corpus. Moreover, before the Supreme Court decision in the Benanti case had been announced appellant's present counsel asserted the very claim now under discussion in the petition below for a new trial. Due diligence required that it be raised seasonably by objection or motion for suppression at or before the trial.
Since we conclude that for lack of diligent discovery and seasonable objection the wiretap evidence does not constitute ground for a new trial, it is unnecessary to discuss the vigorously disputed issues as to whether any of the prosecution's evidence was obtained by wiretaps and if so the extent of its impact on the verdict.
Mail Watch
Appellant by amendment to his motion contends that in violation of 18 U.S.C.A. §§ 1701-1703 the Government had placed a watch upon his mail whereby Post Office employees during specified periods recorded the names and return addresses which appeared on the outside of mail addressed to the appellant and transmitted the information thus obtained to the prosecution for use in tracking down evidence of Costello's expenditures which was material to the presentation of a networth tax evasion case.
Nor do we think there has been any violation of § 1702 which, in pertinent part, declared it to be a crime for anyone to take any letter "* * * out of any post office * * * or which has been in any post office * * * before it has been delivered to the person to whom it was directed, with design to obstruct the correspondence, or to pry into the business or secrets of another * *." It is undisputed that the mail here in question was never taken "out of any post office" prior to delivery, or that it was ever opened as above stated. Nothing more was done than to record the information carried on envelopes addressed to the appellant. We think this does not come within the prohibition against "taking" a letter or prying into another's secrets or business as used in the statute. In Ex parte Jackson, 96 U.S. 727, 24 L. Ed. 877, the Supreme Court's discussion shows that a distinction is to be drawn between material which is sealed and material which is open for inspection. We think the Jackson case necessarily implies that without offense to Constitution or statute writing appearing on the outside of envelopes may be read and used. There seems to be a similar implication in Oliver v. United States, 8 Cir., 239 F.2d 818, petition for certiorari dismissed 353 U.S. 952, 77 S. Ct. 865, 1 L. Ed. 2d 858: certainly that case does not suggest that the law is otherwise.
Section 1703(a) penalizes any "Postal Service employee" who "unlawfully detains, delays, or opens any letter * * * which shall come into his possession * * *." However, as we have held in interpreting that section, detention alone without proof that it was for an unlawful purpose does not constitute a violation of this section. Fliashnick v. United States, 2 Cir., 223 F. 736.
The appellant relies upon a revision of postal regulations made as a result of the report of a Senate Committee which was created to investigate charges that a member of the Senate had been subjected to a mail watch. After holding hearings, the committee reported that although the Chief Inspector of the Post Office Department had testified that the mail must not be delayed or withheld, "it is obvious to your committee that some delay in the mail is unavoidable if the request for coverage is complied with." S.Rep. 2510, 83rd Cong., 2nd Sess., printed at 101 Congressional Record 2564. As a result of this report the Postal Laws and Regulations Sec. 41.4 (1948 ed.), which had expressly sanctioned mail watches at the request of "officers of the law," was rescinded except in so far as applicable to "fugitives from justice." We think, however, that neither the Committee Report nor the revision of the regulations bring a mail watch such as this within the ban of the statutes.
At the hearing on the motion below appellant testified on direct examination that during the periods of the mail watch he and his wife together received on an average, 40 letters a week or about seven a day. It seems unlikely that any delay whatever would result because of the time required to record the data which appeared on the covers of so small a volume. And obviously the action of the Postmaster in revising the regulations as a result of the Committee Report does not amount to a congressional determination either that the regulation was invalid or that the statutes involved were violated.
We conclude that the mail watch was not illegal.
Jurors' Tax Returns
Appellant's third point raises a question of first impression. During the course of the hearing below it developed that prior to appellant's trial the chief prosecutor, for his assistance in selecting a jury, requested an Internal Revenue agent to check the income tax returns of veniremen on the jury panel. The panel consisted of 360 names, but the Revenue Agent testified, without contradiction, that he inspected only 150 returns. From these the agent made, and transmitted to the prosecutor, notes of the taxpayer's occupation, amount and source of income, number of dependents, amount of taxes paid or refunds, and any unusual deductions. The prosecutor in charge testified that the inspection was undertaken in an effort to find out whether any of the prospective jurors had income tax troubles of their own or had other reasons to be unfavorably disposed to the Government: with this information the prosecution was in a position more intelligently to exercise its peremptory challenges.
On the basis of the notes thus derived, together with other information, the prosecutor adopted a numerical system for classifying the jurors, with Class No. 1 composed of those thought probably to be most favorable to the Government, and No. 3 or 4 least favorable. The jury as ultimately constituted contained eight jurors in Class 1 and two each in Class 2 and Class 3. The Government exercised five of its six peremptory challenges: these were exercised against two Class 2 veniremen and against three in Class 3.
The appellant contends that the use by the prosecution of this procedure vitiated his conviction not because it violated any statute or rule of the Supreme Court but because in so doing the prosecution violated the confidential nature of income tax returns and thereby obtained a jury which was "specially conditioned" to find appellant guilty. He contends further that the practice is such that in future cases jurors will be intimidated.
The Government contends that the practice is authorized by Treasury regulations. It relies upon 26 C.F.R. § 458.32 (1949), which declares that employees of the Treasury Department "whose official duties require inspection of returns may inspect any such returns" without making any written application, and also upon 26 C.F.R. § 458.204, which declares that copies of returns "may be furnished to a United States attorney for official use in proceedings before a United States grand jury or in litigation in any court, if the United States is interested in the result, or for the use in preparation for such proceedings or litigation; or to an attorney of the Department of Justice, for like use, upon written request of the Attorney General, the Assistant to the Attorney General, or an Assistant Attorney General * * *."
It is undisputed that no written request was made for these returns. However, we agree with the Government that under § 458.204 it is only when the returns are sought by "an attorney of the Department of Justice," as distinguished from a "United States attorney," that a written request is necessary. We also hold that the same regulation which authorizes copies of tax returns to "be furnished to a United States attorney" is broad enough to sanction the informal arrangement whereby at the United States Attorney's request an Internal Revenue agent abstracted and transmitted the requested data. In any event, we hold, the absence of a written request, if one was required by the regulation, would not of itself warrant a new trial. And the broad language of § 458.204 plainly does not limit the inspection to tax litigations or to tax returns of accused or suspected tax evaders. But even if the language should be narrowly construed, we believe appellant may not complain of the inspection of returns of others. See Goldstein v. United States, 316 U.S. 114, 62 S. Ct. 1000, 86 L. Ed. 1312.
As to the claim of a "specially conditioned" jury, appellant does not say that the jury which was impaneled was prejudiced against him. He does not claim that any of the jurors were approached by the Government on the subject of their taxes. Nor is there any claim that any of the jurors, until the publicity attendant on the hearing below, knew that their income tax returns had been inspected. 3The preparatory technique of which the appellant complains did not result in a "blue ribbon jury" or tend to produce such a jury. For the technique was not applied to the selection of the panel: only after the panel had been convened in accordance with the usual procedure was the technique utilized.
The appellant contends that the trial was unfair in that in exercising its challenges the Government had access to information not available to him or to even the wealthiest defendant. But as appellant admits in his brief, not all information properly available to the prosecution is equally available to the accused. In Best v. United States, 1 Cir., 184 F.2d 131, certiorari denied 340 U.S. 939, 71 S. Ct. 480, 95 L. Ed. 677, and in Christoffel v. United States, 84 U.S.App.D.C. 132, 171 F.2d 1004, reversed on other grounds 338 U.S. 84, 69 S. Ct. 1447, 93 L. Ed. 1826, the courts upheld district court action which refused to permit the defense to inspect FBI reports on the prospective jury panel. And in other phases of a criminal trial the Government may properly obtain and use information not available to the defendant. Thus under Rule 6(e), Fed.Rules Crim.Proc., 18 U.S.C.A., the grand jury minutes are available only to the prosecution.
Appellant further claims that the practice is against public policy in that, once it becomes generally known, prospective jurors will be intimidated or will attempt to avoid jury duty. These, we incline to believe, are farfetched bogies. Prospective jurors whose returns are vulnerable are the very ones whose elimination is facilitated by the practice: knowledge by the others that they were found acceptable to the Government even after an inspection of their returns would hardly be conducive to their intimidation. And the argument that the practice will tend to discourage cheerful jury service, if of any force at all in view of the mandatory nature of such service, would seem not to apply to those having made honest tax returns. There would seem to be no good reason to believe that knowledge that jury service entails exposure of one's tax return to the scrutiny of a district attorney would deter a good citizen from service in the judicial establishment any more than the fierce publicity which beats upon the private affairs of the citizen appointed to high office in the executive department deters acceptance of such appointment. However that may be, we will not attempt to make a policy-determination as to the propriety of the practice by weighing its aid to law enforcement against its limited curtailment of the privacy of tax returns. For we think this court may not assume to proscribe a practice of the United States attorney's office which violates no statute and no rule which the Supreme Court has made in the exercise of its supervisory power over administration in the lower federal courts. Cf. McNabb v. United States, 318 U.S. 332, 63 S. Ct. 608, 87 L. Ed. 819.
Quite apart from these policy considerations, the crucial question here is whether this appellant was tried by a fair and impartial jury. Since none of the jurors in this case had knowledge of the practice there is utterly no basis for the contention that it resulted in a jury "specially conditioned" to convict or otherwise biased or prejudiced against the defendant. At most, the practice led to challenges of jurors who might have been unduly biased in favor of the defendant. The exercise of peremptory challenges is a rejective, rather than a selective, process of which the appellant has no right to complain. United States v. Marchant, 12 Wheat. 480, 25 U.S. 480, 6 L. Ed. 700; Hall v. United States, 83 U.S.App.D.C. 166, 168 F.2d 161, 4 A.L.R. 2d 1193, certiorari denied 334 U.S. 853, 68 S. Ct. 1509, 92 L. Ed. 1775, rehearing denied 335 U.S. 839, 69 S. Ct. 9, 93 L. Ed. 391; United States v. Puff, 2 Cir., 211 F.2d 171, 185, certiorari denied 347 U.S. 963, 74 S. Ct. 713, 98 L. Ed. 1106.
A motion for a new trial is always addressed to the discretion of the district judge. United States v. Johnson, supra; United States v. On Lee, 2 Cir., 201 F.2d 722, certiorari denied 345 U.S. 936, 73 S. Ct. 798, 97 L. Ed. 1364. We conclude that the district judge below properly exercised his discretion in denying the appellant a new trial.
Affirmed.
1. Fed. Rules Cr. Proc. rule 33, Title 18 U.S.C.A. "Rule 33. New Trial "The court may grant a new trial to a defendant if required in the interest of justice. If trial was by the court without a jury the court may vacate the judgment if entered, take additional testimony and direct the entry of a new judgment. A motion for a new trial based on the ground of newly discovered evidence may be made only before or within two years after final judgment, but if an appeal is pending the court may grant the motion only on remand of the case. A motion for a new trial based on any other grounds shall be made within 5 days after verdict or finding of guilty or within such further time as the court may fix during the 5-day period."
2. By virtue of several admissions to bail, appellant, though sentenced in May, 1954, has served but 10 months of his sentence to date.
| https://www.anylaw.com/case/united-states-v-costello/second-circuit/05-20-1958/GICXPWYBTlTomsSBEy7C |
Doctors in NAL, Bangalore - Book Appointment Online, View Fees, and Contact Number
Find doctors in NAL, Bangalore. Book top doctor's appointment online. View fees, address, phone number, user feedback, reviews and appointment timings.
Doctors in NAL
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Dr. Shweta Mutathi
Dr. Shweta Mutathi is a well-known doctor based in Bangalore who specialises in Dentistry.
Having worked with several hospitals, She has 10 years of relevant experience.
Crowns and Bridges Fixing, Impaction / Impacted Tooth Extraction, Complete/Partial Dentures Fixing, Metal Crowns, Porcelain inlays and onlays, Porcelain Veneers are Dr. Shweta Mutathi’s speciality.
Please see Dr. Shweta Mutathi's profile for the complete list.
Happy Smiles Dental Clinic - F4, First Floor, Apurva Sai Kutir, HDFC Building, Belthur, Whitefield., Landmark: Above HDFC Bank Kadugodi Bangalore
Clinic fee: ₹300.0
Dr. Viswanath Reddy
Dr. Viswanath Reddy is an esteemed doctor practising Gastroenterology in Hyderabad.
Having worked with several hospitals, He has 7 years of relevant experience.
Dr. Viswanath Reddy is known for excellence in Video-sigmoidoscopy, Crohn's Disease, Constipation Treatment, DIARRHEA, Esophageal Variceal Band Ligation, Oesophageal and Rectal Manometry.
Please see the profile page for a comprehensive list of Dr. Viswanath Reddy's expertise.
Yashoda Hospital - 18, SP Road, Alexander Road, Landmark: Beside Hari Hara Kala Bhavan Secunderabad Hyderabad
Clinic fee: ₹550.0
Dr. Vinay Nagaraj
Dr. Vinay Nagaraj is a well-known Dermatology in Bangalore.
Dr. Vinay Nagaraj has over 14 years of experience practising medicine in various hospitals and clinics.
Skin Boosters and Fillers, Skin Care, Hair Loss Treatment, Anti Aging Treatment, Skin Rejuvenation, Wrinkle Treatment are Dr. Vinay Nagaraj’s speciality.
A full list of Dr. Vinay Nagaraj's expertise can be found on the profile page.
Kaya Clinic - Ground Floor, SMR Heights, Road Number 1, Kukatpally, Landmark: Beside Tata Docomo Store KPHB Hyderabad
Clinic fee: ₹500.0
Dr. Anitha Shettikeri
Bengaluru-based Dr. Anitha Shettikeri is a well-known doctor specialising in Gynaecology.
Dr. Anitha Shettikeri has been a practicing doctor for over 8 years.
Maternal Fetal Medicine, Gynaecological Ultrasonography, Unilateral Salpingo-Oophorectomy, Cosmetic labiaplasty, Fertility Treatment, Hymenoplasty are Dr. Anitha Shettikeri’s speciality.
Please see Dr. Anitha Shettikeri's profile for the complete list.
Motherhood Clinic- Sai Speciality Center - 201-1, 1st A Cross, 2nd Main Road, East Of NGEF Layout, Landmark: Near BBMP Park Kasturi nagar Bangalore
Clinic fee: ₹400.0
Dr. Kaushik Sutradhar
Dr. Kaushik Sutradhar is an esteemed doctor practising ENT in Bengaluru.
Having worked with several hospitals, Dr. Kaushik Sutradhar has 5 years of relevant experience.
Dr. Kaushik Sutradhar is known for excellence in Tonsillitis Treatment, Tonsillectomy, Nasal Septum Surgery, Tongue Tie Release, ENT Checkup (General), Pediatric Otolaryngology.
Please view the profile for a complete list of Dr. Kaushik Sutradhar's expertise.
Maya Multi Speciality Hospital - PVR Conplex, Panathur Road, Kadubeesanhalli,, Landmark: Opposite Government School Panathur Bangalore
Clinic fee: ₹400.0
Dr. Shilpa T
Bengaluru-based Dr. Shilpa T is a well-known doctor specialising in Obstetrics & Gynaecology.
Having worked with several hospitals, Dr. Shilpa T has 10 years of relevant experience.
Dr. Shilpa T specialises in Complicated Pregnancy Treatment, PCOD/PCOS Treatment, family planning and full contraceptive services, Pre and Post Delivery Care, Irregular Menstruation, Antenatal/Postnatal Care.
Dr. Shilpa T's profile page has the full list of expertise.
Maathru Sparsha Women Clinic - #67,HEBRON COMPLEX, Borewell Road, Nallurahalli ,Whitefield, Bangalore, Landmark: Whitefield Post office Road, Opp. to Sumadhura Anandam Whitefield Bangalore
Clinic fee: ₹300.0
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Dr. Praveen Gangadhara
Dr. Praveen Gangadhara is a well-known Diabetology in Bangalore.
Dr. Praveen Gangadhara has more than 6 years of experience.
Type 2 Diabetes Treatment, Type 1 Diabetes Treatment, Gestational Diabetes Management, Diet Counseling, Diabetic Ulcer Treatment, Diabetes Management are Dr. Praveen Gangadhara’s speciality.
Dr. Praveen Gangadhara's profile page has the full list of expertise.
Dr. Mohan's Diabetes Specialities Centre - 6, Conran Smith Road, Landmark: Near Satyam Cinemas Gopalapuram Chennai
Clinic fee: ₹400.0
Dr. Revathy Suresh
Dr. Revathy Suresh is a renowned doctor in Bengaluru. Dr. Revathy Suresh specialises in Dentistry.
Dr. Revathy Suresh has been a practicing doctor for over 6 years.
Pulpectomy, Dental Restoration, Oral Rehabilitation, Dental prophylaxis, Dental Fillings, General Dentistry are Dr. Revathy Suresh’s speciality.
Dr. Revathy Suresh's profile page has the full list of expertise.
V2 E-City Dental Center - P-7 ELCIA Building, Electronic City Phase 1, Landmark: Opposite Infosys Bus Bay Electronics City Bangalore
Clinic fee: ₹300.0
Dr. Viqat Ara Amjad
Dr. Viqat Ara Amjad is a well-known Gynaecology in Bangalore.
Dr. Viqat Ara Amjad has been a practicing doctor for over 27 years.
Dr. Viqat Ara Amjad is a specialist in In-Vitro Fertilization (IVF), Pre and Post Delivery Care, Adenomyosis Treatment, Maternal Fetal Medicine, Fertilisation In Vitro - Embryo Transfer (IVF - ET), Intra-Uterine Insemination (IUI).
Please view the profile for a complete list of Dr. Viqat Ara Amjad's expertise.
Primecare Hospital - 158, MM Road, Pulikeshi Nagar, Landmark: Opposite Everest Theatre Frazer Town Bangalore
Clinic fee: ₹500.0
Dr. Shaik Mussaveer Ahmed
Dr. Shaik Mussaveer Ahmed is a well-known Dentistry in Bengaluru.
Dr. Shaik Mussaveer Ahmed has more than 5 years of experience.
Dr. Shaik Mussaveer Ahmed specialises in Digital Dental X-Ray, Digital Autoclave for complete sterilization, Tooth Coloured Fillings, Painless tooth exreactions, Surgical Tooth Extraction, Ultrasonic Scaling.
Dr. Shaik Mussaveer Ahmed's profile page has the full list of expertise.
Dental Xpert - 4, Arab Lane 'B' Street, Landmark: Opposite to Arphi Apartments Richmond Town Bangalore
Clinic fee: ₹400.0
Dr. Aparna Satyanarayan
Dr. Aparna Satyanarayan is an esteemed doctor practising Dentistry in Bengaluru.
Dr. Aparna Satyanarayan has been a practicing doctor for over 16 years.
Dr. Aparna Satyanarayan is an expert in Flap Surgery, Gum Disease Treatment/ Surgery, Laser Gum Surgery, Laser Surgery, Periodontal Flap Surgery, Scaling / Polishing.
A full list of Dr. Aparna Satyanarayan's expertise can be found on the profile page.
Dental Medical Center - C11, Devatha Plaza, Number 131, Landmark: Opposite Bishop Cottons Boys School Residency Road Bangalore
and 1 more clinics ➤ More Clinics:Aesthete Lifestyle Dentistry
Clinic fee: ₹400.0
Dr. Shabbir Ulla Khan
Dr. Shabbir Ulla Khan is a well-known Dentistry in Bangalore.
Dr. Shabbir Ulla Khan has over 7 years of experience practising medicine in various hospitals and clinics.
Dr. Shabbir Ulla Khan is an expert in Conservative Dentistry, Crowns and Bridges Fixing, Complete/Partial Dentures Fixing, Tooth Extraction, Dental Fillings, RCT - Root Canal Treatment.
Please view the profile for a complete list of Dr. Shabbir Ulla Khan's expertise.
Bharath Dental Clinic - 1662, Ground Floor, 41st Cross, 18th Main, Jayanagara 4th 'T' Block, Landmark: Near GNR Kalyanamantappa & Opposite. Krishna Kalyanamantappa Jayanagar Bangalore
Clinic fee: ₹250.0
Dr. Kandraju Sai Satish
Hyderabad-based Dr. Kandraju Sai Satish is a well-known doctor specialising in Neurology.
Having worked with several hospitals, Dr. Kandraju Sai Satish has 7 years of relevant experience.
Dr. Kandraju Sai Satish is known for excellence in Chronic Headache, Paralysis, Infections of the Brain and Nervous system, Multiple Sclerosis, Brain Hemorrhage, Epilepsy.
Please see Dr. Kandraju Sai Satish's profile for the complete list.
Yashoda Hospital - 303, New Block, Raj Bhavan Road, Landmark: Near Punjagutta Central Somajiguda Hyderabad
Clinic fee: ₹700.0
Dr. G Ramesh
Hyderabad-based Dr. G Ramesh is a well-known doctor specialising in Cardiology.
With 5 years of experience, Dr. G Ramesh has been associated with various prestigious hospitals and clinics.
Dr. G Ramesh is a specialist in Coronary interventionwith IVUS / FFR, Chest Pain Treatment, Dyslipidemia, Peripheral / Carotid intervention, Aortic stent grafts, Pacemakers including AICD / CRT.
Please view the profile for a complete list of Dr. G Ramesh's expertise.
Yashoda Hospital - 303, New Block, Raj Bhavan Road, Landmark: Near Punjagutta Central Somajiguda Hyderabad
Clinic fee: ₹750.0
Dr. Lalitha Nageshwari
Other
MBBS - Dr BR Ambedkar Medical College, Bangalore
1 Years of Experience
Bala Clinic - 3rd Cross, Malleswaram
Clinic fee: ₹250.0
Dr. Sudha
Dr. Sudha is an esteemed doctor practising Obstetrics & Gynaecology in Bengaluru.
She has over 10 years of experience practising medicine in various hospitals and clinics.
Dr. Sudha is an expert in Normal Vaginal Delivery (NVD), Wellness, High-Risk Pregnancy Care, Infertility Evaluation / Treatment, Well Woman Healthcheck, Obstetrics / Antenatal Care.
Please view the profile for a complete list of Dr. Sudha's expertise.
Metro Health - #65, Brindavana, Shanthivana Road, Kodigehalli Main Road, Sahakarnagar, Landmark: Next to Sterling Park Apartments., Landmark: Near TNT Store Sahakaranagar Bangalore
Clinic fee: ₹250.0
Dr. Harsha
Dr. Harsha is a well-known doctor based in Bangalore who specialises in General Physician.
With 8 years of experience, He has been associated with various prestigious hospitals and clinics.
Dr. Harsha is known for excellence in Anemia Treatment, Dengue Fever Treatment, Diabetes Management, Headache Management, Hypothyroidism, Allergy Treatment.
A full list of Dr. Harsha's expertise can be found on the profile page.
Sri Sai Medicals And Polyclinic - Akshaya's Sai Lakeview, Number 384/4/1, 60ft.Road, D Group Layout Srigandhakaval, Landmark: Next to Reliance Fresh Nagarbhavi Bangalore
Clinic fee: ₹250.0
Dr. C Jagadeesh
Dr. C Jagadeesh is a renowned doctor in Bangalore. He specialises in Dentistry.
He has been a practicing doctor for over 30 years.
Cosmetic/ Aesthetic Dentistry, Crowns and Bridges Fixing, Impaction / Impacted Tooth Extraction, Dental Fillings, Scaling / Polishing, Teeth Whitening are Dr. C Jagadeesh’s speciality.
Dr. C Jagadeesh's profile page has the full list of expertise.
Dr. C Jagadeesh's Dental Clinic - 1st Floor, New Thippasandra Main Road, Landmark: Above Vinayaka Medicals & Near Shiva Temple New Thippasandra Bangalore
Dr. Pavithra
Dr. Pavithra is an esteemed doctor practising Dentistry in Bengaluru.
She has been a practicing doctor for over 10 years.
Dr. Pavithra specialises in Crowns and Bridges Fixing, Tooth Extraction, Complete/Partial Dentures Fixing, Dental Implant Fixing.
Please see Dr. Pavithra's profile for the complete list.
Sri Sai Dental Clinic - # 707, 1st floor , 10th Cross, CK Nagar, Electronic City. Landmark : New Central Jail Road (Hosa Road)., Landmark: Electronics City Bangalore
Clinic fee: ₹100.0
Dr. Ajay B S
Bengaluru-based Dr. Ajay B S is a well-known doctor specialising in Ophthalmology.
With 8 years of experience, Dr. Ajay B S has been associated with various prestigious hospitals and clinics.
2.2 mm Phaco Surgery for Cataract, Laser Refractive & Cataract Surgery, Cataract Surgery, Contact Lens Prescription, Corneal Collagen Cross-Linking, Corneal Surgery are Dr. Ajay B S’s speciality.
Please view the profile for a complete list of Dr. Ajay B S's expertise.
Daksh Eye Care Centre - 2nd floor, #5, Langford Gardens, Landmark: Richmond Town Bangalore
Clinic fee: ₹500.0
Dr. Ramya Rohit
Dr. Ramya Rohit is a well-known doctor based in Bangalore who specialises in Dentistry.
She has over 8 years of experience practising medicine in various hospitals and clinics.
Dr. Ramya Rohit is known for excellence in Discolored Tooth Restoration, Dental X-Ray, Crowns and Bridges Fixing, Endosurgery, RCT - Root Canal Treatment, Teeth Reshaping.
Please see the profile page for a comprehensive list of Dr. Ramya Rohit's expertise.
Dent Stop - 32, Venkatadri Complex, Battarahalli, TC Palya, Landmark: Beside CCD KR Puram Bangalore
Clinic fee: ₹200.0
Dr. Raksha S.K
Bengaluru-based Dr. Raksha S.K is a well-known doctor specialising in Pediatrics.
She has more than 10 years of experience.
Dr. Raksha S.K specialises in Vaccination/ Immunization.
Please see the profile page for a comprehensive list of Dr. Raksha S.K's expertise.
Aruna Kids Clinic - 14/25, Arpana, 7th Main, 8th Cross, Shakambari Nagar, Landmark: Behind Balaji Medicals JP Nagar 1 Phase Bangalore
Clinic fee: ₹250.0
Dr. Sandeep Raghuram
Dr. Sandeep Raghuram is a well-known doctor based in Bangalore who specialises in Dentistry.
Having worked with several hospitals, Dr. Sandeep Raghuram has 6 years of relevant experience.
Dr. Sandeep Raghuram is known for excellence in Dental Checkup (General), Dental Fillings, Dental Crowns, Scaling / Polishing, Tooth Extraction, Pyorrhoea Treatment.
Please view the profile for a complete list of Dr. Sandeep Raghuram's expertise.
Sapphire Dental Clinic - 1, Aishwarya Crystal Layout, Manipal County Road, Landmark: Opposite Divya Jyothi Royal Heights Apartment Singasandra Bangalore
Clinic fee: ₹100.0
Dr. Deepa M
Bengaluru-based Dr. Deepa M is a well-known doctor specialising in Ophthalmology.
She has more than 10 years of experience.
Dr. Deepa M is known for excellence in Laser Refractive & Cataract Surgery, Retina Examination, Myopia Control Program, Avastin Injections, Retinal Diseases, Cataract Surgery.
Please see Dr. Deepa M's profile for the complete list.
Care And Cure Multispeciality Clinic - 849/ 3, 60 Feet Road, Sahakar Nagar "A" Block, Landmark: Beside Kushal Jewellery Sahakaranagar Bangalore
Clinic fee: ₹300.0
| https://www.myupchar.com/en/doctors/bangalore/nal?page=85&ref=raisan-21 |
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<![CDATA[ Reformed Theological Society ]]>
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<![CDATA[
A rediscovery of the priesthood of believers in Ephesians 4:1-16 and its relevance for the Missio Dei and a biblical missional ecumenism
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<![CDATA[ Lotter ]]>
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<![CDATA[ George ]]>
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<![CDATA[ van Aarde ]]>
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<![CDATA[ Timothy ]]>
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<![CDATA[ ,North-West University Faculty of Theology ]]>
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<![CDATA[ ,North-West University Department of Humanities ]]>
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<![CDATA[
This article is dedicated to Professor Sarel van der Merwe as missiologist and what he had done for the cause of the missio Dei in South Africa. The role of the laity in the missio Dei was one of the most significant developments followed by most church denominations. The priesthood of believers was the reformational perspective rediscovered by Martin Luther. The reformed tradition rediscovered the role of the laity in missions, which the Baptist church tradition has now developed most extensively in terms of missions. The Catholic Church has recognised the apostolicity of the laity in a decree called 'Apostolicam Actuositatem' at the Second Vatican Council in response to the crises of the church. The charismatics gave recognition to the role of the laity through the spiritual gifts of each believer. The role of the laity and of the priesthood of believers has its biblical precedent and foundation in 1 Peter 2:5, 9 and Ephesians 4:1-16. The contribution of Ephesians is that it provides the church with a missional mandate for the ordinary believer to participate in the missio Dei -, a mandate that has to be rediscovered in every age. The priesthood of believers provides an orientation for a biblical missional ecumenism.
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<![CDATA[
<p align="right"><font size="2" face="Verdana, Arial, Helvetica, sans-serif"><b>ORIGINAL RESEARCH</b></font></p> <p> </p> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="4"><b><a name="top"></a>A rediscovery of the priesthood of believers in Ephesians 4:1-16 and its r
<![CDATA[
elevance for the <i>Missio Dei</i> and a biblical missional ecumenism</b></font></p> <p> </p> <p> </p> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="2"><b>George Lotter<sup>I</sup>; Timothy van Aarde<sup>II</sup></b></font></p> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="2"><sup>I</sup>Faculty of Theology, Potchefstroom campus, North-West University, South Africa <br> <sup>II</sup>Department of Humanities, Vanderbijlpark campus, North-West University, South Africa</font></p> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="2"><a href="#corresp">Correspondence</a></font></p> <p> </p>
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<![CDATA[
<p> </p> <hr noshade size="1"> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="2"><b>ABSTRACT</b></font></p> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="2">This article is dedicated to Professor Sarel van der Merwe as missiologist and what he had done f
<![CDATA[
or the cause of the <i>missio Dei</i> in South Africa. The role of the laity in the <i>missio Dei</i> was one of the most significant developments followed by most church denominations. The priesthood of believers was the reformational perspective rediscovered by Martin Luther. The reformed
<![CDATA[
tradition rediscovered the role of the laity in missions, which the Baptist church tradition has now developed most extensively in terms of missions. The Catholic Church has recognised the apostolicity of the laity in a decree called '<i>Apostolicam Actuositatem</i>' at the Second Vatican Council in response to the crises of the church. The charismatics gave recognition to the role of the laity through the spiritual gifts of each believer. The role of the laity and of the priesthood of believers has its biblical precedent and foundation in 1 Peter 2:5, 9 and Ephesians 4:1-16. The contribution of Ephesians is that it provides the church with a missional mandate for the ordinary believer to participate in the <i>missio Dei</i> -, a mandate that has to be rediscovered in every age. The priesthood of believers provides an orientation for a biblical missional ecumenism.</font></p> <hr noshade size="1"> <p> </p> <p> </p> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="3"><b>Introduction</b></font></p> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="2">This article is dedicated to Sarel van der Merwe as a missiologist <i>par excellence</i>. Not only was he a missionary in the true sense of the word by being 'out in the field'; he also took it a step further by starting to train missionaries, evangelists and ministers to proclaim the gospel on other levels.</font></p> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="2">It started as a mission project in Mareetsane, developed into the College ya Mojadi and eventually the Department of Theology on the Mafikeng Campus of North-West University and Sarel van der Merwe was instrumental in having all these things happen (Brunsdon & Van der Merwe 2013:295). Even while involved in administration and management, he never lost his 'missionary heart' which was always the driving force in Van der Merwe's life. We therefore commend him for his life and service, and give the glory to God for his work as </font><font size="2">διάκονος</font><font face="Verdana, Arial, Helvetica, sans-serif" size="2"> </font><font size="2">Χριστοῦ</font><font face="Verdana, Arial, Helvetica, sans-serif" size="2"> [servant of Christ] and as one who devoted his whole life to the <i>missio Dei</i>.</font></p> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="2">The priesthood of believers is a practical, lived-out doctrine that facilitates better and deeper church and inter-denominational relationships. It is vital to the fostering of a <i>biblical missional ecumenism</i>. In the era of post-Christendom, all churches and denominations in the West are facing the same challenge of the marginalisation of Christianity to the fringes of society.</font></p> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="2">One of the central questions of the participation of ordinary believers in missions is the following: 'What is the role of the laity in mission, and how can the clergy enhance and promote lay missional movement?' (Sunquist 2013:308). Mission in the West has traditionally been identified as the task of the clergy or missions experts. A movement of the rediscovery of the priesthood of believers through the focus of the <i>missio Dei</i> is critical in an age of post-Christendom in the West, because the special giftedness of the laity exists in a variety of ways for carrying out the mission of God. The task of the clergy in preparing the laity is that of the priestly role of equipping and empowering them to be sent out into their neighbourhoods. 'It is imperative that each local church find ways of releasing and empowering the laity to do the work of the mission of God' (Sunquist 2013:309). One of the reasons for the phenomenal growth of the church in the global south, Africa, Asia and South America is that the laity participates in the <i>missio Dei</i>. David Bosch anchored the participation of the laity in the <i>missio Dei</i> in the Word of God and the sacraments, but this view still excludes the laity's full participation in the <i>missio Dei</i>, because these are administered by the ordained ministry. The Reformation was a movement of the rediscovery of the ministry and mission of the believer and that:</font></p>
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<blockquote> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="2">mission does not proceed from the pope, nor from a missionary order, society, or synod, but from a community gathered around the word and the sacraments and sent into the world. (Bosch 2016:472)</font><
/p> </blockquote> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="2">'The Reformation treasured the priesthood of believers, but it was the revivals and the missionary movement of the nineteenth century in which the priesthood of all believers really took on flesh' (Sunquist 2013:118). The involvement of the believer in the <i>missio Dei</i> necessitates a recovery of the priesthood of believers as the emphatic practice of the Reformation. The <i>missio Dei</i> is central to the missionary movement that will restore the priesthood of the believer to its central place in the church. It will require a reconsideration of the following: the tradition of the separation of the clergy and the laity in the Catholic tradition, the one category of pastor-missionary in the Lutheran tradition, the distinction between the special gifts and administration and leadership gifts in the Pentecostal and charismatic tradition, and the relation of the offices and the laity in the reformed tradition.</font></p> <p> </p> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="3"><b>The need for a new focus on the priesthood of believers</b></font></p> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="2">The Protestant Reformation gave a central focus and relevance to the submerged doctrine of the priesthood of believers (cf. Coleman 2011:216). The accent in the Reformation, however, has been placed on the access to God (Eph 2:18), so that 'the eternal purpose, which God carried out in Jesus Christ' (v. 11), is understood primarily as access to God, 'in whom [<i>Christ</i>] we have boldness and confident access through faith in Him' (v. 12). The result is that there is a disconnection in thought between access to God and the task of the church (Eph 3:8-10), the individual calling (v. 1-3) and task of all believers (v. 7-16). For every believer it is particularly the vertical aspect of access to God and the immediacy of Christ that became the central conception of the priesthood of believers in the 19th century. In most churches the horizontal dimension of 'outreach to our fellow men' is a ministry 'still largely consigned to duly ordained clergyman or especially favored local leaders' (Coleman 2011:216). The priesthood of believers is a fellowship with Christ in which members of his body are also members of one another. A recovery of the complete and comprehensive understanding of the priesthood of believers has to be in terms of the vertical spirituality of the mystical communion of every believer with Christ as well as the horizontal ministry of all believers (Eph 2:18; 3:12; 4:12). Instead of the priesthood of the believers being a unifying doctrine it has become enamoured with our own ecclesiastical distinctiveness to the extent that other members of the universal church are disowned. In terms of its proper function it has the inherent potentiality to be a community-building concept of the church's ministry - a concept by means of which ministry is lifted 'into the daily life of mothers, factory workers, clerks, farmers, students - [<i>in which</i>] every Christ-honouring vocation becomes of service and every location a place of witness' (Coleman 2011:217). The confession that 'there is one Body and one Spirit </font><font size="2">…</font><font face="Verdana, Arial, Helvetica, sans-serif" size="2"> one Lord, one faith, one baptism, one God and Father of all' (Eph 4:4-6) and its relation to the function of the gifts in the church (v. 7-16), is to be read in terms of a plurality of ecclesiastical distinctive groups who, in their distinctive understanding and functioning, contribute to a holistic understanding of the priesthood of the believers. Each ecclesiastical distinctive church group can make a unique contribution to a comprehensive understanding of the priesthood of believers. 'It is imperative that each local church find ways of releasing and empowering the laity to do the work of the mission of God' (Sunquist 2013:309).</font></p> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="2">In this article the understanding of 'the priesthood of believers' and its praxis in the mainline Christian denominations and the Pentecostal-charismatic movement, as one of the largest recent church growth movements, will be explored. The various denominational understandings will be related to a biblical exposition of the priesthood of believers in light of Ephesians, specifically Ephesians 4:1-16.</font></p> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="2"><b>The missional vocation of nurturing</b></font></p> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="2">The missional calling and vocation of the believer is to create a nurturing missional culture in the church. The calling of every believer is to the vocation of nurturing - to both those who are part of the body of Christ and those on the outside. There is no single definitive way to categorise participation of laypersons in lay ministry and missions. The priesthood of believers has the objective of one laity and clergy working together harmoniously for the well-being of the body of Christ, which is the function of the confession of Ephesians 4:4-6. The participation of the laity may take the form of inclusion in the liturgy, which may entail a deeper experience of the liturgy, pastoral visitation, laypersons assisting the clergy at the local homeless shelter, visiting the sick or imprisoned, and discipleship programs and missions. It is the critical challenge of the missional church movement to nurture a missional vocation and calling among all believers so that, through the priesthood of believers, the laity may be involved in mission and, more than this, that they become 'the initiators of mission' (Sunquist 2013:309). The primary function of church leadership is to equip the believers for </font><font size="2">διακονία</font><font face="Verdana, Arial, Helvetica, sans-serif" size="2"> [service] and </font><font size="2">οἰκονομία</font><font face="Verdana, Arial, Helvetica, sans-serif" size="2"> [mission]. It is in Ephesians 4:1-16 that the corporate community is presented as 'the priesthood of believers' to be equipped to serve and fulfil its missional vocation and calling.<sup><a name="top_fn1"></a><a href="#back_fn1">1</a></sup></font></p> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="2"><b>The missional view of the 'gifts of grace'</b></font></p>
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<p><font face="Verdana, Arial, Helvetica, sans-serif" size="2">'The universal priesthood of all believers should be reflected not only in the exercise of authority, but also in the exercise of the different gifts of the Holy Spirit' (Roldán 2004:161). It is the gifts of the Spirit th
at makes the life and mission of the church possible (cf. Roldán 2004:162). John Driver (1976) writes:</font></p> <blockquote> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="2">The church will be truly the body of Christ to the extent that all the gifts of t
he Spirit are recognized and exercised in the community. The plurality (whereby more than one person can exercise a single gift), and the universality (whereby every member has a gift or gifts to use) are part of the very essence of the church. (p. 30)</font></p> </blockquote> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="2">The grounds for the giving of the gifts is indicated in Ephesians 4:8 as the 'captivity of captivity', which means that a new covenant dispensation has been inaugurated in which the ascended Christ has given and continues to give gifts to people. The pre-requisite for the receiving of these <i>gifts of grace</i> is salvation. In the charismatic tradition <i>spiritual gifts</i> are gifts received upon the baptism of the Spirit. In Ephesians 4:8-12 the operation of the gifts of grace is indicated as a consequential development of salvation of the believer in Ephesians 2:1-10 that is worked out in terms of its function in the body of Christ. 'The gifts present in the body are joined together so that the work of each part contributes to the strengthening of the whole' (Van Rheenan & Parker 2014:332). The body is nurtured as each member of the church uses the gifts of grace he or she has received. The intention of the gifts is the nurturing of the body of Christ and through the priesthood of believers in the society. 'All God's people are called and gifted for ministry. This is what is meant by the Protestant teaching about <i>the priesthood of all believers</i>' (Jørgensen 2012:26). According to Balia and Kim (2010), the priesthood of believers is essential to the church structure:</font></p> <blockquote> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="2">We still need priests and pastors, as we need other leadership functions (teacher, evangelist, apostle, prophet - Eph 4:11), but the basic structure for the local church and for mission is the priesthood of all believers. (p. 120)</font></p> </blockquote> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="2"><b>The missional equipping with the 'gifts'</b></font></p> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="2">The church structure in Ephesians is presented as a missional church structure and in the missional church model the saints are to be equipped by the gifted ones for the work of the ministry (Eph 4:12). The gifted ones (Eph 4:11) possess the missional functions of apostle, priest, evangelist, pastor and teacher. It is not the offices in the church that are in view.<sup><a name="top_fn2"></a><a href="#back_fn2">2</a></sup> The gifted ones are people who function in these gifts given to the church to equip the believers to function missionally. Hastings (2012) comments as follows:</font></p> <blockquote> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="2">Whereas the teaching of the pastor-teaching is dominant in many evangelical churches, room will be made in missional churches for the other three strategic leadership gifts of apostle, prophet and evangelist (Eph 4:11), as was evident in Acts. (p. 297)</font></p> </blockquote>
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<p><font face="Verdana, Arial, Helvetica, sans-serif" size="2">The leadership envisaged is servant leadership which specifically has in mind the gifts as gifts for service (</font><font size="2">διακονία</font><font face="Verdana, Arial, Helvetica, sans-
serif" size="2">) and mission (</font><font size="2">οἰκονομία</font><font face="Verdana, Arial, Helvetica, sans-serif" size="2">), apostleship (mission), casting and direction, prophecy (mission), evangelism (service) and preaching (service), a
nd that of pastor-teacher (service). The distinction between the first group (mission, apostleship, casting and direction, prophecy) and the second group (evangelism, preaching and pastor-teacher) is that the first group is directed towards helping the church fulfil its missional calling
in society and outside the community, while the second group is directed inwards to help the church fulfil its calling to the community, that is, the church. A distinction between function and office implies the functions reserved for those set apart for ordained office in contrast to the functions that ordinary believers can perform: this is a necessary pre-requisite for the effective functioning of the body of Christ. 'The primary task of the servant leader is to equip others for service. This is the core of Ephesians 4:11-16 where Paul describes the service/diakonia of all God's people' (Jørgensen 2012:25). The parameters of lay ministry in juxtaposition to the ordained office have to be clarified.</font></p> <p> </p> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="3"><b>The Lutheran view of the 'gifts'</b></font></p> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="2">The term <i>gifts</i> as used in Ephesians indicates that from the perspective of the author there was neither spiritual distinction nor office in view in the use of this term. Luther's view was that the process of ordination did not constitute the clergy as a distinct 'spiritual' (viz. clerical) class, or Christians ontologically distinct from and superior to the 'temporal' (viz. lay) order; instead, he insisted that 'all Christians are of the spiritual estate [Stand], and there is no difference between them except that of office' (cf. Wengert 2011:408-409).</font></p> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="2">In the Lutheran view apostle, prophet, shepherd and teacher are 'gifts' of those who hold offices (Eph 4:11). The 'gifts' of apostle and evangelist are used for ecclesiastical backing of the missionary office. The missionary office is a <i>rite vacates</i> and it is in this respect not different from that of the pastor (cf. Schultz 2009:273). In the Lutheran tradition there is no distinction made between the office of missionary and those of pastor. The apostolic office is continued through the office of preaching (2 Cor 5:19-20; Rom 10:9-10) that involves two aspects, namely outreach and in-reach: a missionary and pastor's office are two aspects of the one apostolic office. The mandate given to the church is a single preaching mandate that is differentiated into two offices: pastor and missionary. The missionary office is, however, not integrated into the leadership of the local church: in the local church context the pastor fulfils both functions and on the mission field the missionary fulfils both functions. According to Holsten (1939):</font></p> <blockquote> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="2">The missionary must be <i>rite vocatus;</i> an individual's call experience does not warrant sufficient legitimization. Essentially, the right to serve as a 'free' standing missionary is rejected and the status of a society's missionary is only legitimate in so far as his calling or commission is not extended from a society that stands in deliberate isolation from the church, which (the church) has no other signs (not) to show forth than the right proclamation of the Gospel and administration of the Sacraments. (p. 14)</font></p> </blockquote> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="2">Luther transformed the use of the words <i>calling</i> and <i>vocation</i> by assigning it to all Christians. In Ephesians 4:1 each and every believer is to live 'in a manner worthy of the calling with which you have been called'.</font></p> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="2"><b>The priesthood of believers in Lutheranism</b></font></p> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="2">It is Martin Luther who affirmed that all Christians have a calling. Luther (in both <i>The Babylonian captivity of the church</i> and <i>Letter to the Christian nobility</i> [<i>An den christlichen Adel deutscher Nation</i> - 1520]) affirmed the priesthood of all believers and denied that a special priesthood belonged to any class in the church (cf. Baldovin 2011:408-409).<sup><a name="top_fn3"></a><a href="#back_fn3">3</a></sup> Luther bases his theology of all believers' equality on the basis of the theology of Baptism and draws on the language of 1 Peter 2:9 in which the whole church is described as a 'royal priesthood' (cf. Wengert 2011:408-409). The Lutheran approach to the priesthood of believers was 'to restore the common Christians access to God' (Rogers 2010:121). The priesthood of believers is understood as having the task of the laity, namely to permeate the world through service and testimony. The task of the laity is the service of love towards one another for the unity of the body of Christ and service to society. Schultz (2009:238) argues that 'such a work of service would also include the task of sharing the Gospel with non-Christians', but this is not the general understanding of the task of the laity. The task is often confined to the 'calling' or 'vocation' to 'live a life worthy of the calling you have received' (1 Cor 7:20 - New International Version). The King James Version (KJV) is followed in the translation of Ephesians 4:11-12 in which a comma is placed after 'saints' and before the prepositional phrase 'for the work of the ministry'. It means that through the insertion of the comma, (not found in the Greek text), the Lutheran Church has adopted in its confessional documents that the work of the ministry is done by the ordained clergy and that it is the exclusive task of the ordained clergy to build up the body of Christ. It is the task of the ordained clergy to perfect both the inward and outward lives of the believers. The priesthood of the believers is limited to the immediacy of access to God (cf. Rogers 2010:121).<sup><a name="top_fn4"></a><a href="#back_fn4">4</a></sup> The task of the laity is thus the obligation to pass witness in his personal sphere of life and sacrifice in service to the neighbour without the verbal preaching of the gospel (cf. Schultz 2009:242). Luther made a distinction between the public and private ministry of God's Word (cf. Rogers 2010:124). More has to be done to recognise the equality of these forms of preaching. 'The emphasis in Luther's doctrine of the priesthood of believers is on Christ's priestly work' (Rogers 2010:122), and the private priestly work of the believer. The priesthood of believers in Luther's understanding is community-centred - with each believer serving as priest to other believers (cf. Rogers 2010:123) - but not world-centred. As a result, the public and private spheres are separated in the Lutheran view - 'a Christian has to live according to two contradicting sets of norms' (Van der Walt 2011:11) - with the result that the priesthood of the believers is practised only in the private sphere. To transform society, it is necessary for Lutherans to integrate the public and private spheres and norms in the exercise of the priesthood of believers.<sup><a name="top_fn5"></a><a href="#back_fn5">5</a></sup> The laity needs to be involved in the performing of functions that have generally been considered to be exclusively priestly functions. The reason that a distinction continues to exist between laity and the clergy is that, although the laity are included in ministry, mission is still conceived of as the task of the ordained ministry. This is a focus the priesthood of believers in Ephesians can address in that the sharing of the gospel by ordinary believers is inseparably connected to 'access to God' - the basis of the priestly role of the believer in the priesthood of the believer.</font></p>
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<p> </p> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="3"><b>The Baptist view of the priesthood of believers</b></font></p> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="2">The priesthood of believers for Baptists is intensely personal but never individ
ualistic (cf. Young 1993:143). It is virtually inseparable from Baptist doctrine (cf. Young 1993:132).<sup><a name="top_fn6"></a><a href="#back_fn6">6</a></sup> 'Until very recently virtually every Baptist would have argued that there is no more basic belief to Baptists than the idea of
the priesthood of the believers' (Young 1993:132). Cyril Eastwood's conclusion is that 'the doctrine of the priesthood of the believers is not incidental but central in Baptist theology' (cf. Young 1993:132).<sup><a name="top_fn7"></a><a href="#back_fn7">7</a></sup> The Baptist concept o
f the priesthood of believers is the '<i>soul competency</i>, meaning that all persons are capable of approaching God directly, without interference or the assistance of an intermediary' [<i>author's emphasis</i>] (Young 1993:131). <i>Soul competency</i> has not been understood from a political perspective but from a sociological perspective as 'religious liberty', meaning the full freedom to worship 'according to their own interests and needs, with no coercion from the state, the church, or individuals' (Young 1993:131), but this is not synonymous with soul competency. Young (1993) also added that:</font></p> <blockquote> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="2">Mullins<sup><a name="top_fn8"></a><a href="#back_fn8">8</a></sup> saw soul competency, which he also called priesthood of the believer and religious liberty, to be an axiom, a truth so basic as to need no proof, so obvious that any intelligent person will agree to it after reasonable consideration. (p. 134)</font></p> </blockquote> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="2">This, however, was a confusion of various concepts. In the Baptist view, the concept of the <i>priesthood of believers</i> is informed by the biblical tradition of an exposition of Exodus 19:5-6. However, in Ephesians 3:11-12, 1 Timothy 2:5 and Revelations 1:4-6, the focus is on the <i>soul competency</i> of the believer (cf. Young 1993:132) which is founded on the believer's relationship with Christ. Mullins equates the priesthood of believers with competency of the soul in which the relationship with Christ is superior to all other relationships. 'Religious liberty' means that 'the Christian should be against any political involvement, because Christian life as such is dirty and evil and a contradiction to the Christian life' (Van der Walt 2011:28). The Baptist concept of <i>religious liberty</i> is framed by a worldview of <i>grace opposes nature</i> that results in practices in which 'the real Christian' is to be against the world, retreating into his alternative church consisting of really holy or separated people (cf. Van der Walt 2011:10). The conceptualisation of soul competency belongs to the private sphere and has the meaning of spiritual access of the believer to God and the immediacy of Christ. 'Religious liberty, for Mullins, is the inevitable counterpart of soul competency' (Young 1993:134). Young identifies 'religious liberty' with the priesthood of believers, which is a confounding of two distinct concepts, with the freedom of religion which belongs to the public sphere, and with soul competency which belongs to the private sphere.<sup><a name="top_fn9"></a><a href="#back_fn9">9</a></sup> The worldview of grace opposes nature is the consequence of the equating of religious freedom and soul competency. Religious freedom, in Mullins' view, was based on the believer's access to God. The confusion of these two distinct spheres results in a <i>radical discontinuity</i> between Christianity and culture. The result is an <i>isolation</i> of Christianity from its surrounding culture (cf. Van der Walt 2011:61). 'Consequently, it cannot really challenge its cultural environment' (Van der Walt 2011:61). A distinction has to be maintained between 'religious liberty' and the freedom of conscience to worship (which is the basis of democratic congregational authority) and soul competency, which is the basis of the believer's relation to God and the priesthood of the believer, the ministry of the believers. Mullins associated soul competency with the Western ideal of individualism.<sup><a name="top_fn10"></a><a href="#back_fn10">10</a></sup> 'He did not talk about the responsibility of each Christian to serve as a priest for his neighbour' (Rogers 2010:131). In Luther's view the believer was a priest to the body - the church - and he did not extend the responsibility to be a priest to society. Mullins' view can be typified as 'the right to private judgement' (Rogers 2010:131) or freedom of conscience. It should not be confused with 'religious liberty', which has to do with the relationship of church and state, and the withdrawal from politics and society. It is only in recognising the distinctiveness of these concepts that Baptists are able to engage injustices in society, which is the social aspect of the priesthood of believers.<sup><a name="top_fn11"></a><a href="#back_fn11">11</a></sup> The priesthood of believers flows out of soul competency, but it is not identical with it. The Baptist approach to missions is individualistic and a mission's emphasis, based on a biblical emphasis on community, is badly needed (cf. Goheen 2014:313). For this reason, missions in the Baptist tradition are to be grounded in more than only <i>soul competency</i>; rather it should not be an almost exclusive focus on the restoration of healthy relationships without considering political, social, cultural and economic dimensions of the gospel.</font></p> <p> </p> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="3"><b>The Catholic view of the priesthood of all believers</b></font></p> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="2">In an important development in Roman Catholic theology, Pope Paul VI issued the decree <i>Apostolicam Actuositatem</i> [Apostate of the Laity], which outlined the important role the laity play in the mission of the church. In the <i>Apostolicam Actuositatem</i>, promulgates on 18 November 1965, Pope Paul VI issued a holy decree on the vocation of the laity and apostate in which he cites Ephesians (Second Vatican Council 1965):</font></p> <blockquote>
<p><font face="Verdana, Arial, Helvetica, sans-serif" size="2">For the Christian vocation by its very nature is also a vocation to the apostolate. No part of the structure of a living body is merely passive but has a share in the functions as well as life of the body: so, too, in the
body of Christ, which is the Church, 'the whole body </font><font size="2">…</font><font face="Verdana, Arial, Helvetica, sans-serif" size="2"> in keeping with the proper activity of each part, derives its increase from its own internal development' (Eph. 4:16). (p. 37).</font><
/p> </blockquote> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="2">Recent decades have seen this theology of mission reinforced, not only in the Catholic Church, but also in global Christianity:</font></p> <blockquote> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="2">In the Church there is a diversity of ministry but a oneness of mission. Christ conferred on the Apostles and their successors the duty of teaching, sanctifying, and ruling in His name and power. But the laity likewise share in the priestly, prophetic, and royal office of Christ and therefore have their own share in the mission of the whole people of God in the Church and in the world. (Sunquist 2013:308)</font></p> </blockquote> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="2">In 1987 a Catholic synod was held in which the role of the pastors was to foster the Holy Spirit's activity in the laity:</font></p> <blockquote> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="2">The New Code of Cannon Law reflects Vatican II's theology of the laity. It says, in can. 275,2, that 'clerics are to acknowledge and promote that mission which lay persons experience in their own way in the church and the world. (Rivers 2005:178)</font></p> </blockquote> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="2">Pope John Paul II pointed out that the task of the ministerial priesthood is essentially to support and encourage the priesthood of the laity (cf. Rivers 2005:173). The parishioner has a calling to engage in lay ministry and discipleship as a means to actively live out their baptismal call in their daily lives (cf. Rivers 2005:174). Baptism in Catholic life and faith has the meaning of the spiritual significance of calling every person to share in the evangelising activities of the parish. 'Through baptism, all the members have gifts to share' (Rivers 2005:179). In the Catholic recovery of the priesthood of the believers through the Second Vatican Council, a richer and deeper meaning to baptism has been advocated that was closer to that of Lutheranism. The vital role of the laity in all aspects of the local parish has been fostered and lay professionals and volunteers have been drawn into service based upon 'the giftedness of baptism' and 'the very partnership of salvation' (Rivers 2005:179). The Catholic view of the separation of clergy and laity is based on the view that <i>grace perfects nature</i> (cf. Van der Walt 2011:25-26).<sup><a name="top_fn12"></a><a href="#back_fn12">12</a></sup> 'To be an ordinary member of the church (a layman) is good, but to belong to the clerical order is better' (Van der Walt 2011:10). The practical application of a transformed practice of the priesthood of believers, if not accompanied by a reformation of the worldview of grace perfects nature, does not result in a reform of the Catholic Church worldview from inside, that is, it remains external or extrinsic and unable to change it internally:</font></p> <blockquote> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="2">It is, however, not in a position to really change or transform nature, because nature has a legitimate place of its own and grace has been separated from it beforehand. (Van der Walt 2011:9)</font></p> </blockquote>
<p><font face="Verdana, Arial, Helvetica, sans-serif" size="2">The traditional Catholic worldview was based on a dualism between everything that is ecclesiastical, elevated and superior to everything in the lower realm of 'ordinary' life (cf. Van der Walt 2001:10), but it was necessary to c
hange this view radically. In the past 'to be an ordinary member of the church (a layman) is good, but to belong to the clerical order is better!' (Van der Walt 2011:10), but with the introduction of 'evangelisation' of John Paul II, the superior-inferior, relationship between priest and
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layman is in the process of transformation. The priesthood of believers is to be understood as having the task that every Catholic should break down the walls of separation between clergy and laity for the priesthood of believers to transform society.<sup><a name="top_fn13"></a><a href="#back_fn13">13</a></sup> Contemporary Roman Catholic mission theology revolves around a number of themes: trinitarian missions, proclamation, liberation, dialogue, inculturation, holistic mission and mission to the modern culture that has been centred in the <i>missio Dei</i>, that mission originates with God with <i>Ad Gentes</i> and the roots of the missionary nature of the church in the mission of the triune God (cf. Goheen 2014:172). The Roman Catholic grounds for the <i>missio Dei</i>, however, are rooted in the tradition of the church and the mission of the triune God as being expressed through the tradition of the church rather than the centrality of the Word of God in the mission of the triune God. In <i>Evangelii Nuntiandi</i>, evangelisation finds its source in the call to the church to continue the mission of Jesus in making known the reign of Christ (cf. Goheen 2014:172). The mission of Jesus and the reign of Christ, however, are identified with liberation in the Roman Catholic tradition. 'The good news proclaims a salvation that is a liberation from everything that oppresses humankind, but above all from sin and Satan so that humankind can know God' (Goheen 2014:173). A dualism, however, exists in Roman Catholic missions between liberation from political, social, cultural and economic dimensions, and spiritual liberation - soul competency in the Baptist view that the priesthood of believers has the potential to address.</font></p> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="2"><b>The turn to 'new evangelisation'</b></font></p> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="2">The Second Vatican Council brought tremendous changes in the role and functions of parishes in the Catholic life. The explosion of lay ministry in the Catholic Church unleashed the evangelising potential of the parish. It 'has changed the shape of the parish <i>ad intra</i> and <i>ad extra</i>' (Rivers 2005:180). The involvement in the parish life was nominal and the influence on society minimal. Today, Catholics <i>choose</i> to be involved in their parishes for spiritual reasons (cf. Rivers 2005:163). The number of priests was in short supply at a time when the Catholic Church was facing a crisis that necessitated (the institution of) the Second Vatican Council. 'Philip Murion and David De Lambo report that in 1999 almost 29, 146 laypeople were involved full - or part time in formal pastoral roles- an increase of 36% from 1992' (Rivers 2005:174). The job description of the local parish priest 'is all but unrecognizable, compared to what it was in past years' (Rivers 2005:163). The influence of the Second Vatican has been astronomical in terms of missions - 'mission does not proceed primarily from the pope, nor from a missionary order, society, or synod, but from a community gathered around the Word of God and the sacraments and sent into the world' (Bosch 2016:483). In the greater inclusion of the laity it has been limited to church life and liturgical participation. The missional church model in the Catholic Church in which one and all understand themselves as uniquely gifted and called by God to their neighbourhood with the message of the gospel has been limited to everyone serving the neighbourhood.<sup><a name="top_fn14"></a><a href="#back_fn14">14</a></sup><i>Evangeli gaudium</i> is the apostolic exhortation on evangelism issued by Pope Francis on 24 November 2014 on evangelism. 'This effort of "new evangelism" is addressed primarily to lukewarm Christians or secular societies that were once Christian' (Woods 2016:65). '<i>Redemptoris missio</i> makes it very clear that the new evangelization does not replace the more traditional missionary and evangelizing activities of the church' (Woods 2016:66). The new evangelisation is directed <i>ad intra</i> to the former members or former Christians; mission <i>ad gentes</i> or mission to the peoples has been directed <i>ad extra</i>. 'The new evangelism is issued as a call to conversion and the re-vitalization of Christian life' (Woods 2016:66). The pope's call for the new evangelisation is not a call to proclaim the gospel to the unsaved, but, according to Goheen (2014):</font></p> <blockquote> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="2">a call to re-evangelize the vast majority of Catholics who no longer practice their faith because they are domesticated by the culture, and the phenomenon of globalization and consumerism as a global culture that impacts the whole world in terms of growing poverty and ecological damage. (p. 175)</font></p> </blockquote> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="2">It is the call to a rich critique of modern Western culture and especially secularisation, pluralism, individualism, globalisation and consumerism than a spiritual renewal and inner transformation, which the priesthood of believers can facilitate.</font></p> <p> </p> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="3"><b>The Pentecostal-charismatic view of the 'gifts'</b></font></p> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="2">It is the charismatic tradition that has developed the equipping of the believers in terms of the Holy Spirit and the giving of spiritual gifts. It was the fourfold or fivefold ministry of Ephesians 4:11 that became a distinguishing characteristic of the charismatic renewal. It was a broadening of leadership to include the laity in which believers were exhorted to find their place of service and ministry in the body of Christ. The spiritual gifts are seen as the ascension gifts of Christ given to the church after his ascension to heaven. These then are special gifts of a spiritual nature and evidence of the baptism in the Spirit. 'Only after He had ascended to heaven did He become the One who would baptize with the Spirit' (Virgo 2011:30). The baptism in the Spirit is a prerequisite for the giving of the spiritual gifts. 'The gifting by the Holy Spirit meant that the division between the clergy and lay persons became less pronounced' (Plüss 2010:259). Wonsuk Ma (2007) explains the paradigm shift that of the Pentecostal movement:</font></p> <blockquote>
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<p><font face="Verdana, Arial, Helvetica, sans-serif" size="2">The 'outpouring' of the Holy Spirit in the early twentieth century brought several powerful paradigm shifts. First, their self-understanding changed drastically: from marginalized too conspicuously 'called' to 'God's minis
try'. Second, it was also seen as a strong eschatological sign for the immediate return of the Lord, and this brought an urgency to their divine call to minister. Third, this 'apostolic' movement had a strong restorational expectation in the early church. Having inherited the hol
iness, spiritual traditions, and supernatural interventions of God, such as healings and miracles, were regularly expected. (p. 29)</font></p> </blockquote> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="2">The gifts of grace in the Pentecostal or charismatic tradition
consisted primarily of the restoration of the apostolic and prophetic office. It is based on the view that grace perfects nature - the spiritual perfects the natural through baptism in the Holy Spirit. 'The coming of the Holy Spirit (or "baptism in the Spirit" as they call it) is for emp
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owerment, and empowerment is for witnessing' (Ma 2007:30) and so the priesthood of believers functions very effectively in this tradition. The apostle and prophetic office in Newfrontiers has a specific function: to mobilise the church for the fulfilment of the mission's mandate:</font></p> <blockquote> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="2">We could become more need-centered instead of apostolic and prophetic, thereby missing God's intention and forgetting the bigger picture, (like) building churches that gradually become foreign to the atmosphere of the New Testament. (Virgo 2011:98)</font></p> </blockquote> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="2">The text of Ephesians 2:20 is read as a foundation laid by the first apostles and prophets. The continuation of apostles and prophets is claimed on the grounds of the reading of 'the mystery' in Ephesians 3:5 as a revelation made by present day apostles and prophets not made known in previous generations (cf. Virgo 2011:114) 'the mystery' indicating a new dispensation. The categories of apostle, prophet, evangelist and pastor-teacher are interpreted as current church offices in the Pentecostal and charismatic tradition. Newfrontiers is unique in its contextualisation of these categories as gifts of the Spirit and not as church offices. It is seen as missional functions and essential to their missional church structure. 'The prophet brings direction and exhortation' (Virgo 2011:118) in the missional expansion of the church. The prophetic ministry directs the church into God's ultimate purpose and spiritual renewal (cf. Virgo 2011:119-120). The spiritual is superior to the natural, and grace stands alongside nature. The prophet does not simply preach a message of prosperity, but in continuation of the Old Testament office 'the prophet's voice needs to come like an axe to the root of our problem. He forces us to ask uncomfortable questions that lead to uncomfortable answers' (Virgo 2011:119, 120). Apostles in the Newfrontiers churches lead and guide the church to mission in the local context and impart a vision to the church for the nations.<sup><a name="top_fn15"></a><a href="#back_fn15">15</a></sup> Roxburg (1996) speaks of the leader as an apostle in the sense that he is:</font></p> <blockquote> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="2">the visionary and the one who turns vision to reality and everyday life by painting the vision before our eyes and making it more attractive than the old world. (p. 70)</font></p> </blockquote> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="2">The priesthood of believers in this tradition mediated through singing and worship that has the potential to bring divided humanity (including the church) together (cf. Ma 2007:33). It is a priesthood in which the 'colour' lines are 'washed in the blood' and there is racial harmony (cf. Ma 2007:32). The Pentecostal tradition of the priesthood of believers, which focuses on the experience of the believer, can be strengthened through an understanding of guidance and direction for life decisions from above, as it is not only based on supernatural spiritual encounters viewed as superior to the natural guidance from below - the human reason and wisdom. In the phrase </font><font size="2">κατὰ</font><font face="Verdana, Arial, Helvetica, sans-serif" size="2"> </font><font size="2">πρόθεσιν</font><font face="Verdana, Arial, Helvetica, sans-serif" size="2"> </font><font size="2">τῶν</font><font face="Verdana, Arial, Helvetica, sans-serif" size="2"> </font><font size="2">αἰώνων</font><font face="Verdana, Arial, Helvetica, sans-serif" size="2"> (Eph 3:11) the idea is that God will always carry out his purpose. The genitive </font><font size="2">τῶν</font><font face="Verdana, Arial, Helvetica, sans-serif" size="2"> </font><font size="2">αἰώνων</font><font face="Verdana, Arial, Helvetica, sans-serif" size="2"> is attributive ('eternal purpose'). The traditional Pentecostal-charismatic approach interprets Ephesians 4:1-16 in terms of a distinction between offices, apostle, prophet and pastor (Eph 4:11) and function the role of the believers in exercising their gifts (Eph 4:12).</font></p> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="2"><b>The Pentecostal-charismatic view of the priesthood of all believers</b></font></p> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="2">Moltmann writes that, 'The charismatic community is a unity in diversity and a diversity in unity. Each one as the Lord calls them, each one as the Lord endows them' (cf. Padilla 2004:172). The charismatic church structure is neither hierarchical nor bureaucratic, but has a networking nature. The charismatic church structure is a fluid structure in which there is freedom for the Holy Spirit to lead and guide the church into missions and missional expression. All the gifts in Ephesians 4:11 are needed for the believers to reach maturity and for the believers 'to be equipped for works of service' (Virgo 2011:147). The priesthood of believers is guided by the vision that every believer has a particular gift and contribution to make to the life of the church (cf. Virgo 2011:147). The role of the present day prophet and apostle is to encourage the believers to function according to the gifts of the Holy Spirit. In the Pentecostal tradition 'ministry' is liberated 'from the elite clergy to the hands of every believer' (Ma 2007:30). In the Pentecostal tradition the emphasis is placed on the prophetic function. It is the reason that Wonsuk Ma (2007) writes:</font></p>
<blockquote> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="2">In the academic realm, a new expression has been suggested 'the prophethood of all believers,' such a possibility becoming an attractive move from the traditional notion of 'the priesthood of believers'. (p. 30)<sup><a name="top_fn16"></a><a href="#back_fn16">16</a></sup></font></p> </blockquote> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="2">Pentecostal-charismatics are to unify the natural and spiritual realms in one realm <i>for the priesthood of believers</i> to transform society.<sup><a name="top_fn17"></a><a href="#back_fn17">17</a></sup></font></p> <p> </p> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="3"><b>The biblical grounds of the priesthood of the believer in Ephesians</b></font></p> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="2">A relationship exists between Ephesians 2:11-22 and 4:1-16 in which there is a link in terms of language -the building metaphor, unity, the foundational role of apostle and prophets, which in Ephesians 4:11 is extended to include evangelists, teachers and pastors. It is used differently so that Ephesians 4:1-16 sheds light on
Ephesians 2:11-22 and vice versa. The relationship between these thought units has been overlooked, because the relation has not been explored in terms of the development of the themes of Ephesians 2:11-22 in 4:1-16 and the missional intent and dimension of the letter.<sup><a name="top_fn18"></a><a href="#back_fn18">18</a></sup> The missional dimension of the metaphor of a building in Ephesians 2:19-22 is used to visibly express the unity of Jew and Gentile,<sup><a name="top_fn19"></a><a href="#back_fn19">19</a></sup> which in its relation to Ephesians 3:8-10 in which the missional intent of the church is expressed and both these aspects are united in Ephesians 4:1-16.<sup><a name="top_fn20"></a><a href="#back_fn20">20</a></sup> It is practically to be a dynamic church structure, of a unified inward and outward structure, of the one building process as expounded in Ephesians 2 and
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4. The believer's access to God and a restored relationship with his or her neighbour are a natural consequence or result of God's eternal plan for the church to have freedom to speak the gospel (Eph 3:11-12). It is practically worked out in terms of God's eternal plan for the church indirectly 'to make known the manifold wisdom of God to the rulers and the authorities in the heavenly realms through the church' (Eph 3:10) as part of God's 'eternal purpose' (Eph 3:11). The focus is not the relationship of believers to one another and to God in Ephesians 3:12, but on the relationship of believers to the world and to Jesus Christ.<sup><a name="top_fn21"></a><a href="#back_fn21">21</a></sup> The manifold or richly abundant wisdom of God is displayed by what the church
collectively does by missions and its self-understanding as being missional rather than by its mere existence that has, for the most part, been the interpretation of Ephesians - specifically Ephesians 3:10. The object in Ephesians 3:11, </font><font size="2">πρόθεσιν</font><font face="Verdana, Arial, Helvetica, sans-serif" size="2">, to which is attributed the qualification of 'eternal' means that God's plan or purpose will always be carried out. This is a basic premise of missions. The traditional interpretation of Ephesians 3:12 is that the believers have access to God as the gift of forgiveness of sins that is apprehended through faith. In this interpretation, access to God is through the justification of the believer. If this interpretation is followed, the relationship between Ephesians 2:18 and 3:12 is that peace is the evidence or result of the righteous declaration
of the believer (Eph 2:18), and access to God (Eph 3:12) the consequence of the forgiveness of sins (Eph 3:12). This interpretation hinges upon faith as the means of apprehending Christ's righteousness. The interpretation gives human freedom a role in the salvation process. In Ephesians 3:12 it is not the appropriating of the work of Christ on the basis of our 'faith in him' and the resultant access to God. In view is our response to the work of Christ, the response of the freedom to make known the good news and the grounds of salvation as 'his faithfulness'.<sup><a name="top_fn22"></a><a href="#back_fn22">22</a></sup> Van Unnik (1961:475) has proposed an alternative interpretation: the reference in Ephesians 3:12 is to the public freedom of speech and refers to the believers' task to proclaim the gospel as opposed to the freedom to approach God. In the
context it is a freedom of speech not primarily to God, but to one's neighbour. 'In the ancient Greek democracy, a citizen had the right to say anything publicly when the population was gathered for an assembly' (Schlier 1957:871). The freedom of believers to approach God is specifically in view in Ephesians 2:18. It is practically developed in Ephesians 3:10-12 as freedom of speech, to speak freely in the church and frankness of speech in the context of friendships and/or freedom to testify and witness to the gospel. In Ephesians 3:12 the freedom to proclaim the mystery is in view. The term </font><font size="2">προσαγωγή</font><font face="Verdana, Arial, Helvetica, sans-serif" size="2"> has in view 'access' to the Father by one Spirit (Eph 2:18). In other words, it has in view the relation between believers in which both the vertical and
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horizontal dimensions are present and inseparably bound together. In Ephesians 3:12, however, the association of </font><font size="2">προσαγωγή</font><font face="Verdana, Arial, Helvetica, sans-serif" size="2"> with such concepts and term
s as </font><font size="2">παρρησία</font><font face="Verdana, Arial, Helvetica, sans-serif" size="2"> [outspokenness] or [openness of speech in the public], [boldness] (New Revised Standard Version) or literal [courage] (cf. Heb 4:16, 10:31), and </font><font size="2">πεποίθμσις</font><font face="Verdana, Arial, Helvetica, sans-serif" size="2"> [confidence], that is 'the extent of placing reliance or trust in or on the extent of placing reliance or trust in or on' (Louw & Nida 1998:31.82), indicate that the freedom of speech to speak the gospel is in view. The missional context and focus of the letter as well as the wider context of Ephesians 3 favour such a reading of </font><font size="2">προσαγωγή</font><font face="Verdana, Arial, Helvetica, sans-serif" size="2">
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in the context.<sup><a name="top_fn23"></a><a href="#back_fn23">23</a></sup> It is the reason that the interpretation of Van Unnik (1961:475) fits the context and the purpose of the letter. The reading of the letter through a missional purpose thus supports such an interpretation. The context of Ephesians 3:10, if interpreted through the lens of the missional purpose of the letter, is that of the spiritual beings intently looking into how the church fulfils its purpose as an instrument of God in the execution of the <i>missio Dei</i> (Eph 3:8-10; Van Aarde 2016). The <i>missio Dei</i> is concretely expressed in Ephesians 1:10 as the plan and purpose of God, and is expounded in Ephesians 1:3-14 in terms of the roles of the Father, Son and Holy Spirit in the plan and purpose
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of God. The concept of the <i>missio Dei</i> is developed and expressed in cosmic terms and dimensions as the mission of the church in Ephesians 1:15-23. It concretely developed in Ephesians 3 in terms of the participation of the church, Jew and Gentile in the <i>missio Dei</i> through the stewardship of the gospel. The priesthood of believers as the doctrine, which most aptly describes Ephesians 4:1-16, supports such an interpretation of Ephesians 3:12. The context in view is the freedom of speech to speak the gospel rather than access to God. The direct access all believers have to God (Eph 2:18) is developed further in Ephesians 3:12 in terms of their freedom to speak as part of the responsibility of every believer to minister to one another, to their unbelieving neighbours and to
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God (Eph 4:12-16). The idea of access to God (Eph 2:18) is connected to boldness and confidence to be publicly outspoken about faith in Christ (Eph 3:12) that is expressed and developed practically as 'speaking the truth in love' (Eph 4:15) to those inside and outside the church.</font></p> <p> </p> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="3"><b>A biblical missional ecumenism</b></font></p> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="2">The 'unity of the Spirit' (Eph 4:3) is more than a unity in terms of theological perspectives, worship style, church government and cultural patterns. It is primarily a unity in terms of the functioning together of the body of Christ that may be termed biblical <i>missional ecumenism</i> (cf. Van Wyk 2014:3, 4 among others). The confession of faith serves to build a biblical missional ecumenism. The goal of growing up into Christ is facilitated through cross-cultural and cross-denominational interaction, and pollination. In Ephesians 4:15 the ultimate goal towards which he and his readers are moving, is that 'together they may grow up into Christ, who is the head' (O'Brien 1999:310). The priesthood of believers has the function and role in <i>missio Dei</i> of binding, building and moving people together. This is the starting point for cross-denominational relations and seeing ways to work together in partnership and participate in God's mission. The goal towards which all believers, church and denominations are to move, is a greater faithfulness to the truth. In Ephesians 4:1-16 Love for the truth is the basis for a biblical missional ecumenism. It necessitates that we 'hold the truth' or 'speak the truth in love' (Eph 4:15). The consensus among interpreters is that the phrase, which literally means 'truthing in love', is to be understood as 'living out the truth in a spirit of love'. It is the truth spoken in love that has, as its basis, 'holding the truth in love'. It has transformative power - power to transform both us and others. What we speak or hold is authenticated by a lifestyle that lovingly expresses the truth. The whole structure or body - the universal church - is fit together. This is a development of the idea of Ephesians 2:21<sup><a name="top_fn24"></a><a href="#back_fn24">24</a></sup> and builds itself up and out in love expressed in Ephesians 4:1-16:</font></p> <blockquote> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="2">It is also important to note that this passage makes it clear that ministry is not the obligation of a few but rather the responsibility of every believer. The unifying force is the oneness in purpose, that is, the use of gifts for body edification, not self-edification. (Hoehner 2002:579)<sup><a name="top_fn25"></a><a href="#back_fn25">25</a></sup></font></p> </blockquote> <p> </p>
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<p><font face="Verdana, Arial, Helvetica, sans-serif" size="3"><b>Conclusion</b></font></p> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="2">In this article it is argued that the role of the laity in the <i>missio Dei</i> was one of the most significant developments followed
by most church denominations. This article was developed along the same lines in the following traditions:</font></p> <ul type="disc"> <li> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="2">The reformed tradition rediscovered the role of the laity in missions that the Baptist church tradition has now developed most extensively in terms of missions. Lutheranism may also be grouped with this division.</font></p> </li> <li> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="2">The Catholic Church has recognised the Apostolicity of the laity in a decree called 'Apostolicam Actuositatem' at the Second Vatican Council in response to the crises of the church.</font></p> </li> <li> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="2">The charismatics gave recognition to the role of the laity through the spiritual gifts of each believer.</font></p> </li> </ul> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="2">It was further argued that the role of the laity and of the priesthood of believers has its biblical precedent and foundation in 1 Peter 2:5, 9 and Ephesians 4:1-16. The contribution of Ephesians is that it provides the church with a missional mandate for the ordinary believer to participate in the <i>missio Dei</i> - a mandate that has to be re-discovered in every age.</font></p>
<p> </p> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="3"><b>Acknowledgements</b></font></p> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="2"><b>Competing interests</b></font></p> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="2">The authors declare that they have no financial or personal relationships which may have inappropriately influenced them in writing this article.</font></p> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="2"><b>Authors' contributions</b></font></p> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="2">T.A.v.A. contributed the missional perspective and insight on Ephesians. G.L. contributed the practical theological perspective and the dedication to Sarel van der Merwe.</font></p> <p> </p> <p><font face="Verdana, Arial, Helvetica, sans-serif" size="3"><b>References</b></font></p> <!-- ref --><p><font face="Verdana, Arial, Helvetica, sans-serif" size="2">Baldovin, J.F., 2011, 'Priesthood of all believers', in I.A. McFarland (ed.), <i>The Cambridge dictionary of Christian theology</i>, pp. 408-409, Cambridge University Press, Cambridge. [ <a href="javascript:void(0);" onclick="javascript: window.open('/scielo.php?script=sci_nlinks&ref=2082784&pid=S2305-0853201700020000700001&lng=','','width=640,height=500,resizable=yes,scrollbars=1,menubar=yes,');">Links</a> ]<!-- end-ref --></font></p>
<![CDATA[
<!-- ref --><p><font face="Verdana, Arial, Helvetica, sans-serif" size="2">Balia, D. & Kim, K., 2010, <i>Edinburg 2010: Witnessing to Christ today</i>, vol. 2, Regnum Books International, Oxford, UK (Regnum Edinburg Centenary Series). [ <a href="javascript:void(0);" onclick="javascript: window.open('/scielo.php?script=sci_nlinks&ref=2082786&pid=S2305-0853201700020000700002&lng=','','width=640,height=500,resizable=yes,scrollbars=1,menubar=yes,');">Links</a> ]<!-- end-ref --></font></p> <!-- ref --><p><font face="Verdana, Arial, Helvetica, sans-serif" size="2">Bosch, D., [1991] 2016, <i>Transforming mission: Paradigm shifts in theology of mission</i>, 20th anniversary edn., Orbis Books, Maryknoll, NY. (American Society of Missiology series, 16). [ <a href="javascript:void(0);" onclick="javascript: window.open('/scielo.php?script=sci_nlinks&ref=2082788&pid=S2305-0853201700020000700003&lng=','','width=640,height=500,resizable=yes,scrollbars=1,menubar=yes,');">Links</a> ]<!-- end-ref --></font></p> <!-- ref --><p><font face="Verdana, Arial, Helvetica, sans-serif" size="2">Brunsdon, A. & Van der Merwe, S., 2013, 'From Mojadi to Mafikeng: Notes on the newfound Department of Theology', <i>Studia Historiae Ecclesiasticae</i> 39(1), 295-313. [ <a href="javascript:void(0);" onclick="javascript: window.open('/scielo.php?script=sci_nlinks&ref=2082790&pid=S2305-0853201700020000700004&lng=','','width=640,height=500,resizable=yes,scrollbars=1,menubar=yes,');">Links</a> ]<!-- end-ref --></font></p> <!-- ref --><p><font face="Verdana, Arial, Helvetica, sans-serif" size="2">Coleman, R.E., 2011, <i>The heart of the gospel: The theology behind the master plan of evangelism</i>, Baker Books, Grand Rapids, MI. [ <a href="javascript:void(0);" onclick="javascript: window.open('/scielo.php?script=sci_nlinks&ref=2082792&pid=S2305-0853201700020000700005&lng=','','width=640,height=500,resizable=yes,scrollbars=1,menubar=yes,');">Links</a> ]<!-- end-ref --></font></p> <!-- ref --><p><font face="Verdana, Arial, Helvetica, sans-serif" size="2">Driver, J., 1976, <i>Community and commitment</i>, Herald Printers, Scottsdale. [ <a href="javascript:void(0);" onclick="javascript: window.open('/scielo.php?script=sci_nlinks&ref=2082794&pid=S2305-0853201700020000700006&lng=','','width=640,height=500,resizable=yes,scrollbars=1,menubar=yes,');">Links</a> ]<!-- end-ref --></font></p>
<![CDATA[
<!-- ref --><p><font face="Verdana, Arial, Helvetica, sans-serif" size="2">Goheen, M.W., 2014, <i>Introducing Christian mission today: Scripture, history and ideas</i>, IVP Academic, Downers Grove, IL. [ <a href="javascript:void(0);" oncl
<![CDATA[
ick="javascript: window.open('/scielo.php?script=sci_nlinks&ref=2082796&pid=S2305-0853201700020000700007&lng=','','width=640,height=500,resizable=yes,scrollbars=1,menubar=yes,');">Links</a> ]<!-- end-ref --></font></p> <!-- ref --><p><font face="Verdana, Arial, Helvetica, sans-serif" size="2">Hastings, R., 2012, <i>Missional God, missional church: Hope for re-evangelizing the west</i>, IVP Academic, Downers Grove, IL. [ <a href="javascript:void(0);" onclick="javascript: window.open('/scielo.php?script=sci_nlinks&ref=2082798&pid=S2305-0853201700020000700008&lng=','','width=640,height=500,resizable=yes,scrollbars=1,menubar=yes,');">Links</a> ]<!-- end-ref --></font></p> <!-- ref --><p><font face="Verdana, Arial, Helvetica, sans-serif" size="2">Hoehner, H.W., 2002, <i>Ephesians: An exegetical commentary</i>, Grand Rapids: Baker Academic. [ <a href="javascript:void(0);" onclick="javascript: window.open('/scielo.php?script=sci_nlinks&ref=2082800&pid=S2305-0853201700020000700009&lng=','','width=640,height=500,resizable=yes,scrollbars=1,menubar=yes,');">Links</a> ]<!-- end-ref --></font></p> <!-- ref --><p><font face="Verdana, Arial, Helvetica, sans-serif" size="2">Holsten, W., 1939, '<i>Das Evangelium und Völker: beiträge zur Geschichte und Theorie der Mission</i>, Buchhandlung der Gosnerischen Mission, Berlin-Friedenau. [ <a href="javascript:void(0);" onclick="javascript: window.open('/scielo.php?script=sci_nlinks&ref=2082802&pid=S2305-0853201700020000700010&lng=','','width=640,height=500,resizable=yes,scrollbars=1,menubar=yes,');">Links</a> ]<!-- end-ref --></font></p> <!-- ref --><p><font face="Verdana, Arial, Helvetica, sans-serif" size="2">Jørgensen, K., 2012, <i>Equipping for service: Christian leadership in church and society</i>, Wipf & Stock, Eugene, OR. [ <a href="javascript:void(0);" onclick="javascript: window.open('/scielo.php?script=sci_nlinks&ref=2082804&pid=S2305-0853201700020000700011&lng=','','width=640,height=500,resizable=yes,scrollbars=1,menubar=yes,');">Links</a> ]<!-- end-ref --></font></p>
| http://www.scielo.org.za/scieloOrg/php/articleXML.php?pid=S2305-08532017000200007 |
GLEEVEC Loss of Exclusivity (LOE). When do the GLEEVEC patents expire, and when will GLEEVEC go generic?
GLEEVEC patent expiration dates, news, international patents, generic launch, and litigation and lawsuits
GLEEVEC Drug Patent Profile
Which patents cover Gleevec, and when can generic versions of Gleevec launch?
Gleevecis a drug marketed byNovartisand is included in two NDAs. There is one patent protecting this drug and one Paragraph IV challenge.This drug hasthirty-five patent family membersin twenty-five countries.The generic ingredient in GLEEVEC is imatinib mesylate. There are thirty-fourdrug master file entriesfor this compound. Twenty-fivesuppliersare listed for this compound. Additional details are available on theimatinib mesylateprofile page.
DrugPatentWatch ® Litigation and Generic Entry Outlook for Gleevec
A generic version of GLEEVEC was approved as imatinib mesylateby SUN PHARM on December 3 rd, 2015.
Summary for GLEEVEC
International Patents: 35 US Patents: 1 Applicants: 1 NDAs: 2 Finished Product Suppliers / Packagers : 1 Raw Ingredient (Bulk) Api Vendors : 150 Clinical Trials : 235 Patent Applications : 785 Formulation / Manufacturing : see details Drug Prices : Drug price information for GLEEVEC Patent Litigation and PTAB cases : See patent lawsuits and PTAB cases for GLEEVEC What excipients (inactive ingredients) are in GLEEVEC? GLEEVEC excipients list DailyMed Link: GLEEVEC at DailyMed
Recent Clinical Trials for GLEEVEC
Identify potential brand extensions & 505(b)(2) entrants
Sponsor Phase Reema A. Patel Phase 2 H. Jean Khoury Cure CML Consortium Phase 2 Research Institute for Gastroenterology and Liver Diseases (RIGLD) Phase 1/Phase 2
Pharmacology for GLEEVEC
Drug Class Kinase Inhibitor Mechanism of Action Bcr-Abl Tyrosine Kinase Inhibitors Cytochrome P450 2D6 Inhibitors Cytochrome P450 3A4 Inhibitors
Anatomical Therapeutic Chemical (ATC) Classes for GLEEVEC
L01EA BCR-ABL tyrosine kinase inhibitors L01E PROTEIN KINASE INHIBITORS L01 ANTINEOPLASTIC AGENTS L Antineoplastic and immunomodulating agents
Paragraph IV (Patent) Challenges for GLEEVEC
Tradename Dosage Ingredient Strength NDA ANDAs Submitted Submissiondate GLEEVEC Tablets imatinib mesylate 100 mg and 400 mg 021588 1 2007-03-12
Singapore Patents for GLEEVEC
Country Patent Number Title Estimated Expiration Search Country Search Patent Number Search Title Search Estimated Expiration Singapore 43859 Pyrimidine derivatives and processes for the preparation thereof ⤷ Try a Trial >Country >Patent Number >Title >Estimated ExpirationSubscribe to access the full database, orTry a Trial
Showing 1 to 1 of 1 entries
US Patents and Regulatory Information for GLEEVEC
Applicant Tradename Generic Name Dosage NDA Approval Date TE Type RLD RS Patent No. Patent Expiration Product Substance Delist Req. Exclusivity Expiration Search Applicant Search Tradename Search Generic Name Search Dosage Search NDA Search Approval Date Search TE Search Type Search RLD Search RS Search Patent No. Search Patent Expiration Search Product Search Substance Search Delist Req. Search Exclusivity Expiration Novartis GLEEVEC imatinib mesylate CAPSULE;ORAL 021335-001 May 10, 2001 DISCN Yes No ⤷ Try a Trial ⤷ Try a Trial ⤷ Try a Trial Novartis GLEEVEC imatinib mesylate CAPSULE;ORAL 021335-002 May 10, 2001 DISCN Yes No ⤷ Try a Trial ⤷ Try a Trial ⤷ Try a Trial Novartis GLEEVEC imatinib mesylate TABLET;ORAL 021588-001 Apr 18, 2003 AB RX Yes No ⤷ Try a Trial ⤷ Try a Trial ⤷ Try a Trial Novartis GLEEVEC imatinib mesylate TABLET;ORAL 021588-002 Apr 18, 2003 AB RX Yes Yes ⤷ Try a Trial ⤷ Try a Trial ⤷ Try a Trial >Applicant >Tradename >Generic Name >Dosage >NDA >Approval Date >TE >Type >RLD >RS >Patent No. >Patent Expiration >Product >Substance >Delist Req. >Exclusivity ExpirationSubscribe to access the full database, orTry a Trial
Showing 1 to 4 of 4 entries
Expired US Patents for GLEEVEC
Applicant Tradename Generic Name Dosage NDA Approval Date Patent No. Patent Expiration Search Applicant Search Tradename Search Generic Name Search Dosage Search NDA Search Approval Date Search Patent No. Search Patent Expiration Novartis GLEEVEC imatinib mesylate TABLET;ORAL 021588-002 Apr 18, 2003 ⤷ Try a Trial ⤷ Try a Trial Novartis GLEEVEC imatinib mesylate TABLET;ORAL 021588-001 Apr 18, 2003 ⤷ Try a Trial ⤷ Try a Trial Novartis GLEEVEC imatinib mesylate CAPSULE;ORAL 021335-001 May 10, 2001 ⤷ Try a Trial ⤷ Try a Trial Novartis GLEEVEC imatinib mesylate CAPSULE;ORAL 021335-002 May 10, 2001 ⤷ Try a Trial ⤷ Try a Trial Novartis GLEEVEC imatinib mesylate CAPSULE;ORAL 021335-001 May 10, 2001 ⤷ Try a Trial ⤷ Try a Trial >Applicant >Tradename >Generic Name >Dosage >NDA >Approval Date >Patent No. >Patent ExpirationSubscribe to access the full database, orTry a Trial
Showing 1 to 5 of 5 entries
International Patents for GLEEVEC
See the table below for patents covering GLEEVEC around the world.
Country Patent Number Title Estimated Expiration Search Country Search Patent Number Search Title Search Estimated Expiration Brazil 1100739 ⤷ Try a Trial Denmark 1332137 ⤷ Try a Trial Israel 133906 ⤷ Try a Trial Japan 4386635 ⤷ Try a Trial Norway 2002001 ⤷ Try a Trial >Country >Patent Number >Title >Estimated ExpirationSubscribe to access the full database, orTry a Trial
Showing 1 to 5 of 5 entries
Supplementary Protection Certificates for GLEEVEC
Patent Number Supplementary Protection Certificate SPC Country SPC Expiration SPC Description Search Patent Number Search Supplementary Protection Certificate Search SPC Country Search SPC Expiration Search SPC Description 0564409 02C0012 France ⤷ Try a Trial PRODUCT NAME: IMATINIB MESILATE; NAT. REGISTRATION NO/DATE: EU/1/01/198/001 20011107; FIRST REGISTRATION: LI - IKS 55 807 20010621 0564409 2002/005 Ireland ⤷ Try a Trial PRODUCT NAME: IMATINIB OR ONE OF ITS PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS, ESPECIALLY THE MONOMETHANESULFONATE SALT; NAT REGISTRATION NO/DATE: EU/1/01/198/001-006 20011107; FIRST REGISTRATION NO/DATE: CH 55807 55807 01 55807 02 20010621; PAEDIATRIC INVESTIGATION PLAN: P/0028/2012 0564409 90908 Luxembourg ⤷ Try a Trial 0564409 C00564409/01 Switzerland ⤷ Try a Trial PRODUCT NAME: IMATINIB; REGISTRATION NO/DATE: IKS 55807 20010621 0564409 C300086 Netherlands ⤷ Try a Trial PRODUCT NAME: IMATINIB, DESGEWENST IN DE VORM VAN EEN FARMACEUTISCH AANVAARDBAAR ZUURADDITIEZOUT, IN HET BIJZONDER HET MESILAAT; NATL. REGISTRATION NO/DATE: EU/1/01/198/001 - 006 20011107; FIRST REGISTRATION: CH IKS 55807 20010621 >Patent Number >Supplementary Protection Certificate >SPC Country >SPC Expiration >SPC DescriptionSubscribe to access the full database, orTry a Trial
Showing 1 to 5 of 5 entries
| https://www.drugpatentwatch.com/p/tradename/GLEEVEC/drug-master-files/drug-master-files/supplier/IMATINIB+MESYLATE/atc-class/L01 |
Furosemide and Metolazone and Supplemental metolazone diuresis in Respiratory Failure and Hypernatremia and Volume Overload - Clinical Trials Registry - ICH GCP
Patients who are on mechanical ventilation in an intensive care unit often require diursis as part of their pre-extubation regimen. The drug of choice for diure...
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Clinical Trial NCT01617798
Stop Hypernatremia, Use Metolazone, for Aggressive, Controlled, Effective Diuresis (SHUM)
June 4, 2019 updated by: Jeffrey Gold, Oregon Health and Science University
Stop Hypernatremia, Use Metolazone for Aggressive, Controlled, Effective Diuresis
Patients who are on mechanical ventilation in an intensive care unit often require diursis as part of their pre-extubation regimen.
The drug of choice for diuresis has traditionally been furosemide.
However, this drug cause hypernatremia (a rise in serum sodium) in a significant proportion of patients.
Hypernatremia is traditionally treated by providing free water supplementation to the patient.
This strategy creates a vicious and unproductive cycle of giving free water, and then diuresing it off.
We propose a strategy for breaking this cycle by using a second diuretic-- metolazone-- which has a tendency to rid the body of more sodium, thereby minimizing hypernatremia.
Study Overview
Status
Withdrawn
Conditions
Respiratory Failure
Hypernatremia
Volume Overload
Intervention / Treatment
Drug: Placebo Comparator: Control-- furosemide (lasix) only
Drug: Supplemental metolazone diuresis
Detailed Description
Mechanical ventilation is a mainstay of Intensive Care.
Weaning from mechanical ventilation remains a significant issue in Intensive Care Unit (ICU) care worldwide.
It is well established that a strategy of diuresis with negative fluid balance shortens the duration of mechanical ventilation in both acute lung injury and cardiogenic pulmonary edema patients.
Despite publication of at least one formalized but complex evidence-based conservative fluid strategy, there is no practical, uniformly implemented protocol for setting or achieving volume status targets.
The default approach at many hospitals involves using ad hoc doses (either intermittent or continuous) of a loop diuretic (usually furosemide) with instructions to monitor fluid balance and follow electrolytes in an attempt to reach arbitrary target volume diuresis.
Moreover, there are barriers to achieving any particular target, including pre-existing renal failure/diuretic resistance, diuretic-induced creatinine elevation, acquired diuretic resistance, hypotension from volume loss, and electrolyte derangements including hypokalemia and hypernatremia.
Strategies exist for preventing or treating the above complications but there is presently no accepted standard for preventing or treating diuretic-induced hypernatremia.
In fact, the standard current intervention is to replace the free water deficit that may be induced by the loop diuretic, while simultaneously perpetuating the free water deficit by continuing to administer the causative loop diuretic.
This approach is circular and does not effectuate the desired negative fluid balance.
We will address the lack of an accepted prevention strategy using a randomized controlled clinical trial in ICU patients with the following specific aims:
Conduct a randomized, pilot trial of standard versus metolazone supplemented diuresis in ICU patients with the primary outcome of improved negative fluid balance.
Assess secondary outcomes including time to extubation, exacerbation of renal failure, and incidence of electrolyte derrangements in the treatment and control arms.
Track whether initial hypernatremia within the control group is a risk factor for poor diuresis with furosemide, and whether it delays extubation.
The anticipated benefits of our proposed intervention involve fundamental ICU and patient care quality measures: avoiding the pitfalls of hypernatremia and diuretic resistance should lead to more effective diuresis, which should in turn lead to a more negative fluid balance, earlier liberation from the ventilator, and a shorter length of stay in the ICU.
Study Type
Interventional
Phase
Not Applicable
Contacts and Locations
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Locations
United States
Oregon
Portland, Oregon, United States, 97239
Oregon Health Sciences University
Participation Criteria
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
Eligibility Criteria
Ages Eligible for Study
Child
Adult
Older Adult
Accepts Healthy Volunteers
No
Genders Eligible for Study
All
Description
Inclusion Criteria:
ICU patients who are intubated and slated for diuresis in anticipation of extubation.
Patients must be hypernatremic (Na > 140 mEq/L) at the time diuresis is initiated or become hypernatremic over the course of receiving loop diuretics in anticipation of extubation.
GFR > 30 ml/min [as calculated by the MedCalc MDRD formula {GFR = 170 x PCr - 0.999 x Age - 0.176 x BUN - 0.170 x Albumin0.318
x 0.762 (for women) x 1.180 (for blacks)} ]
Exclusion Criteria:
History of allergy to furosemide or any thiazide diuretic
Inability to place enteral access
Moribund status
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Design Details
Primary Purpose : Treatment
Allocation : Randomized
Interventional Model : Parallel Assignment
Masking : None (Open Label)
Number of Arms
2
Arms and Interventions
Participant Group / Arm Intervention / Treatment
Placebo Comparator: Control-- furosemide (lasix) only
Control arm receives standard of care diuresis with furosemide(lasix)only.
The treatment team will decide the dosing of furosemide (lasix).
No actual placebo is administered.
Drug: Placebo Comparator: Control-- furosemide (lasix) only
Control arm will receive furosemide as monotherapy for diuresis
Other Names:
furosemide, lasix, metolazone
Active Comparator: Study Arm
Study arm receives evolving standard of care diuresis with furosemide and metolazone.
Drug: Supplemental metolazone diuresis
Patients in the Study Arm will receive supplemental diuresis with metolazone 2.5 mg per dobhoff tube twice daily, in addition to furosemide as the primary team sees fit.
Other Names:
furosemide, lasix
What is the study measuring?
Primary Outcome Measures
Outcome Measure Measure Description
Time Frame
Fluid balance
Time Frame: 24, 36, 48, and 72 hours after either protocol is initiated
Differences in fluid balance (total net liters negative from the time diuresis is initiated) between the study group and control group at the following intervals: 24, 36, 48, and 72 hours after either protocol is initiated.
24, 36, 48, and 72 hours after either protocol is initiated
Secondary Outcome Measures
Outcome Measure Measure Description
Time Frame
Serum sodium
Time Frame: Continuous for 72 hours
Number patients whose Na remains below 145 (meq/L) during the period of diuresis; versus the number of patients whose sodium exceeds 145 (meq/L) and require free water replacement.
Continuous for 72 hours
Hyponatremia
Time Frame: Continuous for up to 72 hours
Number of patients who develop hyponatremia (Na < 136 meq/L)
Continuous for up to 72 hours
Time to extubation
Time Frame: Unitl the patient is actually extubated, undergoes tracheostomy, or expires.
Time in hours from initiation of protocol to extubation (difference between study group and control group
Unitl the patient is actually extubated, undergoes tracheostomy, or expires.
Acute Kidney Injury
Time Frame: Continuous for the first 72 hours
Number of patients who develop acute kidney injury (increase in creatinine by more than 25%)
Continuous for the first 72 hours
Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Sponsor
Oregon Health and Science University
Investigators
Principal Investigator: David Steiger, JD MD, Oregon Health and Science University
Principal Investigator: Dan Hagg, MS MD, Oregon Health and Science University
Study record dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Major Dates
Study Start
June 1, 2012
Primary Completion (Anticipated)
June 1, 2013
Study Completion (Anticipated)
June 1, 2013
Study Registration Dates
First Submitted
June 1, 2012
First Submitted That Met QC Criteria
June 9, 2012
First Posted (Estimate)
June 12, 2012
Study Record Updates
Last Update Posted (Actual)
June 6, 2019
Last Update Submitted That Met QC Criteria
June 4, 2019
Last Verified
June 1, 2019
More Information
Terms related to this study
Additional Relevant MeSH Terms
Metabolic Diseases
Respiratory Tract Diseases
Respiration Disorders
Water-Electrolyte Imbalance
Respiratory Insufficiency
Hypernatremia
Physiological Effects of Drugs
Molecular Mechanisms of Pharmacological Action
Antihypertensive Agents
Natriuretic Agents
Membrane Transport Modulators
Diuretics
Sodium Chloride Symporter Inhibitors
Sodium Potassium Chloride Symporter Inhibitors
Furosemide
Metolazone
Other Study ID Numbers
IRB00007857
This information was retrieved directly from the website clinicaltrials.gov
without any changes. If you have any requests to change, remove or update your study details, please contact
[email protected]
. As soon as a change is implemented on clinicaltrials.gov
, this will be updated automatically on our website as well.
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Sponsors and Collaborators
Thai Nguyen Center for Preventive Medicine
Ariel Precision Medicine
Assiut University
GlaxoSmithKline
Cairo University
Federal ministry of labour and social affairs
Hepanova Inc.
Assistance Publique - Hôpitaux de Paris
Italian Society of Diabetology
National Cancer Institute (NCI)
AstraZeneca
Sarawak MediChem Pharmaceuticals
Alko Do Brasil Industria e Comercio Ltda
M.D. Anderson Cancer Center
Novartis Pharmaceuticals
Mayo Clinic
Kinnov Therapeutics
Pfizer
US Biotest, Inc.
Hospital Barmherzige Brüder Graz
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Medical Conditions
Depression
Home Monitoring Follow-up
Asthma
Coronary Artery Disease (CAD) (E.G., Angina, Myocardial Infarction, and Atherosclerotic Heart Disease (ASHD))
Obesity
Breast Cancer
Prostate Cancer
Mandibular Asymmetry
Coronary Artery Disease
Pain
Hypercholesterolemia or Combined Dyslipidemia
RAS-wild-type
HIV Infections
Stage IV Adult Soft Tissue Sarcoma
ALK-positive NSCLC
Incisional Hernia of Midline of Upper Abdomen
Stroke
Unresectable Stage III Non-small Cell Lung Cancer
Artery Diseases, Peripheral
Hypertension
View Full List
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Olokizumab 64 mg SC q2w
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Ratliff v. Menard, Inc., Case No. 1:11-cv-00888-TWP-DKL - Federal Cases - Case Law - VLEX 884547271
0: [object Object]. 1: [object Object]. 2: [object Object]. 3: [object Object]. 4: [object Object]
Ratliff v. Menard, Inc., Case No. 1:11-cv-00888-TWP-DKL
<table><tbody><tr><td> Court</td><td> United States District Courts. 7th Circuit. United States District Court (Southern District of Indiana)</td></tr><tr><td> Writing for the Court</td><td> Tanya Walton Pratt</td></tr><tr><td> Parties</td><td> CURTIS RATLIFF, Plaintiff, v. MENARD, INC., doing business as MENARDS, Defendant.</td></tr><tr><td> Docket Number</td><td> Case No. 1:11-cv-00888-TWP-DKL</td></tr><tr><td> Decision Date</td><td> 22 October 2012</td></tr></tbody></table>
CURTIS RATLIFF, Plaintiff,
v.
MENARD, INC., doing business as MENARDS, Defendant.
Case No. 1:11-cv-00888-TWP-DKL
UNITED STATES DISTRICT COURT SOUTHERN DISTRICT OF INDIANA INDIANAPOLIS DIVISION
Dated: October 22, 2012
ENTRY ON DEFENDANT'S MOTION FOR SUMMARY JUDGMENT
This matter is before the Court on Defendant Menard, Inc.'s ("Menards") motion for summary judgment (Dkt.38). Plaintiff Curtis Ratliff ("Mr. Ratliff") is an electrician who was hired by Menards as an independent contractor to complete repairs in the Camby, Indiana store. While attempting to reach an outside light fixture, Mr. Ratliff climbed atop a chain-link fence cage structure and fell approximately thirteen feet to the ground when the structure collapsed. Mr. Ratliff filed this suit alleging negligence on behalf of Menards that caused his injuries. Menards counter-claimed for the damage caused to the structure by Mr. Ratliff's fall. Menards has filed for summary judgment on both Mr. Ratliff's claim and its counter-claim. For the following reasons, the motion (Dkt.38) is DENIED.
I. BACKGROUND
Mr. Ratliff is a self-employed electrician and owns Ratliff Electric, Inc. Menards is a home improvement store with numerous locations. Prior to October 13, 2009, Mr. Ratliff had completed electrical work for Menards approximately 200 times; specifically, Mr. Ratliff did
Page 2
electrical work for the Camby, Indiana location approximately once per week. 1The week before October 13, 2009, Mr. Ratliff was contacted by Derek Uran ("Mr. Uran"), the second assistant manager for the Camby Menards location. Mr. Uran and Mr. Ratliff did a walk-through of the store to identify light fixtures that needed repair. One of the light fixtures was located outdoors above a chain-link fence cage structure ("fence cage" or "fence cage structure").
According to Mr. Ratliff, when he saw the outdoor light fixture he told Mr. Uran that a "knuckle lift" was needed to access the light fixture above the fence cage. Mr. Uran told Mr. Ratliff that a lift would cost too much, and implied that Menards would not pay for a lift in the future. Mr. Uran then told Mr. Ratliff that the light fixture could be reached by using two-by-twelve walk-boards and a ladder on top of the walk-boards. 2Mr. Ratliff interpreted Mr. Uran to mean that this method had been used at other Menards locations, of which Mr. Uran had personal knowledge. Mr. Ratliff left the conversation under the impression that Menards would not pay for a lift and that he needed to attempt the ladder and walk-board method to repair the light.
According to Mr. Uran, Mr. Ratliff asked whether a "knuckle lift" could be rented to reach the light fixture. Mr. Uran responded by asking if there was any way the light fixture could be reached without using the lift. Mr. Uran concedes that he made the suggestion that it might be possible to access the light fixture by using a ladder or multiple ladders to save the expense of using a lift. Mr. Uran left the conversation without knowledge of how Mr. Ratliff would ultimately reach the light fixture.
On October 13, 2009, Mr. Ratliff arrived at the Camby Menards store to repair the list of light fixtures. After repairing the indoor light fixtures, Mr. Ratliff and his assistant Matthew Hurt ("Mr. Hurt") pulled their van around to the fence cage. Mr. Ratliff removed a twenty-four
Page 3
foot extension ladder and a ten foot ladder from the van. He inspected the area and did not note any damage to the fence cage. He set up the twenty-four foot ladder against the wall near the fence cage. After climbing the ladder, he grabbed the nearest support bar and shook it to test its strength. Because it felt solid, Mr. Ratliff stepped onto the support bar. At some point, he also placed the ten foot ladder across several of the bars supporting the structure. Once he was standing on the first support bar of the fence cage, Mr. Ratliff told Mr. Hurt to "fetch" the walk-boards. Less than one minute after Mr. Hurt left the area, the fence cage collapsed and Mr. Ratliff fell approximately thirteen or fifteen feet to the ground. Mr. Ratliff sustained injuries as a result of the fall.
Mr. Ratliff filed suit against Menard, Inc. in Marion County Superior Court on June 15, 2011. Menards filed its Notice of Removal on June 30, 2011 (Dkt.1). Thereafter, Menards filed the instant motion on May 29, 2012.
II. LEGAL STANDARD
Federal Rule of Civil Procedure 56 provides that summary judgment is appropriate if "the pleadings, depositions, answers to interrogatories, and admissions on file, together with the affidavits, if any, show that there is no genuine issue as to any material fact and that the moving party is entitled to a judgment as a matter of law." Hemsworth v. Quotesmith.Com, Inc.,476 F.3d 487, 489-90 (7th Cir.2007). In ruling on a motion for summary judgment, the court reviews "the record in the light most favorable to the nonmoving party and draw[s] all reasonable inferences in that party's favor." Zerante v. DeLuca,555 F.3d 582, 584 (7th Cir. 2009) (citation omitted).However, " [a] party who bears the burden of proof on a particular issue may not rest on its pleadings, but must affirmatively demonstrate, by specific factual allegations, that there is a genuine issue of material fact that requires trial." Hemsworth,476 F.3d at 490
Page 4
(citation omitted). "In much the same way that a court is not required to scour the record in search of evidence to defeat a motion for summary judgment, nor is it permitted to conduct a paper trial on the merits of a claim." Ritchie v. Glidden Co.,242 F.3d 713, 723 (7th Cir. 2001) (citation and internal quotations omitted).Finally, "neither the mere existence of some alleged factual dispute between the parties nor the existence of some metaphysical doubt as to the material facts is sufficient to defeat a motion for summary judgment." Chiaramonte v. Fashion Bed Group, Inc.,129 F.3d 391, 395 (7th Cir. 1997) (citations and internal quotations omitted).
III. DISCUSSION
A. Standards for Analysis
Mr. Ratliff alleges Menards is liable for his injuries due to its negligence in failing to maintain its premises in a reasonably safe condition for business invitees, failing to adequately inspect its premises for hazardous conditions, failing to post or otherwise give adequate warnings to its business invitees about the hazardous condition, and failing to remove a known hazardous condition from its premise. In Indiana, the three elements that a plaintiff must prove to succeed on a negligence claim are: (1) a duty owed to the plaintiff, (2) a breach of that duty by the defendant, and (3) the breach proximately caused the plaintiff's damages. Bond v. Walsh & Kelly, Inc.,869 N.E.2d 1264, 1266 (Ind.Ct. App. 2007) (citing Peters v. Foster,804 N.E.2d 736, 742 (Ind. 2004)). Breach of duty and proximate cause are generally issues of fact for a jury, but "whether a duty exists is a question of law for the court to decide." Rhodes v. Wright,805 N.E.2d 382, 386 (Ind. 2004). The court may conclude as a matter of law that a breach of duty has occurred only where the facts are undisputed and lead to but a single inference or conclusion. King v. Ne. Sec., Inc.,790 N.E.2d 474, 484 (Ind. 2003). Under Indiana law, independent contractors are considered business invitees and are owed a duty of care by a landowner.
The law of property owner liability is well settled in Indiana.
Page 5
Indiana law starts with the premise that a property owner is generally under no duty to provide
| https://case-law.vlex.com/vid/ratliff-v-menard-inc-884547271 |
Williams v. Warden, State Prison, No. 14024 - Connecticut - Case Law - VLEX 892908809
0: [object Object]. 1: [object Object]. 2: [object Object]. 3: [object Object]. 4: [object Object]. 5: [object Object]
Connecticut
Williams v. Warden, State Prison, No. 14024
Court Supreme Court of Connecticut Writing for the Court HULL; Thereafter, the petitioner filed a petition for a writ of habeas corpus in the Superior Court. A hearing was held, but on the consent of the parties, the habeas court, Axelrod, J., declared a mistrial. Following a second hearing, the habeas cou Citation 217 Conn. 419,586 A.2d 582 Parties Randy W. WILLIAMS v. WARDEN, STATE PRISON. Decision Date 12 February 1991 Docket Number No. 14024
Page 582
586 A.2d 582
217 Conn. 419
Randy W. WILLIAMS v. WARDEN, STATE PRISON.
No. 14024
Supreme Court of Connecticut.
Argued Dec. 14, 1990. Decided Feb. 12, 1991.
Page 583
[217 Conn. 420] William M. Bloss, Special Public Defender, for appellant (petitioner).
Susann E. Gill, Asst. State's Atty., with whom, on the brief, were Michael Dearington, State's Atty., and Mary Elizabeth Baran, Asst. State's Atty., for appellee (respondent).
Before [217 Conn. 419] SHEA, GLASS, HULL, BORDEN and FRANCIS X. HENNESSY, JJ.
[217 Conn. 420] HULL, Associate Justice.
The principal issue in this appeal is whether the petitioner has established that his conviction of the crimes of first degree robbery and first degree burglary should be overturned because of ineffective assistance of counsel. Following a jury trial, the petitioner, Randy W. Williams, was convicted of robbery in the first degree, in violation of General Statutes § 53a-134(a)(3), 1 and burglary in the first degree, in violation of General Statutes § 53a-101(a)(1). 2 The trial court, Hadden, J., imposed an effective sentence of twenty years imprisonment with execution suspended after ten years. The [217 Conn. 421] petitioner appealed and this court affirmed. State v. Williams, 203 Conn. 159 , 523 A.2d 1284 (1987).
Thereafter, the petitioner filed a petition for a writ of habeas corpus in the Superior Court. A hearing was held, but on the consent of the parties, the habeas court, Axelrod, J., declared a mistrial. Following a second hearing, the habeas court, Kaplan, J., dismissed the petition and the petitioner, upon the granting of certification,
Page 584
appealed to the Appellate Court. We subsequently transferred the appeal to this court pursuant to Practice Book § 4023 and we now affirm.
The facts underlying the petitioner's conviction are as follows. Just before 4 p.m. on January 24, 1985, the victim returned from grocery shopping to an apartment in New Haven where she was staying as a guest. While she was bringing her groceries into the apartment, she noticed a man knocking on the door of the apartment across the hall. The victim informed the man that the occupant of the apartment would not return from work until 4 p.m., and then went back outside to get her child whom she had left in a stroller. As she was returning to her apartment, the victim heard a sound from within the apartment across the hall, so she told the man that it appeared that the occupant might be home after all. The victim then proceeded to enter her apartment, and as she did, the man followed her inside and closed the door behind him. The man displayed a knife and grabbed the victim's purse from a couch. He then ran out of the apartment.
The victim immediately called the New Haven police. Shortly after the police had arrived, the victim described the perpetrator as a fairly dark black man, twenty-five to thirty years old, approximately six feet tall, with a thin moustache, a somewhat muscular build and bearing a shiny mark or scar on the left side of his face. She further stated that the perpetrator had [217 Conn. 422] worn an olive green knit hat. After the victim gave this description, she went to the New Haven police station where she viewed an array of more than two hundred photographs in an attempt to identify the perpetrator. The victim positively identified the petitioner as the perpetrator, after she had selected two photographs of him from the array. Later, she also positively identified the petitioner in court.
In his habeas petition, the petitioner claims that he was deprived of effective assistance of counsel in violation of his federal constitutional rights because his trial attorney: (1) failed to investigate a third party lookalike defense in a timely manner; (2) failed to inform the petitioner adequately of the significance of forgoing use of the lookalike defense; and (3) presented to the petitioner a choice between use or forbearance of the defense. U.S. Const., amends.VI and XIV. The habeas court dismissed the petition, finding that the petitioner had failed to meet his burden of establishing that the representation by his attorney at trial was ineffective and had prejudiced the petitioner.
" 'A convicted defendant's claim that counsel's assistance was so defective as to require reversal of a conviction ... has two components. First, the defendant must show that counsel's performance was deficient.... Second, the defendant must show that the deficient performance prejudiced the defense.... Unless a defendant makes both showings, it cannot be said that the conviction ... resulted from a breakdown in the adversary process that renders the result unreliable.' Strickland v. Washington, 466 U.S. 668 , 687, 104 S.Ct. 2052 , 2064, 80 L.Ed.2d 674 , reh. denied, 467 U.S. 1267, 104 S.Ct. 3562, 82 L.Ed.2d 864 (1984); Aillon v. Meachum, 211 Conn. 352 , 357, 559 A.2d 206 (1989)....
[217 Conn. 423] "Establishing that counsel's performance was deficient 'requires showing that counsel made errors so serious that counsel was not functioning as the "counsel" guaranteed the defendant by the Sixth Amendment.' Strickland v. Washington, supra [466 U.S. at], 687 [104 S.Ct.at 2064]. To demonstrate this 'the defendant must show that counsel's representation fell below an objective standard of reasonableness.' Id., [at] 687-88 [104 S.Ct.at 2064]. 'In any case presenting an ineffectiveness claim, the performance inquiry must be whether counsel's assistance was reasonable considering all the circumstances.' Id., [at] 688 [104 S.Ct.at 2065]. 'Judicial scrutiny of counsel's performance must be highly deferential,' and courts 'must indulge a strong presumption that counsel's conduct falls within the wide range of reasonable professional assistance; that is, the defendant must overcome the presumption that, under the circumstances, the challenged action "might be
Page 585
considered sound trial strategy." ' Id., [at] 689 [104 S.Ct. at 2065], quoting Michel v. Louisiana,
350 U.S. 91
, 101,
76 S.Ct. 158
,
100 L.Ed. 83
(1955), reh. denied, 350 U.S. 955, 76 S.Ct. 340, 100 L.Ed. 831 (1956); see also Burger v. Kemp,
483 U.S. 776
, 788-96,
107 S.Ct. 3114
[3122-27], 97 L.Ed.2d 639, [reh. denied, 483 U.S. 1056, 108 S.Ct. 32, 97 L.Ed.2d 820] (1987); Darden v. Wainwright,
477 U.S. 168
, 185-86,
106 S.Ct. 2464
[2473-74],
91 L.Ed.2d 144
(1986); Aillon v. Meachum, supra, [211 Conn. at], 357 [
559 A.2d 206
]; Valeriano v. Bronson,
209 Conn. 75
, 86,
546 A.2d 1380
(1988); Levine v. Manson,
195 Conn. 636
, 640,
490 A.2d 82
(1985)." Fair v. Warden,
211 Conn. 398
, 402-404,
559 A.2d 1094
, cert. denied, --- U.S. ----, 110 S.Ct. 512, 107 L.Ed.2d 514 (1989).
I
The petitioner first claims that his trial counsel's failure to investigate a third party lookalike defense in a timely manner constituted ineffective assistance of counsel. The petitioner does not challenge the adequacy [217 Conn. 424] of the investigation; see Levine v. Manson, supra, 195 Conn. at 638, 490 A.2d 82 ; Siemon v. Stoughton, 184 Conn. 547 , 554, 440 A.2d 210 (1981); Chace v. Bronson, 19 Conn.App. 674 , 678, 564 A.2d 303 (1989); but only its timing. According to the petitioner, a reasonably competent defense attorney would have initiated an investigation into a third party lookalike defense earlier than did his trial counsel in this case.We do not agree.
During their initial consultation in late March or April, 1985, the petitioner and his attorney, Kenneth Rosenthal, a public defender in the New Haven office, decided to file a motion for a lineup before the victim. Rosenthal asked the petitioner if he knew of anyone who would be willing to participate in a lineup if the motion were granted. In response to this inquiry, the petitioner offered the names of two men presently in the lockup, who had agreed to participate in a lineup for the petitioner. The petitioner also mentioned that one of the men (the third party) had a mark on the left side of his face. Thereafter, Rosenthal filed a motion for a lineup which was later denied. Approximately six months later, during jury selection, after several avenues of defense had gone awry, Rosenthal became aware that the third party who had agreed to stand in a lineup not only had a mark on the left side of his face, but had some other physical similarities to the petitioner as well as robbery charges pending against him. Rosenthal thereupon instructed an investigator to obtain a mugshot of the third party which Rosenthal received the following day. After viewing the mugshot, Rosenthal subpoenaed copies of arrest warrant applications pertaining to the third party from the New Haven police department in order to prepare a lookalike theory of defense. Rosenthal intended to use the third party lookalike evidence to cross-examine the detective who had investigated the robbery in an attempt to show that the investigation was incomplete. [217 Conn. 425] In addition, he intended to present the evidence as an affirmative defense of third party culpability.
Shortly thereafter, Rosenthal discovered that another attorney in the New Haven public defender's office, Robert Sweeney, was representing the third party on an unrelated robbery charge. Rosenthal and Sweeney discussed the matter and decided that because the petitioner was about to proceed to trial, Sweeney would file a motion to withdraw as counsel for the third party. Rosenthal then informed the petitioner that he was preparing a lookalike defense and that despite a conflict of interest problem, he intended to present the defense unless prohibited from doing so.
As the trial commenced, it appeared to Rosenthal that there would not be a ruling on Sweeney's motion before Rosenthal had to cross-examine the detective. After research and reflection, Rosenthal informed the petitioner that due to the unresolved conflict of interest, he could not present the third party lookalike defense as previously indicated and, further, that the petitioner could either...
| https://case-law.vlex.com/vid/williams-v-warden-state-892908809 |
The Oxford Oratory
A sanctuary in the midst of the city
The Oxford Oratory is a vibrant centre of Catholic life. Our church is open every day: join us for Mass, pop in for some quiet prayer, or come and discover more at one of our groups. Our historic church of St Aloysius has been a key feature in the lives of the city’s Catholics for 150 years, attracting people of all ages and from every walk of life. We use beauty to raise hearts and minds to God, faithful to the traditions of St Philip Neri and St John Henry Newman.
On Saturday, Fr Rupert led Men’s Oratory on a walking pilgrimage to Islip, birthplace of St Edward the Confessor. #oxfordoratory
Congratulations to Elizabeth who was received into the Church yesterday evening on the Feast of the Visitation. #oxfordoratory
Congratulations to Livi, baptised on the vigil of Pentecost.
“Therefore, Lord, we pray: graciously accept this oblation of our service, that of your whole family, which we make to you also for those to whom you have been pleased to give the new birth of water and the Holy Spirit, granting them forgiveness of all their sins; order our days in your peace, and command that we be delivered from eternal damnation and counted among the flock of those you have chosen. Through Christ our Lord. Amen.”
#oxfordoratory
Courtesy
I recall how, as a child at school, we were sometimes made to learn poetry. At the time I hated it, and baulked at the idea of having to commit to memory The Ancient Mariner, and in fact, never did. But one poem which did touch me, was Belloc’s Courtesy. It began:
Of Courtesy, it is much lessThan Courage of Heart or Holiness,Yet in my Walks it seems to meThat the Grace of God is in Courtesy.
The poet goes on to tell us how, on one occasion he visited the ‘monks’ at Storrington in Sussex, and that ‘They took me straight into their Hall’where he ‘saw Three Pictures on a wall, And Courtesy was in them all.’
He then tells us the subject of those paintings:
The first the Annunciation;The second the Visitation;The third the Consolation,Of God that was Our Lady’s Son.
The first was of St. Gabriel;On Wings a-flame from Heaven he fell;And as he went upon one kneeHe shone with Heavenly Courtesy.
Our Lady out of Nazareth rode —It was Her month of heavy load;Yet was her face both great and kind,For Courtesy was in Her Mind.
The third it was our Little Lord,Whom all the Kings in arms adored;He was so small you could not seeHis large intent of Courtesy.
Today is the feast of the Visitation, when we celebrate how our Lady made the long and uncomfortable journey to see her older kinswoman, Elizabeth, and her husband Zachariah, who lived in the hill country of Judah. Courtesy seems to me to be a perfect description of what this moment is all about. Imagine the cordial welcome extended to Mary by the older woman, solicitous for her health and how both women were eager to share with one another the joy of the forthcoming births of their sons. Our Lady had herself gone to visit her older cousin, not simply because she wanted to ‘be there’ for her, but because she wanted to share her own good news, which was not hers alone but for her people and, ultimately for the entire world.
This is something Elizabeth seemed to know already! Her enthusiastic greeting is wonderful when she cries out ‘Oh that I should be visited by the Mother of my Lord’. Her unborn son joins in the greeting, kicking and letting his mother know that he too is part of this exciting thing that is happening. Elizabeth’s gracious words: ‘Blessed art thou among women and blessed is the fruit of thy womb’ have been enshrined in our prayer to the Virgin, incorporated with the Angelic Salutation: ‘Hail Mary, full of grace!’
And if today’s feast is about courtesy (so much more than stiff politeness or polished manners, but a warm and real concern for the wellbeing and interest of the other) then it is also about joy. Mary’s presence, together with that of her Divine Son, transformed the home of Elizabeth and Zachariah. ‘Elizabeth was filled with the Holy Spirit’ because of it. St Jose Maria puts it thus: ‘Mary brought joy to her cousin’s home, because she “brought” Christ’. Dame Julian liked to call Jesus ‘our courteous Lord,’ no doubt on account of his gracious dealings with us, flowing from his ‘large intent of Courtesy’!
And this is a supreme friendship of our courteous Lord, that he protects us so tenderly whilst we are in our sins; and furthermore he touches us most secretly, and shows us our sins by the sweet light of mercy and grace. But when we see ourselves so foul, then we believe that God may be angry with us because of our sins. Then we are moved by the Holy Spirit through contrition to prayer, and we desire with all our might an amendment of ourselves to appease God’s anger, until the time that we find rest of soul and ease of conscience. And then we hope that God has forgiven us our sin; and this is true. And then our courteous Lord shows himself to the soul, happily and with the gladdest countenance, welcoming it as a friend, as if it had been in pain and in prison, saying: My dear darling, I am glad that you have come to me in all your woe. I have always been with you, and now you see me loving, and we are made one in bliss.
So sins are forgiven by grace and mercy, and our soul is honourably received in joy, as it will be when it comes into heaven, as often as it comes by the operation of grace of the Holy Spirit and the power of Christ’s Passion.
Even though we have just changed all the light bulbs, our church looks its best when we don’t need to use them.
#oxfordoratory
The flag goes up on feast days!
#oxfordoratory
Blessings with St Philip’s relic after Vespers on Thursday.
#oxfordoratory
Look down from heaven, Holy Father, from the loftiness of that mountain to the lowliness of this valley; from that harbour of quietness and tranquillity to this calamitous sea. And now that the darkness of this world hinders no more those benignant eyes of thine from looking clearly into all things, look down and visit, O most diligent keeper, this vineyard which thy right hand planted with so much labour, anxiety and peril. To thee then we fly; from thee we seek for aid; to thee we give our whole selves unreservedly. Thee we adopt for our patron and defender; undertake the cause of our salvation, protect thy clients. To thee we appeal as our leader; rule thine army fighting against the assaults of the devil. To thee, kindest of pilots, we give up the rudder of our lives; steer this little ship of thine, and, placed as thou art on high, keep us off all the rocks of evil desires, that with thee for our pilot and our guide, we may safely come to the port of eternal bliss.
Our celebrations for St Philip began with First Vespers last night and continue with Masses today. Here St Philip’s relic and altar are incensed during Vespers.
#oxfordoratory
Our new longer term temporary digital organ was hoisted up to the gallery this week in time for First Vespers of Our Holy Father St Philip. Catch up on our YouTube channel if you missed it, and join us for the Solemn Mass at 6pm this Friday.
#oxfordoratory
Vessel of the Holy Spirit
This year the novena in preparation for the feast of Our Holy Father St Philip corresponds almost exactly with the novena of novenas, the first novena, the nine days of prayer between the Ascension and Pentecost when we wait once more with the Apostles for the outpouring of the Holy Spirit. And this is most appropriate, as St Philip was, more than anything else, a man of the Spirit — as we say in his litany, he is the “vessel of the Holy Spirit”. The story of his life, which we read during the novena, really begins with his singular experience of the Spirit on the Vigil of Pentecost 1544 in the catacomb of St Sebastian when the Spirit descended like a ball of fire, entering his mouth and then into his heart. After that experience — Philip’s own Pentecost — his life would never be the same again.
Behind his holiness of life, and his preaching, and his miracles, and his founding of our Institute, there is something fundamental we can learn from St Philip — conveniently for this time in the Church’s liturgical calendar, something about the Holy Spirit. St Philip’s life shows us what happens when we do not simply possess the Holy Spirit, but allow ourselves to be possessed by him. We all have the Holy Spirit dwelling in us — all of us who have been baptised and confirmed. He is in us as much as he was in St Philip Neri, as much as he was in the Apostles at Pentecost. But we are very good at closing ourselves to the Spirit — we, through our sins and our selfishness, our attachments and our self-will, block him out; we ignore his prompting and are deaf to his call, we partition him away into a little forgotten compartment in our souls. Or we make of him a very petty little thing indeed, our God — a God who always agrees with what we say, who wants us to do precisely what we want to do, and makes me right and everyone else wrong.
But this is not the Holy Spirit whom we worship; this is not the awesome power of Almighty God, who hovered over the waters at creation, who raised Jesus from the dead, who came down on the Apostles and Our Lady in the Upper Room, who wonderfully penetrated the heart of St Philip, and who gives power and authority to the Church. The Holy Spirit blows where he wills; his ways are not always our ways; and if we give ourselves to him and allow him to possess us completely — as St Philip did — then we will find that he will do more for us than we ask or even imagine; do more through us and with us. St Philip wanted to be a layman — the Spirit called him to the priesthood; he wanted to be a martyr, the Spirit made him a martyr not of blood, but of charity; Philip wanted to preach the Gospel to the pagans in the Indies, the Holy Spirit had other plans. He wanted to be a humble, hidden servant of the Church, living at San Girolamo and doing what good he could, but the Spirit gave him the gift of preaching and teaching and working miracles and reading men’s hearts and winning souls, and brought him to the Vallicella, and through him founded the Congregation of the Oratory, spread, as it now is, across the world. St Philip loved to be unknown — the Holy Spirit moulded and fashioned and transformed him into one of the most popular saints, the Apostle of Rome. St Philip wanted to reform the hearts and souls of those men and women he met — the Spirit used him to reform the very heart of the Church herself.
It is not enough to have the Holy Spirit — it is not enough even to think we are serving God or doing great things in his honour. We must allow ourselves to be led by the Spirit, formed and transformed by the Spirit. We must be prepared to give up our own desires and plans — even the good ones — and be taken over by the Holy Spirit to be used for his own purposes. If we do this, if we open up to the Spirit who dwells in our hearts, then the life of St Philip Neri, and indeed of all the saints, shows us that the Spirit will do great things for, in, and through us. St Philip, Vessel of the Holy Spirit and Sweetest of Fathers. Pray for us.
A Prayer of Our Holy Father St Philip:
My Lord Jesus, I want to love you but you cannot trust me. If you do not help me, I will never do any good. I do not know you; I look for you but I do not find you. Come to me, O Lord. If I knew you, I would also know myself. If I have never loved you before, I want to love you truly now. I want to do your will alone; putting no trust in myself, I hope in you, O Lord.
The Paschal Candle has been lit for Masses since the Easter Vigil to represent Christ’s presence among us, as with his disciples for forty days. After the Gospel of the Solemn Mass yesterday, it is extinguished to symbolise his ascension into heaven.
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Look up to heaven
On Monday this week some of the Fathers and Brothers spent the day erecting and moving scaffolding — with all due health and safety measures observed — in order to change and improve the lighting on the sanctuary of our church. It is already a great boon for us to see more clearly the beautiful decoration which adorns that focal point of the whole building, as well as being a great help for the priest reading from the missal. Tomorrow as we celebrate the feast of the Ascension, our eyes are directed upwards once more as Our Risen Lord ascends to heaven and for a moment like the Apostles we gaze upwards as he is taken from our sight.
How very much more clearly do we see when we make that effort to lift up our eyes towards the Lord. We not only contemplate his glory but from that vantage point are able to see all things in their fullness, seeing them from the perspective of heaven. Prayer, the lifting of the mind and heart to God, enables us to understand and to see clearly, all those other things of life in which we are otherwise immersed. That daily shifting our focus from the things of this world to the vantage point of heaven is that great encouragement for our daily striving for God, so that where Christ goes we too may follow him.
It is often an effort for us to pull ourselves out of the daily round in order to lift up our heads and our hearts to the things of heaven, but if we are to have the desire for heaven to drive us on, it is essential that we always keep our goal before us. Not only in prayer, but all those things which form the way we see things must have heaven as their vantage point and aim. Monsignor Knox wrote:
In all ages, in all countries, the world acts as a solvent to Catholic piety; breathes an air in which Catholic piety languishes. Man’s intellect always wants to approach things from the human side, from the side from which they can be known by man; shirks and burkes discussion of things from the side of reality, from the side which relates them to God. Man’s art and literary genius is constantly concerned with man at his most human level, his passions, his craven fears, the rebellion of his will against the order in which he lives. All that breathes a poison, for which writers who care about the truth as it is in God have to provide an antidote; they must fight, they must react, but still more they must see things, they must record things, from that higher standpoint which is God’s. You must, sometimes, give the lungs of your soul an airing on these heights, even if the atmosphere of it is more rare, is breathed with more effort, than the other. Or else, the miasma of the modern world will get you down, will weaken your resistance; you will be a prey to the germs of infidelity, to the infection of bad example. And you will forget your Friend.
As the Church invites us then on the Ascension to gaze up towards heaven, to contemplate Our Lord, Risen and Ascended, it is perhaps a good time for us to think on the place we give to the things of heaven in our life each day — not only in terms of the time we give to heaven, but also in terms of what we strive for, on what really all our efforts are in fact based.
And from our gazing upon heaven, we can then go on like the Apostles, down from that mountain and into the world — to teach the Good News and make disciples of all nations, keeping ever in mind that he whom we meet on those heights of prayer is with us always, even to the end of time.
Q: How many Oratorians does it take to change a lightbulb?A: “Change”?
Actually the real answer turns out to be three, plus one very helpful volunteer and a lot of scaffolding. The sanctuary lighting is all working at full brightness again!
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Congratulations to David who was baptised on Saturday!
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One of this month’s relics on display is St Philip’s own copy of Jacapone da Todi’s “Laude”, which St Philip has written his name in. The story of how it was rediscovered in our church — only days before the first Fathers of the Oratory arrived here from Birmingham — is extraordinary. You might find it hard to believe, unless you heard it straight from the priest who found them, who is now the Bishop of Leeds. Read his account from his St Philip’s day sermon on our website:
www.oxfordoratory.org.uk/blog/post/1335-solemnity-of-our-holy-father-saint-philip
The novena to St Philip begins on Tuesday after the evening Mass. You will be able to place your own prayer intentions for the novena in St Philip’s chapel over the weekend.
There will be Solemn Choral Vespers on Thursday 25 May at 6:30pm.
We will welcome Fr Robert Ombres OP from Blackfriars to preach at the Solemn Mass for the feast day itself on Friday 26 May at 6pm.
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May Music
Sunday 7 MaySolemn Mass 11:005th Sunday of EasterMissa Simile est regnum caelorum LoboJubilate Deo universa terra PalestrinaCaro mea vere est cibus Guerrero
Sunday 14 MaySolemn Mass 11:006th Sunday of EasterMissa Regina caeli PalestrinaBenedicite gentes PalestrinaPortio mea White
Thursday 18 MaySolemn Mass 18:00The Ascension of the LordMissa Ascendens Christus VictoriaAscendit Deus PhilipsO Rex gloriae Marenzio
Sunday 21 MaySolemn Mass 11:007th Sunday of EasterMissa Jam Christus astra ascenderat PalestrinaViri Galilaei PalestrinaEgo sum panis vivus Palestrina
Thursday 25 MaySolemn Vespers 18:30Our Holy Father St Philip NeriDeus in adjutorium PadillaMagnificat primi toni VictoriaPangamus Nerio SewellO salutaris hostia LalouxTantum ergo WidorAlleluia GabrieliRespice de caelo Sewell
Friday 26 MaySolemn Mass 18:00Our Holy Father St Philip NeriMissa Papae Marcelli PalestrinaIn spiritu humilitatis CroceJubilate Deo a8 G Gabrieli
Sunday 28 MaySolemn Mass 11:00PentecostMissa De la Batalla GuerreroConfirma hoc deus LassusLoquebantur variis linguis Palestrina
Crowns come in different sizes
One could not have missed the many images of crowns in the past week. On posters and flags, on shop advertisements and on the official emblem of the coronation of His Majesty the King. The whole world, it seems, was caught up in amazement at that moment when St Edward’s crown was placed on the King’s head, the only time it is ever worn, to be replaced by the Imperial State Crown, impressive in its size and its jewels. One could not help but feel a certain sympathy with them — perhaps especially Her Majesty the Queen — as they walked around gingerly with several pounds’ weight of crown on their heads, lest they take a tumble. A crown is a symbol not only of a regal inheritance, but of a sacred anointing and the leadership of a nation. It also shows that one is set apart from the rest, is chosen, is consecrated.
Crowns are a familiar sight even in church. Our Lady’s statue is crowned, there are crowns above the cabinets in the Relic Chapel and they are even to be found, accompanied by palm branches, on the reliquaries placed on the High Altar on feast days. These crowns too stand for those set apart, who are chosen to bear the ultimate witness to the greatest truth.
On Friday we keep the feast of Saints Nereus and Achilleus. Baptised by St Peter himself, these two soldiers having obeyed the cruel orders of their emperor out of fear alone, it is said, came quite suddenly to faith in Christ and in doing so were liberated. They were freed from their obedience to a tyrant to embrace obedience to Christ and in so doing were called to shed their blood in witness to their faith. Theirs is the story of so many brave Christians who saw eternal life as the greatest prize against which everything the world has to offer pales in comparison. St Philip had a great devotion to the saints. Their relics are enshrined at the Roman Oratory and the Venerable Cardinal Baronius was the Cardinal Priest of their ancient church, often frequented by St Philip.
St Philip had a marvellous devotion to the saints and their relics. In his last years we are told he had the lives of the saints read to him daily and took great care to preserve the relics of the saints with devotion at the Vallicella. He saw in the lives of the saints a guide for the rest of us so that where they have gone we might follow.
Earthly crowns fall on the heads of very few men. The crowns on our relic cabinets, on the altar reliquaries and paintings in the church are a reminder to us that there is a lasting crown in store for all of us, a crown of glory that will never fade and is given us by the Lord. It may not be that we have to win it by shedding our blood like Nereus and Achilleus, but rather through the long and arduous path of growing in holiness day by day. We are chosen and set apart, we are consecrated by our baptism to win the crown that is fitted for us. In the eyes of the world it rarely glitters, but it is more lasting than anything the world can dream up. And go for it we must.
And we pray for our King Charles, that the golden crown set on his head a few days ago may always remind him of that crown of glory that awaits him, please God, after a life of service and virtue. May he be helped in seeking that crown by our prayers.
God save the King!
Photo from our Coronation watch party today.
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Title a Role of Formate Dehydrogenase in the Oxalate Metabolism in the Wood-Destroying Basidiomycete Ceriporiopsis Subvermispora - DocsLib
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Kyoto University Research Information Repository A Role
A Role of Formate Dehydrogenase in the OxalateMetabolismTitle in the Wood-destroying Basidiomycete Ceriporiopsis subvermispora
WATANABE, Tomoki; SABRINA, Tengku; HATTORI, Author(s) Takefumi; SHIMADA, Mikio
Wood research : bulletin of the Wood Research Institute Kyoto Citation University (2003), 90: 7-8
Issue Date 2003-09-30
URL http://hdl.handle.net/2433/53104
Right
Type Departmental Bulletin Paper
Textversion publisher
Kyoto University Preliminary
A Role of Formate Dehydrogenase in the Oxalate Metabolism in the Wood-destroying Basidiomycete Ceriporiopsis subvermispora*l
Tomoki WATANABE*2, Tengku SABRINA *3, Takefumi HATTORI*2 and Mikio SHIMADA*2 (Received June 7, 2003)
Keywords: oxalate metabolism, NAD +-dependent formate dehydrogenase, white-rot fungi, Ceriporiopsis subvermispora
metabolism that oxalate decarboxylase (ODO; EO 4.1.1.2) Introduction converts oxalate to formate andcarbon dioxide, and the It is a common physiological trait that brown-rot fungi, formate thus produced is converted to carbon dioxide by including Fomitopsis palustris accumulateoxalic acidin large formate dehydrogenase (FDH; EO 1.2.1.2), yielding quantities in the cultures. Oxalic acid serves as an acid NADH. However, recently, Aguilar et al. successfully catalyst for the hydrolytic breakdown of wood purified oxalate oxidase (OXO ; EO 1.2.3.4) from white polysaccharides during brown-rot wood decay processes. rot fungus Ceriporiopsis subvermispora and they proposed a Furthermore, F. palustris has been reported to acquire novel pathway in which oxalate is metabolized by OXO to energy for growth by "oxalate-fermentation"l). An carbon dioxide, accompanied with the production of 11 oxalate-producingenzyme, glyoxylate dehydrogenase H 20 2 ) (GLOXDH) linked with oxalate biosynthesis, and Thus, we were motivated to investigate whether C. isocitratelyase(IOL) as a key enzyme of the glyoxylate subvermispora has the oxalate-metabolizing systems with ll cycle, have been successfully purified and characterized ODO, FDH and OXO ) We report here preliminary from F. palustrii,3). Furthermore, another oxalate results for the purification and characterization of FDH producing enzyme, oxaloacetase has been detected from and the detection of ODO activity from C. subvermispora. 4 wood-rotting fungi ). The results are discussed in relation to oxalate metabolism On the contrary, white-rot fungi accumulate much by this fungus. smaller amounts of oxalic acid because they have oxalate 5 8 decomposing systems - ). Under the extracellular condi Results and Discussion tion, the two biochemical mediators, including veratryl alcohol cation radicals and Mn3 + produced by lignin Ceriporiopsis subvermispora OS 105 that was kindly provided peroxidase and manganese peroxidase, respectively, have from Dr. Vicuna was cultivated at 2rO in the Kirk's basal l2 been reported to catalyze the decomposition of oxalic acid medium ) containing 2.5% glucose as a carbon source, 3.0 to carbon dioxide9,lO). As a result, oxalic acid seemingly mM ammonium tartrate as a nitrogen source, which was inhibits ligninolytic enzymes4). Furthermore, it has been supplemented with 7-fold minerals. We have purified proposed as a general mechanism for intracellular oxalate FDH from C. subvermispora by varIOUS column
o Route A !JJr2CO, + H,O, TCA a ~COOH) Isocitrate Glyoxylate NAD+ NADH+H+ cycle V .A 2 CO: "-.HCOOH U CO, ® RouteS @
Figure A possible biochemical mechanism for oxalate metabolism in C. subvermispora. Notes: CD Oxalate oxidase, CV Oxalate decarboxylase, ® Formate dehydrogenase.
*1 Laboratory of Biochemical Control, Wood Research Institute, Kyoto University, Uji, Kyoto 611-0011, Japan. *2 North Sumatra University, Indonesia. *3 A part of this work was presented at the 55th Annual Meeting of the Wood Research Society in Fukuoka, March 2003.
-7- WOOD RESEARCH No. 90 (2003) chromatographies. The purified FDH was found to be and the role in white-rot wood decay (Figure). electrophoreticallya single band on SDS-PAGE gel. The purified FDH was similar in molecular mass to the FDHs I3 I4 References purified fromyeasts) and plants ) But the K m value for formate was about one twentieth that of theyeast1) E. MUNIR, J.J. YOON, T. TOKIMATSU, T. HATTORI and M. SHIMADA: Proc. Nat!. Acad. Sci. USA.) 98(20), 11126-11130 enzyme, although the K m value for NAD+ was almost the I3 same ). The enzyme showed greater activities at the (2001). neutral pH range. 2) E. MUNIR, T. HATTORI and M. SHIMADA: Arch. Biochem. Biophys.) 399(2), 225-231 (2002). The optimum temperature for native FDH was at a 3) T. TOKIMATSU, Y. NAGAI, T. HATTORI and M. SHIMADA: room temperature. Formate was the bestsubstrateFEBS Lett.) 437(1-2), 117-121 (1998). among various intermediate organic acids tested. The 4) Y. AKAMATSU, M. TAKAHASHI and M. SHIMADA: Mokuzai FDH activity was inhibited by NADH (60 pM), ATP (10 Gakkaishi) 39, 352-356 (1993). mM), and ADP (10 mM). Interestingly, 2-oxoglutarate 5) H. SHIMAZONO: J. Biolchem.) 42, 321-340 (1955). and oxaloacetate also inhibited theenzymes. These 6) H. SHIMAZONO: Bull. Forest Expt. Station) 33, 393-397 results suggest that these a-ketoacids may control the (1951). enzyme activity intrftcellularly. 7) S. TAKAO: Appl. Microbiol.) 13, 727-732 (1965). The ODe activity was detected from the cell-free 8) M.V. DUTTON, C.S. EVANS, P.T. ATKEY and D.A. WOOD: extracts of C. subvermispora. Thus, the results strongly Appl. Microbiol. Biotechnol.) 39(1), 5-10 (1993). 9) Y. AKAMATSU, D.E. MA, T. HIGUCHI and M. SHIMADA: suggest that C. subvermispora decomposes oxalate to CO2 via formate (Figure, Route B), besides another oxalate FEBS Lett.) 269, 261-263 (1990). metabolizing pathway which was reported by Aguilar et at. 10) D.B. MA, T. HATTORI, Y. AKAMATSU, M. ADACHI and M. (Route A) 11). SHIMADA: Biosci. Biochem. Biotechnol.) 56,1378-1381 (1992). 11) C. AGUILAR, U. URZUA, C. KOENING and R. VICUNA: Arch. We suspect that NADH produced as the results of the Biochem. Biophys.) 366, 275-282 (1999). oxidation of formate may serve as an electron donor for I5 12) T.K. KIRK, E. SCHULTZ, W.]. CONNORS, L.F. LORENZ and ATP generation as in the case ofyeasts ). Alternatively, J.G. ZEICUS: Arch. Microbiol.) 117, 277-285 (1978). NADH may be used as a cosubstrate for several enzymes to 13) T.V. AVILOVA, O.A. EGOROVA, L.S. LOANESYAN and A.M. reduce quinones derived from lignin. It is speculated that EGOROV: Eur. J. Biochem.) 152, 657-662 (1985). white-rot fungi are superior to brown-rot ones in 14) D. PEACOCK and D. BOULTER: Biochem. J.) 120, 763-769 biochemical evolution on conversion of oxalate to an (1970). energy source. However, further research is needed to 15) N. KATO, H. SAHM and F. WANER: Biochim. Biophys. Acta) elucidate the reaction mechanisms for oxalate metabolism 566(1), 12-20 (1979).
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Ancient DNA from Hungary-Christine Gamba et al [Archive] - Eupedia Forum
Thanks to Dienekes for posting the study. Christine Gamba et al: Genome flux and stasis in a five millennium transect of European prehistory: This is the link to the study: http://www.nature.com/ncomms/2014/141021/ncomms6257/full/ncomms6257.html This is the direct link to the Dienekes thread: http://dienekes.blogspot.com/2014/10/ancient-dna-from-ancient-inhabitants-of.html
Thanks to Dienekes for posting the study. Christine Gamba et al: Genome flux and stasis in a five millennium transect of European prehistory: This is the link to the study: http://www.nature.com/ncomms/2014/141021/ncomms6257/full/ncomms6257.html This is the direct link to the Dienekes thread: http://dienekes.blogspot.com/2014/10/ancient-dna-from-ancient-inhabitants-of.html Abstract: The Great Hungarian Plain was a crossroads of cultural transformations that have shaped European prehistory. Here we analyse a 5,000-year transect of human genomes, sampled from petrous bones giving consistently excellent endogenous DNA yields, from 13 Hungarian Neolithic, Copper, Bronze and Iron Age burials including two to high (~22 × ) and seven to ~1 × coverage, to investigate the impact of these on Europe’s genetic landscape. These data suggest genomic shifts with the advent of the Neolithic, Bronze and Iron Ages, with interleaved periods of genome stability. The earliest Neolithic context genome shows a European hunter-gatherer genetic signature and a restricted ancestral population size, suggesting direct contact between cultures after the arrival of the first farmers into Europe. The latest, Iron Age, sample reveals an eastern genomic influence concordant with introduced Steppe burial rites. We observe transition towards lighter pigmentation and surprisingly, no Neolithic presence of lactase persistence. Y DNA: ( A total surprise for me...) Individual KO1, E. Neol Körös (5,650–5,780 BC) = Y-Haplogroup I2a Individual NE5, M. Neol. Late ALP (4,990–5,210 BC) = Y-Haplogroup C6 Individual NE6, M. Neol. LBK Culture (4,950–5,300 BC) = Y-Haplogroup C6 Individual NE7, L. Neol. Lengyel Culture (4,360–4,490 BC) = Y-Haplogroup I2a Individual BR2, L. Bronze, Kyjatice Culture (1,110–1,270 BC) = Y-Haplogroup J2a1 Individual IR1, Iron Age, Pre-Scythian Mezőcsát Culture (830–980 BC) = Y-Haplogroup N Still no R1b anywhere. J2a has finally made an appearance, and it's in a Bronze Age context. First comment on Dienekes: The oldest neolithic sample KO1 is a dark haired blue eyed man with I2a and "Armenian" mDNA R3. I'm not going to say another word until I read the entire paper twice! However, that "Armenian" comment is interesting in light of the tweets from Razib Khan (thanks to him) about the new Lazaridis paper saying that Yamnaya can be modeled as 50% Karelian / 50% "Armenian". https://www.youtube.com/watch?v=VcZAGMEAwrY
The first ancient sample to have fair hair and fair eyes is Neolithic 7: Individual NE7, L. Neol. Lengyel Culture (4,360–4,490 BC) = Y-Haplogroup I2a Following is the PCA plot. The Neolithic samples and Sardinia form a sort of Venn Diagram. Neolithic 7 is right in the intersection autosomally if I'm reading it correctly...not too far from Otzi, actually, who is just to the southwest of Neolithic 7, and just outside the Sardinia group. http://www.nature.com/ncomms/2014/141021/ncomms6257/fig_tab/ncomms6257_F2.html Lactase persistence doesn't show up until the Bronze and Iron Age samples. Amazing. KO1 plots all the way north with La Brana. Then KO2 plots all the way south. The two groups certainly mingled pretty quick in this part of the world, yes? Could a moderator please post the diagram itself? I have no more room. I have to check all of this again.
http://www.nature.com/ncomms/2014/141021/ncomms6257/images/ncomms6257-f2.jpg http://www.nature.com/ncomms/2014/141021/ncomms6257/fig_tab/ncomms6257_F2.html
KO1 plots all the way north with La Brana. Then KO2 plots all the way south. The two groups certainly mingled pretty quick in this part of the world, yes? I suggest KO2 was replacement. New population. The next samples are north of it, which might be caused by bigger incoming KO2-ish population assimilating really small proportion of KO1-ish type hunters in their ranks. Because of "9 to 1"-ish or similar proportions NE circles went just slightly up.
The first ancient sample to have fair hair and fair eyes is Neolithic 7: Individual NE7, L. Neol. Lengyel Culture (4,360–4,490 BC) = Y-Haplogroup I2a Following is the PCA plot. The Neolithic samples and Sardinia form a sort of Venn Diagram. Neolithic 7 is right in the intersection autosomally if I'm reading it correctly...not too far from Otzi, actually, who is just to the southwest of Neolithic 7, and just outside the Sardinia group. http://www.nature.com/ncomms/2014/141021/ncomms6257/fig_tab/ncomms6257_F2.html Lactase persistence doesn't show up until the Bronze and Iron Age samples. Amazing. KO1 plots all the way north with La Brana. Then KO2 plots all the way south. The two groups certainly mingled pretty quick in this part of the world, yes? Could a moderator please post the diagram itself? I have no more room. I have to check all of this again. Ed.Since the ancient samples are "projected" onto the modern ones their placement isn't exact. (although it can give us a general idea) So, I don't think we should get too excited by the fact that the Bronze Age samples seem to plot with the French. Interestingly, though, isn't that about where the one decent "Thracian" sample plotted as well?
The Y-DNA is unfortunately missing deep subclade testing. It would be helpful for all of the samples, and maybe would clarify why all of the Neolithic samples look Mesolithic on the Y line. The Iron Age N would also be interesting to know more about. I'm guessing that the Mesolithic-looking I2a and C6 are just coincidences and that if we had more local samples we'd be seeing more G2a and the like. Well, for every sample but KO1, which seems to be a genuine assimilated hunter-gatherer. As a minor nitpick, the statement by Dienekes that "two other ones were I2a which is what Loschbour and Swedish hunter-gatherers had" and the statement in the paper that KO1's "Y-chromosome lineage, I2a, matches the only haplogroup reported to date in Mesolithic Central and Northern Europeans" aren't quite correct. Motala 2 was I2 but not I2a, and probably was I2c. Several others may have been something other than I2a, because their calls weren't clear. Also, if we count Pitted Ware as Mesolithic (since they were hunter-gatherers), then we can also add Ajvide 70, which wasn't Haplogroup I at all. I went into more details here (http://www.eupedia.com/forum/threads/29799-More-DNA-from-stone-age-European%28Swedish%29-farmers-and-hunter-gatherers?p=441144&viewfull=1#post441144).
OK I need to ask a question here. I know I have said before I feel two steps behind in this area, but I thought I might have been playing myself a little short, now I`m not so sure. Bronze Age in this area, should be R1.. something...no? I'm surprised too, but these are such small sample sizes. The Neolithic period results are surprising too. Maybe, as has been suggested, it's just because it's a small sample, and at this period Hungary was pretty mixed in terms of yDna. We aren't getting much resolution either, so who knows what particular flavor of I2a we have at each time period. We do know that come clades of I2a were incorporated into Neolithic communities and then expanded. Maybe that's what happened here? They're certainly "Neolithic" in autosomal terms. I'm still plowing through the paper. Life is getting in the way. :) I see Dienekes has made some comments. He's certainly right about the pigmentation. Pigmentation changes were taking place before the Indo-Europeans ever showed up, I think, and it was happening among people very much like the Sardinians and Otzi. Why does lactase persistence appear so late in history? Does anyone have any ideas? It must have something to do with pastoralism, yes?( i.e. milk consumption instead of just processed milk products like cheese?) Could that also have speeded up the pigmentation changes? If Bronze Age pastoralists got the light pigmentation alleles from the Neolithic farmers, and their diet was very dairy based, the selection for both would occur, perhaps, given that you need Vitamin D to absorb calcium? http://www.health.harvard.edu/newsweek/vitamin-d-and-your-health.htm Just thinking out loud, folks...
It is fascinating, thanks for posting Angela, and kudos to Hungarian archeologist. Some of these samples are rather surprising. Lot of farmers with hg C and lack of hg G or E! Individual KO1, E. Neol Körös (5,650–5,780 BC) = Y-Haplogroup I2a Individual KO2, E. Neol Körös (5,640 BC) = Y-Haplogroup ? This is very interesting. Times when Hunter Gatherers met first farmers in Hungary. KO1 plots as extreme HG and KO2 as extreme farmer. These two might reset definitions of EEF and WHG. KO1 bones were found in primitive and short lived agricultural village of very early Neolithic in Hungary. I wonder if he was trying his luck in farming or was he a slave or sacrifice to gods done by farmers? Has dark hair and blue eyes. Typical HG look of this period. KO2 has brown hair and brown eyes. Mid Neolithic samples: Individual NE5, M. Neol. Late ALP (4,990–5,210 BC) = Y-Haplogroup C6 Individual NE6, M. Neol. LBK Culture (4,950–5,300 BC) = Y-Haplogroup C6 Individual NE7, L. Neol. Lengyel Culture (4,360–4,490 BC) = Y-Haplogroup I2a Wow. Where are the Gs and Es? C6 is still alive and I2a is farming! The biggest surprise is to find only and very Hunter-Gatherer Y hg I2a and C6 in Neolithic farmers from Hungary! Did HG in Hungary suddenly turned farmers mid Neolithic? Not really, PCA plot tells very different story. They plot exactly with today's Sardinian pop., the most EEF of all europeans. If not HG haplogroups we wouldn't even know that they had some HG heritage looking at autosomal DNA. They plot North from older KO2, this might indicate some HG admixture happening with time, but not more than in modern Sardinians. Haplogroups are surprising but autosomally they are typical EEF farmers from Neolithic. NE7 looks very blond though. More blond than the rest of samples from bronze and iron age. Interesting. Copper Age Individual CO1, L. Neol. Lengyel Culture (2,810 BC) = Y-Haplogroup ? Plots exactly like the rest of Neolithic farmers. Copper age doesn't seem to bring any population change, at least in Hungary. Bronze Age Individual BR1, (2,080 BC) = Y-Haplogroup ? Individual BR2, L. Bronze, Kyjatice Culture (1,110–1,270 BC) = Y-Haplogroup J2a1 Too bad that we have 3 thousand year gap from last neolithic Yhg to BR2 individual. Well at least we can say that J2 existed in central Europe way before Romans could introduce it around their empire from Near East, as some stubbornly insisted. I think it will show up in copper age first (Varna and Cucuteni) but we can't learn this from this study. I still can be right, lol. On the graph we can see a big shift in plotting. Not pure EEF anymore but with admixtures pulling them towards East Europeans and West Asians (ANE?). I would speculate that this is due to Indo-European invasions which started around 2,500 BC. They are also pulled up on a chart toward, I presume, WHG admixture. Iron Age Individual IR1, Iron Age, Pre-Scythian Mezőcsát Culture (830–980 BC) = Y-Haplogroup N Weird, plots somewhere between Russians and Caucasus and has hg N. Perhaps he is the true source of Hungarian language? He has blond hair and brown eyes. Does "Arm" indicate Armeniens?
I'm surprised too, but these are such small sample sizes. The Neolithic period results are surprising too. Maybe, as has been suggested, it's just because it's a small sample, and at this period Hungary was pretty mixed in terms of yDna. Right, got it now. Thanks Angela..:)
The first ancient sample to have fair hair and fair eyes is Neolithic 7: Individual NE7, L. Neol. Lengyel Culture (4,360–4,490 BC) = Y-Haplogroup I2a Blonde hair, Blue eyes, and Light skin! Preceding Indo-Europeans... http://i.imgur.com/9TxOjdC.png?1
It is fascinating, thanks for posting Angela, and kudos to Hungarian archeologist. Some of these samples are rather surprising. Lot of farmers with hg C and lack of hg G or E! Individual KO1, E. Neol Körös (5,650–5,780 BC) = Y-Haplogroup I2a Individual KO2, E. Neol Körös (5,640 BC) = Y-Haplogroup ? This is very interesting. Times when Hunter Gatherers met first farmers in Hungary. KO1 plots as extreme HG and KO2 as extreme farmer. These two might reset definitions of EEF and WHG. KO1 bones were found in primitive and short lived agricultural village of very early Neolithic in Hungary. I wonder if he was trying his luck in farming or was he a slave or sacrifice to gods done by farmers? Has dark hair and blue eyes. Typical HG look of this period. KO2 has brown hair and brown eyes. It will be impossible to infer what KO1 hunter gatherer was doing in agricultural village. The earliest agricultural communities belong to the Körös culture (Criş in Romania), which is part of the Balkan Early Neolithic complex, the “First Temperate Neolithic”10–12. Early Neolithic burials across eastern Europe are characterized by a lack of cemeteries, in contrast to those of later Neolithic periods. Furthermore, the majority of burials are found inside what seem to be refuse pits. In most cases it is not possible to discern whether the artifacts recovered from these pits were simply deposited or discarded into the pit or were rather interred with the person as grave goods 44,45. In the specific case of skeletons from Körös culture sites from Hungary only 13 of the 184 burials were accompanied by objects or fragments of objects that could be identified to belong to a grave assemblage 46
It will be impossible to infer what KO1 hunter gatherer was doing in agricultural village. Whatever he was doing there, the Neolithic Farmer's daughters must have liked him because his DNA was still there 1000 years later. :laughing:
I'm not surprised by the shift from a Sardinian like population to one that includes some eastern mix by the Bronze Age, and the skin and eye colour results would suggest a dietary influence. And the Y haplotype I2 isn't surprising but the C certainly is - if C haplotype hunter gatherers made the transition to agriculture, why did C later become rare. And I'm surprised there's no R1a in the Bronze or Iron Age samples. I'd agree that maybe the Y haplotypes aren't going to prove to be typical examples.
Whatever he was doing there, the Neolithic Farmer's daughters must have liked him because his DNA was still there 1000 years later. :laughing: That's why her father thrown him into the garbage, lol, or whatever was left after he was done with him. Seriously, KO1 lived in primitive farming village, which existed only couple of generations. Was it unsuccesful farming experiment by HGs, or more likely these first farmers/pioneers were wiped out by HGs? Wild West style. There is a definitive slight shift in later farmers towards HGs. Definitely there was some mixing at the beginning, not much but there was some and it shows on PCA. After this initial mixing there is no change in Neolithic PCA values till Bronze Age. Even this blond farmer NE7 plots like Sardinians. Perhaps there were no more HGs left to mate with? At least in Hungary.
I'm not surprised by the shift from a Sardinian like population to one that includes some eastern mix by the Bronze Age, and the skin and eye colour results would suggest a dietary influence. And the Y haplotype I2 isn't surprising but the C certainly is - if C haplotype hunter gatherers made the transition to agriculture, why did C later become rare. And I'm surprised there's no R1a in the Bronze or Iron Age samples. I'd agree that maybe the Y haplotypes aren't going to prove to be typical examples. These could be I-M26 haplotypes, or dead branches of I2a, which are not necessarily from the same movement of people as the I2-M423 Dinaric population haplotypes common in Hungary today. If I recall I2a* and I-M26 aren't very common at all in eastern Europe. I did not read the paper yet as I'm still working in the real world... Is there any indication these remains were separate burials from the other farmers of the time? Strange that all the LBK stuff turns up G-P15 or F-M89, then suddenly all this hunter-gatherer YDNA in a group together.
That's why her father thrown him into the garbage, lol, or whatever was left after he was done with him. Seriously, KO1 lived in primitive farming village, which existed only couple of generations. Was it unsuccesful farming experiment by HGs, or more likely these first farmers/pioneers were wiped out by HGs? Wild West style. There is a definitive slight shift in later farmers towards HGs. Definitely there was some mixing at the beginning, not much but there was some and it shows on PCA. After this initial mixing there is no change in Neolithic PCA values till Bronze Age. Even this blond farmer NE7 plots like Sardinians. Perhaps there were no more HGs left to mate with? At least in Hungary. Its probably a situation similar to that of the R1b hotspot in sub-saharan africa (chad/cameroon). It would only take a few generations of a small group of HG's autosomal traits to be diluted out of existence in a much larger population.
That's why her father thrown him into the garbage, lol, or whatever was left after he was done with him. Seriously, KO1 lived in primitive farming village, which existed only couple of generations. Was it unsuccesful farming experiment by HGs, or more likely these first farmers/pioneers were wiped out by HGs? Wild West style. There is a definitive slight shift in later farmers towards HGs. Definitely there was some mixing at the beginning, not much but there was some and it shows on PCA. After this initial mixing there is no change in Neolithic PCA values till Bronze Age. Even this blond farmer NE7 plots like Sardinians. Perhaps there were no more HGs left to mate with? At least in Hungary. Most of them are still south of Otzi though, and the Sardinians, so slightly less WHG even after whatever mixing went on. Until we get the precise figures from the new Lazaridis paper and/or the right ancient samples, we won't know how much of the WHG in modern Europeans is from the groups who were in Europe proper when the farmers arrived, and how much might have been picked up by Yamnaya or come down from the far north east, yes? If the abstract from the new Sardinia paper is correct, there was very little Bronze Age movement into Sardinia, so their WHG is largely from the first "original" admixture. (Some must have come along with U-152.) I don't think there were any roving bands of fisher hunters left in southern Europe. I'm not sure about Central Europe. Maybe not. I bet there were some left in the far northeast, and maybe Ireland and Scotland? Personally, in terms of Sardinia, I find it interesting how most Tuscans just look like eastern shifted Sardinians. Can the divergence really have been 10,000 years ago as one of the proposed models would have it? Isn't it more likely that until 2500 BC or even later all of southern Europe and most of Central Europe at least was Sardinian like? Still, of course, that means they've largely been their own breeding group for what,3500 years? (By the way, even though I complained that Hellenthal et al didn't, in their prior paper, explain their sampling conditions, I really want to see their new map...150 clusters in Europe!) Aberdeen:And the Y haplotype I2 isn't surprising but the C certainly is - if C haplotype hunter gatherers made the transition to agriculture, why did C later become rare. That "C" is definitely a shocker. Before they found it in a WHG sample, other stray sightings were put down to easterners wandering west but it seems some C is "home grown". I don't know why it disappeared, but Aaron 1981 makes a good point...those I2a lineages may either be of the "Sardinian" variety or an extinct variety. Either way, they may have nothing to do with the I2a in the area now. Without more resolution we just won't know. I bet they wish they had known about this new extraction procedure for ancient dna. Which reminds me...the Lazaridis authors are still in the process of doing the y DNA analysis, or so the rumor goes, although we know how well that can turn out! Never again. :) Anyway, that may mean it will be a while till we get it.I definitely have a lot of questions about those Razib Khan tweets about Lazaridis' oral presentation. Oh, doesn't the paper say that it was a very small group in the Mesolithic, or words to that effect? I've always held to the old formulation that it takes a lot of territory to support hunter/gatherers, although I suppose fisher/gatherers might have needed less.
we know r1a and r1b were in bronze age Germany, but nowhere else so far! Not even in bronze-age/Iron-Age Hungary, Ucraine, or Bulgaria! It sure looks like they're not the original IE haplogroups after all, which are leading more towards J2a/J2b.
Table 1: Result summary from 13 Hungarian petrous bone samples. From Genome flux and stasis in a five millennium transect of European prehistory (http://www.nature.com/ncomms/2014/141021/ncomms6257/full/ncomms6257.html) Cristina Gamba (http://www.nature.com/ncomms/2014/141021/ncomms6257/fig_tab/ncomms6257_T1.html#auth-1), Eppie R. Jones (http://www.nature.com/ncomms/2014/141021/ncomms6257/fig_tab/ncomms6257_T1.html#auth-2), Matthew D. Teasdale (http://www.nature.com/ncomms/2014/141021/ncomms6257/fig_tab/ncomms6257_T1.html#auth-3), Russell L. McLaughlin (http://www.nature.com/ncomms/2014/141021/ncomms6257/fig_tab/ncomms6257_T1.html#auth-4), Gloria Gonzalez-Fortes (http://www.nature.com/ncomms/2014/141021/ncomms6257/fig_tab/ncomms6257_T1.html#auth-5), Valeria Mattiangeli (http://www.nature.com/ncomms/2014/141021/ncomms6257/fig_tab/ncomms6257_T1.html#auth-6), László Domboróczki (http://www.nature.com/ncomms/2014/141021/ncomms6257/fig_tab/ncomms6257_T1.html#auth-7), Ivett Kővári (http://www.nature.com/ncomms/2014/141021/ncomms6257/fig_tab/ncomms6257_T1.html#auth-8), Ildikó Pap (http://www.nature.com/ncomms/2014/141021/ncomms6257/fig_tab/ncomms6257_T1.html#auth-9), Alexandra Anders (http://www.nature.com/ncomms/2014/141021/ncomms6257/fig_tab/ncomms6257_T1.html#auth-10), Alasdair Whittle (http://www.nature.com/ncomms/2014/141021/ncomms6257/fig_tab/ncomms6257_T1.html#auth-11), János Dani (http://www.nature.com/ncomms/2014/141021/ncomms6257/fig_tab/ncomms6257_T1.html#auth-12), Pál Raczky (http://www.nature.com/ncomms/2014/141021/ncomms6257/fig_tab/ncomms6257_T1.html#auth-13), Thomas F. G. Higham (http://www.nature.com/ncomms/2014/141021/ncomms6257/fig_tab/ncomms6257_T1.html#auth-14), Michael Hofreiter (http://www.nature.com/ncomms/2014/141021/ncomms6257/fig_tab/ncomms6257_T1.html#auth-15), Daniel G. Bradley (http://www.nature.com/ncomms/2014/141021/ncomms6257/fig_tab/ncomms6257_T1.html#auth-16) & Ron Pinhasi (http://www.nature.com/ncomms/2014/141021/ncomms6257/fig_tab/ncomms6257_T1.html#auth-17) Nature Communications 5,Article number:5257doi:10.1038/ncomms6257 back to article (http://www.nature.com/ncomms/2014/141021/ncomms6257/full/ncomms6257.html#t1) Table 1: Result summary from 13 Hungarian petrous bone samples. Individual Mean coverage Human DNA (%) Period and culture Site Age (cal BC) Sex mtDNA haplogroup Y Haplogroup ALP, Alföld Linear Pottery; E.,early; F, female; KO1, Körös Neolithic; L., late; LBK, Linearbandkeramik; M, male; M., middle; mtDNA, mitochondrial DNA; Neol., Neolithic. Dates are in calibrated years BC at 2 s.d., 95.4% confidence interval calibrated using OxCal 4.2 and rounded to the decade. For the individual NE4 two dates were obtained. KO1 1.24 62.80 E. Neol. Körös Tiszaszőlős-Domaháza 5,650–5,780 M R3 I2a KO2 0.13 10.13 E. Neol. Körös Berettyóújfalu-Morotva-liget 5,570–5,710 F K1 — NE1 22.12 86.85 M. Neol. ALP Polgár-Ferenci-hát 5,070–5,310 F U5b2c — NE2 0.19 45.85 M. Neol. ALP Esztár Group Debrecen Tócópart Erdõalja 5,060–5,290 F H — NE3 0.13 37.60 M. Neol. Bükk Culture Garadna 5,010–5,210 F X2b — NE4 0.10 15.16 M. Neol. Tiszadob-Bükk Culture Polgár-Ferenci-hát 5,050–5,290 5,030–5,280 F J1c — NE5 1.04 71.02 M. Neol. Late ALP Kompolt-Kigyósér 4,990–5,210 M J1c1 C6 NE6 1.18 80.36 M. Neol. LBK Culture Apc-Berekalja I. 4,950–5,300 M K1a3a3 C6 NE7 1.14 62.81 L. Neol. Lengyel Culture Apc-Berekalja I. 4,360–4,490 M N1a1a1a I2a CO1 1.13 34.57 L. Copper Age, Baden Culture Apc-Berekalja I. 2,700–2,900 F H — BR1 0.81 70.85 E. Bronze, Makó Culture Kompolt-Kigyósér 1,980–2,190 F K1c1 — BR2 21.25 55.31 L. Bronze, Kyjatice Culture Ludas-Varjú-dűlő 1,110–1,270 M K1a1a J2a1 IR1 1.31 56.37 Iron Age, Pre-Scythian Mezőcsát Culture Ludas-Varjú-dűlő 830–980 M G2a1 N The mtdna is interesting...many K's
Very interesting study. A few thoughts. 1) I wasn't too surprised to find I2a among Neolithic farmers. I2a was already found in Neolithic Seribia (Starcevo) and France (Cardium Pottery) alongside G2a. KO1 (c. 5700 BCE) is clearly an assimilated hunter-gatherer based on the autosomal DNA. The other I2a is NE7, who lived 1300 years later, by which time his autosomal DNA had become typically Neolithic, like that of other samples. It is a further confirmation that some I2a lineages were integrated early among Neolithic farmers, and later spread with them. It also confirms my hypothesis that I2a in Sardinia and the Basque country may not be indigenous but came from central or south-east Europe with Neolithic farmers. 2) A bigger surprise was the presence of haplogroup C6. But if other Mesolithic lineages (I2a, I1 and F) were assimilated by Neolithic farmers, why not C6 too ? This was we have the full Paleolithic/Mesolithic European package present among H-G who adopted agriculture. 3) The autosomal data and mitochondrial haplogroups are completely in line with that of previous studies. The only odd piece of data in my eyes is the Iron Age Pre-Scythian sample (IR1), which has typically Siberia Y-DNA (N) and mtDNA (G2a1), but fits right in the middle of modern Armenians autosomally. It is only moderatly strange, since modern Armenians do have 0.5% of Y-haplogroup N, as well as a few percent's of Siberian mtDNA and autosomes. What it means is that this Siberian gene flow into Armenia is probably older than 1000 BCE, or even 1500 BCE, since it takes at least a few centuries for Siberian genomes to get completely diluted and look completely like modern Armenians. I am not a specialist of Armenian history, but I cannot think of any migration from Russia to Armenia around this period. Even before that there was only incursions from the Steppes into the Caucasus during the Yamna and Catacomb periods. In this case the sample is from Hungary, so that prompts the question: how did an Armenian-looking genome with Siberian Y-DNA and mtDNA end up in Hungary c. 900 BCE ? Did it actually come directly from the Caucasus region ? Through which migration ? If we had only the Y-DNA and mtDNA we could presume that this was a direct migration from the Ural region to Hungary, which happened many times in practically all periods of prehistory. But since the autosomal DNA is not Siberian at all, nor eastern/central European, but South Caucasian, it's a real mystery how it ended up in Hungary undiluted. 4) The data on pigmentation is also in agreement with earlier data. KO1, who is the only Mesolithic-looking genome, has blue eyes, dark hair and probably dark skin, just like La Braña. The only other sample with blue eyes is the other I2a, even though by then he has become more Sardinian-like autosomally and acquired fair hair (apparently a contradiction since Sardinians have the lowest incidence and fair hair and blue eyes in Europe). Hair and skin colour both seems to get fairer over time from the Late Neolithic onwards, but the transition to modern pigmentation is not nearly complete by the early Iron Age.
3) The autosomal data and mitochondrial haplogroups are completely in line with that of previous studies. The only odd piece of data in my eyes is the Iron Age Pre-Scythian sample (IR1), which has typically Siberia Y-DNA (N) and mtDNA (G2a1), but fits right in the middle of modern Armenians autosomally. It is only moderatly strange, since modern Armenians do have 0.5% of Y-haplogroup N, as well as a few percent's of Siberian mtDNA and autosomes. What it means is that this Siberian gene flow into Armenia is probably older than 1000 BCE, or even 1500 BCE, since it takes at least a few centuries for Siberian genomes to get completely diluted and look completely like modern Armenians. I am not a specialist of Armenian history, but I cannot think of any migration from Russia to Armenia around this period. Even before that there was only incursions from the Steppes into the Caucasus during the Yamna and Catacomb periods. In this case the sample is from Hungary, so that prompts the question: how did an Armenian-looking genome with Siberian Y-DNA and mtDNA end up in Hungary c. 900 BCE ? Did it actually come directly from the Caucasus region ? Through which migration ? If we had only the Y-DNA and mtDNA we could presume that this was a direct migration from the Ural region to Hungary, which happened many times in practically all periods of prehistory. But since the autosomal DNA is not Siberian at all, nor eastern/central European, but South Caucasian, it's a real mystery how it ended up in Hungary undiluted. http://en.wikipedia.org/wiki/History_of_Hungary_before_the_Hungarian_Conquest see iron age : the cimmerians they lived on the western part of the Pontic steppe 7-800 BC they were ousted by the Scyths and they split in 2 : 1 part fled west to the Carpathian basin another part fled south and crossed the Caucasus : first they assaulted Urartu (Armenia) and after they started wandering all across Anatolia with their horses and steel swords http://en.wikipedia.org/wiki/Cimmerians
http://en.wikipedia.org/wiki/History_of_Hungary_before_the_Hungarian_Conquest see iron age : the cimmerians they lived on the western part of the Pontic steppe 7-800 BC they were ousted by the Scyths and they split in 2 : 1 part fled west to the Carpathian basin another part fled south and crossed the Caucasus : first they assaulted Urartu (Armenia) and after they started wandering all across Anatolia with their horses and steel swords http://en.wikipedia.org/wiki/Cimmerians Ok, but the Cimmerian invasion of Armenia (Urartu) postdate the IR1 sample by a few centuries. Additionally the Cimmerians came from present-day Ukraine, not from Siberia. Finally, nobody knows what happened of the Cimmerians after their migration to Anatolia and Armenia. But even if they migrated back to central Europe, that would have been many centuries after IR1.
we know r1a and r1b were in bronze age Germany, but nowhere else so far! Not even in bronze-age/Iron-Age Hungary, Ucraine, or Bulgaria! It sure looks like they're not the original IE haplogroups after all, which are leading more towards J2a/J2b. Note that this study did not test any Y-DNA between 4,400 BCE and 1,100 BCE. The Indo-Europeans (mostly R1b branch) would have started invading eastern Romania and Bulgaria from c. 4000 to 3500 BCE, and would have reached Hungary around 3000 to 2500 BCE, which is right in the middle of the period not covered. But we know from Lee et al. (2012) (http://onlinelibrary.wiley.com/doi/10.1002/ajpa.22074/abstract;jsessionid=A85EB7928A7552C314EEE7CAF65063 29.f04t04) that R1b was in East Germany (Thuringia) c. 2500 BCE.
Ok, but the Cimmerian invasion of Armenia (Urartu) postdate the IR1 sample by a few centuries. Additionally the Cimmerians came from present-day Ukraine, not from Siberia. Finally, nobody knows what happened of the Cimmerians after their migration to Anatolia and Armenia. But even if they migrated back to central Europe, that would have been many centuries after IR1. I have said for many years, one group of cimmerains went to pannonia ( hungaria ) http://books.google.com.au/books?id=TA1zVKTTsXUC&pg=PA29&lpg=PA29&dq=cimmerians+in+pannonia&source=bl&ots=X71Uq3bQBs&sig=h4tXYfzFxAkhWKmpdJTbM5u5SPY&hl=en&sa=X&ei=x3RHVNe8EOPCmQXl8oHgCg&ved=0CDMQ6AEwAw#v=onepage&q=cimmerians%20in%20pannonia&f=false there are many papers on this http://historylib.org/historybooks/E-V-YArovoy_Drevneyshie-obshchnosti-zemledeltsev-i-skotovodov-Severnogo-Prichernomorya--V-tys--do-n-e----V-vek-n-e--/58
Note that this study did not test any Y-DNA between 4,400 BCE and 1,100 BCE. The Indo-Europeans (mostly R1b branch) would have started invading eastern Romania and Bulgaria from c. 4000 to 3500 BCE, and would have reached Hungary around 3000 to 2500 BCE, which is right in the middle of the period not covered. But we know from Lee et al. (2012) (http://onlinelibrary.wiley.com/doi/10.1002/ajpa.22074/abstract;jsessionid=A85EB7928A7552C314EEE7CAF65063 29.f04t04) that R1b was in East Germany (Thuringia) c. 2500 BCE. This is Mr. Hammer account that R-U106 began in east Germany
N + G2a1 are those Syberian autosomally in Modern samples or were they mostly Syberian before 3000 years already?
that is true, but the IR1 sample comes from Mezőcsát Culture who were Iranian tribes, equestrian nomads with iron tools and believed to be under control of the Cimmerians Cimmerians are believed to descend from Srubnaya culture and Iranian, so probably R1a, I guess some tribes from the forest-steppe zone (I2a1b and N1c) mixed with them, which would account for the IR1 sample to be N and also for pre-Slavic presence of I2a1b in the Balkan Then another Iranian tribe. But that still doesn't explain the Armenian autosomal DNA. It would be interesting to run this same in Dodecad and Eurogenes to determine the exact admixtures.
Then another Iranian tribe. But that still doesn't explain the Armenian autosomal DNA. It would be interesting to run this same in Dodecad and Eurogenes to determine the exact admixtures. it is simple, the present-day Armenians didn't get their Armenian-looking genoom from Armenians, but (in part) from Cimmerians, and so did the IR1 sample
One interesting thing is that KO2 seems less WHG admixted than the other, later neolithic samples. The Iceman, Sardinians and the NE1 - NE& samples all seem to have similar WHG admixture, whereas GOK4 seem top have even more WHG admixture. Also, pretty much every present day populations show lean more to WHG than their neolithic ancestors. This does mean slow but continuous uptake of WHG genetic material. As Angela keeps telling, hunter-gatherers need a large territory to feed themselves. Furthermore, farmers probably have a larger child survival rate. This means, IMHO, more evidence that parts of Europe's HG survived as (semi-)farmers and fishermen, as continuous gene flow from a community to another doesn't seem feasible if the former isn't thriving, or at least is keeping up. I think the Körös culture finds are very interesting, in that respect.
Then another Iranian tribe. But that still doesn't explain the Armenian autosomal DNA. It would be interesting to run this same in Dodecad and Eurogenes to determine the exact admixtures. But what armenian dna are you talking about ? I don't see any prove of that. On the PCa he is not even shifting towards them (in the axis from Hungarians) he is pulling towards northern Caucasus, not armenians, also on the position he is, he could as well be a Balkanite with some siberian admix (given his haplogroups), since on the Admixture anylisis he looks quite european, altough the yellow component (North-east Euro) probably is hiding the east-asian-like admix (since no asian samples are present).
Very interesting study. A few thoughts. 1) I wasn't too surprised to find I2a among Neolithic farmers. I2a was already found in Neolithic Seribia (Starcevo) and France (Cardium Pottery) alongside G2a. KO1 (c. 5700 BCE) is clearly an assimilated hunter-gatherer based on the autosomal DNA. The other I2a is NE7, who lived 1300 years later, by which time his autosomal DNA had become typically Neolithic, like that of other samples. It is a further confirmation that some I2a lineages were integrated early among Neolithic farmers, and later spread with them. It also confirms my hypothesis that I2a in Sardinia and the Basque country may not be indigenous but came from central or south-east Europe with Neolithic farmers. 2) A bigger surprise was the presence of haplogroup C6. But if other Mesolithic lineages (I2a, I1 and F) were assimilated by Neolithic farmers, why not C6 too ? This was we have the full Paleolithic/Mesolithic European package present among H-G who adopted agriculture. 1) It's a pitty we don't have subclades, as I2a was and is all over Europe, but each subclade of I2a is confined over a specific area of Europe 2/ C6 appears to have been more frequent than it is today. But because it is so rare today, we don't know much about it, and there are not many subclades. I doubt these 2 C6 have much to do with the mesolithic La Brana sample. These 2 e.g. may have their origin in neolithic Anatolia, the probably didn't come from Iberia. The La Brana C6 may well have split from these 2 neolithic C6 before the last ice age, each surviving in their own refuge. Anyway, much of the C6 is extinct today.
The data on pigmentation is also in agreement with earlier data. KO1, who is the only Mesolithic-looking genome, has blue eyes, dark hair and probably dark skin, just like La Braña. The only other sample with blue eyes is the other I2a, even though by then he has become more Sardinian-like autosomally and acquired fair hair (apparently a contradiction since Sardinians have the lowest incidence and fair hair and blue eyes in Europe). Hair and skin colour both seems to get fairer over time from the Late Neolithic onwards, but the transition to modern pigmentation is not nearly complete by the early Iron Age. The spread of pigmentation / lactase persisistance and probably also other alleles seem very difficult to grasp Natural selection must have played a bigger role than for SNP spread R1 is said to be the origin of light pigmentation. That origin would lie in the Pontic steppe, some 6500 years ago. R1 is spread pretty much all over Europe today. Yet I is also omnipresent in Europe. I suspect I also played a role in the spread of light pigmentation, which is only confirmed by blue eye colour uptill now. On the other hand, the 8000 year old La Brana is supposed to be mixed with I neighbours, and he was still darkhaired and darkskinned.
Note that this study did not test any Y-DNA between 4,400 BCE and 1,100 BCE. The Indo-Europeans (mostly R1b branch) would have started invading eastern Romania and Bulgaria from c. 4000 to 3500 BCE, and would have reached Hungary around 3000 to 2500 BCE, which is right in the middle of the period not covered. But we know from Lee et al. (2012) (http://onlinelibrary.wiley.com/doi/10.1002/ajpa.22074/abstract;jsessionid=A85EB7928A7552C314EEE7CAF65063 29.f04t04) that R1b was in East Germany (Thuringia) c. 2500 BCE. The common belief so far has been that R1b came from Caucasus/Anatolia/Balkans into Western Europe with the Indo-Europeans, since the older/parent clades of West-Euro R1b are in Caucasus/Anatolia/Balkans. The current problem with that theory is that we're not finding any R1b in Bronze-Age/Iron-Age Balkans or Ukraine, which should have been there by that time. So maybe R1b in Balkans came from Germany sometime between 2500-500 BC, and it's the older clades because that is what was around at that time. And since it's a "late" arrival, it never made it past 20-30%, which is currently common in that area. It is >50% in Germany, because it has always been like that since 2500 BC. Just rearanging theories to fit the recent data...
The common belief so far has been that R1b came from Caucasus/Anatolia/Balkans into Western Europe with the Indo-Europeans, since the older/parent clades of West-Euro R1b are in Caucasus/Anatolia/Balkans. The current problem with that theory is that we're not finding any R1b in Bronze-Age/Iron-Age Balkans or Ukraine, which should have been there by that time. So maybe R1b in Balkans came from Germany sometime between 2500-500 BC, and it's the older clades because that is what was around at that time. And since it's a "late" arrival, it never made it past 20-30%, which is currently common in that area. It is >50% in Germany, because it has always been like that since 2500 BC. Just rearanging theories to fit the recent data... just wait for DNA from Unetice culture and maybe also some more Bell Beker DNA
So now is the final prove that I was right. The first appearance of J2 in Europe came during Bronze-Iron Age most likely with Indo Europeans. J2 and R1a/B are probably pastoralist Haplogroups and reached Europe with the Indo Europeans. Also that the Iron Age Hungarians end up somewhere between Europeans and Caucasians is another bullet prove that the "West Asian" like component reached Europe probably with Indo Europeans for the first time. The proto Indo Europeans were probably something like a cross between modern Europeans and northern West Asians. Imagine a half Lezgian half Russian or half Georgians half Lithuanians Individual. There you have your proto Indo Europeans. The two Bronze Age samples are more like modern continental Europeans but not exactly like modern Hungarians. The Iron Age sample is in the no-man's land between Europe and the Caucasus and his "Asian" Y chromosome and mtDNA seems to agree that this is no ordinary European. http://dienekes.blogspot.de/2014/10/ancient-dna-from-prehistoric.html First the Thracian individuals which showed a strong Caucasus_Gedrosia signature and now Hungarian Iron Age individuals which appear like a crossing between Europeans and Caucasians. For at least 5 years have I preached that Indo Europeans must have been something between modern Northern West Asian and Europeans simply out of the logic that most Indo European groups in Western Asia do have significant amount of North European genes while most Indo Europeans in Europe show significant amoung of Caucasus_Gedrosia like genes, while both groups have significant Mediterranean farmer genes. This can only be explained the way that Proto Indo Europeans had both Caucasus-Gedrosia and North European (ANE impact!) like genes in combination with farmer component of course.
On Dianekes they discuss that it could be just mistype error with iron age sample. It could rather be ydna G and mtdna N :) Which would make some more Caucasian sense.
On Dianekes they discuss that it could be just mistype error with iron age sample. It could rather be ydna G and mtdna N :) Which would make some more Caucasian sense. Are you readiny my mind I was just about to post that too :laughing: Yes it looks like they mixed up mt with yDNA. The individual was probably G2a1 yDNA and N mtdna makes much more sense.
I don't think we should draw too many conclusions on the basis of these samples, unless we want to conclude that the population of Hungary changed massively since the Iron Age, which admittedly is a good possibility. Half of the individuals have Y haplotypes (C and N) that are rare in Hungary today and the other half have haplotypes that are minority haplotypes in Hungary today and are now more common in the Balkans (I2 and J). Without deep subclade analysis, it's pointless to speculate whether these particular I2 individuals belong to a subclade that thrived or became extinct, so I see the presence of I2 in a farming village during the Neolithic simply as more proof that I2 hunter gatherers did take to farming fairly early. But if Hap C folk did as well, why did they more or less disappear later? And what do the Bronze Age and Iron Age samples have to tell us about the levels of ANE in Europe - that part is a mystery. I think it's best to assume that these results aren't typical for Hungary unless and until we get confirmation in the form of more samples.
On Dianekes they discuss that it could be just mistype error with iron age sample. It could rather be ydna G and mtdna N :) Which would make some more Caucasian sense. That would indeed make more sense, especially since it would be the Caucasian G2a1 Y-DNA !
I don't think we should draw too many conclusions on the basis of these samples, unless we want to conclude that the population of Hungary changed massively since the Iron Age, which admittedly is a good possibility. Half of the individuals have Y haplotypes (C and N) that are rare in Hungary today and the other half have haplotypes that are minority haplotypes in Hungary today and are now more common in the Balkans (I2 and J). Without deep subclade analysis, it's pointless to speculate whether these particular I2 individuals belong to a subclade that thrived or became extinct, so I see the presence of I2 in a farming village during the Neolithic simply as more proof that I2 hunter gatherers did take to farming fairly early. But if Hap C folk did as well, why did they more or less disappear later? And what do the Bronze Age and Iron Age samples have to tell us about the levels of ANE in Europe - that part is a mystery. I think it's best to assume that these results aren't typical for Hungary unless and until we get confirmation in the form of more samples. some good observations! For sure their y-dna has changed massively since the Iron Age, to name a few factors: the huns, the germanic migrations, the slavic migrations, numerous plagues etc. Why is C completely gone, is a mystery to me. N is still found around that area in low %. The young I2a-din, probably the descendant of this I2a, now has moved more South (maybe pushed by the Huns). What I'm not sure is, is their R1a from the Huns or the Slavs? or are they the same population at different points in time?
I've been thinking about the J2 sample. I have been assuming that J spread from the Middle East via the Phoenicians and from the Balkans via the Greeks, being later spread around Europe by the Romans. But what if J2 was a major factor in the IE movement into Europe, as some people have suggested in the past? Although obviously the northern IE folk were mostly and perhaps completely R1a. Nah, I'm going to go with this J2 sample being an anomaly.
These I2a lineages might be extinct as well as C6. There is still 4 thousand years till I2a Dinaric showed up. There are no records telling us that Slavs were Huns, or the Huns spoke Slavic. On other hand we know that Slavs came from agricultural culture, and Huns were nomads, horse riding warriors. If Huns spoke IE language it would have been some Iranic dialect like Scythian or Sarmatian. Huns were basically a nomad community of Sycthians and Mongols. The once which moved into Europe (White Huns) were probably the Scythian portion.
These I2a lineages might be extinct as well as C6. There is still 4 thousand years till I2a Dinaric showed up. ......... Pointless speculation, IMO. Those I2a Dinarics didn't appear out of nowhere, and estimates for the ages of subclades have often turned out to be wildly inaccurate. Without knowing what subclade these I2 samples are, there's no reason to assume they belonged to an extinct subclade, except for the fact that they were living with C type farmers.
I've been thinking about the J2 sample. I have been assuming that J spread from the Middle East via the Phoenicians and from the Balkans via the Greeks, being later spread around Europe by the Romans. But what if J2 was a major factor in the IE movement into Europe, as some people have suggested in the past? Although obviously the northern IE folk were mostly and perhaps completely R1a. Nah, I'm going to go with this J2 sample being an anomaly. Dienekes has been advocating the J2 Indo-European connection for a long time. It wouldn't be a surprise if modern Armenia and Lake Sevan was the original PIE homeland. Hittites were believed to be a mountain folk. Could explain the full about face and movement back to Anatolia by the Celts (folk memory). All the new recent information about the interaction between Northern Mesopotamia, the Caucasus, and Steppe during the early Bronze Age helps. Could help to prove that both R1b and R1a were assimilated PIE folk in the Steppe (Yamna). It would explain the Basque connection with R1b (the original language of R1b).
I've been thinking about the J2 sample. I have been assuming that J spread from the Middle East via the Phoenicians and from the Balkans via the Greeks, being later spread around Europe by the Romans. But what if J2 was a major factor in the IE movement into Europe, as some people have suggested in the past? Although obviously the northern IE folk were mostly and perhaps completely R1a. Nah, I'm going to go with this J2 sample being an anomaly. why? it is possible. we play with % and if R1b pass from gedrosia to south west caucas and then to steppe, it is possible to get IEized. we speak about possibilities, and wits fits most.
These I2a lineages might be extinct as well as C6. There is still 4 thousand years till I2a Dinaric showed up. There are no records telling us that Slavs were Huns, or the Huns spoke Slavic. On other hand we know that Slavs came from agricultural culture, and Huns were nomads, horse riding warriors. If Huns spoke IE language it would have been some Iranic dialect like Scythian or Sarmatian. Huns were basically a nomad community of Sycthians and Mongols. The once which moved into Europe (White Huns) were probably the Scythian portion. The linguistic (and ethnic) affiliation of the Huns is a matter that has to my knowledge gone back and forth, mainly due to the scarcity of data. I agree that a Scytho-Sarmatian language is a very real possibility (these languages dominated a large swath of Eurasia for centuries, after all), but so is - in my opinion - Turkic. We don't even know for certain if the Xiongnu of Chinese sources are even the same as the Huns that show up a bit later in Western sources. What is clear about the Slavs, and I agree unanimously here with LeBrok, is that their language is not one of invaders from the steppe.
At last we can for certainly say that J2a in Europe is not from the Romans, lol. From the very first beginning I was telling you guys that the J2a was actually a proto-Indo-European marker that migrated together with R1 from the Iranian Plateau into the Maykop horizon and from there into the Yamna horizon before migrating into the Europe. Indo-Europeans that Indo-Europized the Europe were already heavily diluted with native the Pontic-Caspian Steppes people. They were no more proto-Indo-European at all. J2a folks that mixed with R1a* folks on the Iranian Plateau and South Central Asia, became later known as 'Irani' or simply 'Aryans'. With other words, proto-Iranic, ancient Iranic folks were most probably of Caucaso-Gedrosia admixture. Those people invaded Northern India and raided the Pontic Caspian Sea Horizon. The homeland of the Iranic tribes, Aryana Verta, was a mountainous area. So I'm sure it was located somewhere between the Kurdistan Zagros Mountains and the South-Central Asia.
it is simple, the present-day Armenians didn't get their Armenian-looking genoom from Armenians, but (in part) from Cimmerians, and so did the IR1 sample In Hungary there were also Sigynes (Iranian tribe? or proto-Slavic tribe, the reconstruction of proto-Slavic shows that they came from the Steppes), possibly before the Cimmerians
In Hungary there were also Sigynes (Iranian tribe?), possible before the CimmeriansBingo! I'm proposing exactly the same thing. J2a in Hungary is most probably from the Massagetae, or the Solar Medes, the Sauromatians. J2a in Hungary can be already a fully evolved 'Iranic' marker, that has nothing to do with so called proto-Indo-Europeans.
In Hungary there were also Sigynes (Iranian tribe? or proto-Slavic tribe, the reconstruction of proto-Slavic shows that they came from the Steppes), possibly before the Cimmerians I checked he's positive for NO and N snps so he have N haplogroup, Slavic populations in Balkans have haplogroup N1a (also in Slovakia you may find N1a) And he was there before the Cimmerians, the Sigynes is a good proposal
It is not strange that he was Armenian like in central Asia you may find Y-Dna haplogroup N, and in Caucasus and Cent.Asia you find mtdna G. In Iron age the Cent.Asians wasn't so diferent from South Caucasians
I checked he's positive for NO and N snps so he have N haplogroup, Slavic populations in Balkans have haplogroup N1a (also in Slovakia you may find N1a) And he was there before the Cimmerians, the Sigynes is a good proposal who are the Sigynes? what is their origin?
Bingo! I'm proposing exactly the same thing. J2a in Hungary is most probably from the Massagetae, or the Solar Medes, the Sauromatians. J2a in Hungary can be already a fully evolved 'Iranic' marker, that has nothing to do with so called proto-Indo-Europeans. not the J2a1 sample mentioned in the study, which is dated +/- 1200 BC the tribes you mention arrived in the west much later, after the Cimmerians and after the Scyths
I remember that somewhere on Dienekes' site there is a thread(s) which discusses the fact that a few Armenians plot pretty far away from the mass of Armenians, and there was some speculation that perhaps it was because of Russian admixture. (I just spent a half hour trying to find it, but I couldn't. If I have time later, I'll try again.) I'm just suggesting that those may be the few Armenians among whom IR plots. If you look closely at the mass of samples in the Near East you'll find that most of the Armenians plot down there somewhere around eastern Turkey, which makes sense.) However, given the tweets from Razib Khan about the upcoming Lazaridis paper on Samarra, I don't see why the fact that IR plots near a "possibly" mixed Armenian/Russian sample is either surprising or upsetting. #ASHG14 (https://twitter.com/hashtag/ASHG14?src=hash) eastern hg from Karelia and sammara. ANE related to Eastern hg. yamnaya had near East and Caucasus #ASHG14 (https://twitter.com/hashtag/ASHG14?src=hash) ANE in Europe from eastern hg groups? (via yamnaya) #ASHG14 (https://twitter.com/hashtag/ASHG14?src=hash) yamnaya better source for intrusive group into north Europe late Neolithic bronze age #ASHG14 (https://twitter.com/hashtag/ASHG14?src=hash) corded ware 36% nonlocal ancestry. Karelian. low bound #ASHG14 (https://twitter.com/hashtag/ASHG14?src=hash) yamnaya modeled as 50/50 Armenian Karelian. corded ware 75% yamnaya #ASHG14 (https://twitter.com/hashtag/ASHG14?src=hash) yamnaya % peaks in north Europe. lower in south Europe. lowest in Sardinia #ASHG14 (https://twitter.com/hashtag/ASHG14?src=hash) yamnaya = proto-indoeuropean Perhaps there was Caucasus influence even back in the Bronze Age. much less the Iron Age. I'm told there is now a mad scramble to analyze his data. Of course, I don't know what he'll turn out to be...I'm willing to wait for analyses to be done, and I have no personal stake in the outcome. Anyway, I'm not going to get into speculating based on fragmentary results or rumors posted by people on other sites. I had enough of that. I'll wait for the paper. All I'm saying is that the plotting of IR shouldn't be a total surprise. I don't think we can make any judgments about the I2a or the C6 because the subclades aren't resolved enough for either the Mesolithic samples or the ones under discussion. We don't even know if all the I2a in these samples is the same one. Epoch:One interesting thing is that KO2 seems less WHG admixted than the other, later neolithic samples. We don't know if the y dna of the two samples, K01 and K02, are the same. Koros 1: I2a subclade unknown Koros 2: Y dna unknown What we do know is that Koros 1 looks like a Mesolithic hunter/fisher-gatherer. I'm leaning toward LeBrok's speculation that he was either a hunter-gatherer trying to learn how to farm, or a local absorbed into a very early attempt at settlement by Neolithic farmers. Koros2 is a very southward plotting Neolithic farmer. He looks to me like an example of what these people were like when they first arrived. Also, take a look at the dates: Koros 1:5,650–5,780 Koros 2: 5,570–5,710 They're also two different sites. The rest of the Neolithic samples are from a later time period. Enough time to have absorbed a little hunter gatherer. However, it's not as much as was absorbed apparently by the farmers in the west, because quite a few of them plot south of Otzi. Or maybe it was just a little bit over the centuries? Otzi and the Copper Age sample from this study plot at about the same latitude don't they? Also, can anybody find Stuttgart on there? Even my bifocals aren't working that well. :) Oh, and of the NE 1-7, two of them are C6, and 1 is I2a, but who knows of what variety. Four of them are missing Y dna. Ed. to remove some rumour mongering of my own. Also, thanks to Epoch for checking the gender identification of these Neolithic samples, and catching that Koros 2 was female, as were NE 1-4. Thanks to Arvisto as well. We don't know what the ydna of their fathers might have been.
not the J2a1 sample mentioned in the study, which is dated +/- 1200 BC the tribes you mention arrived in the west much later, after the Cimmerians and after the ScythsYeah, you're right. I made a mistake. Thanks for correcting me. Somehow I thought that Sauromatians were older than the Cimmerians. But it's actually vice versa! Never came into my mind that the Cimmerians lived around at the same time as Mitanni (proto-Medes). Althought Mitanni (proto-Medes) existed already second millennium BC. But if this is true, then Cimmerians were actually related or even the same as Mitanni, and therefore related to the ancient Medes, or in this case Sauromatians, the Solar Medes. So, what I'm trying to say is that the Cimmerians were basically the same as the Mitanni. But later on Cimmerians became known as the Sauromatians and the Mitanni became known simply as Medes.
who are the Sigynes? what is their origin? Sigynes lived close to Danube, to the north from Enetians, they had Horses, and they wear Median(Iranic) clothes http://books.google.gr/books?id=ZuUaAAAAMAAJ&pg=PA4&lpg=PA4&dq=Sigynes+herodotus&source=bl&ots=Zo27C9oCaC&sig=FFB8Nt4BsfN_lhOTNdIj2FV2DNs&hl=el&sa=X&ei=fP5HVMyIGqmu7AauyYHwDw&redir_esc=y#v=onepage&q=Sigynes%20herodotus&f=false
I checked the legend. Annoyingly, they didn't project Stuttgart onto the PCA. I also forget to post this quote: Affinities of our observed Y-chromosome lineages (I2 and C6 haplogroups, Table 1 (http://www.nature.com/ncomms/2014/141021/ncomms6257/full/ncomms6257.html#t1)) with a Mesolithic background5 (http://www.nature.com/ncomms/2014/141021/ncomms6257/full/ncomms6257.html#ref5), 7 (http://www.nature.com/ncomms/2014/141021/ncomms6257/full/ncomms6257.html#ref7) and our mtDNA haplogroups with farming communities (especially the N1a haplogroup, Table 1 (http://www.nature.com/ncomms/2014/141021/ncomms6257/full/ncomms6257.html#t1))24 (http://www.nature.com/ncomms/2014/141021/ncomms6257/full/ncomms6257.html#ref24) tentatively support the incorporation of local male hunter-gatherers into farming communities during the Central European Neolithic (Table 1 (http://www.nature.com/ncomms/2014/141021/ncomms6257/full/ncomms6257.html#t1)), in contrast to the male-dominated diffusion of farmers suggested for the Mediterranean route25 (http://www.nature.com/ncomms/2014/141021/ncomms6257/full/ncomms6257.html#ref25). I don't know if I buy this. Over-interpretation? There's no Y dna for 5 of the Neolithic samples. Plus, one of the I2a is obviously a hunter at the very beginning of the encounter, we don't know the ydna of Koros 2, and we also don't know the ydna of NE 1-4. Also, what do they imagine happened? The H/G men couldn't stand their own women, traveled to southern Europe and stole Neolithic ones who then taught them all about farming? It's not just one brand of mtDna either, although mtDna "K" has a very strong presence. This is another important quote in light of the tweets about Lazaridis et al: A third genomic shift occurs around the turn of the first millennium BC. The single Iron Age genome, sampled from the pre-Scythian Mezőcsát Culture (Iron Age (IR1), 830–980 cal BC), shows a distinct shift towards Eastern Eurasian genotypes, specifically in the direction of several Caucasus population samples within the reference data set. This result, supported by mtDNA and Y-chromosome haplogroups (N and G2a1, respectively, both with Asian affinities) suggests genomic influences from the East. This is supported by the archaeological record which indicates increased technological and typological affinities with Steppe cultures at this time, including the importation of horse riding, carts, chariots and metallurgical techniques26 (http://www.nature.com/ncomms/2014/141021/ncomms6257/full/ncomms6257.html#ref26). Modern Hungarians occupy an intermediate position between the IR1 and more Western Bronze Age genomes, most likely reflecting the continuation of admixture in the Central European gene pool since this time. Ed.Ed. I want to be clear that all I'm trying to say about the plotting of IR is that it shouldn't be all that surprising that he plots near "possibly" part Russian/part Armenian samples. Influence from the Caucasus on some Iron Age groups is known. Perhaps the Samarra paper will show that there was some Caucasus like or at least eastern end of the Black Sea farmer influence on Yamnaya. I don't know, but I think we have to let go of all our pre-conceptions, based, perhaps, even unconsciously, on late 19th century formulations of the peopling of Europe.
Sigynes lived close to Danube, to the north from Enetians, they had Horses, and they wear Median(Iranic) clothes http://books.google.gr/books?id=ZuUaAAAAMAAJ&pg=PA4&lpg=PA4&dq=Sigynes+herodotus&source=bl&ots=Zo27C9oCaC&sig=FFB8Nt4BsfN_lhOTNdIj2FV2DNs&hl=el&sa=X&ei=fP5HVMyIGqmu7AauyYHwDw&redir_esc=y#v=onepage&q=Sigynes%20herodotus&f=false Could it be that the Cimmerians and the Sigynes are the same? Herodotus reports of the Cimmerians being expelled by the Scyths, and fleeing across the Caucasus. But he does not report about Cimmerians fleeing west. Archeological evidence suggests a group of the same origin settled in the Balkans.
Yeah, you're right. I made a mistake. Thanks for correcting me. Somehow I thought that Sauromatians were older than the Cimmerians. But it's actually vice versa! Never came into my mind that the Cimmerians lived around at the same time as Mitanni (proto-Medes). Althought Mitanni (proto-Medes) existed already second millennium BC. But if this is true, than Cimmerians were actually related or even the same as Mitanni, and therefore related to the ancient Medes, or in this case Sauromatians, the Solar Medes. So, what I'm trying to say is that the Cimmerians were basically the same as the Mitanni. But later on Cimmerians became known as the Sauromatians and the Mitanni became known simply as Medes. Indo-Iranic split into Indic and Iranic, around 2000 BC, probably on the steppe, just east of the Urals. (Andronovo culture) Indic moved south. They replaced the BMAC culture. The Mitanni arrived 1500 BC and were Indic. Cimmerians, Scyths, Saromats were Iranic. They appeared in history later.
Angela, y-dna of other samples is not known because those girls never had it. You must have missed their gender :) C6 is quite intrigue.
Indo-Iranic split into Indic and Iranic, around 2000 BC, probably on the steppe, just east of the Urals. (Andronovo culture) Indic moved south. They replaced the BMAC culture. The Mitanni arrived 1500 BC and were Indic. Cimmerians, Scyths, Saromats were Iranic. They appeared in history later.BMAC was an East-Iranic culture. Indic culture NEVER replaced East-Iranic culture in South-Central Asia! No, it's a misconception that Mitanni were Indic. This is pure propaganda. Mitanni were actually proto-Iranic and were descendants of the Sumerians. Later, the Mitanni in Kurdistan became known as the Medes. Like the Sumerians they were the 'Sun' worshippers. I have still that native Iranic religion, and I'm still the 'Sun' worshipper to. We call our God, Xode Shems (Ezide Sor), translated: the Sun God. Mitanni were native to the Iranian Plateau. 1 part stayed in Kurdistan and became the Medes, while the other part went to the South-Central Asia and became 'East Iranic' and then invaded Northern India and mixed with the Dravidians.
The linguistic (and ethnic) affiliation of the Huns is a matter that has to my knowledge gone back and forth, mainly due to the scarcity of data. I agree that a Scytho-Sarmatian language is a very real possibility (these languages dominated a large swath of Eurasia for centuries, after all), but so is - in my opinion - Turkic. We don't even know for certain if the Xiongnu of Chinese sources are even the same as the Huns that show up a bit later in Western sources. What is clear about the Slavs, and I agree unanimously here with LeBrok, is that their language is not one of invaders from the steppe. At the times of the Huns there wasn't yet a language or people known as Turkic. Huns were basically a confederation of Scythian and Mongolian tribes and might have give birth to the first Turkic speakers. The Huns might have give birth to the Turkic speakers. But they weren't Turkic themselves yet.
BMAC was an East-Iranic culture. Indic culture NEVER replaced East-Iranic culture in South-Central Asia! No it's a misconception that Mitanni were Indic. This is pure propaganda. Mitanni were actually proto-Iranic and were descendants of the Sumerians. Later, the Mitanni in Kurdistan became known as the Medes. Like the Sumerians they were the 'Sun' worshippers. I have still that native Iranic religion, and I'm still the 'Sun' worshipper to. We call our God, Xode Shems (Ezide Sor), translated: the Sun God. Mitanni were native to the Iranian Plateau. 1 part went to the West and became the Medes, while the other part went to the South-Central Asia and became 'East Iranic' and then invaded Northern India and mixed with the Dravidians.But I never realized that the Cimmerians were almost as old as the Mitanni and therefore much older than the East Iranic tribes, like the East Iranic Scythians (aka Saka) in the Pontic-Caspian Steppes!
It is also possible that J2a migrated into the Pontic Caspian Steppes together with the R1a* and NOT R1b* at all! But it's also possible that J2a came into Europe with the 'Iranic' people. Because Iranic people sometimes invaded Europe. Think about the Alanians. J2a in Europe can be from the Massagetae (proto-Alanians) or even the Medes (Mitanni) or simply the Sauromatians, the Solar Medes… The sample is from Bronze Age. The Indo Europeans hadn't yet evolved into different groups.
I remember that somewhere on Dienekes' site there is a thread(s) which discusses the fact that a few Armenians plot pretty far away from the mass of Armenians, and there was some speculation that perhaps it was because of Russian admixture. (I just spent a half hour trying to find it, but I couldn't. If I have time later, I'll try again.) I'm just suggesting that those may be the few Armenians among whom IR plots. If you look closely at the mass of samples in the Near East you'll find that most of the Armenians plot down there somewhere around eastern Turkey, which makes sense.) However, given the tweets from Razib Khan about the upcoming Lazaridis paper on Samarra, I don't see why the fact that IR plots near a "possibly" mixed Armenian/Russian sample is either surprising or upsetting. #ASHG14 (https://twitter.com/hashtag/ASHG14?src=hash) eastern hg from Karelia and sammara. ANE related to Eastern hg. yamnaya had near East and Caucasus #ASHG14 (https://twitter.com/hashtag/ASHG14?src=hash) ANE in Europe from eastern hg groups? (via yamnaya) #ASHG14 (https://twitter.com/hashtag/ASHG14?src=hash) yamnaya better source for intrusive group into north Europe late Neolithic bronze age #ASHG14 (https://twitter.com/hashtag/ASHG14?src=hash) corded ware 36% nonlocal ancestry. Karelian. low bound #ASHG14 (https://twitter.com/hashtag/ASHG14?src=hash) yamnaya modeled as 50/50 Armenian Karelian. corded ware 75% yamnaya #ASHG14 (https://twitter.com/hashtag/ASHG14?src=hash) yamnaya % peaks in north Europe. lower in south Europe. lowest in Sardinia #ASHG14 (https://twitter.com/hashtag/ASHG14?src=hash) yamnaya = proto-indoeuropean Well, I could speculate that maybe the idea that Yamnaya people were half "Armenian like" is anathema on "racial" grounds to some people, in addition to falsifying years of opinions and conclusions about the nature of the "Indo-Europeans". I don't like to think that's the case, however. Maybe that's just rumor mongering too. I'm told there is now a mad scramble to analyze his data. Of course, I don't know what he'll turn out to be...I'm willing to wait for analyses to be done, and I have no personal stake in the outcome. Anyway, I'm not going to get into speculating based on fragmentary results or rumors posted by people on other sites. I had enough of that. I'll wait for the paper. All I'm saying is that the plotting of IR shouldn't be a total surprise. I don't think we can make any judgments about the I2a or the C6 because the subclades aren't resolved enough for either the Mesolithic samples or the ones under discussion. We don't even know if all the I2a in these samples is the same one. We don't know if the y dna of the two samples, K01 and K02, are the same. Koros 1: I2a subclade unknown Koros 2: Y dna unknown What we do know is that Koros 1 looks like a Mesolithic hunter/fisher-gatherer. I'm leaning toward LeBrok's speculation that he was either a hunter-gatherer trying to learn how to farm, or a local absorbed into a very early attempt at settlement by Neolithic farmers. Koros2 is a very southward plotting Neolithic farmer. He looks to me like an example of what these people were like when they first arrived. Also, take a look at the dates: Koros 1:5,650–5,780 Koros 2: 5,570–5,710 They're also two different sites. The rest of the Neolithic samples are from a later time period. Enough time to have absorbed a little hunter gatherer. However, it's not as much as was absorbed apparently by the farmers in the west, because quite a few of them plot south of Otzi. Or maybe it was just a little bit over the centuries? Otzi and the Copper Age sample from this study plot at about the same latitude don't they? Also, can anybody find Stuttgart on there? Even my bifocals aren't working that well. :) Oh, and of the NE 1-7, two of them are C6, and 1 is I2a, but who knows of what variety. Four of them are missing Y dna. How about BR2 - Y DNA J2a1? Wouldn't you expect such a haplogroup somewhere in the Near East on the PCA chart? No he is not, he is somewhere in France - Italy - Spain.
I remember that somewhere on Dienekes' site there is a thread(s) which discusses the fact that a few Armenians plot pretty far away from the mass of Armenians, and there was some speculation that perhaps it was because of Russian admixture. (I just spent a half hour trying to find it, but I couldn't. If I have time later, I'll try again.) I'm just suggesting that those may be the few Armenians among whom IR plots. If you look closely at the mass of samples in the Near East you'll find that most of the Armenians plot down there somewhere around eastern Turkey, which makes sense.) Exactly I saw and red the same. Those few Armenian samples were out of the mass and were probably mixed. They ended up among North Caucasians.
The sample is from Bronze Age. The Indo Europeans hadn't yet evolved into different groups.This is what it is saying: "Individual BR2, L. Bronze, Kyjatice Culture (1,110–1,270 BC) = Y-Haplogroup J2a1". At that time (around 1250 BC) even the West Iranian people were fully evolved. Same time when the Mitanni became the Medes in Kurdistan.
The Mitanni arrived 1500 BC and were Indic. Thats not an accepted fact but more of a good theory. The Mitanni Elite spoke a very archaic Indo_Iranic dialct which tended more towards the Indo_Aryan group but can simply be explained with the fact that Proto Indo_Iranic would come closer to Indo_Aryan because Indo_Aryan has obtained much more archaic features like Lithuanian. So the more archaic the Indo_iranic language is, the more it will tend towards Indo_Aryan, because IndoAryans has preserved itself better.
This is what it is saying: "Individual BR2, L. Bronze, Kyjatice Culture (1,110–1,270 BC) = Y-Haplogroup J2a1". At that time (around 1250 BC) even the West Iranian people were fully evolved. Same time when the Mitanni became the Medes in Kurdistan. OK but it is unlikely that the Medes had yet reached any part of this area if even Scythians weren't yet there.
Thanks for that correction Epoch. I missed that. I better go back and check on NE 1-4. I'm getting sloppy. No you don't ;-)
OK but it is unlikely that the Medes had yet reached any part of this area if even Scythians weren't yet there. No, not the Medes, but the relatives of the Mitanni reached that part of the area (Hungary?) . Cimmerians can be older than the Medes, and if this true then the Cimmerians actually could be closely related to the Mitanni. That's why I'm saying that the Cimmerians could evolve into the Saomartians and the Mitanni simply evolved into the Medes. That also explains why there are many links between Saomartians (Solar Medes) and the Medes, simply because they share the same ancestors (Cimmerians/Mitanni)!
No, not the Medes, but the relatives of the Mitanni reached that part of the area (Hungary?) . Cimmerians can be older than the Medes, and if this true then the Cimmerians actually could be closely related to the Mitanni. That's why I'm saying that the Cimmerians could evolve into Saomartians and the Mitanni simply evolved into the Medes. That also explains why there are many links between Saomartians (Solar Medes) and the Medes, simply because they share the same ancestors (Cimmerians/Mitanni)! Scythians, Sarmatians, Medes, Cimmerians etc they all share same ancestors. The question is how far back those ancestors go. And it is hard to tell and we can only speculate.
Scythians, Sarmatians, Medes, Cimmerians etc they all share same ancestors. The question is how far back those ancestors go. And it is hard to tell and we can only speculate. From what I learned today is that the Cimmerians are OLDER than Scythians (East Iranians) and the Medes (West Iranians). Cimmerians lived almost at the same times as Mitanni!; before the Medes, Saomartians, Scythians (Saka) etc.
Angela, y-dna of other samples is not known because those girls never had it. You must have missed their gender :) C6 is quite intrigue. Thanks, Arvistro. I credited both you and Epoch in ed. to the post upthread. :)
Could it be that the Cimmerians and the Sigynes are the same? Herodotus reports of the Cimmerians being expelled by the Scyths, and fleeing across the Caucasus. But he does not report about Cimmerians fleeing west. Archeological evidence suggests a group of the same origin settled in the Balkans. I don't think so, there are many Cimmerian and Scythian Kurgans in West Caucasus, and they influenced also South Caucasus. But no N haplogroup is there. Sigynes had different Horses, than Scythians and Cimmerians
Exactly I saw and red the same. Those few Armenian samples were out of the mass and were probably mixed. They ended up among North Caucasians. Indo-European languages must have originated from an area between the Caucasus and where ever the proto Finn-Ugrians were. We know that for sure since both North Caucasian languages as well as Finn-Ugrian langueages have loanwords from proto-IE.
Pointless speculation, IMO. Those I2a Dinarics didn't appear out of nowhere, and estimates for the ages of subclades have often turned out to be wildly inaccurate. Without knowing what subclade these I2 samples are, there's no reason to assume they belonged to an extinct subclade, except for the fact that they were living with C type farmers. Kamani was being much more speculative than LeBrok by suggesting that I2a-Din is "probably the descendant of this I2a." LeBrok was correctly pointing out that these could be an extinct subclade. Or they could be I2a-M26. Or something else. There's no reason to assume that they belonged to any particular subclade, extinct or not. We've already seen some I2 diversity among hunter-gatherer samples (although farmers seem to have been I2a-M26 as a whole so far). By the way, have "estimates for the ages of subclades" "turned out to be wildly inaccurate" for anything that used the Nordtvedt method so far? I can only recall errors on the order of 30% for it when compared against SNP estimates and the like. Certainly there has been nothing to suggest that I2a-Din is anywhere near as old as these samples. And if we're talking about I2a-Din's origins, why not take the actual I2a1b ancient samples in Luxembourg and Sweden as pointers to its origin rather than these that may not even be on that branch?
Indo-European languages must have originated from an area between the Caucasus and where ever the proto Finn-Ugrians were. We know that for sure since both North Caucasian languages as well as Finn-Ugrian langueages have loanwords from proto-IE. Not necessary because most of the Indo European lones in Finno Ugric are of Indo_Iranian and Germanic origin and could simply be from Scythians/Cimmerians and Vikings. But than Finno_Ugric, Caucasian and Indo European have a common origin. But I agree with you and yet would extend it from Caucasus_ Finno_Ugric homeland to Mesopotamia/Iranian Plateau all the way into South Central Asia.
This is another important quote in light of the tweets about Lazaridis et al: A third genomic shift occurs around the turn of the first millennium BC. The single Iron Age genome, sampled from the pre-Scythian Mezőcsát Culture (Iron Age (IR1), 830–980 cal BC), shows a distinct shift towards Eastern Eurasian genotypes, specifically in the direction of several Caucasus population samples within the reference data set. This result, supported by mtDNA and Y-chromosome haplogroups (N and G2a1, respectively, both with Asian affinities) suggests genomic influences from the East. This is supported by the archaeological record which indicates increased technological and typological affinities with Steppe cultures at this time, including the importation of horse riding, carts, chariots and metallurgical techniques26 (http://www.nature.com/ncomms/2014/141021/ncomms6257/full/ncomms6257.html#ref26). Modern Hungarians occupy an intermediate position between the IR1 and more Western Bronze Age genomes, most likely reflecting the continuation of admixture in the Central European gene pool since this time. So indeed IR1 individual had Y hg G2a1 and mt hg N. Or is it still unsure thing?
http://cdn.eupedia.com/forum/images/misc/quote_icon.png Originally Posted by Angela http://cdn.eupedia.com/forum/images/buttons/viewpost-right.png (http://www.eupedia.com/forum/showthread.php?p=442468#post442468) We don't know if the y dna of the two samples, K01 and K02, are the same. Koros 1: I2a subclade unknown Koros 2: Y dna unknown KO2 is a female. So no Y-DNA. Perhaps another misspel? Quote from the paper, sup. page 30: Grave 44 (specimen KO2, Supplementary Table 1) is of an adult male, which was excavated at the western border of the main area
So indeed IR1 individual had Y hg G2a1 and mt hg N. Or is it still unsure thing? Looks like it is really Yhg N. Check table 13 page 23.
Looks like it is really Yhg N. Check table 13 page 23. I agree. It's plainly part of the Y Dna Table. They must have just reversed it in the body of the paper. Also, on Supplementary Table 12 pg. 22, labeled Mitochondrial Haplogroups, it shows: Ir1: G2a1-95.5%
I found the PCA's pretty interesting. DISCLAIMER: I know the ancient samples are projected onto the modern samples, so it isn't exact. I get it. However, if it didn't give a general idea...if it was worthless, they wouldn't be doing it. Also, people have to be consistent. We can't use them when we like the results and discard them when we don't. The one on Page 6 is for NE1 and Br2 and projects them onto the HGDP data set: NE1 is Southeast of Sardinians BR2 (J2a1) is at the tail end of the French, but it looks as if the sample is south of the Hungarians...parallel to some Bulgarians and Romanians, but west of them. In the PCA on page 9, interestingly enough, BR1 plots quite a bit north of approximately where BR2 was...still with the French, but this time parallel to the Basques, just east of them. Nowhere near the Orcadians, however, much less north eastern populations like the Lithuanians. Isn't this strangely reminiscent of the results for the "Thracians" in that paper that were felt to be too badly analyzed, or so fragmentary, or unreliable once again because they were "projected" onto modern samples, or whatever it was, to be taken seriously? Maybe there were problems with them, but when seen in the light of these new samples, there's a definite western European signature to these new Bronze Age people who show up in the Balkans and also in Hungary. The one on Page 8 projects a number of the ancient samples onto the 1000 Genomes data set: NE1 is far to the south by itself. This population no longer exists. KO1, the sample from a Neolithic context, but who is H/G autosomally, is up near the Finns although he doesn't land on them. The Finns really occupy a whole section of the PCA by themselves. Interestingly, a tweet from the Conference said that the new Hellenthal paper will show that they break out first from Europe, then the Scandinavians, and then the Irish? Is that right? BR2 lands practically on top of the southernmost CEU sample. There's that NW European thing going on again. IR1 doesn't land on any of the European clusters, but he is to the left of the Northern European one, and nowhere near the Southern European one. I'm reminded of all those F3 statistics showing the link between Northern Europeans and West Asians that Dienekes used to post. Anyway, I'm coming to no hard and firm conclusions, but it's certainly interesting.
BR2 (J2a1) is at the tail end of the French, but it looks as if the sample is south of the Hungarians...parallel to some Bulgarians and Romanians, but west of them. In the PCA on page 9, interestingly enough, BR1 plots quite a bit north of approximately where BR2 was...still with the French, but this time parallel to the Basques, just east of them. Nowhere near the Orcadians, however, much less north eastern populations like the Lithuanians. Isn't this strangely reminiscent of the results for the "Thracians" in that paper that were felt to be too badly analyzed, or so fragmentary, or unreliable once again because they were "projected" onto modern samples, or whatever it was, to be taken seriously? Maybe there were problems with them, but when seen in the light of these new samples, there's a definite western European signature to these new Bronze Age people who show up in the Balkans and also in Hungary. I've been saying this for years. But now we have some autosomal evidence conferming what the ancient Greek mythology says: "Illyrians, Celts and Gauls, are the 3 sons of Polyphemus and Galatea" (assuming that Thracians and Illyrians were close enough genetically and their signature extended all the way up to Hungary)
I am a bit stunned, why, basically no R1 has been found recently in these ancients ( on the continent) , yet 2 out of 2 for the latest britons ( hinxton ) where R1, I was wondering why nothing from a period of 5500BC to 880BC for R1 on the continent I then found The published Y haplogroup for KO1 was I2a, but the calls below further show that he was I2a1*. but he has also some R positive markers with in him ( as well as T markers) R1b1a2a1a2c1k-S730 R1b1a2a2c-L150.2!/PF6274.2! T-PF5607 T1a-PF5604 I am confused on what this all means, any ideas? I can understand having markers of A, B, C etc .........but positive markers for R and T which are younger than I is puzzling
I am a bit stunned, why, basically no R1 has been found recently in these ancients ( on the continent) , yet 2 out of 2 for the latest britons ( hinxton ) where R1, I was wondering why nothing from a period of 5500BC to 880BC for R1 on the continent Seriously? The Britons are from a much later time period (A.D. in fact). I then found The published Y haplogroup for KO1 was I2a, but the calls below further show that he was I2a1*. I can tell from the wording that you're referencing Genetiker. For those interested, here is his Y-DNA analysis of KO1: https://genetiker.wordpress.com/y-snp-calls-for-an-early-neolithic-hungarian-genome/ As for KO1 being I2a1*, Genetiker is not quite right. Based on those calls, KO1 could be I2a1*, I2a1c*, or I2a1e. But either way, he was for sure not on the same branch as I2a-Din or I2a-M26. but he has also some R positive markers with in him ( as well as T markers) R1b1a2a1a2c1k-S730 R1b1a2a2c-L150.2!/PF6274.2! T-PF5607 T1a-PF5604 I am confused on what this all means, any ideas? False positives. We can tell because lots of upstream and phyloequivalent SNPs are negative for those. On the other hand, the I2a1 calls are consistent.
Scythians, Sarmatians, Medes, Cimmerians etc they all share same ancestors. The question is how far back those ancestors go. And it is hard to tell and we can only speculate. of course, they are all the same age, but they entered history through Greek historians or Assyrians writings Cimmerians came into history first because they were in the Pontic steppe the others came later inot history when they moved west and became known to the Greek historians
I can tell from the wording that you're referencing Genetiker. For those interested, here is his Y-DNA analysis of KO1: https://genetiker.wordpress.com/y-snp-calls-for-an-early-neolithic-hungarian-genome/ As for KO1 being I2a1*, Genetiker is not quite right. Based on those calls, KO1 could be I2a1*, I2a1c*, or I2a1e. But either way, he was for sure not on the same branch as I2a-Din or I2a-M26. so the most likely is some line of I2a1 that is now extinct ?
so the most likely is some line of I2a1 that is now extinct ? The possibilities are (1) extinct or unknown branch, (2) related to the somewhat rare, Western Europe-oriented I2a1c* branch, or (3) related to the very rare France-oriented I2a1e branch. I'm not sure I'm ready to guess which is most likely.
The possibilities are (1) extinct or unknown branch, (2) related to the somewhat rare, Western Europe-oriented I2a1c* branch, or (3) related to the very rare France-oriented I2a1e branch. I'm not sure I'm ready to guess which is most likely. technically I2a1c and I2a1e do not exist : M26, I2a1c, I2a1d and I2a1e have a common SNP : CTS595 it's time ISOGG updates the tree
Another thing: What does the fact that a clear HG (Y-DNA as well as autosomal) man shows up among clear farmers say about patrilocality of either HG of farmers? If his bones were found in a proper grave it would mean that he was a valid member of this farming community. However his bone were found in village's garbage pit. He might have been a discarded slave. This particular village only existed for couple of generations. What does this mean? Unsuccessful experiment of HGs in farming? A village of pioneer farmers who went into HGs territory and was wiped out by unhappy HGs?
The possibilities are (1) extinct or unknown branch, (2) related to the somewhat rare, Western Europe-oriented I2a1c* branch, or (3) related to the very rare France-oriented I2a1e branch. I'm not sure I'm ready to guess which is most likely. what about: I2a2 M423, I2a2a M359 / P41.2 ?
I'm surprised too, but these are such small sample sizes. The Neolithic period results are surprising too. Maybe, as has been suggested, it's just because it's a small sample, and at this period Hungary was pretty mixed in terms of yDna. We aren't getting much resolution either, so who knows what particular flavor of I2a we have at each time period. We do know that come clades of I2a were incorporated into Neolithic communities and then expanded. Maybe that's what happened here? They're certainly "Neolithic" in autosomal terms. I'm still plowing through the paper. Life is getting in the way. :) I see Dienekes has made some comments. He's certainly right about the pigmentation. Pigmentation changes were taking place before the Indo-Europeans ever showed up, I think, and it was happening among people very much like the Sardinians and Otzi. Why does lactase persistence appear so late in history? Does anyone have any ideas? It must have something to do with pastoralism, yes?( i.e. milk consumption instead of just processed milk products like cheese?) Could that also have speeded up the pigmentation changes? If Bronze Age pastoralists got the light pigmentation alleles from the Neolithic farmers, and their diet was very dairy based, the selection for both would occur, perhaps, given that you need Vitamin D to absorb calcium? http://www.health.harvard.edu/newsweek/vitamin-d-and-your-health.htm Just thinking out loud, folks... "Why does lactase persistence appear so late in history? Does anyone have any ideas?" Atlantic coast imo. 1) The Atlantic coast is its own ecozone. 2) LBK didn't spread all the way west to the Atlantic coast. 3) The Atlantic Megalith culture originally stuck to the coast (seafood). Those imply to me that the Atlantic climate zone was unsuitable for the original neolithic crops producing a low yield. If correct this would have led to a HG zone between LBK and Megalith on the continent and in the interior of the Isles. As soon as a way of expanding into that climate zone was found the population that found it could expand into that whole zone very rapidly. Maybe mixing the low yielding cereals with milk was the solution found. (edit: the same argument might also appliy to the Funnelbeaker zone)
OK I need to ask a question here. I know I have said before I feel two steps behind in this area, but I thought I might have been playing myself a little short, now I`m not so sure. Bronze Age in this area, should be R1.. something...no? If R1 was originally west and north of the Black Sea and wanted to move west but LBK (or equivalent relatively high population density farmers) were in the way then maybe initially they had to go around them i.e. 1) north of the Carpathians 2) along the Danube then divert through Croatia into northern Italy -> Southern France -> Iberia 3) maritime route to Iberia etc various options but all initially forced to divert around that central bloc
I'm not surprised by the shift from a Sardinian like population to one that includes some eastern mix by the Bronze Age, and the skin and eye colour results would suggest a dietary influence. And the Y haplotype I2 isn't surprising but the C certainly is - if C haplotype hunter gatherers made the transition to agriculture, why did C later become rare. And I'm surprised there's no R1a in the Bronze or Iron Age samples. I'd agree that maybe the Y haplotypes aren't going to prove to be typical examples. "why did C later become rare" If there was a conquest and a two-tier society developed with y dna C as part of the lower layer then maybe it declined gradually over time through "droit de seigneur" i.e. in each generation a higher percentage of the lower layer females had kids by the upper layer males than vice versa. http://en.wikipedia.org/wiki/Droit_du_seigneur
Ok, but the Cimmerian invasion of Armenia (Urartu) postdate the IR1 sample by a few centuries. Additionally the Cimmerians came from present-day Ukraine, not from Siberia. Finally, nobody knows what happened of the Cimmerians after their migration to Anatolia and Armenia. But even if they migrated back to central Europe, that would have been many centuries after IR1. Could Armenians have originally come from the same place? If Cimmerians took that route to Armenia after being displaced from the steppe maybe the Armenians did too i.e. what if the Armenians used to live on the west pontic steppe and crossed over to Armenia after some event or other? Just a thought.
One interesting thing is that KO2 seems less WHG admixted than the other, later neolithic samples. The Iceman, Sardinians and the NE1 - NE& samples all seem to have similar WHG admixture, whereas GOK4 seem top have even more WHG admixture. Also, pretty much every present day populations show lean more to WHG than their neolithic ancestors. This does mean slow but continuous uptake of WHG genetic material. As Angela keeps telling, hunter-gatherers need a large territory to feed themselves. Furthermore, farmers probably have a larger child survival rate. This means, IMHO, more evidence that parts of Europe's HG survived as (semi-)farmers and fishermen, as continuous gene flow from a community to another doesn't seem feasible if the former isn't thriving, or at least is keeping up. I think the Körös culture finds are very interesting, in that respect. One possibility might be a conquest leading to a two-tier society. Remains from the early days of the conquest might be definitely identifiable as individuals from either one of the two tiers but remains from a later period might be mixed.
IR1 in Iron Age Hungary was N1a, he have these snps of haplogroup N1a tested Y6503+, Y6511+, Y6559+, Y6560+, Y6561+, Y6562+, Y6564+, Y6566+, Y6470+, Y6482+, Y6494+, Y6515+, Y6518+, Y6521+, Y6523+, Y6525+, Y6536+, Y6537+, Y6541+, Y6542+, Y6543+, Y6544+, Y6546+, Y6548+, Y6549+, Y6553+, Y6557+, Y6569+, Y6570+, Y6571+, Y6572+, Y6576+, Y6577+, Y6586+, Y6587+, Y6589+ P189-, Y6466-, Y6498-, Y6504-, Y6505-, Y6508-, Y6509-, Y6512-, Y6565-, Y6468-, Y6471-, Y6473-, Y6476-, Y6478-, Y6481-, Y6486-, Y6488-, Y6514-, Y6522-, Y6528-, Y6533-, Y6539-, Y6540-, Y6550-, Y6551-, Y6556-, Y6558-, Y6573-, Y6580-, Y6581-, Y6583-
IR1 in Iron Age Hungary was N1a, he have these snps of haplogroup N1a tested Y6503+, Y6511+, Y6559+, Y6560+, Y6561+, Y6562+, Y6564+, Y6566+, Y6470+, Y6482+, Y6494+, Y6515+, Y6518+, Y6521+, Y6523+, Y6525+, Y6536+, Y6537+, Y6541+, Y6542+, Y6543+, Y6544+, Y6546+, Y6548+, Y6549+, Y6553+, Y6557+, Y6569+, Y6570+, Y6571+, Y6572+, Y6576+, Y6577+, Y6586+, Y6587+, Y6589+ P189-, Y6466-, Y6498-, Y6504-, Y6505-, Y6508-, Y6509-, Y6512-, Y6565-, Y6468-, Y6471-, Y6473-, Y6476-, Y6478-, Y6481-, Y6486-, Y6488-, Y6514-, Y6522-, Y6528-, Y6533-, Y6539-, Y6540-, Y6550-, Y6551-, Y6556-, Y6558-, Y6573-, Y6580-, Y6581-, Y6583- So the IR1 is parental to Balkanian N1a haplogroup The Administrator of YFull compared his results from BAM File with other N1a http://forum.molgen.org/index.php/topic,7459.msg261520.html#msg261520 And he shares these snps with other N1a Y6503+, Y6511+, Y6559+, Y6560+, Y6561+, Y6562+, Y6564+, Y6566+, Y6470+, Y6482+, Y6494+, Y6515+, Y6518+, Y6521+, Y6523+, Y6525+, Y6536+, Y6537+, Y6541+, Y6542+, Y6543+, Y6544+, Y6546+, Y6548+, Y6549+, Y6553+, Y6557+, Y6569+, Y6570+, Y6571+, Y6572+, Y6576+, Y6577+, Y6586+, Y6587+, Y6589+ But he is negative for these snps that N1a from Serbia do have P189-, Y6466-, Y6498-, Y6504-, Y6505-, Y6508-, Y6509-, Y6512-, Y6565-, Y6468-, Y6471-, Y6473-, Y6476-, Y6478-, Y6481-, Y6486-, Y6488-, Y6514-, Y6522-, Y6528-, Y6533-, Y6539-, Y6540-, Y6550-, Y6551-, Y6556-, Y6558-, Y6573-, Y6580-, Y6581-, Y6583-
I am a bit stunned, why, basically no R1 has been found recently in these ancients ( on the continent) , yet 2 out of 2 for the latest britons ( hinxton ) where R1, I was wondering why nothing from a period of 5500BC to 880BC for R1 on the continent I then found The published Y haplogroup for KO1 was I2a, but the calls below further show that he was I2a1*. but he has also some R positive markers with in him ( as well as T markers) R1b1a2a1a2c1k-S730 R1b1a2a2c-L150.2!/PF6274.2! T-PF5607 T1a-PF5604 I am confused on what this all means, any ideas? I can understand having markers of A, B, C etc .........but positive markers for R and T which are younger than I is puzzling If the Carpathian basin was heavily populated maybe initially R1 had to go around it and the big fight came later.
what about: I2a2 M423, I2a2a M359 / P41.2 ? We're using the ISOGG 2014 tree, so M423 is "I2a1b" and M359 is "I2a1b1". Several phyloequivalent SNPs to M423 were negative and M359 was tested directly and was negative. So we can say pretty comfortably that KO1 is not I2a1b.
The Thracian individuals were also descriped as more "French, Tuscan like". And turned out 50% Caucasus_ Gedrosia. This could be in context to other ancient samples, which completely lacked anything West Asian like beside the one Tuscan individual which showed first signals. Also keep in mind Gedrosia among Europeans peaks in Western Europeans.
Maybe mixing the low yielding cereals with milk was the solution found. That's right. I think Lactose Persistence developed in Northern Europe during Bronze Age collapse, when climate got cooler and cereal crops were failing. LP fully developing during Dark Ages, another period of cooler and drier spells, when Europe got depopulated again. In last cooling phase of Little Ice Age we don't see drop in demographics of North and no signs of civilization decline. That means that by Little Ice Age lactose tolerance was spread already in most of populations, plus variations of northern cereals like rye was suitable to grow even in colder weather. Farming technologies and transportation network were more advanced too, helping food production and even growth of economies and demographics in 19th century in particular. It is a good sign, that we crossed the threshold in technological development to keep food production even in worst times and prevent civilization from collapsing anymore. A bit of topic, but very optimistic note. :)
That's right. I think Lactose Persistence developed in Northern Europe during Bronze Age collapse, when climate got cooler and cereal crops were failing. LP fully developing during Dark Ages, another period of cooler and drier spells, when Europe got depopulated again. In last cooling phase of Little Ice Age we don't see drop in demographics of North and no signs of civilization decline. That means that by Little Ice Age lactose tolerance was spread already in most of populations, plus variations of northern cereals like rye was suitable to grow even in colder weather. Farming technologies and transportation network were more advanced too, helping food production and even growth of economies and demographics in 19th century in particular. It is a good sign, that we crossed the threshold in technological development to keep food production even in worst times and prevent civilization from collapsing anymore. A bit of topic, but very optimistic note. :) "plus variations of northern cereals like rye was suitable to grow even in colder weather" Yes, over time the crops were adapted. It might have only been critical at a particular moment in time (and then occasionally later with famines etc).
"Why does lactase persistence appear so late in history? Does anyone have any ideas?" Atlantic coast imo. 1) The Atlantic coast is its own ecozone. 2) LBK didn't spread all the way west to the Atlantic coast. 3) The Atlantic Megalith culture originally stuck to the coast (seafood). Those imply to me that the Atlantic climate zone was unsuitable for the original neolithic crops producing a low yield. If correct this would have led to a HG zone between LBK and Megalith on the continent and in the interior of the Isles. As soon as a way of expanding into that climate zone was found the population that found it could expand into that whole zone very rapidly. Maybe mixing the low yielding cereals with milk was the solution found. (edit: the same argument might also appliy to the Funnelbeaker zone) That's a very plausible argument for why there would be a strong selective sweep for lactase persistence along the Atlantic (climate favoring dairying not farming, plus low sunlight), but in the context of this paper we're talking about a very late sample in Hungary. The sweep there must have been affected by slightly different although perhaps related factors, yes? According to the author of this paper: Selection on this variant was undoubtedly driven by dairying, but despite evidence for milk residues in ceramic vessels from a Körös context in the 6th millenium BC (ref. 36 (http://www.nature.com/ncomms/2014/141021/ncomms6257/full/ncomms6257.html#ref36)) this variant remains absent throughout the 10 Neolithic/Copper Age stages of our transect. Absence of the lactase persistence allele has been reported before from Neolithic specimens37 (http://www.nature.com/ncomms/2014/141021/ncomms6257/full/ncomms6257.html#ref37), 38 (http://www.nature.com/ncomms/2014/141021/ncomms6257/full/ncomms6257.html#ref38), although the selective sweep has been modelled as originating between Central Europe and the Balkans ~4–6,000 years BC (ref. 34 (http://www.nature.com/ncomms/2014/141021/ncomms6257/full/ncomms6257.html#ref34)). Its absence here until the late Bronze Age, ~1,000 years BC, suggests a more recent dating of this extremely interesting episode in the dynamic history of European genomes. The paper that did that modelling is: Itan, Y., Powell, A., Beaumont, M. A., Burger, J. & Thomas, M. G. The origins of lactase persistence in Europe. PLoS Comput. Biol. 5, e1000491 (2009). Where the sweeps occurred and why is also, of course, different from where the mutation first occurred, although that's of much less importance. The human genome mutates all the time. Most are irrelevant, some are harmful, and some turn out to come in handy given certain environmental conditions, and there is selection for those Unless you're suggesting that the mutation and the first sweep took place along the Atlantic and then went all the way east to reach Hungary? Ed. LeBrok: That's right. I think Lactose Persistence developed in Northern Europe during Bronze Age collapse, when climate got cooler and cereal crops were failing. LP fully developing during Dark Ages, another period of cooler and drier spells, when Europe got depopulated again. In last cooling phase of Little Ice Age we don't see drop in demographics of North and no signs of civilization decline. That means that by Little Ice Age lactose tolerance was spread already in most of populations, plus variations of northern cereals like rye was suitable to grow even in colder weather. Farming technologies and transportation network were more advanced too, helping food production and even growth of economies and demographics in 19th century in particular. It is a good sign, that we crossed the threshold in technological development to keep food production even in worst times and prevent civilization from collapsing anymore. A bit of topic, but very optimistic note. :) Sorry, LeBrock, cross post. Yes, that makes sense. The sweep would not have been as complete where climate didn't change as much and where large cow herds could not be maintained, although migration into those areas from more northern zones would have introduced it whether it was really necessary or not. (I depend on you to provide the optimism, LeBrok. :))
That's right. I think Lactose Persistence developed in Northern Europe during Bronze Age collapse, when climate got cooler and cereal crops were failing. LP fully developing during Dark Ages, another period of cooler and drier spells, when Europe got depopulated again. In last cooling phase of Little Ice Age we don't see drop in demographics of North and no signs of civilization decline. That means that by Little Ice Age lactose tolerance was spread already in most of populations, plus variations of northern cereals like rye was suitable to grow even in colder weather. Farming technologies and transportation network were more advanced too, helping food production and even growth of economies and demographics in 19th century in particular. It is a good sign, that we crossed the threshold in technological development to keep food production even in worst times and prevent civilization from collapsing anymore. A bit of topic, but very optimistic note. :) That seems like a very logical explanation, which doesn't necessarily mean that it's completely correct. Lactase persistence could originally have been brought to Europe by people with a Y haplotype of the R sort, and the genetic adaptation could have gradually spread into the general population because people with lactase persistence had a better chance of survival, for the reasons you mentioned. There are no R haplotype folk in these samples.
So the IR1 is parental to Balkanian N1a haplogroup I could not find anything on google re Balkanian N1a. It is all full with mtd N1a.. Can you share a good link on Balkan N1a?
That's a very plausible argument for why there would be a strong selective sweep for lactase persistence along the Atlantic (climate favoring dairying not farming, plus low sunlight), but in the context of this paper we're talking about a very late sample in Hungary. The sweep there must have been affected by slightly different although perhaps related factors, yes? According to the author of this paper: Selection on this variant was undoubtedly driven by dairying, but despite evidence for milk residues in ceramic vessels from a Körös context in the 6th millenium BC (ref. 36 (http://www.nature.com/ncomms/2014/141021/ncomms6257/full/ncomms6257.html#ref36)) this variant remains absent throughout the 10 Neolithic/Copper Age stages of our transect. Absence of the lactase persistence allele has been reported before from Neolithic specimens37 (http://www.nature.com/ncomms/2014/141021/ncomms6257/full/ncomms6257.html#ref37), 38 (http://www.nature.com/ncomms/2014/141021/ncomms6257/full/ncomms6257.html#ref38), although the selective sweep has been modelled as originating between Central Europe and the Balkans ~4–6,000 years BC (ref. 34 (http://www.nature.com/ncomms/2014/141021/ncomms6257/full/ncomms6257.html#ref34)). Its absence here until the late Bronze Age, ~1,000 years BC, suggests a more recent dating of this extremely interesting episode in the dynamic history of European genomes. The paper that did that modelling is: Itan, Y., Powell, A., Beaumont, M. A., Burger, J. & Thomas, M. G. The origins of lactase persistence in Europe. PLoS Comput. Biol. 5, e1000491 (2009). Where the sweeps occurred and why is also, of course, different from where the mutation first occurred, although that's of much less importance. The human genome mutates all the time. Most are irrelevant, some are harmful, and some turn out to come in handy given certain environmental conditions, and there is selection for those Unless you're suggesting that the mutation and the first sweep took place along the Atlantic and then went all the way east to reach Hungary? Ed. Sorry, LeBrock, cross post. Yes, that makes sense. The sweep would not have been as complete where climate didn't change as much and where large cow herds could not be maintained, although migration into those areas from more northern zones would have introduced it whether it was really necessary or not. (I depend on you to provide the optimism, LeBrok. :)) "Unless you're suggesting that the mutation and the first sweep took place along the Atlantic and then went all the way east to reach Hungary?" I think the mutation could have come from anywhere - random mutation - but the chance of finding it among the limited remains of a long ago population with a low percentage must be pretty low. On the other hand given the later Celtic advance down the Danube from the west it could have spread back that way i.e. it might have come up the Danube as a low frequency adaptation, expanded greatly along the Atlantic coast and then spread back down the Danube again in the opposite direction. But as you say I don't think where it arose matters that much. The critical part is the environment (or environments) that produced the sweep. Plus there may have been more than one stage i.e. an increase on the steppe due to pastoralism but not quite as life or death so not reaching NW Euro levels and then some of those people fetching up along the Atlantic coast pre-prepared for that environment and a rapid expansion. edit: misunderstood your point - yes i think it quite possible LP existed at lower frequencies moving west and then came back east with the Celts at higher frequencies.
IR1 in Iron Age Hungary was N1a, he have these snps of haplogroup N1a tested Y6503+, Y6511+, Y6559+, Y6560+, Y6561+, Y6562+, Y6564+, Y6566+, Y6470+, Y6482+, Y6494+, Y6515+, Y6518+, Y6521+, Y6523+, Y6525+, Y6536+, Y6537+, Y6541+, Y6542+, Y6543+, Y6544+, Y6546+, Y6548+, Y6549+, Y6553+, Y6557+, Y6569+, Y6570+, Y6571+, Y6572+, Y6576+, Y6577+, Y6586+, Y6587+, Y6589+ P189-, Y6466-, Y6498-, Y6504-, Y6505-, Y6508-, Y6509-, Y6512-, Y6565-, Y6468-, Y6471-, Y6473-, Y6476-, Y6478-, Y6481-, Y6486-, Y6488-, Y6514-, Y6522-, Y6528-, Y6533-, Y6539-, Y6540-, Y6550-, Y6551-, Y6556-, Y6558-, Y6573-, Y6580-, Y6581-, Y6583- Is this N1a the same type as found in the croatian islands of Krk etc.............home of the liburnians?
I could not find anything on google re Balkanian N1a. It is all full with mtd N1a.. Can you share a good link on Balkan N1a? I do not know if these are the best available links but here you go: http://eng.molgen.org/viewtopic.php?f=80&t=572 (a bit old but anyway...) https://www.familytreedna.com/public/N%20Russia%20%20DNA%20Project/
where did you get that info? I have N1c2b2-L665 http://genetiker.wordpress.com/y-snp-calls-for-an-iron-age-hungarian-genome/ You're wrong too. :wary2: Read Genetiker more closely: "The calls show that IR1 belonged to haplogroup N, but not to N1a or N1c." L665 is downstream of several SNPs that were negative, so it must be considered a false positive. Looks like IR1 could be N1b-L732. Seems rare but within range (http://www.semargl.me/en/dna/ydna/map-snp/1546/).
You're wrong too. :wary2: Read Genetiker more closely: "The calls show that IR1 belonged to haplogroup N, but not to N1a or N1c." L665 is downstream of several SNPs that were negative, so it must be considered a false positive. Looks like IR1 could be N1b-L732. Seems rare but within range (http://www.semargl.me/en/dna/ydna/map-snp/1546/). some state origins as gulf of bothnia a Finnish particular clade that emerges after the Uralic mtDNA Z contribution) and an Y-DNA legacy (e.g. Y-DNA haplogroup N1b and N1c1). also 18% in the lands of the Veps Veps or Vepsians are Finnic (http://en.wikipedia.org/wiki/Finnic_peoples) people that speak the Veps language (http://en.wikipedia.org/wiki/Veps_language), which belongs to the Finnic branch of the Uralic languages (http://en.wikipedia.org/wiki/Uralic_languages).
where did you get that info? I have N1c2b2-L665 http://genetiker.wordpress.com/y-snp-calls-for-an-iron-age-hungarian-genome/ The Administrator of YFull compared his results from BAM File with other N1a http://forum.molgen.org/index.php/topic,7459.msg261520.html#msg261520 And he shares these snps with other N1a Y6503+, Y6511+, Y6559+, Y6560+, Y6561+, Y6562+, Y6564+, Y6566+, Y6470+, Y6482+, Y6494+, Y6515+, Y6518+, Y6521+, Y6523+, Y6525+, Y6536+, Y6537+, Y6541+, Y6542+, Y6543+, Y6544+, Y6546+, Y6548+, Y6549+, Y6553+, Y6557+, Y6569+, Y6570+, Y6571+, Y6572+, Y6576+, Y6577+, Y6586+, Y6587+, Y6589+ But he is negative for these snps that N1a from Serbia do have P189-, Y6466-, Y6498-, Y6504-, Y6505-, Y6508-, Y6509-, Y6512-, Y6565-, Y6468-, Y6471-, Y6473-, Y6476-, Y6478-, Y6481-, Y6486-, Y6488-, Y6514-, Y6522-, Y6528-, Y6533-, Y6539-, Y6540-, Y6550-, Y6551-, Y6556-, Y6558-, Y6573-, Y6580-, Y6581-, Y6583-
The admixture run from the paper hasn't been referenced yet. I think it's interesting when you look at the comparison between the "Hunter-Gatherer", the Neolithic sample, the Bronze Age samples, and the Iron Age sample: 6786 The green component is modal in the Neolithic samples, the royal blue in Armenians (and the Druze, but present at large levels throughout the Middle East), and the red component is strongest in the Bedouin. The yellow orange color is obviously the "hunter-gatherer". The whole chart can be found as Supplementary Figure 10, page 10: http://www.nature.com/ncomms/2014/141021/ncomms6257/extref/ncomms6257-s1.pdf It's interesting that there seems to be the beginning of a genetic change in the Copper Age, but the changes in culture in this area, at least, seem to stem more from cultural diffusion for that period, not migration, as LeBrok alluded to upthread. Of course, we're only looking at one sample, so it may not be representative, but according to the authors the archaeology does not show the arrival of intrusive elements. The change in the Bronze Age is obvious, and then again in the pre-Scythian Iron Age sample. Of course, we have to keep in mind that like any of the other admixture components they are made up of the three ancestral populations as per Lazaridis et al. So, that royal blue component is made up of EEF and perhaps larger percentages of ANE than we have currently in Europe? Perhaps some UHG as well? I know Lazaridis said that their algorithm couldn't be used for Near Easterners, so I don't know if we have a good handle on that. The Sardinians have, in this run, a bit of the blue "West Asian" and they have the yellow HG, at levels which seem similar to the levels for them in Lazaridis et al. In this regard I searched this site for the discussion about the "Thracian" late Iron Age sample, K8. In that discussion, Sile published some admixture results which were apparently produced by Genetiker. These are the Dodecad K7 results for K8: K7b 46.44% Atlantic_Baltic 36.25% West_Asian 17.30% Southern 0.00% African 0.00% East_Asian 0.00% Siberian 0.00% South_Asian Ed. The attachment is drawn from Figure 10 of the supplement, not Figure 4 of the body of the paper. The link is now correct.
The Administrator of YFull compared his results from BAM File, with other N1a http://forum.molgen.org/index.php/topic,7459.msg261520.html#msg261520 And he shares these snps with other N1a Y6503+, Y6511+, Y6559+, Y6560+, Y6561+, Y6562+, Y6564+, Y6566+, Y6470+, Y6482+, Y6494+, Y6515+, Y6518+, Y6521+, Y6523+, Y6525+, Y6536+, Y6537+, Y6541+, Y6542+, Y6543+, Y6544+, Y6546+, Y6548+, Y6549+, Y6553+, Y6557+, Y6569+, Y6570+, Y6571+, Y6572+, Y6576+, Y6577+, Y6586+, Y6587+, Y6589+ But he is negative for these snps that N1a from Serbia do have P189-, Y6466-, Y6498-, Y6504-, Y6505-, Y6508-, Y6509-, Y6512-, Y6565-, Y6468-, Y6471-, Y6473-, Y6476-, Y6478-, Y6481-, Y6486-, Y6488-, Y6514-, Y6522-, Y6528-, Y6533-, Y6539-, Y6540-, Y6550-, Y6551-, Y6556-, Y6558-, Y6573-, Y6580-, Y6581-, Y6583-
You're wrong too. :wary2: Read Genetiker more closely: "The calls show that IR1 belonged to haplogroup N, but not to N1a or N1c." L665 is downstream of several SNPs that were negative, so it must be considered a false positive. Looks like IR1 could be N1b-L732. Seems rare but within range (http://www.semargl.me/en/dna/ydna/map-snp/1546/). ok, I see you're right he hasn't been tested for N1b, and neither for N1 he couldn't have been pre-N1c either, as N1c1 is estimated 14000 years old why do you think N1b and not simply N* or N1*? is it because of present-day distributions?
ok, I see you're right he hasn't been tested for N1b, and neither for N1 he couldn't have been pre-N1c either, as N1c1 is estimated 14000 years old why do you think N1b and not simply N* or N1*? is it because of present-day distributions? N1b was the only alternative I saw at the project link Kristiina gave. Admittedly, I'm not an expert on haplogroup N. Where are N* and N1* found? China?
The whole chart is Figure 4 in the paper: http://www.nature.com/ncomms/2014/141021/ncomms6257/fig_tab/ncomms6257_F4.html It's interesting that there seems to be the beginning of a genetic change in the Copper Age, but the changes in culture in this area, at least, seem to stem more from cultural diffusion for that period, not migration, as LeBrok alluded to upthread. Of course, we're only looking at one sample, so it may not be representative, but according to the authors the archaeology does not show the arrival of intrusive elements. The change in the Bronze Age is obvious, and then again in the pre-Scythian Iron Age sample. Of course, we have to keep in mind that like any of the other admixture components they are made up of the three ancestral populations as per Lazaridis et al. So, that royal blue component is made up of EEF and perhaps larger percentages of ANE than we have currently in Europe? Perhaps some UHG as well? I know Lazaridis said that their algorithm couldn't be used for Near Easterners, so I don't know if we have a good handle on that. The Sardinians have, in this run, a bit of the blue "West Asian" and they have the yellow HG, at levels which seem similar to the levels for them in Lazaridis et al. It looks to me like this admixture analysis in Figure 4 tends to group the "West-Asian EEF-ANE" mix under blue rather than EEF-like orange, which is misleading for Sardinians and neolithic farmers who likely posess no real ANE. Probably this blue is just a common mediterranean ancestry of both, "West Asian" and EEF farmers. At the same time it tends to group other ANE mixtures with the orange WHG (approximation) color, as happened for BR1/2, French and Orcadians, which might be a hint for an admixture in these peoples from north-east (steppe? R1b?), because in the PCA plot (http://1.bp.blogspot.com/-xPGV13M4lSM/VEaknJoP-jI/AAAAAAAAJ0I/XmX-S48tr2A/s1600/ncomms6257-f2.jpg) they are actually heavily eastern-shifted compared to Sardinians, Basques and neolithic farmers. In summary: I believe it subsumes north-eastern admixtures as orange and over-amplifies south-eastern admixture as blue (= false-positive "West Asian"). Also that WHG part which is part of K15 "Atlantic" seems to be subsumed under the green color (as happened in KO1 for example), indicating false-positive EEF-farmer admixture.
as per angela's post......the K8 thracian is contaminated due to modern human intervention, only focus on other 3 thracians both gok4 and P192-1 form a clade with Sardinians like the Iceman, although with less bootstrap support (gok4 83%, P192-1 56%). Finally, although K8 clusters with Northern European populations, its position in the tree is not resolved (3% Bootstrap). We note however that despite the reduced number of SNPs for K8, the relationships among the modern populations are consistent with the full dataset and generally well supported (bootstrap >90%), except within the Southern European group (minimum bootstrap 53%). It is therefore possible that the inconclusive pattern for K8 either reflects a possible higher level of modern DNA contamination (see Table S4 (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4014435/#pgen.1004353.s014) in [15] (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4014435/#pgen.1004353-Carpenter1)) or a more complex relationship to the modern populations included in the analysis. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4014435/
It looks to me like this admixture analysis in Figure 4 tends to group the "West-Asian EEF-ANE" mix under blue rather than EEF-like orange, which is misleading for Sardinians and neolithic farmers who likely posess no real ANE. Probably this blue is just a common mediterranean ancestry of both, "West Asian" and EEF farmers. At the same time it tends to group other ANE mixtures with the orange WHG (approximation) color, as happened for BR1/2, French and Orcadians, which might be a hint for an admixture in these peoples from north-east (steppe? R1b?), because in the PCA plot (http://1.bp.blogspot.com/-xPGV13M4lSM/VEaknJoP-jI/AAAAAAAAJ0I/XmX-S48tr2A/s1600/ncomms6257-f2.jpg) they are actually heavily eastern-shifted compared to Sardinians, Basques and neolithic farmers. In summary: I believe it subsumes north-eastern admixtures as orange and over-amplifies south-eastern admixture as blue (= false-positive "West Asian"). Also that WHG part which is part of K15 "Atlantic" seems to be subsumed under the green color (as happened in KO1 for example), indicating false-positive EEF-farmer admixture. I'm sorry, El Horsto, in my original post I carelessly linked to Figure 8 in the body of the paper but was discussing Figure 10, p. 10 of the Supplement. I went back later and edited the post, but I guess you saw the original link. This is the correct one here: http://www.nature.com/ncomms/2014/14...mms6257-s1.pdf (http://www.nature.com/ncomms/2014/141021/ncomms6257/extref/ncomms6257-s1.pdf) I deliberately was talking about Figure 10 because it made more sense to me than Figure 4. If you have a chance to take a look at it I'd be interested to know your interpretation of it.
The Administrator of YFull, compared IR1 results from BAM File with other N1a http://forum.molgen.org/index.php/topic,7459.msg261520.html#msg261520 And he shares these snps with other N1a Y6503+, Y6511+, Y6559+, Y6560+, Y6561+, Y6562+, Y6564+, Y6566+, Y6470+, Y6482+, Y6494+, Y6515+, Y6518+, Y6521+, Y6523+, Y6525+, Y6536+, Y6537+, Y6541+, Y6542+, Y6543+, Y6544+, Y6546+, Y6548+, Y6549+, Y6553+, Y6557+, Y6569+, Y6570+, Y6571+, Y6572+, Y6576+, Y6577+, Y6586+, Y6587+, Y6589+ But he is negative for these snps that N1a from Serbia do have P189-, Y6466-, Y6498-, Y6504-, Y6505-, Y6508-, Y6509-, Y6512-, Y6565-, Y6468-, Y6471-, Y6473-, Y6476-, Y6478-, Y6481-, Y6486-, Y6488-, Y6514-, Y6522-, Y6528-, Y6533-, Y6539-, Y6540-, Y6550-, Y6551-, Y6556-, Y6558-, Y6573-, Y6580-, Y6581-, Y6583-
I'm sorry, El Horsto, in my original post I carelessly linked to Figure 8 in the body of the paper but was discussing Figure 10, p. 10 of the Supplement. I went back later and edited the post, but I guess you saw the original link. This is the correct one here: http://www.nature.com/ncomms/2014/14...mms6257-s1.pdf (http://www.nature.com/ncomms/2014/141021/ncomms6257/extref/ncomms6257-s1.pdf) I deliberately was talking about Figure 10 because it made more sense to me than Figure 4. If you have a chance to take a look at it I'd be interested to know your interpretation of it. Yes, Supplementary Figure 10 makes more sense to me as well. It shows the eastern admixture (blue) in BR1/2 and contemporary West Europeans (excl. Basques, Sardinians) in accordance with their east-shift in the PCA plot and our historic model. Also the blue traces still visible in Basques makes sense considering their R1b and assuming our theory of eastern R1b origin is true. I remember K12b was suggesting this too by showing lower WGH/EEF ("North-euro"/"Atlantic-med") ratio than the neighbours, indicating a more northern than southern east-admixture in non-basques, while basques probably possess rather local WHG. In general I find the results not surprising and well supportive of our main theory here of bronze-age expansion into west and east europe, while mostly omitting the Basques and Sardinians. Although PCA plots reduce information, this one makes much sense. The iron age IR1 was already WHG admixed, but his ancestors were probably dinaric looking I guess (not having seen his skull), somewhat similar to some carpathian East-Europeans and Armenians, and probably also South-Eastern europe in general, incl. Greece and Italy, and some continental celts. Such iron age people are probably the main responsibles for the much higher "West Asian" admixture in SE europe, although dinarics were also already present during Bronze-Age, as attested by Bell-Beaker skeletons.
The iron age IR1 was already WHG admixed, but his ancestors were probably dinaric looking I guess (not having seen his skull), somewhat similar to some carpathian East-Europeans and Armenians, and probably also South-Eastern europe in general, incl. Greece and Italy, and some continental celts. Such iron age people are probably the main responsibles for the much higher "West Asian" admixture in SE europe, although dinarics were also already present during Bronze-Age, as attested by Bell-Beaker skeletons. IR1 lacks EEF (green) admixture like a caucasian.
N1b was the only alternative I saw at the project link Kristiina gave. Admittedly, I'm not an expert on haplogroup N. Where are N* and N1* found? China? N* is Chinese N1* moved north toward Manchuria probably long time ago, also some Turkic people are N1*, but Turkic probably hadn't reached Europe by 1100 BC so, it depends whether the IR1 tribe survived or not I guess, if they have descendants today, they probably were N1b, if not N1*
Yes, Supplementary Figure 10 makes more sense to me as well. It shows the eastern admixture (blue) in BR1/2 and contemporary West Europeans (excl. Basques, Sardinians) in accordance with their east-shift in the PCA plot and our historic model. Also the blue traces still visible in Basques makes sense considering their R1b and assuming our theory of eastern R1b origin is true. I remember K12b was suggesting this too by showing lower WGH/EEF ("North-euro"/"Atlantic-med") ratio than the neighbours, indicating a more northern than southern east-admixture in non-basques, while basques probably possess rather local WHG. In general I find the results not surprising and well supportive of our main theory here of bronze-age expansion into west and east europe, while mostly omitting the Basques and Sardinians. Although PCA plots reduce information, this one makes much sense. The iron age IR1 was already WHG admixed, but his ancestors were probably dinaric looking I guess (not having seen his skull), somewhat similar to some carpathian East-Europeans and Armenians, and probably also South-Eastern europe in general, incl. Greece and Italy, and some continental celts. Such iron age people are probably the main responsibles for the much higher "West Asian" admixture in SE europe, although dinarics were also already present during Bronze-Age, as attested by Bell-Beaker skeletons. I think this admixture chart correlates very well with the Lazaridis figures for EEF if you add up the green, blue and red. The Hungarians are at about 50% (the Germans would be about the same then if the pattern holds?), the North Italians and Bulgarians at 71-72%, the Tuscans at 75%, the Ukrainians here look about 40% when they're actually at about 46%, but it's pretty darn close. Interesting also that the "Bedouin" component is at roughly similar levels? The really nice part is that it shows the varying proportions of what perhaps we could call a more "LBK" and "Cardial" like EEF, and a more eastern "shifted" EEF? Perhaps, as you say, more Caucasus like? I'm not sure how to interpret that though. From everything we've seen so far, the EEF are a pretty homogenous group. Is it just drift? Unless, just as Stuttgart has some small percentage of WHG, the eastern shifted farmers picked up some small portion of ANE? I think there might have been some ANE there in the east before the "Indo-Europeans" started moving east. In that regard, this article purportedly recounts a conversation with Lazaridis: "By examining admixture levels in these groups, they found that an early European farmer split off from the rest of the European farmers early on and mixed with eastern European hunter-gatherers to form the Yamnaya population, which lived on the Steppes, Lazaridis said." Now, I'm always a little leery of reports from journalists, even science journalists, plus it's a little vague. Does he mean that the EEF component in Yamnaya came only from the west, or was some of it from the Caucasus region? As to the "Dinaric" component, (if it can be partly identified with the "blue" component) I'm not sure that it came only from Iron Age migrations. As you pointed out, that blue is already present in the Bronze Age, and Beaker skulls show it, as do the ones in the early northern Italian sites. The Iron Age might just have increased it. I do think it was present in the Continental Celts as well, going by the proportions in the French. I think what the chart also shows is that since it came from the east it grows progressively less as you move west. Note how the proportions in Ukraine, and the Balkans, which would have been the first affected, are higher for the "eastern" component. (Interestingly enough, though, in this admixture chart the Spaniards and the Northern Italians have about the same amount.) The Russians and the northeastern Europeans seem to have gotten the great majority of their farmer ancestry from these later migrations, although I don't know offhand whether the archaeology would show when more of it came, the Bronze Age migrations or the Iron Age ones. Btw, I think we have a clue now as to how those "African" mtDna haplogroups wound up all the way in Finland. Speaking of mtDna, although I don't have time to go back over all the papers and the frequency distributions, I think we can see why there is an "eastern" type of farmer mtDna, and a "western" type in Europe. Physical Anthropology is not my forte, but isn't "Dinaric" supposed to fit with "mountain" origin? The Caucasus would certainly fit with that.
Interesting that modern Lithuanians in that chart is the only population that absolutely lacks Bedoine red. Modern Russians roughly equal IR1. Modern Central Europeans - BR1 and BR2. Since I am Baltic as well, what is this shiny red bedoine thing that everyone has except Lithuanians? If I read chart correct half of Basques, Orcadians, Belarussians also dont have it.
Interesting that modern Lithuanians in that chart is the only population that absolutely lacks Bedoine red. Modern Russians roughly equal IR1. Modern Central Europeans - BR1 and BR2. Since I am Baltic as well, what is this shiny red bedoine thing that everyone has except Lithuanians? If I read chart correct half of Basques, Orcadians, Belarussians also dont have it. Actually, a few Lithuanians do have a smidgen of it, but generally that's correct. (I think it's the Ukrainians, and therefore central Russia probably by implication that's so much like IR1, but even then there is a difference in that they do have some of the "green" component.) I don't know what the red is. It can't be the "Red Sea" component that Dienekes was chasing, can it? It's a huge portion of the Bedouin genome. Maybe just far southwest Asian? At any rate, when you have such a small component, and then you have small, isolated populations, it's easy to lose it just through drift, I think. I understand all of this in the far northeastern and northwestern populations. What I don't understand is the Basques. I've been in the Pyrennees. They're by no means impassable. Unless they were isolated by their language. What puzzles me is how the Bronze Age people coming in from the steppe can be so similar to, as you say, modern central Europeans. Were the population crashes so extreme that there were very few people of any variety left there when the incursions began? I guess we'll get a better handle on it when the Lazaridis paper comes out.
What puzzles me is how the Bronze Age people coming in from the steppe can be so similar to, as you say, modern central Europeans. Were the population crashes so extreme that there were very few people of any variety left there when the incursions began? I guess we'll get a better handle on it when the Lazaridis paper comes out. For that reason I believe that BR1&2 are not fresh arrivals from the East. They have been their for few generations (beginning of Bronze Age) and already had mixed with locals well, same way modern Europeans are. If they were the fresh arrivals they would have looked more like IR1, the extreme outlier.
In that regard, this article purportedly recounts a conversation with Lazaridis: "By examining admixture levels in these groups, they found that an early European farmer split off from the rest of the European farmers early on and mixed with eastern European hunter-gatherers to form the Yamnaya population, which lived on the Steppes, Lazaridis said." Now, I'm always a little leery of reports from journalists, even science journalists, plus it's a little vague. Does he mean that the EEF component in Yamnaya came only from the west, or was some of it from the Caucasus region? Yamnaya is heck of a interesting case. It is at the northern frontier which Farmers never completely breached and didn't fully assimilate Hunter Gatherers living there. We have very successful Cucuteni farmers to the west and north-west of Black Sea, and Yamnaya HGs to the North. Were the HGs too numerous around these big rivers' fishing grounds? Were winters there too long and too harsh for ancient farmers and their crops? Probably the combination. Some historians (like David Anthony) believe that Corded Ware culture arose from combination of Cucuteni and Yamnaya. They've become farmers who could supplement their diet by hunting wild games, in case their crops failed. Perhaps the beginning of Indo Europeans? I think these Bronze Age Corded folks' genom will be very close to modern North-Eastern European one. I don't think there was huge population change afterwards, although some shift towards more ANE could have happened with time.
Another interesting and baffling at same time is how modern Near East plots so far away from EEF. Supposed origin of EEF is in Fertile Crescent (~80%?). Why then the distance of EEF to Near East is as vast as to Eastern Europeans who has 40% EEF ancestry? Does this indicate huge invasions from the east, from central Asia? Inversions and mixing which pulled original population so much towards central Asian admixtures, ANE included. Eastern European case is easier to decipher, because they never became fully Neolithic Farmers, unlike central and south Europeans, and experienced known invasions from the east, to shift them east on PCA plot. Near Easterners however started as original farmers, closely related to EEF, but still managed to build up similar distance as Eastern Europeans. The only population who resisted too much pull are some Bedouins, who plot exactly south to EEF. Actually going by separate axis is more understandable, and I should correct myself somewhat. On North-South axes Near East and Caucasus plots very close to EEF, especially KO2, denoting similar farming past and admixture, I guess. However on West-East axes, they were pulled extremely to the East, same or more than Eastern Europeans, and even more than Russians. Where the original NEF farmers coming from very small population over imposing themselves over already diversified population of Near East HGs? But in this case shouldn't we see the effect of almost total population replacement, like in Southern Europe? EEF like farmers all around the whole area. I believe this is most likely the scenario. Following this logic, the strong pull to the East started after Neolithic in Bronze Age, through Indo Iranian invasions, Scythians, Turks, who else, ending with last Mongol invasion. Deep penetration of R1b folks in Near East, Egypt and Sub Saharan Africa fit the bill. Later colonialists, Russians included, could only pull it back West, so they don't count. Surprisingly Lebanese and Syrians are having as strong pull to the east as Ukrainians and Lithuanians. In this case, we might be talking about Huge, really huge, invasions into Near East, on a scale of partial population replacement. In this case IR1 invader from the east is nothing weird at all. He is just a fresh arrival and didn't have time to mix with locals yet to get the "proper" admixtures for the region. By the same process pulling the region East. Can't wait for any samples from Near East already! http://www.nature.com/ncomms/2014/141021/ncomms6257/images/ncomms6257-f2.jpg
LeBrok:For that reason I believe that BR1&2 are not fresh arrivals from the East. They have been their for few generations (beginning of Bronze Age) and already had mixed with locals well, same way modern Europeans are. If they were the fresh arrivals they would have looked more like IR1, the extreme outlier. I see your point, but for the percentages to work out wouldn't the Indo-Europeans have had to move across Europe in the course of a generation or two? Otherwise, if it were in stages, with the BR1's and BR2's moving from Hungary after a couple of generations and then mixing in the west, the end result in France wouldn't still look like BR1 and BR2. Does that make sense? Some historians (like David Anthony) believe that Corded Ware culture arose from combination of Cucuteni and Yamnaya. They've become farmers who could supplement their diet by hunting wild games, in case their crops failed. Perhaps the beginning of Indo Europeans? From what I know generally about the Indo-Europeans, Yamnaya is the Indo-Europeans. Everything radiated out from there. Also, there was that tweet from the conference that literally said it: Yamnaya=Indo-Europeans. Then there was the tweet that said Corded really only applied to North Europe and part of Central Euope. I think they're only part of the story. I know Anthony has icon status, and he's consulting or whatever on the Samarra paper. I think that's both a very good and a questionable thing. I know I'm always saying geneticists should pay more attention to historians and archaeologists, but I think when they're in the room, so to speak, and are going to be listed as co-authors, politics becomes part of the equation. You would think they would want to look at it "clean", with no preconceptions, at least at first. Actually going by separate axis is more understandable, and I should correct myself somewhat. On North-South axes Near East and Caucasus plots very close to EEF, especially KO2, denoting similar farming past and admixture, I guess. However on West-East axes, they were pulled extremely to the East, same or more than Eastern Europeans, and even more than Russians. The Near East and the Caucasus are both pulled east and slightly north. The populations that resisted the pull the most are, I think, those that in the more southern regions (Bedouins, Palestinians, etc.)got additional SSA in more recent millennia. (Or maybe that SSA admixture pulled the Bedouin south?)They're also the populations that got a lot less ANE. ANE levels in the Caucasus, for example, which was pulled the furthest to the north and east, are very high. I think it's an infusion of a much more ANE admixed group or groups. Then, as you say, you have to add in the Turks, and the Mongols as well, and perhaps some backflow from Indic regions as well. It has seemed to me for a long time, and I've said it often enough to be really boring I'm sure, that the modern Near Easterners are not the same as the original farming populations that went to settle in Europe.
Eastern Europe and Balkans are pulled more east than the rest, due to consecutive encroachments of Huns, Bulgars, Mongols, Avars, Scythians and alike. That's not the only reason. The mere lack of EEF also causes an eastward shift. Balts for instance appear east of Orcadians, but not because they have more ANE (they don't, when divided by the WHG amount), but because they have less EEF. It's more the Balkan populations and south Italians who experienced Caucasic, Iranian and alike admixtures. As we know, mongol admixture is only relevant in Finns, Uralics and Russians, but even there it is still very minor and also it is not known which shift east-asian admixture would cause (East Asians have less ANE than most europeans, see here (https://docs.google.com/spreadsheets/d/1v4zYizoWtsoW1MNBN7SUrLf8R62NHPbMRySUJ2J48_Q/edit?pli=1#gid=1410860471) (reference (http://polishgenes.blogspot.de/2014/09/ancient-north-eurasian-ane-admixture.html)).). East asian is very different from "West-Asian" and would be an own dimension, almost impossible to squeeze into the two-dimensions of a PCA plot. The PCA plot looks quite nice because it mostly represents approximately the three main populations from Lazaridis' et al paper, which still are easy enough to fit into a two-dimension plot. And then ANE has more than one source. In northern Europe it is more often of mesolithic origin, especially in NE-Europe, as can be seen by the ANE/WHG ratio which is not at all higher in NE Europe than elsewhere. Only in SE-central Europe and Italy (skyrocketing ANE/WHG ratio) but also (to a lesser extent) NW-Europe it also more-or-less came as "West-Asian" package from Caucasus-like and iranic peoples or IEans. Mongols are completely different.
Modern Russians roughly equal IR1. I believe this is because the blue bar does not differentiate between mesolithic ANE, which is usually "shipped" together with WHG, and "West-Asian" blended ANE. The Russians, who are heavily admixed by Finns and Uralics, certainly possess more of mesolithic ANE than Near-Eastern/Caucasian ANE. EDIT: now I recall that IR1 possessed Y-HG N. Could it be that IR1 was not Caucasian-like but rather Russian-like, coming from NE-Europe? That would be too strange. I rather keep the Caucasus origin hypothesis for now, despite the finnic hints. Afterall, the PCA plot shows that IR1 is closer to Bulgarians and Romanians than Russians.
The Russians and the northeastern Europeans seem to have gotten the great majority of their farmer ancestry from these later migrations, although I don't know offhand whether the archaeology would show when more of it came, the Bronze Age migrations or the Iron Age ones. I'm inclined towards Iron Age. By the way, here is a thread (http://www.eupedia.com/forum/threads/29405-Predicted-%28Indo-%29European-faces?highlight=georgian+armenian+russian+lithuani an+spanish) about an interesting experiment done by somebody. Mixing an average Armenian (as 'West-Asian' ANE representative) with an average Spaniard (EEF) and Lithuanian (WHG) results in a russian-looking face. When using Georgian instead of Armenian, the result is more average-central european, probably because Georgians are much less dinarid-looking than Armenians (armenian 'dinarid' is called 'armenid', but it is fundamentally the same in my opinion). Physical Anthropology is not my forte, but isn't "Dinaric" supposed to fit with "mountain" origin? The Caucasus would certainly fit with that. My anthropology is amateurish, so caution! But I still feel safe enough to make statements in light of the vast amount of aged pseudo-scientific literature. Yeah, 'dinaric' is remarkably strong in mountains: Caucasus (although diversity there is huge with completely un-dinaric populations neighbouring; many separating valleys probably created different populations; some say that Armenia actually experienced balkanic migrations!), Carpathian, Balkans-Greece-Anatolia (very mountainous as a whole), Alpes (Tyrolians are often dinarid, for instance the Duke of Liechtenstein (http://theroyalcorrespondent.files.wordpress.com/2012/01/2050506171.jpg)). But in more western and northern mountains 'dinarid' seems to become rare (Coon has shown some english dinarids, but they are exceptions). I personally think they didn't completely disappear, they just blended out, resulting in some particular types, often falsely classified as cro-magnoids because of their squareish skulls for instance.
El Horsto:It's more the Balkan populations and south Italians who experienced Caucasic, Iranian and alike admixtures. I'm sorry, El Horsto, but I don't see how this applies to southern Italians at all, or even necessarily to the Greeks, although they are nearby at least, and this is ignoring the documented presence in Ukraine, the Hungarian plain and even other areas. Just for reference purposes so we know what areas we're talking about, I did a little research on Wiki. Yes, I know, but I checked a lot of the citations where they were available and they seem fine. Where there were none, the statements comported with everything I remember about the various groups. Of course, if someone has some papers which challenge these views, I think it's important that we see them. Let's start with the pre-Scythians, and see what the paper under discussion has to say: “Iron metallurgy first appeared in central Europe during the lst millennium BC. During the early phase of the Iron Age the regions east and west of the Danube were parts of two separate cultural provinces 53 The Eastern variant of the Central European Hallstatt culture prevailed in Transdanubia, while pre-Scythian, and later Scythian, cultures inhabited the Great Hungarian Plain and the northern mountainous regions. Despite decades of extensive excavations there are only a handful of Iron Age settlements on the Great Hungarian Plain. This is due to the fact that the pre-Scythian populations practiced a form of nomadic stockbreeding and their transient settlements left few traces in the archaeological record 54. The origin of the pre-Scythian populations of the Great Hungarian Plain (the so called ‘Mezőcsát communities’) remains unclear. The excavation of Early Iron Age burials from this region has provided important new information as burial rites resembled the mortuary practices of the pre-Scythian period in the steppe, suggesting that the Mezőcsát communities were not descendants of the local Late Bronze Age population but most likely arrived to the Great Hungarian Plain from the East 54 in the last phase of the Neolithic, around 4,500 BC, at the end of the Atlantic Period. Here are some excerpts from Wiki on the Scythians. The region known to classical authors as Scythia included: The Pontic-Caspian steppe (http://en.wikipedia.org/wiki/Pontic-Caspian_steppe): Ukraine (http://en.wikipedia.org/wiki/Ukraine), southern Russia (http://en.wikipedia.org/wiki/Southern_Federal_District) and western Kazakhstan (http://en.wikipedia.org/wiki/Kazakhstan) (inhabited by Scythians from at least the 8th century BC)[5] (http://en.wikipedia.org/wiki/Scythia#cite_note-5) Sarmatia (http://en.wikipedia.org/wiki/Sarmatia), corresponding to Ukraine (http://en.wikipedia.org/wiki/Ukraine) and the eastern Balkans (http://en.wikipedia.org/wiki/Balkans)[6] (http://en.wikipedia.org/wiki/Scythia#cite_note-6) Scythia Minor (http://en.wikipedia.org/wiki/Scythia_Minor): corresponding to the lower Danube (http://en.wikipedia.org/wiki/Danube) river area west of the Black Sea (http://en.wikipedia.org/wiki/Black_Sea), with a part in Romania (http://en.wikipedia.org/wiki/Romania) and a part in Bulgaria (http://en.wikipedia.org/wiki/Bulgaria) The northern Caucasus (http://en.wikipedia.org/wiki/Caucasus) area Where do you see Italy mentioned here, or even Greece for that matter, although Greece is at least nearby? In the second half of that century, Scythians succeeded in dominating the agricultural tribes of the forest-steppe (http://en.wikipedia.org/wiki/Forest-steppe) and placed them under tribute.Written sources tell that expansion of the Scythian state before the 4th century BC was mainly to the west. An area of Thrace (http://en.wikipedia.org/wiki/Thrace) was subjugated and levied with severe duties. During the 90 year life of Ateas (http://en.wikipedia.org/wiki/Ateas), the Scythians settled firmly in Thrace (http://en.wikipedia.org/wiki/Thrace) and became an important factor in political games in the Balkans (http://en.wikipedia.org/wiki/Balkans). At the same time, both the nomadic and agricultural Scythian populations increased along the Dniester (http://en.wikipedia.org/wiki/Dniester) river. From the story of Polyaenus and Frontin, it follows that in the 4th century BC Scythia had a layer of dependent population, which consisted of impoverished Scythian nomads and local indigenous agricultural tribes, socially deprived, dependent and exploited, who did not participate in the wars, but were engaged in servile agriculture and cattle husbandry. So, from all of that, I see a Scythian influence on the greater Hungarian plain, extending northwards into the mountains, and even beyond that, because the forest-steppe people were a subject, exploited population, and in Thrace, i.e. the eastern Balkans, Bulgaria and Romania. If you have papers that refute of all this, could you provide some links? I don’t pretend to have a specialty in the Scythians. Ed. For spelling and spacing. I'm not saying that it couldn't have moved further west and then south into northern Italy. However, as an analysis in a subsequent post shows, the northern Italian and even Tuscan numbers are in line with the rest of eastern and central Europe. We have no data on southern Italy.
You also mentioned the Avars, so let’s take a look at them. From the Wiki article on the European Avars: The Avars / (http://en.wikipedia.org/wiki/Help:IPA_for_English)ˈ (http://en.wikipedia.org/wiki/Help:IPA_for_English#Key)æ (http://en.wikipedia.org/wiki/Help:IPA_for_English#Key)v (http://en.wikipedia.org/wiki/Help:IPA_for_English#Key)ɑr (http://en.wikipedia.org/wiki/Help:IPA_for_English#Key)z (http://en.wikipedia.org/wiki/Help:IPA_for_English#Key)/ (http://en.wikipedia.org/wiki/Help:IPA_for_English) were a group of equestrian warrior nomads[1] (http://en.wikipedia.org/wiki/Eurasian_Avars#cite_note-1) of Altaic (http://en.wikipedia.org/wiki/Altaic) extraction[2] (http://en.wikipedia.org/wiki/Eurasian_Avars#cite_note-2) who established an empire spanning considerable areas of Central and Eastern Europe (http://en.wikipedia.org/wiki/Central_and_Eastern_Europe) from the late 6th to the early 9th century.[3] (http://en.wikipedia.org/wiki/Eurasian_Avars#cite_note-Pohl26-3) Although the name Avar first appeared in the mid-5th century, the Avars of Europe enter the historical scene in the mid-6th century AD,[4] (http://en.wikipedia.org/wiki/Eurasian_Avars#cite_note-Curta2006-4) having formed as a mixed band of warriors in the Pontic-Caspian steppe (http://en.wikipedia.org/wiki/Pontic-Caspian_steppe) wishing to escape Göktürk (http://en.wikipedia.org/wiki/G%C3%B6kturks) rule. Their linguistic affiliation may be tentatively deduced from a variety of sources, betraying a variety of languages spoken by ruling and subject clans. Oghur (http://en.wikipedia.org/wiki/Oghur_languages), a distinct branch of the Turkic languages (http://en.wikipedia.org/wiki/Turkic_languages), figures prominently for the original Avar language.[5] (http://en.wikipedia.org/wiki/Eurasian_Avars#cite_note-books.google.com-5) In any event, Slavic (http://en.wikipedia.org/wiki/Slavic_languages) ultimately became the lingua franca in the Avar Khaganate (http://en.wikipedia.org/wiki/Avar_Khaganate).[6] (http://en.wikipedia.org/wiki/Eurasian_Avars#cite_note-Curta2004-6) 1. Many steppe empires were founded by groups who had been defeated in previous power struggles but had fled from the dominion of the stronger group. The Avars were likely a losing faction previously subordinate to the (legitimate) Ashina clan (http://en.wikipedia.org/wiki/Ashina_%28clan%29) in the West Turk khanate (http://en.wikipedia.org/w/index.php?title=West_Turk_khanate&action=edit&redlink=1), this fled west of the Dnieper (http://en.wikipedia.org/wiki/Dnieper). 2. These groups usually were of mixed origin, and each of its components was part of a previous group. Anthropological (http://en.wikipedia.org/wiki/Anthropological) research has revealed few skeletons with Mongoloid (http://en.wikipedia.org/wiki/Mongoloid)-type features, although there was continuing cultural influence from the Eurasian nomadic steppe. The late Avar period shows more hybridization, resulting in higher frequencies of Euro-Mongoloids (http://en.wikipedia.org/w/index.php?title=Euro-Mongoloids&action=edit&redlink=1).[15] (http://en.wikipedia.org/wiki/Eurasian_Avars#cite_note-15) Mongoloid and Euro-Mongoloid types compose about one-third of the total population of the Avar graves of the eighth century.[16] (http://en.wikipedia.org/wiki/Eurasian_Avars#cite_note-16) According to Pál Lipták (http://en.wikipedia.org/wiki/P%C3%A1l_Lipt%C3%A1k) the early Avar anthropological material was almost exclusively Europoid (http://en.wikipedia.org/wiki/Europoid) in the 7th century, while grave-goods indicated Middle and Central Asian (http://en.wikipedia.org/wiki/Central_Asian) parallels.[17] (http://en.wikipedia.org/wiki/Eurasian_Avars#cite_note-F.C3.B3thi-17) On the other hand, cemeteries dated for the 8th century contained Mongoloid elements among others. The Avar army was composed from numerous other groups: Slavic, Gepidic and Bulgar military units. The Carpathian basin (http://en.wikipedia.org/wiki/Carpathian_basin) was the centre of the Avar power-base. The Avars re-settled captives from the peripheries of their empire to more central regions. Avar material culture is found south to Macedonia (http://en.wikipedia.org/wiki/Macedonia_%28region%29) Initially, the Avars and their subjects lived separately, except for Slavic and Germanic women who married Avar men. Eventually, the Germanic and Slavic peoples were included in the Avaric social order and culture, itself Persian-Byzantine in fashion.[19] (http://en.wikipedia.org/wiki/Eurasian_Avars#cite_note-History_of_Transylvania-19) Scholars have identified a fused, Avar-Slavic culture, characterized by ornaments such as half-moon-shaped earrings, Byzantine-styled buckles, beads, and bracelets with horn-shaped ends.[19] (http://en.wikipedia.org/wiki/Eurasian_Avars#cite_note-History_of_Transylvania-19) Paul Fouracre (http://en.wikipedia.org/w/index.php?title=Paul_Fouracre&action=edit&redlink=1) notes, "[T]here appears in the seventh century a mixed Slavic-Avar material culture, interpreted as peaceful and harmonious relationships between Avar warriors and Slavic peasants. It is thought possible that at least some of the leaders of the Slavic tribes could have become part of the Avar aristocracy".[20] (http://en.wikipedia.org/wiki/Eurasian_Avars#cite_note-20)
We can then turn to the Alans and the Huns: As to the Alans, here is what I have found: "Archaeological finds support the written sources. P. D. Rau (1927) first identified late Sarmatian sites with the historical Alans. Based on the archaeological material, they were one of the Iranian-speaking nomadic tribes that began to enter the Sarmatian area between the middle of the 1st and the 2nd centuries." "By the beginning of the 1st century, the Alans had occupied lands in the northeast Azov Sea (http://en.wikipedia.org/wiki/Azov_Sea) area, along the Don (http://en.wikipedia.org/wiki/Don_River,_Russia) and by the 2nd century had amalgamated or joined with the Yancai of the early Chinese records to extend their control all the way along the trade routes from the Black Sea (http://en.wikipedia.org/wiki/Black_Sea) to the north of the Caspian and Aral seas. The written sources suggest that from the end of the 1st century to the second half of the 4th century the Alans had supremacy over the tribal union and created a powerful confederation of Sarmatian tribes. From a Western point-of-view the Alans presented a serious problem for the Roman Empire (http://en.wikipedia.org/wiki/Roman_Empire), with incursions into both the Danubian and the Caucasian provinces in the 2nd and 3rd centuries." Also, "Roman sources first mention the Alani in the 1st century and later describe them as a warlike people who specialized in horse breeding. They frequently raided the Parthian empire (http://en.wikipedia.org/wiki/Parthian_empire) and the Caucasian provinces of the Roman Empire. In the Vologeses inscription[17] (http://en.wikipedia.org/wiki/Alans#cite_note-17) one can read that Vologeses I (http://en.wikipedia.org/wiki/Vologeses_I), the Parthian king c. AD 51-78, in the 11th year of his reign, battled Kuluk (http://en.wikipedia.org/w/index.php?title=Kuluk&action=edit&redlink=1), king of the Alani." Here is a map of the Alan incursions. It does show some pillaging, or whatever, into northern Italy, but it's similar to the rest of western Europe, and there's nothing in southern Italy. http://en.wikipedia.org/wiki/Alans#mediaviewer/File:Alani_map.jpg* Now let's look at the Huns. In that regard, some of the comments in the Avar article bear repeating. "Such views are mirrored by Csanad Balint (http://en.wikipedia.org/w/index.php?title=Csanad_Balint&action=edit&redlink=1). "The ethnogenesis (http://en.wikipedia.org/wiki/Ethnogenesis) of early medieval peoples of steppe origin cannot be conceived in a single linear fashion due to their great and constant mobility", with no ethnogenetic "point zero", theoretical "proto-people" or proto-language.[13] (http://en.wikipedia.org/wiki/Eurasian_Avars#cite_note-13) The name for a new group of steppe riders was often taken from a repertoire of prestigious names which did not necessarily denote any direct affiliation to or descent from groups of the same name; in the early middle ages, Huns, Avars, Bulgars (http://en.wikipedia.org/wiki/Bulgars), and Ogurs, or names connected with -(o)gur (Cutrigurs (http://en.wikipedia.org/w/index.php?title=Cutrigurs&action=edit&redlink=1), Utigurs (http://en.wikipedia.org/wiki/Utigurs), Onogurs (http://en.wikipedia.org/wiki/Onogurs), etc.), were most important. In the process of name-giving, both perceptions by outsiders and self-designation played a role. These names were also connected with prestigious traditions that directly expressed political pretensions and programmes, and had to be endorsed by success. In the world of the steppe, where agglomerations of groups were rather fluid, it was vital to know how to deal with a newly-emergent power. The symbolical hierarchy of prestige expressed through names provided some orientation for friend and foe alike." "The Huns were a nomadic (http://en.wikipedia.org/wiki/Nomad) people or peoples, who are known to have lived in Eastern Europe (http://en.wikipedia.org/wiki/Eastern_Europe), the Caucasus (http://en.wikipedia.org/wiki/Caucasus) and Central Asia (http://en.wikipedia.org/wiki/Central_Asia) between the 1st century AD and the 7th century. They were first reported living east of the Volga River (http://en.wikipedia.org/wiki/Volga_River), in an area that was part of Scythia (http://en.wikipedia.org/wiki/Scythia) at the time; the Huns' arrival is associated with the migration westward of a Scythian people, the Alans (http://en.wikipedia.org/wiki/Alans).[1] (http://en.wikipedia.org/wiki/Huns#cite_note-Sinor1990-1) They were first mentioned as Hunnoi by Tacitus (http://en.wikipedia.org/wiki/Tacitus). In 91 AD, the Huns were said to be living near the Caspian Sea (http://en.wikipedia.org/wiki/Caspian_Sea) and by about 150 AD had migrated southeast into the Caucasus (http://en.wikipedia.org/wiki/Caucasus).[2] (http://en.wikipedia.org/wiki/Huns#cite_note-2) By 370 AD, the Huns had established a vast, if short-lived, dominion in Europe. There is no scholarly consensus on a direct connection between the dominant element of the Xiongnu and that of the Huns.[4] (http://en.wikipedia.org/wiki/Huns#cite_note-4) Priscus (http://en.wikipedia.org/wiki/Priscus) mentions that the Huns had a language of their own (http://en.wikipedia.org/wiki/Hunnic_language); little of it has survived and its relationships have been the subject of debate for centuries. Numerous other languages were spoken within the Hun Empire, including Gothic (East Germanic) (http://en.wikipedia.org/wiki/Gothic_language). Their main military technique was mounted archery (http://en.wikipedia.org/wiki/Mounted_archery). Their descendants, or successors with similar names, are recorded by neighbouring populations to the south, east and west as having occupied parts of Eastern Europe (http://en.wikipedia.org/wiki/Eastern_Europe) and Central Asia (http://en.wikipedia.org/wiki/Central_Asia) approximately from the 4th century to the 6th century. Variants of the Hun name are recorded in the Caucasus (http://en.wikipedia.org/wiki/Caucasus) until the early 8th century. Contemporary literary sources do not have a clear consensus of the Hun origins. The Huns seem to "suddenly appear", first mentioned during an attack on the Alans (http://en.wikipedia.org/wiki/Alans), who are generally connected to the River Don (http://en.wikipedia.org/wiki/Don_River_%28Russia%29) (Tanais). Scholarship from the early 20th century literature connected the sudden and apparently devastating Hun appearance as a predatory migration from the more easterly parts of the steppe (http://en.wikipedia.org/wiki/Steppe), i.e. Central Asia. More recent theories view the nomadic confederacies, such as the Huns, as the formation of several different cultural, political and linguistic entities that could dissolve as quickly as they formed, entailing a process of ethnogenesis (http://en.wikipedia.org/wiki/Ethnogenesis).[8] (http://en.wikipedia.org/wiki/Huns#cite_note-8)[9] (http://en.wikipedia.org/wiki/Huns#cite_note-Pohl-9)[10] (http://en.wikipedia.org/wiki/Huns#cite_note-10) A group of "warrior" horse-nomads would conquer and/or be joined by other warrior groups throughout western Eurasia, and in turn extracted tribute over a territory that included other social and ethnic groups, including sedentary agricultural peoples. In steppe society, clans could forge new alliances and subservience by incorporating other clans, creating a new common ancestral lineage descended from an early heroic leader. Thus, one cannot expect to find a clear origin. "All we can say safely," says Walter Pohl (http://en.wikipedia.org/wiki/Walter_Pohl), "is that the name Huns, in late antiquity (http://en.wikipedia.org/wiki/Late_antiquity) (4th century), described prestigious ruling groups of steppe warriors."[9] (http://en.wikipedia.org/wiki/Huns#cite_note-Pohl-9) This is the Hunnic empire at its height. http://upload.wikimedia.org/wikipedia/commons/4/43/Huns_empire.png In 451, Attila's forces entered Gaul (http://en.wikipedia.org/wiki/Gaul), accumulating contingents from the Franks (http://en.wikipedia.org/wiki/Franks), Goths (http://en.wikipedia.org/wiki/Goths) and Burgundian (http://en.wikipedia.org/wiki/Burgundians) tribes en route. Once in Gaul, the Huns first attacked Metz (http://en.wikipedia.org/wiki/Metz), then his armies continued westwards, passing both Paris and Troyes (http://en.wikipedia.org/wiki/Troyes) to lay siege to Orléans (http://en.wikipedia.org/wiki/Orl%C3%A9ans). Many Huns were employed as mercenaries by both East and West Romans and by the Goths. Uldin (http://en.wikipedia.org/wiki/Uldin), the first Hun known by name,[15] (http://en.wikipedia.org/wiki/Huns#cite_note-Thompson1996-15) headed a group of Huns and Alans fighting against Radagaisus in defense of Italy. Leading his horde across the Alps and into Northern Italy, he sacked and razed the cities of Aquileia (http://en.wikipedia.org/wiki/Aquileia), Vicetia (http://en.wikipedia.org/wiki/Vicetia), Verona (http://en.wikipedia.org/wiki/Verona), Brixia (http://en.wikipedia.org/wiki/Brixia), Bergamum (http://en.wikipedia.org/wiki/Bergamum) and Milan (http://en.wikipedia.org/wiki/Milan). Hoping to avoid the sack of Rome, Emperor Valentinian III sent three envoys, the high civilian officers Gennadius Avienus and Trigetius, as well as Pope Leo I (http://en.wikipedia.org/wiki/Pope_Leo_I), who met Attila at Mincio (http://en.wikipedia.org/wiki/Mincio) in the vicinity of Mantua (http://en.wikipedia.org/wiki/Mantua), and obtained from him the promise that he would withdraw from Italy and negotiate peace with the emperor. That tangential reference is the only one that I can find with regard to the Huns, and it applies only to northern Italy, and involves only a battle and some raiding. So, if you want to leave out the Mongols, go ahead for now. There's plenty of "eastern" "Iranic" ancestry pumping into Russia, the Slavic areas, central Hungary, and the Balkans without them. Ed.*There is a little offshoot after much traveling into Sicily.
So, we’re going to have to look elsewhere for the source of any heightened “Iranic” or “West Asian” gene flow into Southern Italy. I think it’s highly problematic, by the way, to take the figures in the Dodecad runs, for example, as any precise estimation. In those runs, even the Northern Italians have quite a bit more than the Spaniards, for example, yet here, when we have actual ancient genomes, the Northern Italians and the Spaniards have the same amount of "blue", which while not necessarily the exact same thing, is highly suggestive. It remains to be seen what percentage the southern Italians actually have…too bad they weren’t included in this run. Still, as I said, it certainly didn’t come from these migrations that you mentioned. Btw, I hope I don't come across as hectoring you about all this, or trying to "pound a nail into a coffin". It's just that as we're going to be thinking about and talking about the Iron Age as well as Bronze Age migrations in the coming weeks and months, it's as well to get it clear where these people settled and therefore had their most important genetic impact. Now turning to your formulation about the “blue bar”. If we go with the tweets coming out about the upcoming papers on Corded Ware and Samarra, I think it’s pretty clear that both the “orange” component on this admixture chart and the blue component probably have some ANE, and I would guess the orange component has more . However, how can the “blue bar” be seen as anything but highly EEF? I don’t put too much stock on the various calculators for Near Easterners, but many people do, and they are “highly” EEF even if there are other elements that have shifted them from being precisely like the farmers who first set sail for Europe. As for the Baltics, perhaps it’s my fault, but I don’t get your point precisely. How do you know that the ANE that was present in the Mesolithic Scandinavian hunters is the same ANE that is present in Baltic populations today? What if that was a small outlier group that died out? I think it’s a pretty good bet that some of it hung around, but we don’t know that yet. What would prevent the proportions in the Baltics today from stemming from the particular mix that arrived there from further south? I don't necessarily think that the "Indo-European" groups were necessarily uniform from north to south. As for the eastward pull of the Caucasus and Asia Minor, the excerpts I have posted show that these Iranic groups had much more influence in those areas than even in eastern Europe and the Balkans, so I think the explanation is still valid. We also don’t know how “eastern” these eastern HG’s were. If they were heavily ANE they might indeed plot more "eastern" in comparison to WHG and EEF. Finally, it’s pretty clear from mtDna lineages that the “farmer” component in a lot of eastern Europe contains a much larger percentage of "eastern" types than those that can be attributed to LBK and Cardial. I don't see why hypothesizing that some of it came with Iron Age migrations is so outlandish. Ed. I think it's informative to look at the "blue bloc" in a population like the Tuscans. It's much less than the amount present in the Russians, less than in most Hungarians and Romanians, about the same as in the Ukrainians, and pretty close to the amount in the Belorussians. Even about half the French seem to have about the same amount. (As I said, the North Italian and Spanish levels on this run are about equal, the French are variable but some are a little less, and the Orcadians less again, not to mention the Basques and the Sardinians, of course.) So, did some of it bleed down from northern Italy and increase a bit from perhaps some elite migration from Anatolia in the Bronze Age? But then, if there is an appreciable increase in southern Italy (we don't know how much using these ancient samples), where did it come from? Was there some movement of some more "blue" shifted peoples during the Copper and Bronze Ages? During the Iron Age, the only at all large folk type migrations into the south were from Greece, but where did they get it? Did it seep down from the Balkans? Were the Dorians involved? There is some documentation that the Dorians did have a presence in Sicily. Wouldn't it be a kick if the so-called "Nordic" invaders of Greece turn out to have had a large "Iranic" component in them? One more surprise if that's the case. I think there are still a lot of open questions here. Ed. Just a note to add that Otzi on some of the old Dodecad runs had a bit of "Caucasus". Was the composition of the Indo-Europeans different depending on their north/south position along the front? If that was the case, were the Bronze Age people (and maybe Copper Age peoples before them) who went into southern Europe slightly different than the ones who went north? Maybe more J2a1?
In this regard I searched this site for the discussion about the "Thracian" late Iron Age sample, K8. In that discussion, Sile published some admixture results which were apparently produced by Genetiker. These are the Dodecad K7 results for K8: K7b 46.44% Atlantic_Baltic 36.25% West_Asian 17.30% Southern 0.00% African 0.00% East_Asian 0.00% Siberian 0.00% South_Asian Ed. The attachment is drawn from Figure 10 of the supplement, not Figure 4 of the body of the paper. The link is now correct. Regarding his results, they look like a Lezgian with Ukrainian admixture (Ukrainian admixed because he tends more towards Lezgin direction). Lezgin Atlantic Baltic 24.90% West Asian 56.70% Southern 13.90% Ukrainian Atlantic Baltic 74.80% West Asian 14.50% Southern 7.8%
Regarding his results, they look like a Ukrainian admixed Adygei sample (Ukrainian admixed because they tend more towards Adygei direction). Adygei Atlantic Baltic 23.40% West Asian 52.50% Southern 18.70% Ukrainian Atlantic Baltic 74.80% West Asian 14.50% Southern 7.8% Thanks. As I said, I recognize that there was some degree of contamination in this sample, but given what we see with IR1, I doubt it was all that contaminated. This kind of result makes perfect sense.
Angela I edited my post because it seems Lezgin does fit better. Contamination can cause weird results like Austranesian or SSA admixture but with what should it be contaminated to give more West Asia if it is a well documented part of ANE and reaches higher levels in that samples than any possible Balkanian individual might have.
Angela I edited my post because it seems Lezgin does fit better. Contamination can cause weird results like Austranesian or SSA admixture but with what should it be contaminated to give more West Asia if it is a well documented part of ANE and reaches higher levels in that samples than any possible Balkanian individual might have. Interesting. Wasn't Dienekes chasing the Lezghins for a while in his runs?
That's not the only reason. The mere lack of EEF also causes an eastward shift. Balts for instance appear east of Orcadians, but not because they have more ANE (they don't, when divided by the WHG amount), but because they have less EEF. The PCA plot looks quite nice because it mostly represents approximately the three main populations from Lazaridis' et al paper, which still are easy enough to fit into a two-dimension plot. First, as you noticed yourself, the admixtures are just approximated on PCA plot. Second point is that, if you find lower EEF admixture it automatically increases other admixture in whole genome. If lower EEF doesn't increase ANE or WHG then we can deduct that there is one more, or few more admixtures in play in PCA. In case of Balts versus Orcadians, there is 4th (or more) admixture in play, the unknown admixture which pulls Balts to the east, or pulls Orcadians west. Lower EEF might also result in pull straight north if only WHG increases and ANE and other eastern admixtures are constant. Increased African admixtures might result in pull south-west like in Beduins. If one admixture decreases, some other admixture(s) MUST increase.
First, as you noticed yourself, the admixtures are just approximated on PCA plot. Second point is that, if you find lower EEF admixture it automatically increases other admixture in whole genome. If lower EEF doesn't increase ANE or WHG then we can deduct that there is one more, or few more admixtures in play in PCA. In case of Balts versus Orcadians, there is 4th (or more) admixture in play, the unknown admixture which pulls Balts to the east, or pulls Orcadians west. Lower EEF might also result in pull straight north if only WHG increases and ANE and other eastern admixtures are constant. Increased African admixtures might result in pull south-west like in Beduins. If one admixture decreases, some other admixture(s) MUST increase. By the last sentence you disprove your initial statement about a 4th admixture necessary for the more north-eastern shift of Balts. In fact just adding more ANE and WHG to Orcadians (or BR1&2) would already do the job, because it MUST reduce EEF. Getting again more down-to-earth: What I meant is that you can draw a straight line from Sardinians to Lithuanians and you'll find BR1&2 and Orcadians situating at this line. Coincidentally their positions at that line correspond to their EEF values: Lith.: 0.364 Orc.: 0.457 Sard.: 0.817 I wonder whether this tells us something. Since there is enough EEF in all these populations available to sacrifice in favour of ANE+WHG, I don't think there is a significant 4th admixture in Lithuanians necessary. Afterall, I never saw such exotic admixtures like Siberian or East-Asian for Lithuanians in any admixture analysis. You also might remember this map for asian admixture, where there is none in Lithuanians: 6796 @Angela: Draw a straight line from Sardinians to Nogays, and you'll find Bulgarians, Tuscans and IR1 about at the same line in between. This is what I meant. Regarding Italian history I'm a nobody, I'm mostly looking at admixtue numbers. You know much more about Italy and I won't argue. Regarding mongol invasions into east-europe, I know all this. But look at the map above, if it is correct, then there are not many genetic traces left.
We can then turn to the Alans and the Huns: . . . That tangential reference is the only one that I can find with regard to the Huns, and it applies only to northern Italy, and involves only a battle and some raiding. So, if you want to leave out the Mongols, go ahead for now. There's plenty of "eastern" "Iranic" ancestry pumping into Russia, the Slavic areas, central Hungary, and the Balkans without them. Ed.*There is a little offshoot after much traveling into Sicily. Thank you, but I don't know why you are telling me all this. I have only two questions: 1. How much mongol genetic traces are still in Europe? 2. I know about iranic admixture in slavs, some medieval historians even equal Antes and Slavs. But why are Russians relatively close to Lithuanians, Hungarians and other Europeans, while being still distant from Caucasians and even IR1? Note that PCA projections often diminish distances, but never create false distances out of nothing, so this distance must be real. Also note that in other PCA plots Russians appear close to Finns. Significant Iranic, Caucasian, IR1-like, Near-eastern, whatever, I can not be more specific at the moment admixtue, is visible mostly in Balkans, especially Bulgaria and Romania, which are distant from Russians. I'm just describing what I see. You are welcome to make historical interpretations.
By the last sentence you disprove your initial statement about a 4th admixture necessary for the more north-eastern shift of Balts. In fact just adding more ANE and WHG to Orcadians (or BR1&2) would already do the job, because it MUST reduce EEF. If they have same ANE level, as you mentioned, how one can be more eastern than the other? I wonder whether this tells us something. Since there is enough EEF in all these populations available to sacrifice in favour of ANE+WHG, I don't think there is a significant 4th admixture in Lithuanians necessary. Afterall, I never saw such exotic admixtures like Siberian or East-Asian for Lithuanians in any admixture analysis. You also might remember this map for asian admixture, where there is none in Lithuanians: 6796 This admixture can also pull samples to the east on the PCA plot. ANE is a main one, I believe, but there could be few minor ones. Thanks for the map, this East Asian admixture can fully explain why Turkey is pulled much farther east than the rest of Near East. I guess, the invasion of Turks. The East Europe could have gotten it from Huns, Mongols and Tatars.
results from Felix Ancient Hungarian genome (BR2) Y-DNA and mtDNA I was able to peek into Y-DNA and mt-DNA of Ancient Hungarian genome - BR2 (SRR1186791 (http://trace.ncbi.nlm.nih.gov/Traces/sra/?run=SRR1186791)) before the completion of the processing. Since it is processed with BAM Analysis Kit 1.5 (http://www.y-str.org/2014/04/bam-analysis-kit.html) which has upgraded lobSTR 3.0.2 (http://melissagymrek.com/lobstr-code/index.html), it has more accurate Y-STR values as well. Y-Haplogroup The Y-Haplogroup is J-M67 (or J2a1b as per ISOGG tree). The authors has mentioned it as J2a1. However, it is also positive for M67 and http://1.bp.blogspot.com/-2bmgv9hI6SI/VE1P4XPoQTI/AAAAAAAAeoI/r2zYg6Emvwo/s1600/J2a1b.PNG (http://1.bp.blogspot.com/-2bmgv9hI6SI/VE1P4XPoQTI/AAAAAAAAeoI/r2zYg6Emvwo/s1600/J2a1b.PNG)
If you want to know the extent of Mongol or Turkic ancestry in West Eurasia, you should study this admixture analysis: http://biorxiv.org/content/biorxiv/suppl/2014/07/30/005850.DC1/005850-1.pdf In K14, the specifically Turkic-Mongol ancestry is the light orange component. The highest frequencies are found in Kalmyks, Kyrgyz, Karakalpaks, Kazakhs, Altaians, Tuvans, Buryats and Mongols). Its frequency in Europe is marginal, usually it is non-existant. It is nearly non-existant also in Karelians and Russians. It is more frequent in Asia. There is a small amount in Turks, Azeris, Balkars and Adyge, and a clearly higher amount in Bashkirs. This recent Turkic-Mongol ancestry does not explain the East Asian component of Norteast Europeans.
Genetiker has posted results from runs of Dodecad and MDLP for both BR1 and IR1. Felix has not yet posted results for them, so I'll use the Genetiker ones. I'm not sure if they're exactly precise, but I wanted to do a comparison between them, and for that purpose it's not that important. I just want to see how they differ. As I don't know where the population averages are for every MDLP run, I used the Dodecad ones. (This is just an editorial comment, but how are you supposed to check if the results are accurate if you don't have easily accessible population averages?) Anyway, these are the K-7b results for the two ancient samples: K7b BR1 75.40% Atlantic_Baltic 16.21% Southern 4.94% West_Asian 1.69% African 1.34% East_Asian 0.28% Siberian 0.15% South_Asian K7b-IR1 50.15% Atlantic_Baltic 25.61% West_Asian 12.04% Southern 6.55% Siberian 2.56% South_Asian 1.78% East_Asian 1.32% African IR1 has much lower Atlantic Baltic, and much, much higher "West Asian". (The Iron Age man has 25 points less Atlantic-Baltic, and 20 points more "West Asian". Now, whether this is because the Bronze Age peoples of the Steppe were different from the get go, (with perhaps more Atlantic-Baltic and less West Asian from the beginning), or because they had already spent quite a bit of time in central Europe, admixing with the people already there, or both, I don't know. The "Southern" scores aren't that different. (The Bronze Age person has 4 points more.) BR1 has East Asian, (1.34) but only a trace of Siberian. (.28) It's reversed for IR1, who has about the same amount of East Asian (1.78), but who has quite a bit more Siberian (6.55) If these IR Age people came back down from around Andronovo, wouldn't this make sense? Then I looked at the populaton averages for modern peoples. Here the analysis is "iffier", because I don't know how accurate the Genetiker runs are going to prove to be... I don't think the French Basque are a good match for any of the ancient samples, but not even for BR1: Southern 26.8 Atlantic Baltic: 73.2 See Ed. below Here are the French: Atlantic Baltic 69.7 Southern 19.9 West Asian 10.4 When compared to the BR1 sample, they lost 5 points of Atlantic Baltic, gained 4 points of Southern, and gained 5 points of West Asian. All the minority East Asian and Siberian is gone. So, did both Metal Ages Waves reach France, or is subsequent migration during the Roman era, for example. Just for comparison, here the scores for the Hungarians, who were in the path of both waves: Atlantic Baltic 69.2 Southern 14.7 West Asian 14.5 Siberian 1.5 E.Asian .1 S. Asian .1 Could we say that there's perhaps more influence from BR1, but that both Metal Ages migrations had an impact here? Now let's look at the English: Atlantic Baltic 76.6 Southern 13.1 West Asian 9.7 For Southern, they have 7 points less than the French, but only 3 points less than BR1. They have about the same Atlantic Baltic as the Bronze Age sample, which makes sense because they have less Southern. Tey have about the same amount of West Asian, which is about 5 points more than BR1. Finally, the Bulgarians: Atlantic Baltic 54.3 Southern 22.7 West Asian 21.5 Siberian 1.1 East Asian .4 The higher "Southern" impacts all the other numbers, of course, but can we see a mixture here as well but perhaps more balanced in terms of the two migrations, i.e. slightly more Iron Age influence? Just a reminder that all these "Admixture" components obscure the levels of the 3 ancient civilizations within them, except perhaps for "Southern". The K-7b Atlantic Baltic, for example, is about 1/3 Atlantic Med, 2/3 North Euro from the K=12b run. I did these on the run, so if anyone looks at them and I got something wrong, please correct as necessary. If I have time later maybe I'll fo the same thing for K-12b or Globe 13. This is not supposed to be gospel, folks, just give us clues. Ed. The French Basque are not a perfect fit, but not bad.
Great job Angela. Can we have, for comparison, one of NE samples run with calculators? Even Ice Man would do, as his genome fits neatly with other Neolithic samples.
Great job Angela. Can we have, for comparison, one of NE samples run with calculators? Even Ice Man would do, as his genome fits neatly with other Neolithic samples. All of this comes from this thread on the Dienekes Blog, which also discusses the Portalon Iberian farmer: http://dienekes.blogspot.com/2013/11/iberian-neolithic-farmer-dna.html Be aware I think we now how better quality reads of his genome and a new Gok genome, but I think this should still be OK for general comparisons. Otzi-K7b At/Baltic 43.1 Southern 51.9 West Asian 1.4 E.Asian 2.8 African .8 Siberian 0 Gok 4 K-7b At/Baltic 59.1 Southern 40.9 Just for fun: Sardinians: At/Baltic 52.7 Southern 47.3 French Basques again: At/Baltic 73.2 Southern 26.8 North Italians: (Just because Italians are my main area of interest :)) At/Baltic 55.7 Southern 30.2 West Asian 14.1 No wonder Italians plot near Gok 4 on some analyses. Southern and West Asian could perhaps be see as just "western" and "eastern" versions of EEF? El Horsto may be onto something in positing that Italy was subject to the Iron Age Migrations, even if it doesn't show up in the historical record. I don't know if it's a trickle down from Central Europe-the Hungarians have the same amount of West Asian. It's just that Northern Italians have more of the Stuttgart type EEF and therefore less At/Baltic. Or did some come up from the south? The Romans did a lot of founding of colonies in the north. Here are the Greeks for comparison At/Baltic 41.2 Southern 33.9 West Asian 24.8 The West Asian scores for the volunteer Greek Dodecad population and the volunteer Southern Italians/Sicilians are .6% apart. Of course, neither are scientifically representative samples. Oh, since someone brought up the Lithuanians: At/Baltic 87.6 (Remember, about 1/3 of this is Atlantic Med with buried Stuttgart farmer) West Asian: 10.4 Siberian: 1.3 S. Asian .3 Does it look like a larger WHG refugia than other places in Europe (maybe the same thing went on in the far northwest), with some farmer coming with central Med farmers and the West Asian with the Metal Ages? I've going to edit the prior post. The French Basque actually aren't a bad fit for the BR1 sample. Oh, for the sake of completeness, a Portuguese sample: At/Baltic 59.8 Southern 29.8 W. Asian 6.5 S. Asian 1.3 African 2.5 By the time you get to the Atlantic Coast, some of the "Indo-European" distinctiveness has sort of what, washed out?
I was musing somewhat at the PCA chart with various pullings in relation to 3 major admixtures. 1. Why Basques are located exactly above EEF/NE farmers, and not to the east? When the former contain substantial ANE, which EEF shouldn't have at all. Basques should be east from NE samples, much closer to Spanish ones. 2. Sardinian and NE farmers don't have ANE admixture, however Sardinians plot to the West from NE but on same latitude. Actually they, with extra WHG mixture, should have plotted exactly North off NE samples. In place of Basques. 3. La Brania HG, Bra2 sample, plots way to the West from the rest of Hunter Gatherers. http://www.nature.com/ncomms/2014/141021/ncomms6257/images/ncomms6257-f2.jpg I came up with this explanation. There is one extra component in the game. The "Western" component which pulls samples, not affected by ANE, along West-East axes. It causes EEF samples to fluctuate West-East while ANE admixture is completely missing, therefore unable to perform such action. Farthermore, I think that this Western component (possibly related to ancient North African Hunter Gatherer admixture?) is contained in WHG admixture. I suppose there are 2 major elements in WHG admixture. One is strongly pulling West the other North, with compounded vector of pull towards North-West. Hunter Gatherers in Iberian refuge during LGM met HGs from west Africa? Completing creation of WHG from their combine genome, if I may unleash my fantasy. :) This Western in WHG component is strong in Basques, equalises ANE easterly pull and holds them on par with EEF on W-E axes. It pulls Sardinians and Ice Man to the West from EEF (although Sardinians might gotten some extra pull West from more recent migrations from Africa?). It pulls HG Bra2, born in Spain, most westernly in regards to the rest of HGs. The effect of West component seems to be 3-5 times weaker than pull of North component. WHG genome = 75% North, 25% West. Mind that North and West are not locations but directions of pull.
If they have same ANE level, as you mentioned, how one can be more eastern than the other? I said, they have the same ANE level when divided by WHG level. This admixture can also pull samples to the east on the PCA plot. ANE is a main one, I believe, but there could be few minor ones. Thanks for the map, this East Asian admixture can fully explain why Turkey is pulled much farther east than the rest of Near East. I guess, the invasion of Turks. The East Europe could have gotten it from Huns, Mongols and Tatars. But how much? In this map east european levels of 'mongol' are only ~1.5% average (<0.5% in Poles, Lithuanians and Latvians), while Turks have 5%-10%. So Turks have above 10 times more than Poles and Balts. You are not convincing me that this <0.5% is responsible for most of the east shift. Also Turks are primarily shifted towards east because they share so much "West-Asian" with neighbouring Georgians and Armenians, the latter having the most "West-Asian" (look at any admixture analysis you prefer, I'll not dig out again the numbers, sorry. There are good hyperlinks already provided in this thread.). Turks are primarily Caucasians, second Near-Easteners and third Mongol/Siberian. It is possible that Mongol adds a little bit more to the east, I don't care for now, because most important is "West-Asian", which is the main carrier of ANE, accompanied by specific EEF. On the other hand, look at Ir8 and how close Lithuanians are. They could pass as almost pure north-eastern Hunter-Gatherers, with perhaps a very very tiny bit of "West-Asian" admixture from IR1-like peoples, or some older unknown origin. In general the Hunter-Gatherers at the top are most likely a spectrum created by different ANE levels (not West-Asian exactly, because we still must assume lack of farmer admixture in HG), which is impossible to stem from recent metal ages. It is likely that the hunter-gatherers further east had even more ANE, eventually showing up as "Siberian" admixture, just because ANE is also part of "Siberian".
Measuring West WHG component in Baque. Typical Basque: EEF .60, WHG .30, ANE .10 In Basques all ANE pulling East is totally counterbalanced, and rendering it virtually nonexistent, by West element in their WHG admixture. That why Basques plot exactly as Neolithic Farmers on West-East axes. If ANE in Basque equals 0.10 of whole genome, then I suppose, it is counterbalanced by West WHG , which is also 0.10 of genome. Full WHG admixture equals to 0.30, therefore West in it must be 0.10, one third of whole WHG component. The levels for "West-Asian" or ANE in Basques are AFAIK conflicting, even within the Laz paper (big difference between French Basque and Spanish Basque), so it is inconclusive. In the recent admixture analysis, incl. from Laz., they show only tiny traces of ANE/West-Asian, similar to Sardinians, and I'm inclined to think that this makes more sense, at the moment. Earlier I had a different opinion, because they showed much "Gedrosian" in K12b. Afterall, Basques actually appear slightly more east than Sardinians in this PCA plot.
Genetiker has posted results from runs of Dodecad and MDLP for both BR1 and IR1. Felix has not yet posted results for them, so I'll use the Genetiker ones. I'm not sure if they're exactly precise, but I wanted to do a comparison between them, and for that purpose it's not that important. I just want to see how they differ. As I don't know where the population averages are for every MDLP run, I used the Dodecad ones. (This is just an editorial comment, but how are you supposed to check if the results are accurate if you don't have easily accessible population averages?) Anyway, these are the K-7b results for the two ancient samples: K7b BR1 75.40% Atlantic_Baltic 16.21% Southern 4.94% West_Asian 1.69% African 1.34% East_Asian 0.28% Siberian 0.15% South_Asian K7b-IR1 50.15% Atlantic_Baltic 25.61% West_Asian 12.04% Southern 6.55% Siberian 2.56% South_Asian 1.78% East_Asian 1.32% African IR1 has much lower Atlantic Baltic, and much, much higher "West Asian". (The Iron Age man has 25 points less Atlantic-Baltic, and 20 points more "West Asian". Now, whether this is because the Bronze Age peoples of the Steppe were different from the get go, (with perhaps more Atlantic-Baltic and less West Asian from the beginning), or because they had already spent quite a bit of time in central Europe, admixing with the people already there, or both, I don't know. . The IR1 results are quite similar to the Thracian K8 individual with a bit more Atlantic_Baltic and a bit less West Asian. So this is why I would go with the second theory, that he had been around in Central Europe for quite some time and absorbed some additional farmer+H&G admixture (Atlantic_Baltic is not completely H&G, it is significantly farmer admixed). The results of IR1 look like what an Ossetian and Russian mixed individual would look like. @Angela West Asian can be explained as Early Near Eastern farmer with 1/3 ANE admixture. West Asian is highland-herder DNA imo.
I've tried to stay out of this discussion because I don't know nearly as much about genetics as most of the people posting in this thread. But I'm increasingly wondering whether the ANE classification is really relevant for discussing the genetics of Bronze Age Europe and what impact the Indo-Europeans had on the genetics of different parts of Europe. If Mal'ta Boy and his relatives who presumably had descendants = ANE, there were a lot of millennia for those descendants to spread and mingle with others. So West Asian is apparently 1/3 ANE. But I suspect that at least some of the Eastern Hunter Gatherers had high levels of ANE, and in fact we know that the Corded War people had a lot of ANE. I don't think saying "proto-IE" explains it. The hunter gatherers living in the Russian forest probably had high levels of ANE and many of them probably had Y haplotype R1a. And now we're hearing of tweets from the big conference saying that the Yamna folk who were probably proto-IE test genetically as a mixture of EHG and Armenian. I suspect that a lot of the ANE found in eastern European populations doesn't come from Indo-Europeans but from the EHG folk they conquered. So comparing ANE levels in Basques and Lithuanians may not make sense if it came from different populations. And any ANE in R1b types in Anatolia may have gotten there by a very different route than the ANE in the Baltic.
If ANE was originally simply a marker for people with some kind of Y haplotype R before they spread out and mixed with other people, we might expect to find some ANE wherever we find R1a or R1b, although of course I realize that the amount of ANE in a particular population can't necessarily be predicted by the frequency of the R1a or R1b haplotype since ANE is an autosomal measurement. Nevertheless, I wonder whether ANE could be detected in a West African tribe such as the Oldeme, which has over 90% R1b. ANE would probably still be detectable, but that wouldn't tell us anything about the Indo-European expansion. So why assume that all the ANE found in Lithuania or Poland was brought by Indo-Europeans?
The IR1 results are quite similar to the Thracian K8 individual with a bit more Atlantic_Baltic and a bit less West Asian. So this is why I would go with the second theory, that he had been around in Central Europe for quite some time and absorbed some additional farmer+H&G admixture (Atlantic_Baltic is not completely H&G, it is significantly farmer admixed). The results of IR1 look like what an Ossetian and Russian mixed individual would look like. @Angela West Asian can be explained as Early Near Eastern farmer with 1/3 ANE admixture. West Asian is highland-herder DNA imo. Do you mean that BR1 had been around eastern and central Europe for a while but the original Yamnaya folks were more like IR1? Or do you think that IR1 was different from what the original Yamnaya people would have been like? As to "West Asian" in K7b I'm not sure if it's one third ANE. How did you arrive at that precise figure? Is that a blogger computed figure? Also, could you take a look at these Lithuanian figures and tell me what you think? EEF: 36.4 WHG: 46.4 ANE: .172 K7b: (This is the academic sample. The Dodecad sample is slightly different. ) At/Baltic 87.6 Southern .4 W.Asian 10.4 Siberian 1.3 South Asian .3 If you take 2/3 of the West Asian, plus Southern, you have to take a certain amount of points from Atlantic/Baltic and label it EEF to get to that 36.4 number. Does that number fit with your view of the proportions in Atlantic/Baltic? There's also the fact that in the admixture chart, I think all the "farmer" in the Lithuanians was blue, correct? I had always assumed the EEF in Atlantic/Baltic was Stuttgart. Ed. People are going back to equating Atlantic/Baltic with H/G. There's an EEF component in there. Even Otzi had 43.1 Atlantic/Baltic. (See post #162)
Afterall, Basques actually appear slightly more east than Sardinians in this PCA plot. I can only see 2 workarounds to consolidate Basque position on PCA chart. Either they didn't have ANE at all, therefore match Neolithic Farmers on the plot on WE axes, or something else is pulling them West counteracting ANE pull East. Knowing that ANE was already found in Basques and that they were fairly secluded group in mountains, second scenario is more plausible. I think it is lurking inside some of WHG admixture.
I said, they have the same ANE level when divided by WHG level. Sorry, didn't get that at first. Do you mean proportional? I can see what you mean now. It make sense in most of the cases, but only when ANE component is present. In case of Sardinians, lowering EEF level, therefore increase of WHG, can cause a pull to the West instead. What about UHG in NE Europeans? This 4th admixture might have NE pull on PCA chart too. Distorting the simple story of 3 main admixtures.
I've tried to stay out of this discussion because I don't know nearly as much about genetics as most of the people posting in this thread. But I'm increasingly wondering whether the ANE classification is really relevant for discussing the genetics of Bronze Age Europe and what impact the Indo-Europeans had on the genetics of different parts of Europe. If Mal'ta Boy and his relatives who presumably had descendants = ANE, there were a lot of millennia for those descendants to spread and mingle with others. So West Asian is apparently 1/3 ANE. But I suspect that at least some of the Eastern Hunter Gatherers had high levels of ANE, and in fact we know that the Corded War people had a lot of ANE. I don't think saying "proto-IE" explains it. The hunter gatherers living in the Russian forest probably had high levels of ANE and many of them probably had Y haplotype R1a. And now we're hearing of tweets from the big conference saying that the Yamna folk who were probably proto-IE test genetically as a mixture of EHG and Armenian. I suspect that a lot of the ANE found in eastern European populations doesn't come from Indo-Europeans but from the EHG folk they conquered. So comparing ANE levels in Basques and Lithuanians may not make sense if it came from different populations. And any ANE in R1b types in Anatolia may have gotten there by a very different route than the ANE in the Baltic. If ANE was originally simply a marker for people with some kind of Y haplotype R before they spread out and mixed with other people, we might expect to find some ANE wherever we find R1a or R1b, although of course I realize that the amount of ANE in a particular population can't necessarily be predicted by the frequency of the R1a or R1b haplotype since ANE is an autosomal measurement. Nevertheless, I wonder whether ANE could be detected in a West African tribe such as the Oldeme, which has over 90% R1b. ANE would probably still be detectable, but that wouldn't tell us anything about the Indo-European expansion. So why assume that all the ANE found in Lithuania or Poland was brought by Indo-Europeans? Before I respond, I don't know if you saw Razib's comment on all of this in his blog: http://www.unz.com/gnxp/r1a1a-what-is-best-in-life/ In it he says... Over at Greg Cochran’s blog he’s been posting (http://westhunt.wordpress.com/2014/10/27/centum-and-satem-2/) on Indo-Europeans (http://westhunt.wordpress.com/2014/10/26/yamna-and-corded-ware/). He’s had many of these ideas for a long time, but after I recounted to him some more information from ASHG 2014 it crystallized a lot in terms of specifical detail. For example, the Kalash of Pakistan share a lot of drift with “Ancestral North Eurasians” (ANE). By “a lot”, I mean in the same range as North Caucasus and Eastern European groups. Other HGDP samples from Pakistan are somewhat lower in their signals, but it still noticeable.* In Iosif Lazaridis’ presentation at ASHG 2014 he outlined the likelihood that the widespread distribution of ANE ancestry in Europe probably had something to do with the migrations of the Yamna culture (http://en.wikipedia.org/wiki/Yamna_culture), from which derived the Battle Axe Culture (http://en.wikipedia.org/wiki/Corded_Ware_culture). The genetic variation you see in eastern and central Europe today is representative of the Yamna people. They know because they have ancient samples from those regions. The Yamna themselves are a mix of an Armenian-like Middle Eastern population, and “Eastern Hunter-Gatherers” (EHG) which resemble those to the west but have a higher fraction of ANE (so the are WHG + ANE, while the Armenian-like population is similar to, but not exactly the same as, the “European First Farmers” (EFF). First thing is that the people from the Reigh lab, if the tweets were accurate, definitely seem to be saying that Yamnaya equals the Indo-Europeans. If Razib is right in his interpretation, and as Alan proposed, the farmer portion of the Yamnaya was very similar to, but not exactly the same as EEF. As I had speculated, while EEF had some WHG, the "Armenian like" farmer population probably had some ANE. I'm not sure it's 33%, however. I guess we'll see when the paper comes out. The more interesting portion to me is the "Hunter-Gatherer". We know the WHG are far in the West. Thousands of years before the ANE were far to the east. Motala, whom we could call a Scandinavian Hunter Gatherer, was 19% ANE? (So, I agree with you that we don't know which migration delivered exactly what percent of ANE. However, given there was no ANE in the western Mesolithic, couldn't we say that for western Europeans it came from the east, whether from Scandinavia or Yamnaya? Also, since the Lithuanians have, according to this paper, virtually no Stuttgart ancestry the blue bloc would have had to have come with the Indo-Europeans? So doesn't it make sense that some of their ANE also came from them? This would suggest to me that the level of ANE in that area might not have been at 19% levels when the Indo-Europeans arrived.) Now, this EHG is really an ancient Karelian. I'm sure you know where Karelia is, but for anyone reading this who doesn't know... http://www.balticuniv.uu.se/images/stories/images/Karelia/Karelia.png More interestingly, this is their mtDNA from the Dersarkassian paper: http://2.bp.blogspot.com/-FTrvKmfSuWg/UKu2bjfUS1I/AAAAAAAABTI/OUA0Xer8CFI/s1600/DersarkissianT1Kar.png This may be why, as has been reported, Reich and company, while believing that the ancient Karelians had "lots" of ANE, are having a problem figuring out the precise number. (This comes from Fire-Haired's thread. I have no personal knowledge of it.) To me, there's a definite "East Asian" flavor in the mtDNA. So, these EHG were, I think, quite different from the WHG. Maybe the ultimate model will be WHG, EHG, Early Near Eastern farmer (if we ever get the genome of one). Anyway, I have no idea where the boundary line between WHG and EHG would have existed. Perhaps there was a sort of mixed no man's land in the border areas? As I said, however, I don't know where that border area would have been located. It's clear that the ANE exists all the way south into Central Asia.( the Kalash as Razib Khan pointed out ) Whether that was there before the Indo-European migration, or as a result of the Indo-European migrations I also don't know, and I don't know how anyone else can know either. I will say that I have been surprised at how different the Indo-Europeans are from the way that people had envisioned them. Is it my imagination, or is the bloom off the rose for some people as a result? I could swear I get the sense that all of a sudden being descended from them doesn't have quite the cachet it used to have, although they changed the world in a major way. Of course, I tend to think the worst of people. You never go wrong that way. :) Oh, and the Iron Age people fit the lifestyle that people imagined for them far more, I think, than the Yamnaya folk do... This is all what I think tonight. I may reconsider tomorrow. :)
Well I've always posted here that I did not believe my Baltic ancestors coming to current lands on their chariots and shiny weapons :) Some clans figured out how to do simple but somewhat better farming + animals in forests. This let them populate huge areas in North Europe as corded. However this is only (first bunch of r1a) half of IE story, history of r1b + later Iranic r1a could be much more violent...
BR2 from Hungarian Bronze Age is J2a1b-Y3021* His clade is Parental to Vainakhs(Chechens and Ingushs) and to Toscanian man http://www.yfull.com/tree/J-Y3021/ https://docs.google.com/spreadsheets/d/168jduUNpiWNc7Y2X8lDrMpM8svuPDdwJq5w-g2fQz-0/edit#gid=856950630
Thanks for your comments, Angela, but perhaps I wasn't clear enough about what I was saying. I'm not at all surprised that IE=EHF + farmers from the Caucausus. Nor am I surprised that the farmers from the Caucausus are a mixture of early Middle Eastern Farmer and ANE. But I'm also not surprised that EHF seems to be a mixture of WHG (or something similar and ANE - that was kind of my point. ANE may tell us less than we'd hoped about the IE dispersal in Eastern Europe, simply because ANE was already present in Eastern Europe before the Bronze Age. Whereas it presumably wasn't present in Western Europe until the spread of R1b. So I'm not sure it's helpful to compare ANE levels in Basques and Lithuanians in order to try to figure out anything about the Indo-European dispersal. As for the idea that the replacement of earlier languages by IE languages in Europe happened in many cases during the Iron Age, history already tells us that. But, IMO, that calls into question the idea that IE folk raced across Europe on horseback to create the massive amounts of R1b in Atlantic Europe. IMO, either that happened during the Iron Age or Atlantic R1b arrived during the late Neolithic and wasn't IE.
I guess my problem with referring to EHG as Karelians is that modern Karelians are a linguistic group who speak a language that didn't yet exist when Proto-IE was being developed. I think that if someone wants to plot modern population groups based on older groups, it should be based on WHG, EEF, EHG and West Asian, while recognizing that the latter two both included ANE. And while I wouldn't be too quick to reject the bloody image of IE warriors, given that they were apparently the first people to manufacture large amounts of bronze weapons, the dominance of IE in Europe seems to have been created by the Celtic expansion, the Greek colonization of Italy, the Roman Empire, the creation of the German language and subsequent German expansion and the Slavic expansion. The first two are a mixture of Bronze Age and Iron Age and the last three are Iron Age events.
Well I've always posted here that I did not believe my Baltic ancestors coming to current lands on their chariots and shiny weapons :) Some clans figured out how to do simple but somewhat better farming + animals in forests. This let them populate huge areas in North Europe as corded. However this is only (first bunch of r1a) half of IE story, history of r1b + later Iranic r1a could be much more violent... I'm not sure I follow. If the advance notice about the Corded Ware paper is correct, Corded Ware culture was an offshoot of Yamnaya, yes? I'm not saying, of course, that their advance wouldn't have incorporated northern "hunter-gatherer" types who perhaps already had some ANE. Plus, people like the Lithuanians had to get their 36% EEF from somewhere, and if the Admixture chart on this paper is correct, none of it is Stuttgart. I totally agree that chariots would not have been part of the original advances. As I've pointed out before, chariots were only "invented" about 2,000 BC, and I think it's still an open question whether the whole idea came from south of the Caucasus. Regardless, you're right, they wouldn't have been of much use in dense forest, or in the Alps, for example. :)
Yamnaya is heck of a interesting case. It is at the northern frontier which Farmers never completely breached and didn't fully assimilate Hunter Gatherers living there. We have very successful Cucuteni farmers to the west and north-west of Black Sea, and Yamnaya HGs to the North. Were the HGs too numerous around these big rivers' fishing grounds? Were winters there too long and too harsh for ancient farmers and their crops? Probably the combination. Some historians (like David Anthony) believe that Corded Ware culture arose from combination of Cucuteni and Yamnaya. They've become farmers who could supplement their diet by hunting wild games, in case their crops failed. Perhaps the beginning of Indo Europeans? I think these Bronze Age Corded folks' genom will be very close to modern North-Eastern European one. I don't think there was huge population change afterwards, although some shift towards more ANE could have happened with time. "Were the HGs too numerous around these big rivers' fishing grounds?" There were pottery using sedentary HG cultures around the Black Sea before agriculture so I think that implies high food density and therefore relatively high population density (for foragers). As a secondary thought sedentary pottery using foragers would be partially pre-adapted for farming. My guess is with lower sea levels the current rims of the Black, Caspian and Baltic seas were actually dense wetlands supporting large forager populations.
That's not the only reason. The mere lack of EEF also causes an eastward shift. Balts for instance appear east of Orcadians, but not because they have more ANE (they don't, when divided by the WHG amount), but because they have less EEF. It's more the Balkan populations and south Italians who experienced Caucasic, Iranian and alike admixtures. As we know, mongol admixture is only relevant in Finns, Uralics and Russians, but even there it is still very minor and also it is not known which shift east-asian admixture would cause (East Asians have less ANE than most europeans, see here (https://docs.google.com/spreadsheets/d/1v4zYizoWtsoW1MNBN7SUrLf8R62NHPbMRySUJ2J48_Q/edit?pli=1#gid=1410860471) (reference (http://polishgenes.blogspot.de/2014/09/ancient-north-eurasian-ane-admixture.html)).). East asian is very different from "West-Asian" and would be an own dimension, almost impossible to squeeze into the two-dimensions of a PCA plot. The PCA plot looks quite nice because it mostly represents approximately the three main populations from Lazaridis' et al paper, which still are easy enough to fit into a two-dimension plot. And then ANE has more than one source. In northern Europe it is more often of mesolithic origin, especially in NE-Europe, as can be seen by the ANE/WHG ratio which is not at all higher in NE Europe than elsewhere. Only in SE-central Europe and Italy (skyrocketing ANE/WHG ratio) but also (to a lesser extent) NW-Europe it also more-or-less came as "West-Asian" package from Caucasus-like and iranic peoples or IEans. Mongols are completely different. "And then ANE has more than one source." I think it may turn out that there is an IE segment of ANE (which expanded dramatically and became the biggest) and various non-IE segments tucked away in regions that weren't suitable for horse pastoralists with the various segments having a substrate layer in common e.g. bits of their mythology.
Aberdeen;443000] ANE may tell us less than we'd hoped about the IE dispersal in Eastern Europe, simply because ANE was already present in Eastern Europe before the Bronze Age. Whereas it presumably wasn't present in Western Europe until the spread of R1b. So I'm not sure it's helpful to compare ANE levels in Basques and Lithuanians in order to try to figure out anything about the Indo-European dispersal. I agree that it's not going to be as informative a "marker" as we'd hoped, especially as Reich and company are having problems figuring out how much was present in the Ancient Karelians, and I don't know if they'd be able to figure out if any ANE remained from the SHGs. As for the idea that the replacement of earlier languages by IE languages in Europe happened in many cases during the Iron Age, history already tells us that. But, IMO, that calls into question the idea that IE folk raced across Europe on horseback to create the massive amounts of R1b in Atlantic Europe. IMO, either that happened during the Iron Age or Atlantic R1b arrived during the late Neolithic and wasn't IE. Hopefully, the Samarra paper should be able to tell us if the yDna in Yamnaya included R1a and R1b or not. For all we know, other people are testing Yamnaya remains as well. Wherever R1a and R1b were, I don't think they could have been too separated spatially. Also from Razib Khan's blog: " One showed a Bayesian skyline plot (http://mbe.oxfordjournals.org/content/22/5/1185.full) which illustrated that many of the Y chromosomal lineages you know and love went through very rapid population expansion on the order of 5 to 10 thousand years ago. A second poster had a phylogeny of Y chromosomes derived from high coverage whole genome sequencing. They had four individuals from the R1 lineages, two of them from R1a1a. One individual was Indian and the other was Russian. The coalescence was ~5,000 years ago. The individual who did this analysis was not aware of the Bayesian skyline plot poster, so she immediately ran off to look at it when I told her. The coalescence with R1b for the R1a individuals was ~10,000 years ago." I could see both of them on the steppe, perhaps with R1a slightly north of R1b. However, there are other possibilities. Perhaps R1b was more toward the Caucasus and also a bit south of the Caucasus (We certainly have R1b V88 south of the Caucasus, although that split off earlier.) and R1a initially just north of the Caucasus. Whether R1b headed west earlier, I don't know. Aberdeen: I think that if someone wants to plot modern population groups based on older groups, it should be based on WHG, EEF, EHG and West Asian, while recognizing that the latter two both included ANE. My proposal was WHG, EHG, and an early Near Eastern farmer (when we get a good sample), plus ANE. You may be right, and ANE won't prove as helpful as a category, and shouldn't be part of the model, although we'd have to keep in mind that EHG contained "lots" of ANE. Now that you bring it up, I do think that EEF is important as a category as well, as that gives us a way to track the movement of groups like LBK all through Europe. I think we agree that the model will change. The Lazardis paper said that it would change as they got more ancient samples. The important one will be getting a good quality sample for one of the first Near Eastern farmers, hopefully before they set sail for Europe. At the same time, different models are helpful for tracking different population movements. What we have to get our heads around is that there's been admixture upon admixture in western Eurasia, jumbling up the genes so that disentangling it is very difficult. I guess my problem with referring to EHG as Karelians is that modern Karelians are a linguistic group who speak a language that didn't yet exist when Proto-IE was being developed. Maybe the entire area from near Finland to the Black Sea and east from there was populated by ancient Karelian type people. Uralic languages and Indo-European languages developed near each other, Uralic to the north and Indo-European in the rest of the area. Aberdeen...the dominance of IE in Europe seems to have been created by the Celtic expansion, the Greek colonization of Italy, the Roman Empire, the creation of the German language and subsequent German expansion and the Slavic expansion. The first two are a mixture of Bronze Age and Iron Age and the last three are Iron Age events. Again, we agree here. I even think we've already discussed it on this site. It has always seemed to me that a lot of this changed very late, especially in terms of language. When the Romans conquered Iberia, a huge chunk of it was still not speaking Indo-European languages. Even genetically, that central European signal into Iberia is dated to around 2,000 BC. The genetics of southern Italy was heavily impacted, perhaps, by Greek colonization starting around, what, 800 BC? What about the impact of the various Gothic tribes and Lombard tribes on Central Europe and perhaps eastern Europe? (By the time they got to Italy and Spain, it seems that they were too few in number and too admixed to have made much of an autosomal impact.)Then we have changes genetically going on in certain parts of Europe into the early Medieval period, i.e. Anglo-Saxons and then Vikings into Britain. Then look at the huge impact the Slavic migrations had on the Balkans and east into places like Germany perhaps. The paper that included the "Thracian" individuals showed that we still had groups of very "Otzi" like people living among very IR1 steppe nomad like people very late in European history. I know you didn't raise this issue, but as to this "catchphrase" about the revenge of the hunter-gatherers, I'm afraid it misses the point. Had the H/G's of Europe not adopted agriculture, whether through incorporation into EEF communities or admixture with EEF communities, or because they were later "Indo-Europeanized" and therefore learned farming and herding (which after all is an outgrowth of farming) along with getting an infusion of some new genes, they would have wound up as few in number and as isolated as the SAAMI. Once they did adopt it, their numbers were able to increase. Now, how many of the HG's in far northeastern and far northwestern refugia came south over thousands of years in a sort of steady drip, how many were incorporated in far eastern Europe and came west with the Indo-Europeans, and how many came into Central and northwestern Europe via the Goths etc. (and how admixed they were by that time) in the early medieval period, I don't know.
I've tried to stay out of this discussion because I don't know nearly as much about genetics as most of the people posting in this thread. But I'm increasingly wondering whether the ANE classification is really relevant for discussing the genetics of Bronze Age Europe and what impact the Indo-Europeans had on the genetics of different parts of Europe. If Mal'ta Boy and his relatives who presumably had descendants = ANE, there were a lot of millennia for those descendants to spread and mingle with others. So West Asian is apparently 1/3 ANE. But I suspect that at least some of the Eastern Hunter Gatherers had high levels of ANE, and in fact we know that the Corded War people had a lot of ANE. I don't think saying "proto-IE" explains it. The hunter gatherers living in the Russian forest probably had high levels of ANE and many of them probably had Y haplotype R1a. And now we're hearing of tweets from the big conference saying that the Yamna folk who were probably proto-IE test genetically as a mixture of EHG and Armenian. I suspect that a lot of the ANE found in eastern European populations doesn't come from Indo-Europeans but from the EHG folk they conquered. So comparing ANE levels in Basques and Lithuanians may not make sense if it came from different populations. And any ANE in R1b types in Anatolia may have gotten there by a very different route than the ANE in the Baltic. A simple explanation would be if EHG were all ANE and then IE derived from one segment of EHG before expanding dramatically. If so there would be both IE clades of R1a and non-IE clades of R1a.
I was musing somewhat at the PCA chart with various pullings in relation to 3 major admixtures. 1. Why Basques are located exactly above EEF/NE farmers, and not to the east? When the former contain substantial ANE, which EEF shouldn't have at all. Basques should be east from NE samples, much closer to Spanish ones. 2. Sardinian and NE farmers don't have ANE admixture, however Sardinians plot to the West from NE but on same latitude. Actually they, with extra WHG mixture, should have plotted exactly North off NE samples. In place of Basques. 3. La Brania HG, Bra2 sample, plots way to the West from the rest of Hunter Gatherers. http://www.nature.com/ncomms/2014/141021/ncomms6257/images/ncomms6257-f2.jpg I came up with this explanation. There is one extra component in the game. The "Western" component which pulls samples, not affected by ANE, along West-East axes. It causes EEF samples to fluctuate West-East while ANE admixture is completely missing, therefore unable to perform such action. Farthermore, I think that this Western component (possibly related to ancient North African Hunter Gatherer admixture?) is contained in WHG admixture. I suppose there are 2 major elements in WHG admixture. One is strongly pulling West the other North, with compounded vector of pull towards North-West. Hunter Gatherers in Iberian refuge during LGM met HGs from west Africa? Completing creation of WHG from their combine genome, if I may unleash my fantasy. :) This Western in WHG component is strong in Basques, equalises ANE easterly pull and holds them on par with EEF on W-E axes. It pulls Sardinians and Ice Man to the West from EEF (although Sardinians might gotten some extra pull West from more recent migrations from Africa?). It pulls HG Bra2, born in Spain, most westernly in regards to the rest of HGs. The effect of West component seems to be 3-5 times weaker than pull of North component. WHG genome = 75% North, 25% West. Mind that North and West are not locations but directions of pull. I'm wondering about this as well - two components in WHG, a northern one and a southern, possibly NW African related, one, not huge but big enough to distort.
There is a post under Ancient DNA which says Corded was 70% Yamnaya which is more than any modern pop, and of modern populations Balts (+Estonians) are the closest to Yamnaya. Hence my wild assumption. Yamnaya -> Corded -> Balts. I believe this is where we got our r1a dads and our Balt language. You're making a few leaps here. What is the Y Dna break down for the Balts and Estonians? Subclades for R1a would be very important in trying to figure out the source and timing for the different types of R1a. Of course, we don't even know the precise breakdown for the Yamnaya Y DNA yet. Also, let's not forget that autosomally, it's been leaked that the Yamnaya were 50% ancient Karelian type hunter and 50% Armenian type farmer.
Thanks for your comments, Angela, but perhaps I wasn't clear enough about what I was saying. I'm not at all surprised that IE=EHF + farmers from the Caucausus. Nor am I surprised that the farmers from the Caucausus are a mixture of early Middle Eastern Farmer and ANE. But I'm also not surprised that EHF seems to be a mixture of WHG (or something similar and ANE - that was kind of my point. ANE may tell us less than we'd hoped about the IE dispersal in Eastern Europe, simply because ANE was already present in Eastern Europe before the Bronze Age. Whereas it presumably wasn't present in Western Europe until the spread of R1b. So I'm not sure it's helpful to compare ANE levels in Basques and Lithuanians in order to try to figure out anything about the Indo-European dispersal. As for the idea that the replacement of earlier languages by IE languages in Europe happened in many cases during the Iron Age, history already tells us that. But, IMO, that calls into question the idea that IE folk raced across Europe on horseback to create the massive amounts of R1b in Atlantic Europe. IMO, either that happened during the Iron Age or Atlantic R1b arrived during the late Neolithic and wasn't IE. "But, IMO, that calls into question the idea that IE folk raced across Europe on horseback to create the massive amounts of R1b in Atlantic Europe. IMO, either that happened during the Iron Age or Atlantic R1b arrived during the late Neolithic and wasn't IE." Or maybe that the IE label needs sub-dividing into two? Stage 1) PIE where steppe HGs transition into pastoralists Stage 2) Full IE horse culture package so maybe R1b from stage (1) and R1a from stage (2).
There is a post under Ancient DNA which says Corded was 70% Yamnaya which is more than any modern pop, and of modern populations Balts (+Estonians) are the closest to Yamnaya. Hence my wild assumption. Yamnaya -> Corded -> Balts. I believe this is where we got our r1a dads and our Balt language. IMO corded ware were R1a Yamnaya people moving north and northwest and some of their tribes spoke proto-Baltic but i don't know : did they come all the way till Latvia some 2900 BC, or did they arrive later, in a subsequent move?
You're making a few leaps here. What is the Y Dna break down for the Balts and Estonians? Subclades for R1a would be very important in trying to figure out the source and timing for the different types of R1a. Of course, we don't even know the precise breakdown for the Yamnaya Y DNA yet. Also, let's not forget that autosomally, it's been leaked that the Yamnaya were 50% ancient Karelian type hunter and 50% Armenian type farmer. It is only my intuition. On the points raised: R1a in Balts should be OK for that reason. Different (Euro) clades and subclades according to some study. I calculated a bit based on wild assumptions and figure 10 from Hungarian Paper. I assumed Karelians would look 50/50 orange/blue Armenians from paper 50/16/16/16 blue/red/green/orange Yamna assumed as 50/50 of above then looks 50/33/8/8 blue/orange/green/red. Which is actually according same paper most similar to ...... Adygeys. And capital of Adygea is ........ Maykop. Cool, is not it? :) I googled Adygeys and my mouth opened wide :) As to Balts (Lithuanians), if we assume 50% of average Yamna related ancestry then other 50% would on average come from folk 80% orange/20% green to match figure 10 proportions. If Karelian assumption is wrong in orange/blue proportions, then the Other 50% folk would have to also be more blue/orange.
Arvistro:There is a post under Ancient DNA which says Corded was 70% Yamnaya which is more than any modern pop, and of modern populations Balts (+Estonians) are the closest to Yamnaya. Hence my wild assumption. Yamnaya -> Corded -> Balts. I believe this is where we got our r1a dads and our Balt language. [QUOTE]Angela: You're making a few leaps here. What is the Y Dna break down for the Balts and Estonians? Subclades for R1a would be very important in trying to figure out the source and timing for the different types of R1a. Of course, we don't even know the precise breakdown for the Yamnaya Y DNA yet. Also, let's not forget that autosomally, it's been leaked that the Yamnaya were 50% ancient Karelian type hunter and 50% Armenian type farmer. As to Corded Ware, if they were 70% Yamnaya, and Yamnaya was 50% "Armenian type" farmer, then Corded Ware would have been 35% "Armenian type" farmer? Some of that might be going into the ANE category. Still, that is pretty close to the 36% EEF number for the Lithuanians. However, what was the remaining 30% of Corded Ware? What combination of farmer and hunter gatherer? I suppose the upcoming Lazaridis paper will tell us. Interesting that they found "G" and "I" or "J" in two Corded remains from 2800 B.C. I had assumed it was "G2a" of Stuttgart variety and maybe I2a of WHG variety. However, given that there's "G" of a more Caucasus type and we now have a Bronze Age Indo European with J2a1, maybe not. See Jean Manco's page on Copper Age ancient dna: http://www.ancestraljourneys.org/ancientdna.shtml Off topic, but it just occurred to me that the royal houses of Europe may have preserved the yDna signatures (and maybe even the phenotype) of these steppe people more than the rest of us. If the Bourbons were really G2a, maybe it was G2a of a type that arrived with Iron Age people, and not with the early European farmers. There was that paper, which I can't put my hands on now, that found G2a in knights of the Medieval period.
For what it's worth my model is (currently) Stage 1) I think ANE = mammoth steppe HG and WHG = coastal rim HG and if you look at a map of the extent of the mammoth steppe http://en.wikipedia.org/wiki/Mammoth_steppe#mediaviewer/File:Last_glacial_vegetation_map.png you can see although the center of gravity is far to the east the edges reach right into western Europe so as the ice retreated it wouldn't be surprising that the northwest of Europe would be repopulated by both WHG and ANE while the northeast was repopulated by mostly ANE. So in simple terms after the LGM i think the population of Europe was split into roughly four quadrants: SW Europe = WHG SE Europe = WHG NW Europe = WHG + ANE NE Europe = ANE (although as a separate issue i think there's also two components buried inside WHG) Stage 2) Farmers from somewhere expanded into Europe displacing the HGs almost everywhere except the peripheries (Atlantic coast and northern forests) and some interior regions that were too mountainous or swampy to farm and became c. 90% of the population of Europe. This eventually leading to a densely settled southern and central Europe and a much more lightly settled northern forest and western Atlantic coastal periphery. Stage 3) Something happened on the edge of the steppe that led to R1b moving south and west - possibly being pushed by forces from the east - but not as conquerors (as the distribution of R1b and R1a doesn't fit that imo) so instead of attacking densely settled Cardium and LBK instead they went around them by three routes: a) north of the Carpathians b) up the Danube but then diverted away from LBK through Croatia into northern Italy and southern France c) maritime with either one or other of (b) or (c) or both at different times leading to their arrival in Iberia and movement along the Atlantic coast. Stage 4) It's only when R1b - possibly pre-adapted with LP from their steppe or near-steppe origins - arrive in the northern forest and Atlantic coastal zones on the periphery of Europe where crop farming is weak that they experience a major population explosion (and LP sweep) through a cattle-centric dairying form of farming and it's that population explosion (incorporating HG survivors) that leads to the big fight with LBK and a significant bouncing back of the original displaced HGs. The last echoes of this west to east and north to south expansion extending into historical times with the eastward Celtic expansion down the Danube. Stage 5) Not really a separate stage but ongoing during stages (3) and (4) is an ongoing gradual push of R1a (at least the IE variants of R1a) westwards into the Balkans and eastern Europe.
BR2 from Hungarian Bronze Age is J2a1b-Y3021* His clade is Parental to Vainakhs(Chechens and Ingushs) and to Toscanian man http://www.yfull.com/tree/J-Y3021/ https://docs.google.com/spreadsheets/d/168jduUNpiWNc7Y2X8lDrMpM8svuPDdwJq5w-g2fQz-0/edit#gid=856950630 What "Toscanian" man?
"But, IMO, that calls into question the idea that IE folk raced across Europe on horseback to create the massive amounts of R1b in Atlantic Europe. IMO, either that happened during the Iron Age or Atlantic R1b arrived during the late Neolithic and wasn't IE." Or maybe that the IE label needs sub-dividing into two? Stage 1) PIE where steppe HGs transition into pastoralists Stage 2) Full IE horse culture package so maybe R1b from stage (1) and R1a from stage (2). Which flavor of R1a? Were the R1a forest steppe people a different type of R1a from the Yamnaya Indo European R1a, presuming it's there? Or was there an R1a which was the original Yamnaya R1a and then a more "Iranic" type of R1a that showed up with the Iron Age invasions?
What "Toscanian" man? J-Y3021* id:NA20534 TSI TSI=Toscani in Italia http://www.yfull.com/tree/J-Y3021/
Which flavor of R1a? Were the R1a forest steppe people a different type of R1a from the Yamnaya Indo European R1a, presuming it's there? Or was there an R1a which was the original Yamnaya R1a and then a more "Iranic" type of R1a that showed up with the Iron Age invasions? Yes quite - labeling on this is a nightmare. I think "IE" may need three sub-divisions or three labels: 1) a very early mammoth steppe HG version with some cultural similarities extending over a huge area from Europe to America 2) a pastoralist but pre horse culture version which expanded over the steppe and near the edges 3) a specific population within (2) that developed the full horse pastoralist culture, expanded, and probably displaced most of (2) who weren't protected by terrain. So I think there may be HG descended R1a clades tucked away in very remote regions, early pastoralist clades tucked away in semi-remote regions and the main IE clades which came to dominate the space originally shared with lots of other ANE sub-groups. In the context of my previous comment I was talking about the latter - the traditional full horse pastoralist version of IE.
J-Y3021* id:NA20534 TSI TSI=Toscani in Italia http://www.yfull.com/tree/J-Y3021/ what is this TSI mean? Is it the old system of 4 years ago when it meant , Italy, Alps and Balkans or is it something different? some of the old ones below ASW - African ancestry in Southwest USA CEU - Utah residents with Northern and Western European ancestry from the CEPH collection CHB - Han Chinese in Beijing, China CHD - Chinese in Metropolitan Denver, Colorado GIH - Gujarati Indians in Houston, Texas JPT - Japanese in Tokyo, Japan LWK - Luhya in Webuye, Kenya MXL - Mexican ancestry in Los Angeles, California MKK - Maasai in Kinyawa, Kenya TSI - Toscani in Italia YRI - Yoruba in Ibadan, Nigeria and more
Yes quite - labeling on this is a nightmare. I think "IE" may need three sub-divisions or three labels: 1) a very early mammoth steppe HG version with some cultural similarities extending over a huge area from Europe to America 2) a pastoralist but pre horse culture version which expanded over the steppe and near the edges 3) a specific population within (2) that developed the full horse pastoralist culture, expanded, and probably displaced most of (2) who weren't protected by terrain. So I think there may be HG descended R1a clades tucked away in very remote regions, early pastoralist clades tucked away in semi-remote regions and the main IE clades which came to dominate the space originally shared with lots of other ANE sub-groups. In the context of my previous comment I was talking about the latter - the traditional full horse pastoralist version of IE. Indo-European is a specific cultural and linguistic term, and Proto-Indo-European is probably much younger than the split of R1 into R1a and R1b. And if Yamna culture is a mixture of EHG and a Caucasian group, it probably has more than one Y haplotype. You can't just equate R1a with IE, even though I think it likely that the EHG part of Yamna was predominantly R1a.
For what it's worth my model is (currently) Stage 1) I think ANE = mammoth steppe HG and WHG = coastal rim HG and if you look at a map of the extent of the mammoth steppe http://en.wikipedia.org/wiki/Mammoth_steppe#mediaviewer/File:Last_glacial_vegetation_map.png you can see although the center of gravity is far to the east the edges reach right into western Europe so as the ice retreated it wouldn't be surprising that the northwest of Europe would be repopulated by both WHG and ANE while the northeast was repopulated by mostly ANE. So in simple terms after the LGM i think the population of Europe was split into roughly four quadrants: SW Europe = WHG SE Europe = WHG NW Europe = WHG + ANE NE Europe = ANE (although as a separate issue i think there's also two components buried inside WHG) ................ No. EHG is only partly ANE and WHG doesn't contain ANE.
Indo-European is a specific cultural and linguistic term, and Proto-Indo-European is probably much younger than the split of R1 into R1a and R1b. And if Yamna culture is a mixture of EHG and a Caucasian group, it probably has more than one Y haplotype. You can't just equate R1a with IE, even though I think it likely that the EHG part of Yamna was predominantly R1a. I think you can if the full package was developed in one place by one patrilineal clan or more likely by a small number of related patrilineal clans with only one lineage avoiding extinction over time. I agree it's after the fact though i.e. it's an association with a *surviving* lineage and not necessarily a *founding* lineage.
No. EHG is only partly ANE and WHG doesn't contain ANE. I'm not saying WHG contains ANE I'm saying if ANE represents the mammoth steppe HGs then given how far west that ecozone would have extended after the LGM then the repopulation of the northwest as the ice retreated could easily have involved groups from both WHG and ANE. This could explain the relatively high levels of ANE in places like Scotland and Scandinavia separately from IE expansion (if the clades were different from the IE clades - if they weren't different then the theory would be wrong).
what is this TSI mean? Is it the old system of 4 years ago when it meant , Italy, Alps and Balkans or is it something different? some of the old ones below ASW - African ancestry in Southwest USA CEU - Utah residents with Northern and Western European ancestry from the CEPH collection CHB - Han Chinese in Beijing, China CHD - Chinese in Metropolitan Denver, Colorado GIH - Gujarati Indians in Houston, Texas JPT - Japanese in Tokyo, Japan LWK - Luhya in Webuye, Kenya MXL - Mexican ancestry in Los Angeles, California MKK - Maasai in Kinyawa, Kenya TSI - Toscani in Italia YRI - Yoruba in Ibadan, Nigeria and more If you will put your cursor into the "TSI" after 2-3 seconds in a small white window you will see the "Toscani in Italia" Same for "RUS" If you will put your cursor into it, after 2-3 seconds you will see in the small window "Russia"
Yes quite - labeling on this is a nightmare. I think "IE" may need three sub-divisions or three labels: 1) a very early mammoth steppe HG version with some cultural similarities extending over a huge area from Europe to America 2) a pastoralist but pre horse culture version which expanded over the steppe and near the edges 3) a specific population within (2) that developed the full horse pastoralist culture, expanded, and probably displaced most of (2) who weren't protected by terrain. So I think there may be HG descended R1a clades tucked away in very remote regions, early pastoralist clades tucked away in semi-remote regions and the main IE clades which came to dominate the space originally shared with lots of other ANE sub-groups. In the context of my previous comment I was talking about the latter - the traditional full horse pastoralist version of IE. I can see where you're going with 2 and 3, but I don't think number 1 has anything to do with the Indo-Europeans except as one of the "feeder" populations that went into their ethnogenesis. Those are just ancient ANE type HG's who wound up speaking a bunch of different languages, including North American Indian ones. As Aberdeen pointed out, many of them in Europe wound up speaking Uralic languages. The Indo-Europeans are a specific linguistic and cultural group. If we lose sight of that then the term becomes meaningless. It was that package which so changed the world, and the people who created that package were mixed "ethnically". As I've annoyed people by insisting before, no hunter/ gatherer or fisher/gatherer living in a cave or a yurt or a brush shelter in a marsh is going, imo, to magically transform into a pastoralist (which of course is just an off-shoot of a farmer) and a highly sophisticated bronze worker, without input from prior cultures that did farm, and keep domestic animals, and experiment with metallurgy. I hope I can find some time to go back and re-read Michael Frachetti and listen to his lecture again too. I think he's the go to person for that Central Asian type pastoralist, "horse" culture. This is the link to one of his seminal papers: From sheep to (some) horses: 4500 years of herd structure at the pastoralist settlement of Begash (south-eastern Kazakhstan) http://antiquity.ac.uk/ant/083/ant0831023.htm A discussion of it: http://dienekes.blogspot.com/2011/05/horse-not-important-for-emergence-of.html His lecture at Penn (don't let the title fool you): http://www.youtube.com/watch?v=r7qq9__GWN0 He's had a book out for quite a while called Pastoralist Landscapes and Social Interaction in Bronze Age Eurasia, but it's pricey. I doubt my library can get it even on loan, but maybe I'll try. I sure hope they're factoring his findings into the Samarra paper.
I can see where you're going with 2 and 3, but I don't think number 1 has anything to do with the Indo-Europeans except as one of the "feeder" populations that went into their ethnogenesis. Those are just ancient ANE type HG's who wound up speaking a bunch of different languages, including North American Indian ones. As Aberdeen pointed out, many of them in Europe wound up speaking Uralic languages. The Indo-Europeans are a specific linguistic and cultural group. If we lose sight of that then the term becomes meaningless. It was that package which so changed the world, and the people who created that package were mixed "ethnically". As I've annoyed people by insisting before, no hunter/ gatherer or fisher/gatherer living in a cave or a yurt or a brush shelter in a marsh is going, imo, to magically transform into a pastoralist (which of course is just an off-shoot of a farmer) and a highly sophisticated bronze worker, without input from prior cultures that did farm, and keep domestic animals, and experiment with metallurgy. I hope I can find some time to go back and re-read Michael Frachetti and listen to his lecture again too. I think he's the go to person for that Central Asian type pastoralist, "horse" culture. This is the link to one of his seminal papers: From sheep to (some) horses: 4500 years of herd structure at the pastoralist settlement of Begash (south-eastern Kazakhstan) http://antiquity.ac.uk/ant/083/ant0831023.htm A discussion of it: http://dienekes.blogspot.com/2011/05/horse-not-important-for-emergence-of.html His lecture at Penn (don't let the title fool you): http://www.youtube.com/watch?v=r7qq9__GWN0 He's had a book out for quite a while called Pastoralist Landscapes and Social Interaction in Bronze Age Eurasia, but it's pricey. I doubt my library can get it even on loan, but maybe I'll try. I sure hope they're factoring his findings into the Samarra paper. "I can see where you're going with 2 and 3, but I don't think number 1 has anything to do with the Indo-Europeans except as one of the "feeder" populations that went into their ethnogenesis. " Yeah it's translating the private labeling in my head to the "page" that causes the issues. re Frachetti The idea of a first wave of wagon-based pastoralists expanding over a range and then somewhere within that range a horse-culture develops which eventually turns into the traditional IE second wave makes a lot of sense to me. My only quibble is I think the first wave were sort-of-IE-but-not-quite.
IMO corded ware were R1a Yamnaya people moving north and northwest and some of their tribes spoke proto-Baltic but i don't know : did they come all the way till Latvia some 2900 BC, or did they arrive later, in a subsequent move? I can't find exact chronology of corded ware in Latvia. It seems they estimated graves age by pottery types mostly... According to Gimbutas, since 2000 BC Corded Ware same Baltic culture continued in around same area. As noted here in Violet http://upload.wikimedia.org/wikipedia/commons/0/07/East_europe_5-6cc.png Initial 2000 BC and/or before area was wider, I think she believes Fatyanovo (also Corded) was East Baltic. So, Balts are children of Corded. If Corded is child of Yamna, Balts are grandsons of Yamna. But has lower Yamna related ancestry than Corded.
If you will put your cursor into the "TSI" after 2-3 seconds in a small white window you will see the "Toscani in Italia" Same for "RUS" If you will put your cursor into it, after 2-3 seconds you will see in the small window "Russia" This means nothing as they do not have for swiss or austrians or french etc..............as I said what area of europe does TSI incorporate , Italy and ? edit - do not bother replying , they use the same system as I mentioned
This means nothing as they do not have for swiss or austrians or french etc..............as I said what area of europe does TSI incorporate , Italy and ? edit - do not bother replying , they use the same system as I mentioned Only european ones TSI RUS = russians IBS = iberians CEU = western atlantic I do not know of any others
As to "West Asian" in K7b I'm not sure if it's one third ANE. How did you arrive at that precise figure? Is that a blogger computed figure? On Eurogenes blogspot under an article about Mal'ta genome. Davidski commented to a question that West Asian is probably 40% ANE derived and the rest beeing Early Near Eastern Farmer. I think 40% is a little bit too high so I think it might actually be 1/3.
K12b analysis based on the Genetiker runs: The usual disclaimers apply. I don’t know if these percentages are exact, but since I’m just comparing one sample to another sample using an analysis done by one person and using the same calculator it should give us some clues. I’ve removed anything below .5%. I think it’s good to keep in mind that the K12b “North Euro” component is mostly At/Baltic (which has some At/Med in it) plus some West Asian. The K12b “Caucasus” component is about 50% of the K7b West Asian, a chunk of Southern, plus a bit of Atlantic Baltic. For our purposes I think we could perhaps view it as mostly an eastern shifted EEF, yes? AJV70 North Euro 76.4 At.Ned 20.6 Siberian 1.6 SSA 1.3 AJV52 North Euro 77.5 At Med 13.3 S.Asian 4.9 SSA 4.3 K01 Mesolithic HG part of Neolithic Farming Community at Koros 70.14% North_European 27.50% Atlantic_Med 1.72% Sub_Saharan 0.40% Siberian 0.21% Southeast_Asian Otzi North Euro 0 At/Med 57.7 Caucasus 22.3 S.W.Asian 7.6 NWAfrican 5.7 East African 24 S.E.Asian 2 S.Asian 1.5 E,Asian .7 Gok 4 North Euro 5.5 At/Med 81 Caucasus 4.2 S.W.Asian 8.6 E. African .7 K02 Early Neolithic Körös 5570–5710 BC. 47.77% Atlantic_Med 27.46% Caucasus 13.95% Southwest_Asian 10.17% Northwest_African 0.60% East_Asian 0.05% Southeast_Asian C01-Baden Copper Age Culture 2700-2900 51.30% Atlantic_Med 22.93% Caucasus 9.69% Southwest_Asian 9.25% North_European 5.77% Northwest_African 0.78% Sub_Saharan 0.22% Siberian 0.05% Southeast_Asian CO1 had more of the North European components and less of the Caucasus components than KO2. Like KO2, CO1 didn’t have any of the K12b Gedrosia component, BR1 Early Bronze Age Mako Culture 1980-2190 BC (roughly 800 years later) 48.74% North_European 34.34% Atlantic_Med 9.46% Caucasus 3.87% Southwest_Asian 1.12% Sub_Saharan 0.78% South_Asian 0.77% East_African 0.63% East_Asian 0.25% Southeast_Asian BR2 Late Bronze Kyjatice culture dated to 1110–1270 BC (800 years later) 41.61% North_European 35.99% Atlantic_Med 16.30% Caucasus 3.51% Southwest_Asian 1.34% Sub_Saharan 1.12% Gedrosia 0.10% Northwest_African IR1- pre-Scythian Iron Age Mezőcsát culture of Hungary. 830–980 BC. 34.63% North_European 19.54% Atlantic_Med 16.66% Caucasus 15.22% Gedrosia 4.90% Siberian 3.30% East_Asian 2.38% Southwest_Asian 1.53% Northwest_African 1.08% Sub_Saharan 0.77% South_Asian KO1, the Mesolithic HG who became part of the Early Neolithic at Koros, is within a few points of Ajv 70 and 52, so basically the same.. The KO2 sample, the southern most early Neolithic farmer, definitely seems to have a slightly more “eastern” tilt than Oetzi, and certainly more than the more admixed Gok 4. Otzi’s Atlantic Med is roughly 58%, to KO2’s 48%, (and Gok 4’s 81%). Otzi has 22% Caucasus, KO27% and Gok 4 4%. Gok 4 has 9% S.W.Asian, Otzi 8%, but KO2 14%. Now it’s clear why most of these Neolithic farmers plot Southeast of Otzi. This raises an interesting question. Otzi was a Copper Age person from around 3200 B.C.and Gok 4 a TRB farmer from 3100 BC. Is the change in her numbers because of more admixture?Dienekes had speculated that perhaps this group was related to Coon’s Long Barrow Group. I don’t know. (Of course, her admixture has nothing to do with the amount of EEF in modern people. That’s supposedly based on a comparison with Stuttgart (and Otzi?), and KO2 still seems pretty similar to Otzi, although definitely a little to the south and east of him.) Then, in the 3,000 years from the early Neolithic Koros culture to the Copper Age Baden Culture the change was very minimal. The only change, which appears to have taken place around the time of the Copper Age, is that there was an infusion of about 10% “North Euro”. This increased the Atlantic Med by 3, lowered the “Caucasus” by 4, and lowered the Southwest Asian by 4. You also suddenly get a smidgeon of Siberian, .22, and surprisingly, .78 of SSA. I think it may be that the first steppe people were starting to arrive, but, in this part of Europe, it was about 10% of the total genome. What’s more amazing to me is that for about 3,000 years, the people in Hungary didn’t change. Whatever WHG they had was incorporated very early, perhaps further south near the Danube Gorges, and after that there seems not to have been any admixture with hunter-gatherers. Whether that’s because a sort of strict apartheid was enforced after the first admixture, as happened in parts of the Spanish New World, for example, or whether there just weren’t any left in the vicinity, I don’tknow. (I don’t understand why it’s so hard to locate a good carbon dated map of Neolithic and forager settlements in central Europe in, say, the Neolithic, so this doesn’t all have to be guesswork. I’ve tried, and I can’t find it.) The Early Bronze sees a much greater change. Eight hundred years later, the “North Euro” has jumped from 9% to 49%. Atlantic Med has dropped from 51% to 34%. Caucasus has dropped from 23 to 9%, S.W.Asian has dropped from 10 to 4%. Also, there are trace amounts of south, southeast and east Asian, a bit of East African, and SSA increases. I’m not quite sure what to make of this. Is Genetiker’s run just too noisy? These are all over .5%, however. Is it possible it’s telling us these Bronze Age invaders were both more “eastern” shifted and more “southern” shifted than the EEF and WHG of Europe? I don’t know. Eight hundred years later in the late Bronze things have slightly shifted again. North Euro has dropped by 7 points. Atlantic Med has stayed about the same, but “Caucasus” has gone back up by about 7 points. Southwest Asian and SSA stay about the same, but the really “Asian” traces have disappeared. Interestingly, Gedrosia has shown up for the first time, but only to the tune of 1%.So, what happened? Did a fresh wave, somewhat different from the first, come in from the steppes, or was the change the product of admixture with the prior inhabitants, or a little of both? (Just to isolate North Euro for a moment, it went from 0 in the Early Neolithic to 9% in the Copper Age, to 49% in the early Bronze, back down to 42% in the Late Bronze Age.) The Iron Age steppe person is from another eight hundred years later. (He is a child with a G2a1 mtDna, so it seems these people from the steppe did bring some of their own women with them, as was also clear with some mtDna studies. )His North Euro drops from 42 to 35, Atlantic Med from 36 to 20. Caucasus and SW Asian and SSA stays the same, but Gedrosia jumps from 1% to 15%. Interestingly, Siberian now shows up at 5% and East Asian at 3%. I’m not sure how to interpret this change, other than to point out the obvious that Gedrosia seems to appear mostly during the Iron Age. Also, there's definitely a more southern, but also again a more eastern shift in these people. Is it because we’ve sort of “captured” someone “fresher” off the steppe? Or, did the steppe population itself change slightly between the Bronze and the Iron Age, in that it became even more “eastern”? I do think that the EEF in the steppe populations was more eastern and southern shifted compared to central European EEF. Their hunter gatherer was also much more eastern shifted. I don’t think we’ll know much more until we see the Samarra samples and the Yamnaya samples I did this in a rush, so if anyone sees errors just let me know. The only other thing I'll do is take a look at the modern populations to see if it's the same pattern as for the K7b analysis.
And how did he work out 40% and West Asian for the siberian Mal'ta boy, when Mal'ta boy is neither in the R1 nor R2 branches ?:kaioken: Mal'ta boys genome itself showed 26% West Asian related genes. That means at least 26% of WA is ANE derived. How he came to the 40% conclusion I don't know. But 1/3 doesn't look that wrong at all. Also the fact that Near Eastern groups which almost completely lack North European with some 50% "West Asian", yet have 12-14% ANE speaks for it. How else could they end up with so much ANE if there is no other source it might have come from?
KO1, the Mesolithic HG who became part of the Early Neolithic at Koros, is within a few points of Ajv 70 and 52, so basically the same.. What surprises me is higher Atl_Med in KO1 and yet he ended up farther North on PCA plot. I’m not sure how to interpret this change, other than to point out the obvious that Gedrosia seems to appear mostly during the Iron Age. Also, there's definitely a more southern, but also again a more eastern shift in these people. Is it because we’ve sort of “captured” someone “fresher” off the steppe? Or, did the steppe population itself change slightly between the Bronze and the Iron Age, in that it became even more “eastern”? I do think that the EEF in the steppe populations was more eastern and southern shifted compared to central European EEF. Their hunter gatherer was also much more eastern shifted. Bronze Age invaders came from East, from the Steppe. Iron Age invasions came from Caucasus through Anatolia?
Just quickly eyeballing the population averages for K12b, BR1 doesn't look bad for German D population, and BR2 approaches the Dutch D population. IR1 looks like it could have definitely been a feeder population into the Bulgarians, but the Bulgarians have 10 points more Caucasus and a lot less Gedrosia. Gedrosia shows up more in the more western populations. K12b may not be as good as K7b for these purposes. At least, the K7b gets you closer to the PCA in Cristina Gamba's paper. Anyway, this is from just quickly looking over the K12b spreadsheet at Dodecad. Someone who likes to play with the numbers could produce much more accurate results. Personally, I'm wondering about the Tuscans, as I'm sort of half quasi-Tuscan, and I usually plot midway between Bergamo and Firenze in all the Dodecad runs. (I'm also a project member.) R1b is the most common y lineage in Toscana, but there's quite a bit of J2a as well. People have speculated that this is the Etruscan lineage, as some people have claimed there was at least an elite migration from Anatolia, which has a lot of J2a, in the first millenium BC. I have no idea if that's accurate. The other factor that has to be considered is that Etruscan related languages have been found in the eastern Med and in the Alps. Most people have speculated that the Raetic in the Alps comes from Etruscans to the south. I don't know if that's the case either. However, a finding of J2a1 in the BR2 sample, and an actual y dna match between that sample and a Tuscan in the TSI sample opens up some other possibilities, including, I suppose, that a Caucasus heavy steppe group came through central Europe and down into Italy. Given the language difference, we would have to suppose that some of the early steppe groups actually didn't speak an Indo-European language. Something similar has been posited, I think, for the Basques, i.e. that it is a Copper Age language of the Caucasus. I don't know what the story is...the language is just a problem for me with this theory. Of course, I may be resisting this new idea because I've always preferred to think that they were a remnant of Old Europe, or at least connected to Crete or something. However, as I keep saying, you have to try and be as objective about the data as possible. Someone is just going to have to fund full genomes sequences of some ancient Etruscans. I feel as if I should start an online fund drive or something! :) @LeBrok I think some of the migrations may have gone south through the Caucasus, or from the Steppe, down through the Balkans, then into Anatolia, and then who knows, maybe back west along a southern route, but I think some, at least, probably came straight across and then either west through Central Europe (explaining the Gedrosia all the way in the Northwest, a Gedrosia that only makes a big appearance with IR1) or south, southwest into the Balkans and Greece, i.e. the Dorians. From Greece it could have spread all over. The impression I am getting is that in the Bronze Age there were movements in all directions, as there was in the Neolithic thousands of years before. The movements continued in the Iron Age all the way into the early Medieval period. Europe has only been "at rest" in terms of major population migrations for about 1000 years.
Mal'ta boys genome itself showed 26% West Asian related genes. That means at least 26% of WA is ANE derived. I am not sure it works that linearly. What were other 74% of Mal'ta? Although I don't argue the estimate you mentioned (30-40%), just I think this reasoning might not always be true. Then again I could be wrong.
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I am not sure it works that linearly. What were other 74% of Mal'ta? Although I don't argue the estimate you mentioned (30-40%), just I think this reasoning might not always be true. Then again I could be wrong. the rest of the genome was 30% North Euro like, 25% Amerindian like and some 20% Southeast Asian, ASI like. Another example for my estimation. ANE in North Caucasians reaches levels of 23 to 30%. Lets take 26% as average. On Dodecad k12b average "North European" in North Caucasus is 23% and average West Asian of K7b is 55%. If we take that 1/3% of "North European" is ANE. That would make roughly ~8% out of 23%. If we assume 1/3 of West Asian is ANE that would make ~19% out of 55%. 8%+19%= 27% ANE. Thats very simplistic and definitely not 100% accurate of course, but it gives a good picture imo.
On a second thought maybe it makes sense mathematically. Since we are going from 3 (ANE+WHG+EEF) to 12 (West Asian + North Euro + ...). In most scenarious your logic would fit. It would not fit going from 12 to 3. Also it would not work in some extreme 3 to 12 cases. If ANE ancestry was really low in all 12, say max 10% in one population and present only in few of those, so that adding % points from all is less than 100%. I read some more about these things, and I would like to check my understanding. The whole thing I picture as kind of red+blue+yellow turned into 7 (K7) or 12 (K12) colors. And then we go by saying something like red is 40% of Dark Orange, 20% of Light Orange and 40% of Violet (ANE is x% of West Asian + ...). Although since it all is still young, maybe we are not talking about red+blue+yellow. Maybe we are talking "light orange"+"green"+"violet". Who knows?
I can only see 2 workarounds to consolidate Basque position on PCA chart. Either they didn't have ANE at all, therefore match Neolithic Farmers on the plot on WE axes, or something else is pulling them West counteracting ANE pull East. Knowing that ANE was already found in Basques and that they were fairly secluded group in mountains, second scenario is more plausible. I think it is lurking inside some of WHG admixture. To me all data until now are part-positive and part-negative for ANE-related admixture in Basques. Look for instance at Figure 10 (http://www.nature.com/ncomms/2014/141021/ncomms6257/extref/ncomms6257-s1.pdf) from this Gamba et al paper: It's Basques and Sardinians who almost have no blue ("caucasic") color, while all other contemp. populations do have it. If you really have proof that there is similar high ANE in Basques as in other europeans, I'd be interested to learn about it. By the way, I have to correct my initial statement where I said that Basques are slightly east-shifted when compared to Sardinians in the PCA plot. They actually look north/up-shifted due to their higher WHG compared to Sardinians, which also much better fits to the admixture analysis from Fig. 10.
Sorry, didn't get that at first. Do you mean proportional? I can see what you mean now. It make sense in most of the cases, but only when ANE component is present. In case of Sardinians, lowering EEF level, therefore increase of WHG, can cause a pull to the West instead. I'm not sure but to me it looks like adding WHG to Sardinians would shift them to the upper-middle, in the directions where Basques are, because all WHG samples seem to accumulate at the top-middle. It would be a poor PCA analysis if major components like EEF and WHG would occupy the same direction (left). I think there is a triangle-like structure: bottom-left: EEF, top-middle: WHG, somewhere in the right: ANE-related. What about UHG in NE Europeans? This 4th admixture might have NE pull on PCA chart too. Distorting the simple story of 3 main admixtures. Well, the 'U' in UHG stands for "unknown", right? :) So I don't know either. Of course I also think there are other admixtures in play besides those three. The fact that Mal'ta is so much older than EEF and WHG samples is also a bit unperfect I think. Yet I personally don't expect any big surprises anymore with regards to western Hunter-Gatherers from the mesolithic/neolithic. They look surprisingly similar despite they come from very distant locations (Spain-Hungary-Scandinavia), or at least there is no clear east-west cline which would corresponds to their finding locations (Karelian HG probably will look more eastern though). The strong "northern" WHG composition of the Hungarian H-G KO1 also reduces somewhat the chances of a special, perhaps more EEF-like Hunter-Gatherer population in the Balkans (Hungary is almost Balkans), as I once speculated. I'm not claiming they were all the same, but I think that we already have a crude impression of their diversity and that they were all mostly WHG and ancestral to many later admixture components. I also think that Hunter-Gatherers were more ready to admix with other tribes while farmers were more conservative I guess, that's why I don't expect another hidden isolated and very different Hunter-Gatherer population in mesolithic Europe. But this is just my current opinion, ready to be adapted by future knowledge.
To me all data until now are part-positive and part-negative for ANE-related admixture in Basques. Look for instance at Figure 10 (http://www.nature.com/ncomms/2014/141021/ncomms6257/extref/ncomms6257-s1.pdf) from this Gamba et al paper: It's Basques and Sardinians who almost have no blue ("caucasic") color, while all other contemp. populations do have it. If you really have proof that there is similar high ANE in Basques as in other europeans, I'd be interested to learn about it. From Lazaridis paper 2013, Basques have same level of ANE as Tuscans and slightly less than Spanish (1/10th less). Yet they plot with Neolithic and HGs (east-west). Let's assume ANE in Basque is a mistake. We still need good explanation why Bra2 plots as far from Bra1 as Sardinians from rest of Europe. Granted the older the sample the less dna can be recovered in good shape. Smaller the genome for statistical runs, the bigger are errors and discrepancies.
I'm not sure but to me it looks like adding WHG to Sardinians would shift them to the upper-middle, in the directions where Basques are, because all WHG samples seem to accumulate at the top-middle. It would be a poor PCA analysis if major components like EEF and WHG would occupy the same direction (left). I think there is a triangle-like structure: bottom-left: EEF, top-middle: WHG, somewhere in the right: ANE-related. ANE - pulls straight East, WHG - North, EEF - South, additionally something is pulling North East, and something is pulling West, and something from Africa is pulling beduins SW. I think these additional pulls are making whole picture a bit muddy, except central Europe and Neolithic Farmers. If EEF is pulling South-West (bottom-left) it would mean that Bedouins are closest to the pure ENF, first farmers?
From Lazaridis paper 2013, Basques have same level of ANE as Tuscans and slightly less than Spanish (1/10th less). Yet they plot with Neolithic and HGs (east-west). Let's assume ANE in Basque is a mistake. We still need good explanation why Bra2 plots as far from Bra1 as Sardinians from rest of Europe. Granted the older the sample the less dna can be recovered in good shape. Smaller the genome for statistical runs, the bigger are errors and discrepancies. http://dienekes.blogspot.ca/2012/07/bronze-age-indo-european-invasion-of.html In K7 runs Bra have about 9% African admixture. I think they run 2 la brania together, Bra2 might have even more African, I'm not sure though. It might be the case that Bra2 is 91% WHG and 9% East African HG. This African admixture pulls it West on PCA. http://4.bp.blogspot.com/-c85cMFdDxb8/T_Agm5HYwCI/AAAAAAAAE7Y/jJgDnywjhUk/s1600/ancientdna.png In this Blog Bra1 is shown with 1.2 African admixture, therefore Bra2 might have it much more than 9%. http://dienekes.blogspot.ca/2012/10/ancient-european-dna-assessment-with.html
From Lazaridis paper 2013, Basques have same level of ANE as Tuscans and slightly less than Spanish (1/10th less). Yet they plot with Neolithic and HGs (east-west). Let's assume ANE in Basque is a mistake. We still need good explanation why Bra2 plots as far from Bra1 as Sardinians from rest of Europe. Granted the older the sample the less dna can be recovered in good shape. Smaller the genome for statistical runs, the bigger are errors and discrepancies. Given the high levels of R1b among Basques, I would expect more ANE and more certainty that it actually is there. So, regardless of how Basque R1b got there, it must be very diluted. The same would apply to Sardinian R1b, so I don't think it arrived there recently unless it was already very diluted when it arrived.
ANE - pulls straight East, WHG - North, EEF - South, additionally something is pulling North East, and something is pulling West, and something from Africa is pulling beduins SW. I think these additional pulls are making whole picture a bit muddy, except central Europe and Neolithic Farmers. If EEF is pulling South-West (bottom-left) it would mean that Bedouins are closest to the pure ENF, first farmers? Lazaridis tried to use them in his models as proxies for the first farmers. They are the most "southern" and have the least ANE, perhaps none. The problem is that they have additional SSA, some much more than others, depending on the tribe or clan,and there's been drift. I don't know what's going on with the northeast. Does the ancient Karelian genome provide a clue? Or is it later Siberian etc, which makes the Finns impossible to fit into the three population model? (I know that in some runs none shows up in the Baltic countries, but I wonder if some could be hiding in "East European" etc. The other posters may have a better handle on it. You're right about the ANE in the French Basque in the Lazaridis paper. (There is a slight difference between them and Pais Vasco on the Dodecad runs, by the way), and I think you may be onto something with the "African" in La Brana. I don't think it's actually "East African", however. East African is a mix of "African" and "West Asian".
"Yet I personally don't expect any big surprises anymore with regards to western Hunter-Gatherers from the mesolithic/neolithic." If WHG has two components, a main one and a much smaller one but the much smaller one is particularly divergent would that distort its influence - especially if the smaller component is strongly clustered?
From Lazaridis paper 2013, Basques have same level of ANE as Tuscans and slightly less than Spanish (1/10th less). Yet they plot with Neolithic and HGs (east-west). Let's assume ANE in Basque is a mistake. We still need good explanation why Bra2 plots as far from Bra1 as Sardinians from rest of Europe. Granted the older the sample the less dna can be recovered in good shape. Smaller the genome for statistical runs, the bigger are errors and discrepancies. I now have another idea: before Lazaridis et al, we used to talk about "Amerindian" admixture, which later turned out to be ANE. I was predicing something like ANE for Hunter-Gatherers already before, although I guessed it to be related to Y-HQ Q (which still might turn out to be partially true). Now Basques show condradicting data for ANE possibly because their ANE is of north-eastern origin rather than the usual West-Asian. The smoking gun here could be "Amerindian", which Basques consistently possess, contrary to Sardinians, Bedouins and Palestinians, who have zero (check out for instance the table (https://genetiker.wordpress.com/2013/10/27/k-26-admixture-analysis-of-amerindians-and-mestizos/) in the middle of this article from Genetiker; Globe4 also shows it, but I couldn't find data for Sardinians there). So maybe Basque ANE came from North-Eastern EHG, either during Bronze-Age (R1b northern-route), OR maybe yet during the late mesolithic (finnish-basque language similarity?), which would again open the door for a partial mesolithic R1b origin, although much more recent than in Spencer Well's terms of course. Basques also possess some Y-HG Q (0.5%). Looking at various admixture runs together it could be that Basques were affected only by north-eastern ANE invasion, Bronze-Age and North-Europeans by some north-eastern ANE + West-Asian, and South-East Euros more by West-Asian. Going back to the PCA plot, comparing Basques and Sardinians: whether Basques are shifted to the top-middle (WHG) or rather top-right (ANE) would barely be visible since they still have much more WHG than ANE, and since top-middle and top-right is not much of a difference. So maybe "Amerindian"="EHG/North-Eastern ANE" and "West-Asian"="Caucasus/South-Eastern ANE" What you say about african amixture in Europe is also possible.
I now have another idea: before Lazaridis et al, we used to talk about "Amerindian" admixture, which later turned out to be ANE. I was predicing something like ANE for Hunter-Gatherers already before, although I guessed it to be related to Y-HQ Q (which still might turn out to be partially true). Now Basques show condradicting data for ANE possibly because their ANE is of north-eastern origin rather than the usual West-Asian. The smoking gun here could be "Amerindian", which Basques consistently possess, contrary to Sardinians, Bedouins and Palestinians, who have zero (check out for instance the table (https://genetiker.wordpress.com/2013/10/27/k-26-admixture-analysis-of-amerindians-and-mestizos/) in the middle of this article from Genetiker; Globe4 also shows it, but I couldn't find data for Sardinians there). So maybe Basque ANE came from North-Eastern EHG, either during Bronze-Age (R1b northern-route), OR maybe yet during the late mesolithic (finnish-basque language similarity?), which would again open the door for a partial mesolithic R1b origin, although much more recent than in Spencer Well's terms of course. Basques also possess some Y-HG Q (0.5%). Looking at various admixture runs together it could be that Basques were affected only by north-eastern ANE invasion, Bronze-Age and North-Europeans by some north-eastern ANE + West-Asian, and South-East Euros more by West-Asian. Going back to the PCA plot, comparing Basques and Sardinians: whether Basques are shifted to the top-middle (WHG) or rather top-right (ANE) would barely be visible since they still have much more WHG than ANE. So maybe "Amerindian"="EHG/North-Eastern ANE" and "West-Asian"="Caucasus/South-Eastern ANE" What you say about african amixture in Europe is also possible. A northern coastal flow from the Baltic (and possibly beyond) and a southern coastal flow from northwest Africa (and possibly beyond) would produce some odd results I expect.
"Yet I personally don't expect any big surprises anymore with regards to western Hunter-Gatherers from the mesolithic/neolithic." If WHG has two components, a main one and a much smaller one but the much smaller one is particularly divergent would that distort its influence - especially if the smaller component is strongly clustered? I guess this population would require sufficient isolation within WHG.
but I couldn't find data for Sardinians there Here are the world4 'Karitiana' admixtures for various populations (https://docs.google.com/spreadsheet/ccc?key=0ArJDEoCgzRKedGR2ZWRoQ0VaWTc0dlV1cHh4ZUNJR UE#gid=1): (French)Basque: (5.1)4.6 Sardinian:1.7 from Dienekes (http://dodecad.blogspot.de/2012/10/globe4-calculator.html) So according to this, Sardinians have not exactly zero, but still lowest Amerindian. Bedouins have still zero. Interestingly, Armenians also have zero 0.0 and Lezgin only 4.6, while Finns and Russians have max. (10%-12%), so this really is something north-eastern-european. EDIT: Now it would be good to know the Amerindian admixture (not ANE directly) in WHG to estimate the possibility of mesolithic ANE influx.
C01 from Baden Copper Age Culture 2700-2900 is almost same autosomaly as the Neolithic Europeans, The Baden culture has some of the earliest attestation of wheeled vehicles in central Europe, the so-called waggon-models in pottery. Page 10 http://www.nature.com/ncomms/2014/141021/ncomms6257/extref/ncomms6257-s1.pdf
C01 from Baden Copper Age Culture 2700-2900 is almost same autosomaly as the Neolithic Europeans, The Baden culture has some of the earliest attestation of wheeled vehicles in central Europe, the so-called waggon-models in pottery. Page 10 http://www.nature.com/ncomms/2014/141021/ncomms6257/extref/ncomms6257-s1.pdf Wagons are known to Neolithic cultures, unlike chariots which are the indication of Indo Europeans.
Here are the world4 'Karitiana' admixtures for various populations (https://docs.google.com/spreadsheet/ccc?key=0ArJDEoCgzRKedGR2ZWRoQ0VaWTc0dlV1cHh4ZUNJR UE#gid=1): (French)Basque: (5.1)4.6 Sardinian:1.7 from Dienekes (http://dodecad.blogspot.de/2012/10/globe4-calculator.html) So according to this, Sardinians have not exactly zero, but still lowest Amerindian. Bedouins have still zero. Interestingly, Armenians also have zero 0.0 and Lezgin only 4.6, while Finns and Russians have max. (10%-12%), so this really is something north-eastern-european. EDIT: Now it would be good to know the Amerindian admixture (not ANE directly) in WHG to estimate the possibility of mesolithic ANE influx. And the modeling for a Yamnaya person is 50% Ancient Karelian (which is about as far north east you can go and remain in Europe) and an " Armenian like" farmer.
That's part of why so many people were convinced that the big changes in genetics would show up in a Copper Age Culture, but it's not there, or at least it's not there in this sample. This brings us back to all those discussions we had on chariots. (There's even a separate thread on it I think.) There were wheeled vehicles and even wheeled war wagons south of the Caucasus. It's just that they seem to have been solid wheels. The theory by Anthony is that spoked wheels were attached to the carts around 2000 B.C. in Sintashta. Even that is only based on indentations in the ground. No part of those wheels have ever been found. At any rate, BR1 is dated to 1980-2190 BC. Even that is cutting it pretty close. I couldn't quickly find anything that says the Early Bronze Mako culture had them (Unetice is later (1800–1600) . BR2 Kyjatice culture is dated to 1110–1270 BC. and is certainly late enough, as of course is the pre-Scythian IR1. If this article and map is correct, it didn't reach the area under discussion until about 1500 BC. http://en.wikipedia.org/wiki/Chariot don't ask me the source, just read it somewhere .. Mycenians had chariots 1600 BC before it was assumed chariots spread from there to the Balkans now archeologists doubt that and think it was the other way around
I guess this population would require sufficient isolation within WHG. Yes, mountains and swamps. (I also wonder if the signal from East African / Bedouin in EEF may get mixed up with this (imo) NW African signal scattered along the Atlantic coast (if it exists).
Wagons are known to Neolithic cultures, unlike chariots which are the indication of Indo Europeans. Chariots is an Indo-Iranian innovation of two-wheeled carts Those two-wheeled carts were from local people in southern part of Central Asia (local proto-Burushaski or proto-Dravidian) http://en.wikipedia.org/wiki/Altyndepe
K12b analysis based on the Genetiker runs: The usual disclaimers apply. I don’t know if these percentages are exact, but since I’m just comparing one sample to another sample using an analysis done by one person and using the same calculator it should give us some clues. I’ve removed anything below .5%. I think it’s good to keep in mind that the K12b “North Euro” component is mostly At/Baltic (which has some At/Med in it) plus some West Asian. The K12b “Caucasus” component is about 50% of the K7b West Asian, a chunk of Southern, plus a bit of Atlantic Baltic. For our purposes I think we could perhaps view it as mostly an eastern shifted EEF, yes? AJV70 North Euro 76.4 At.Ned 20.6 Siberian 1.6 SSA 1.3 AJV52 North Euro 77.5 At Med 13.3 S.Asian 4.9 SSA 4.3 K01 Mesolithic HG part of Neolithic Farming Community at Koros 70.14% North_European 27.50% Atlantic_Med 1.72% Sub_Saharan 0.40% Siberian 0.21% Southeast_Asian Otzi North Euro 0 At/Med 57.7 Caucasus 22.3 S.W.Asian 7.6 NWAfrican 5.7 East African 24 S.E.Asian 2 S.Asian 1.5 E,Asian .7 Gok 4 North Euro 5.5 At/Med 81 Caucasus 4.2 S.W.Asian 8.6 E. African .7 K02 Early Neolithic Körös 5570–5710 BC. 47.77% Atlantic_Med 27.46% Caucasus 13.95% Southwest_Asian 10.17% Northwest_African 0.60% East_Asian 0.05% Southeast_Asian C01-Baden Copper Age Culture 2700-2900 51.30% Atlantic_Med 22.93% Caucasus 9.69% Southwest_Asian 9.25% North_European 5.77% Northwest_African 0.78% Sub_Saharan 0.22% Siberian 0.05% Southeast_Asian CO1 had more of the North European components and less of the Caucasus components than KO2. Like KO2, CO1 didn’t have any of the K12b Gedrosia component, BR1 Early Bronze Age Mako Culture 1980-2190 BC (roughly 800 years later) 48.74% North_European 34.34% Atlantic_Med 9.46% Caucasus 3.87% Southwest_Asian 1.12% Sub_Saharan 0.78% South_Asian 0.77% East_African 0.63% East_Asian 0.25% Southeast_Asian BR2 Late Bronze Kyjatice culture dated to 1110–1270 BC (800 years later) 41.61% North_European 35.99% Atlantic_Med 16.30% Caucasus 3.51% Southwest_Asian 1.34% Sub_Saharan 1.12% Gedrosia 0.10% Northwest_African IR1- pre-Scythian Iron Age Mezőcsát culture of Hungary. 830–980 BC. 34.63% North_European 19.54% Atlantic_Med 16.66% Caucasus 15.22% Gedrosia 4.90% Siberian 3.30% East_Asian 2.38% Southwest_Asian 1.53% Northwest_African 1.08% Sub_Saharan 0.77% South_Asian KO1, the Mesolithic HG who became part of the Early Neolithic at Koros, is within a few points of Ajv 70 and 52, so basically the same.. The KO2 sample, the southern most early Neolithic farmer, definitely seems to have a slightly more “eastern” tilt than Oetzi, and certainly more than the more admixed Gok 4. Otzi’s Atlantic Med is roughly 58%, to KO2’s 48%, (and Gok 4’s 81%). Otzi has 22% Caucasus, KO27% and Gok 4 4%. Gok 4 has 9% S.W.Asian, Otzi 8%, but KO2 14%. Now it’s clear why most of these Neolithic farmers plot Southeast of Otzi. This raises an interesting question. Otzi was a Copper Age person from around 3200 B.C.and Gok 4 a TRB farmer from 3100 BC. Is the change in her numbers because of more admixture?Dienekes had speculated that perhaps this group was related to Coon’s Long Barrow Group. I don’t know. (Of course, her admixture has nothing to do with the amount of EEF in modern people. That’s supposedly based on a comparison with Stuttgart (and Otzi?), and KO2 still seems pretty similar to Otzi, although definitely a little to the south and east of him.) Then, in the 3,000 years from the early Neolithic Koros culture to the Copper Age Baden Culture the change was very minimal. The only change, which appears to have taken place around the time of the Copper Age, is that there was an infusion of about 10% “North Euro”. This increased the Atlantic Med by 3, lowered the “Caucasus” by 4, and lowered the Southwest Asian by 4. You also suddenly get a smidgeon of Siberian, .22, and surprisingly, .78 of SSA. I think it may be that the first steppe people were starting to arrive, but, in this part of Europe, it was about 10% of the total genome. What’s more amazing to me is that for about 3,000 years, the people in Hungary didn’t change. Whatever WHG they had was incorporated very early, perhaps further south near the Danube Gorges, and after that there seems not to have been any admixture with hunter-gatherers. Whether that’s because a sort of strict apartheid was enforced after the first admixture, as happened in parts of the Spanish New World, for example, or whether there just weren’t any left in the vicinity, I don’tknow. (I don’t understand why it’s so hard to locate a good carbon dated map of Neolithic and forager settlements in central Europe in, say, the Neolithic, so this doesn’t all have to be guesswork. I’ve tried, and I can’t find it.) The Early Bronze sees a much greater change. Eight hundred years later, the “North Euro” has jumped from 9% to 49%. Atlantic Med has dropped from 51% to 34%. Caucasus has dropped from 23 to 9%, S.W.Asian has dropped from 10 to 4%. Also, there are trace amounts of south, southeast and east Asian, a bit of East African, and SSA increases. I’m not quite sure what to make of this. Is Genetiker’s run just too noisy? These are all over .5%, however. Is it possible it’s telling us these Bronze Age invaders were both more “eastern” shifted and more “southern” shifted than the EEF and WHG of Europe? I don’t know. Eight hundred years later in the late Bronze things have slightly shifted again. North Euro has dropped by 7 points. Atlantic Med has stayed about the same, but “Caucasus” has gone back up by about 7 points. Southwest Asian and SSA stay about the same, but the really “Asian” traces have disappeared. Interestingly, Gedrosia has shown up for the first time, but only to the tune of 1%.So, what happened? Did a fresh wave, somewhat different from the first, come in from the steppes, or was the change the product of admixture with the prior inhabitants, or a little of both? (Just to isolate North Euro for a moment, it went from 0 in the Early Neolithic to 9% in the Copper Age, to 49% in the early Bronze, back down to 42% in the Late Bronze Age.) The Iron Age steppe person is from another eight hundred years later. (He is a child with a G2a1 mtDna, so it seems these people from the steppe did bring some of their own women with them, as was also clear with some mtDna studies. )His North Euro drops from 42 to 35, Atlantic Med from 36 to 20. Caucasus and SW Asian and SSA stays the same, but Gedrosia jumps from 1% to 15%. Interestingly, Siberian now shows up at 5% and East Asian at 3%. I’m not sure how to interpret this change, other than to point out the obvious that Gedrosia seems to appear mostly during the Iron Age. Also, there's definitely a more southern, but also again a more eastern shift in these people. Is it because we’ve sort of “captured” someone “fresher” off the steppe? Or, did the steppe population itself change slightly between the Bronze and the Iron Age, in that it became even more “eastern”? I do think that the EEF in the steppe populations was more eastern and southern shifted compared to central European EEF. Their hunter gatherer was also much more eastern shifted. I don’t think we’ll know much more until we see the Samarra samples and the Yamnaya samples I did this in a rush, so if anyone sees errors just let me know. The only other thing I'll do is take a look at the modern populations to see if it's the same pattern as for the K7b analysis. I think we're looking at a conveyor belt effect with waves coming off the steppes every n hundred years with each wave being replaced from further east. So the first wave is the western most and very similar to the existing population in the west so the change isn't very noticeable while the later waves have more eastern components. I also wonder if one of the waves took out Cucuteni and then incorporated them with the combined population moving west. So something like 1st wave: WHG + ANE (similar to the existing western pop. but with more ANE) 2nd wave: ANE + conquered Cucuteni (with the resulting mix being less SW Asian shifted than the central euro farmers) 3rd wave: ANE + traces of siberia 4th wave: ANE + more Siberia etc (This model implies the 1st wave went around Cucuteni) I think the Siberian component is making people think they came from that far away in one go whereas I think it was more of a glacier effect where dna from a long way away was gradually being sucked west by the vaccuum made as each wave moved off the steppe.
The waves were not only from the east, but also towards the east. For example here are the comparisons of Neolithic and Mesolithic Europeans with modern populations http://verenich.wordpress.com/2014/10/27/%D1%81%D1%80%D0%B0%D0%B2%D0%BD%D0%B5%D0%BD%D0%B8%D 0%B5-%D0%B4%D0%B2%D1%83%D1%85-%D0%B4%D1%80%D0%B5%D0%B2%D0%BD%D0%B8%D1%85-%D0%B5%D0%B2%D1%80%D0%BE%D0%BF%D0%B5%D0%B9%D1%86%D 0%B5%D0%B2-%D0%B8-%D0%BE/ Here, Neolithic components are reaching Mongols and Yakuts https://verenich.files.wordpress.com/2014/10/lbkibd.png And Mesolithic reaching Uyghurs https://verenich.files.wordpress.com/2014/10/loschbouribd.png ---- And the comparison of Malta Boy https://verenich.files.wordpress.com/2014/10/maltaibd.png
I think we're looking at a conveyor belt effect with waves coming off the steppes every n hundred years with each wave being replaced from further east. So the first wave is the western most and very similar to the existing population in the west so the change isn't very noticeable while the later waves have more eastern components. I also wonder if one of the waves took out Cucuteni and then incorporated them with the combined population moving west. So something like 1st wave: WHG + ANE (similar to the existing western pop. but with more ANE) 2nd wave: ANE + conquered Cucuteni (with the resulting mix being less SW Asian shifted than the central euro farmers) 3rd wave: ANE + traces of siberia 4th wave: ANE + more Siberia etc (This model implies the 1st wave went around Cucuteni) I think the Siberian component is making people think they came from that far away in one go whereas I think it was more of a glacier effect where dna from a long way away was gradually being sucked west by the vaccuum made as each wave moved off the steppe. That seems to fly in the face of the data. The existing western civilizations were heavily EEF, even TRB and especially central European cultures like Baden. The Balkans were probably just as EEF as Baden, if years later in the Thracian Iron Age we still have an Otzi like individual. Plus, if Yamnaya people were half ancient Karelian like and half modern "Armenian like" they weren't like the populations they encountered and they again weren't like the populations in the west. The Bronze Age samples probably represent, as LeBrok initially pointed out, people who had already admixed. The IR1 sample is different, whether he was "captured" soon after his group came off the steppe, or because his group came from further east, I don't know In that regard, you might want to take a look at this mission statement and map by Burger and company.
That seems to fly in the face of the data. The existing western civilizations were heavily EEF, even TRB and especially central European cultures like Baden. The Balkans were probably just as EEF as Baden, if years later in the Thracian Iron Age we still have an Otzi like individual. Plus, if Yamnaya people were half ancient Karelian like and half modern "Armenian like" they weren't like the populations they encountered and they again weren't like the populations in the west. The Bronze Age samples probably represent, as LeBrok initially pointed out, people who had already admixed. The IR1 sample is different, whether he was "captured" soon after his group came off the steppe, or because his group came from further east, I don't know In that regard, you might want to take a look at this mission statement and map by Burger and company. Sorry about that...this is the link... http://www.uni-mainz.de/FB/Biologie/Anthropologie/MolA/English/Research/CentralAsia.html Unless, of course, the half Ancient Karelian and half modern Armenian model is for the Samara people, and the ones closer to the western steppe had more WHG. The jump in north Euro has to be explained: K01 70.14 K02 0 C01 Baden 9.25 BR1 48.74 BR2 41.61 IR1 34.63
according to Genetiker BR2 is J2a1b-M67 these are Nakh people probably spreading from northeast Caucasus : J2a1-M67 is the most common subclade in the Caucasus (Vainakhs, Ingushs, Chechens, Georgians, Ossetians, Balkars) into all directions : the Levant (Lebanese, Jews). western India, the Arabian Peninsula, Anatolia (esp. north-west), Greece (esp. Crete), Italy (esp. Marche and Abruzzo)
Thanks, Bicicleur. In this regard, the recent paper on Middle Eastern J2 is interesting: Ancient Migratory Events in the Middle East:New clues from the Y Chromosome Variation of Modern Iranians http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0041252 This is a graphic from the paper: http://4.bp.blogspot.com/-xY5E4itZfp4/UAhdqN0yyII/AAAAAAAAFDY/PBV8g-b9jWE/s1600/journal.pone.0041252.g002.jpg Interestingly, it looks as if the highest frequency of J2a M67 is in Portugal. The question is, why? The spread is definitely east/west, no nonsense about it came from North Africa in the Mesolithic or Neolithic. It's also got something to do with the "Indo-European" metal age migrations, at least in eastern Europe, Greece and Italy. I have to mull this over and look at some more papers but I doubt that it originated north of the Caucasus. The most likely scenario is that it comes from the Iranian plateau, and some of it went north through the Caucasus into the Pontic Caspian steppe. Is this the same migration path responsible for the "Armenian like" ancestry in Samara? From there it seems to go east to Ukraine, Hungary etc. and it looks to me as if it then went south into the Balkans, and from there to Greece and also southwest to Italy through the Balkans or,perhaps, mainland Greece. I think that has to be the path, doesn't it, for M67, as it is higher in North Central Italy than in southern Italy? So, rather than Cretan flow into Italy, it flowed south into Crete and perhaps, at least partly, separately, into Italy. This would explain the higher levels in Marche and Abruzzo, both in eastern Italy, and across the Adriatic from the Balkans and mainland Greece. There is also the documented trade route for that part of Italy with the Myceneans to consider, and the Mycenean gene flow into Crete. If J2a in general flowed into Anatolia, as well, it could then have gone west with Sea Peoples etc. I'm rather amazed that all of this J2a and J2b could be so recent in most of the Middle East. From Wiki: J-M67 (Called J2f in older papers) has its highest frequencies associated with Nakh peoples (http://en.wikipedia.org/wiki/Nakh_peoples). Found at very high (majority) frequencies among Ingush in Malgobek (87.4%), Chechens in Dagestan (58%), Chechens in Chechnya (56.8%) and Chechens in Malgobek, Ingushetia (50.9%) (Balanovsky 2011 (http://en.wikipedia.org/wiki/Haplogroup_J-M172#CITEREFBalanovsky2011)). In the Caucasus, it is found at significant frequencies among Georgians (13.3%) (Semino 2004 (http://en.wikipedia.org/wiki/Haplogroup_J-M172#CITEREFSemino2004)), Iron Ossetes (11.3%), South Caucasian Balkars (6.3%) (Semino 2004 (http://en.wikipedia.org/wiki/Haplogroup_J-M172#CITEREFSemino2004)), Digor Ossetes (5.5%), Abkhaz (6.9%), and Cherkess (5.6%) (Balanovsky 2011 (http://en.wikipedia.org/wiki/Haplogroup_J-M172#CITEREFBalanovsky2011)). It is also found at notable frequencies in the Mediterranean and Middle East, including Cretans (10.2%), North-central Italians (9.6%), Southern Italians (4.2%; only 0.8% among N. Italians), Anatolian Turks (2.7-5.4%), Greeks (4-4.3%), Albanians (3.6%), Ashkenazi Jews (4.9%), Sephardis (2.4%), Catalans (3.9%), Andalusians (3.2%), Calabrians (3.3%), Albanian Calabrians (8.9%) (see Di Giacomo 2004 (http://en.wikipedia.org/wiki/Haplogroup_J-M172#CITEREFDi_Giacomo2004) and Semino 2004 (http://en.wikipedia.org/wiki/Haplogroup_J-M172#CITEREFSemino2004)). Ed. I have to run through the papers when I have a chance...I've seen higher numbers than that in some southern Italian areas.
according to Genetiker BR2 is J2a1b-M67 these are Nakh people probably spreading from northeast Caucasus : J2a1-M67 is the most common subclade in the Caucasus (Vainakhs, Ingushs, Chechens, Georgians, Ossetians, Balkars) into all directions : the Levant (Lebanese, Jews). western India, the Arabian Peninsula, Anatolia (esp. north-west), Greece (esp. Crete), Italy (esp. Marche and Abruzzo) Per a post by Ted Kandell - "BR2 is a new Y-DNA subclade under J2a-CTS900*, and shares 42 SNPs with a 1000 Genomes Puerto Rican, HG01402. Both the SNPs and the STRs indicate that BR2 is in a new CTS6804- subclade which includes Georgians, Armenians, a North Italian, and Hispanics. " Do an Internet search of "Ancient Hungarian genome (BR2) Y-DNA and mtDNA" to find the post. CTS900 is on the YFull tree and it has the HG01402 individual.
Thanks, Bicicleur. In this regard, the recent paper on Middle Eastern J2 is interesting: Ancient Migratory Events in the Middle East:New clues from the Y Chromosome Variation of Modern Iranians http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0041252 This is a graphic from the paper: http://4.bp.blogspot.com/-xY5E4itZfp4/UAhdqN0yyII/AAAAAAAAFDY/PBV8g-b9jWE/s1600/journal.pone.0041252.g002.jpg Interestingly, it looks as if the highest frequency of J2a M67 is in Portugal. The question is, why? The spread is definitely east/west, no nonsense about it came from North Africa in the Mesolithic or Neolithic. It's also got something to do with the "Indo-European" metal age migrations, at least in eastern Europe, Greece and Italy. interesting to see the variance distributions according to the paper : while the high M67* variance in Central Italy is likely due to a stratification of seaborne migrations of Middle Eastern/Asia Minor peoples, the diversification observed in Iran and the Aegean Islands can be explained by a first Near Eastern, and possibly Anatolian, diffusion of the lineage followed by a Levantine expansion. according to wikipedia http://en.wikipedia.org/wiki/Nakh_peoples the origin of the Nakh people is not very clear there are theories about arrival from the fertile crescent as early as 8-10000 year BC IMO the Natufians were J2a, who started spreading agriculture (in a still very primitive form) from the Levant after the end of the youngest dryas (11600 years ago) Maybe J2a-M67 then split in some tribe staying in the Levant and another expanding over a large area - the Caucasus - Armenia - NW Iran Nakh people would be a remnant of this 2nd J2a-M67 tribe (the first tribe could have been part of the 1st neolithic expansion from the Levant to Cyprus 10800 years ago and Crete 9000 years ago) the BR2 sample would hint toward a much later expansion - late bronze age - from northern Caucasus via the Pontic steppe to the Balkans and further I know this is very speculative, I'm just figuring out a possible scenario. It doesn't take into account the expansion times estimates mentioned in the study. I have the feeling there are almost as many different expansion time estimates as there are different studies. ( I have little faith in them )
Thanks, Bicicleur. In this regard, the recent paper on Middle Eastern J2 is interesting: Ancient Migratory Events in the Middle East:New clues from the Y Chromosome Variation of Modern Iranians http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0041252 This is a graphic from the paper: http://4.bp.blogspot.com/-xY5E4itZfp4/UAhdqN0yyII/AAAAAAAAFDY/PBV8g-b9jWE/s1600/journal.pone.0041252.g002.jpg Interestingly, it looks as if the highest frequency of J2a M67 is in Portugal. The question is, why? The spread is definitely east/west, no nonsense about it came from North Africa in the Mesolithic or Neolithic. It's also got something to do with the "Indo-European" metal age migrations, at least in eastern Europe, Greece and Italy. I have to mull this over and look at some more papers but I doubt that it originated north of the Caucasus. The most likely scenario is that it comes from the Iranian plateau, and some of it went north through the Caucasus into the Pontic Caspian steppe. Is this the same migration path responsible for the "Armenian like" ancestry in Samara? From there it seems to go east to Ukraine, Hungary etc. and it looks to me as if it then went south into the Balkans, and from there to Greece and also southwest to Italy through the Balkans or,perhaps, mainland Greece. I think that has to be the path, doesn't it, for M67, as it is higher in North Central Italy than in southern Italy? So, rather than Cretan flow into Italy, it flowed south into Crete and perhaps, at least partly, separately, into Italy. This would explain the higher levels in Marche and Abruzzo, both in eastern Italy, and across the Adriatic from the Balkans and mainland Greece. There is also the documented trade route for that part of Italy with the Myceneans to consider, and the Mycenean gene flow into Crete. If J2a in general flowed into Anatolia, as well, it could then have gone west with Sea Peoples etc. I'm rather amazed that all of this J2a and J2b could be so recent in most of the Middle East. From Wiki: J-M67 (Called J2f in older papers) has its highest frequencies associated with Nakh peoples (http://en.wikipedia.org/wiki/Nakh_peoples). Found at very high (majority) frequencies among Ingush in Malgobek (87.4%), Chechens in Dagestan (58%), Chechens in Chechnya (56.8%) and Chechens in Malgobek, Ingushetia (50.9%) (Balanovsky 2011 (http://en.wikipedia.org/wiki/Haplogroup_J-M172#CITEREFBalanovsky2011)). In the Caucasus, it is found at significant frequencies among Georgians (13.3%) (Semino 2004 (http://en.wikipedia.org/wiki/Haplogroup_J-M172#CITEREFSemino2004)), Iron Ossetes (11.3%), South Caucasian Balkars (6.3%) (Semino 2004 (http://en.wikipedia.org/wiki/Haplogroup_J-M172#CITEREFSemino2004)), Digor Ossetes (5.5%), Abkhaz (6.9%), and Cherkess (5.6%) (Balanovsky 2011 (http://en.wikipedia.org/wiki/Haplogroup_J-M172#CITEREFBalanovsky2011)). It is also found at notable frequencies in the Mediterranean and Middle East, including Cretans (10.2%), North-central Italians (9.6%), Southern Italians (4.2%; only 0.8% among N. Italians), Anatolian Turks (2.7-5.4%), Greeks (4-4.3%), Albanians (3.6%), Ashkenazi Jews (4.9%), Sephardis (2.4%), Catalans (3.9%), Andalusians (3.2%), Calabrians (3.3%), Albanian Calabrians (8.9%) (see Di Giacomo 2004 (http://en.wikipedia.org/wiki/Haplogroup_J-M172#CITEREFDi_Giacomo2004) and Semino 2004 (http://en.wikipedia.org/wiki/Haplogroup_J-M172#CITEREFSemino2004)). Ed. I have to run through the papers when I have a chance...I've seen higher numbers than that in some southern Italian areas. "From there it seems to go east to Ukraine, Hungary etc. and it looks to me as if it then went south into the Balkans, and from there to Greece and also southwest to Italy through the Balkans or,perhaps, mainland Greece." I have two thoughts with J 1) North Euro I1 seems to me to have become attached to the northern branch of R1b at some point and expanded with them and I wonder if the same happened with J and the G farmers. If so and it arrived in Ukraine (from wherever) with farmers might some of those subsequent movements (if they are subsequent) have been a retreat from the steppe expansions? 2) Mountains and coasts make me think of mining and trade networks so the other thought is a culture somewhere at the center of a trade network with arms reaching out in various directions and small groups settled along those arms among other populations. If correct then one of the current hotspots for J2 may have been that original center or the main center got squished along the way (not surprising if it was the center of a trade network based on a valuable commodity) and the current distribution represents the orphaned branches of the original center. So the questions that pop into my mind based on those two thoughts are: 1) Are J2 hotspots always correlated with either E1 or G or not? 2) Are any of the current J2 hotspots in places that used to be the center of a valuable early trade good like obsidian, jadeitite, gold, silver, copper etc or alternatively do they create a branching pattern along ancient trade routes which could lead to deducing a possible center point that got squished? edit: for example in the second case (if it wasn't for such high frequencies in the Caucasus) i'd be thinking maybe somewhere between Crete or Sicily as a possible lost center point.
"From there it seems to go east to Ukraine, Hungary etc. and it looks to me as if it then went south into the Balkans, and from there to Greece and also southwest to Italy through the Balkans or,perhaps, mainland Greece." I have two thoughts with J 1) North Euro I1 seems to me to have become attached to the northern branch of R1b at some point and expanded with them and I wonder if the same happened with J and the G farmers. If so and it arrived in Ukraine (from wherever) with farmers might some of those subsequent movements (if they are subsequent) have been a retreat from the steppe expansions? 2) Mountains and coasts make me think of mining and trade networks so the other thought is a culture somewhere at the center of a trade network with arms reaching out in various directions and small groups settled along those arms among other populations. If correct then one of the current hotspots for J2 may have been that original center or the main center got squished along the way (not surprising if it was the center of a trade network based on a valuable commodity) and the current distribution represents the orphaned branches of the original center. So the questions that pop into my mind based on those two thoughts are: 1) Are J2 hotspots always correlated with either E1 or G or not? 2) Are any of the current J2 hotspots in places that used to be the center of a valuable early trade good like obsidian, jadeitite, gold, silver, copper etc or alternatively do they create a branching pattern along ancient trade routes which could lead to deducing a possible center point that got squished? edit: for example in the second case (if it wasn't for such high frequencies in the Caucasus) i'd be thinking maybe somewhere between Crete or Sicily as a possible lost center point. 10.4% of this marker is in the italian alps as per coia 2013 paper...........more so with G than E , but its not unreasonable if the J was middle-east branch instead of the Caucasus branch like the raetics
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Double-blind injectable hydromorphone versus diacetylmorphine for the treatment of opioid dependence: A pilot study | Request PDF
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Article
Double-blind injectable hydromorphone versus diacetylmorphine for the treatment of opioid dependence: A pilot study
March 2010 Journal of Substance Abuse Treatment 38(4):408-11
DOI: 10.1016/j.jsat.2010.03.003
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Eugenia Oviedo-Joekes
University of British Columbia - Vancouver
Daphne Guh
Daphne Guh
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Suzanne Brissette
Suzanne Brissette
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David C Marsh
Northern Ontario School of Medicine
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... Lastly, injectable hydromorphone should be evaluated as an alternative to diamorphine. The Canadian NAOMI study, a double-blind study with injectable hydromorphone and diamorphine, demonstrated that patients were unable to detect which one they received (71)
. The authors stated: "the fact that most patients in the hydromorphone group thought they were receiving heroin suggests that hydromorphone can effectively treat and retain opioid-dependent individuals" (71). ...
... The Canadian NAOMI study, a double-blind study with injectable hydromorphone and diamorphine, demonstrated that patients were unable to detect which one they received (71). The authors stated: "the fact that most patients in the hydromorphone group thought they were receiving heroin suggests that hydromorphone can effectively treat and retain opioid-dependent individuals" (71)
. The SALOME study provided evidence that the injectable hydromorphone was non-inferior to diamorphine for longterm opioid use disorders (72). ...
Switzerland’s Dependence on a Diamorphine Monopoly
Article Full-text available
May 2022
Caroline Schmitt-Koopmann Carole-Anne Baud Valerie Junod Olivier Simon
In 2021, the manufacturer of diamorphine reported a possible impending shortage for Switzerland and Germany. This led us to investigate this controlled medicine’s manufacture, market, and regulatory constraints. Based on our analysis of legal texts and gray literature in the form of reports and documents, we propose recommendations to prevent and address diamorphine shortages in Switzerland. Diamorphine, also known as pharmaceutical “heroin,” is used medically to treat persons with severe opioid use disorder in a handful of countries. The controlled medicine is manufactured from morphine, which, in turn, is extracted from opium poppies. Studying data from the International Narcotics Control Board for 2019, we find that Switzerland accounts for almost half of the worldwide medical consumption of diamorphine. It manufactures more than half of the worldwide total and keeps the largest stocks. Moreover, Switzerland is dependent on a sole supplier of diamorphine (monopoly). As a niche product, diamorphine has an increased risk of shortage. Such a shortage would immediately threaten a valuable public health program for around 1,660 Swiss patients. We believe it is urgent to curtail the monopoly and ensure a stable supply for the future.
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... The putative pharmacological similarities between heroin and hydromorphone have led to hydromorphone being evaluated as an alternative to heroin maintenance. A pilot study that randomized treatment-resistant methadone patients to maintenance on heroin (N = 115) or hydromorphone (N = 25) reported similar improvements in retention and illicit opioid use for both groups at the end of 12 months, with no medication-based differences in adverse event profiles (Oviedo-Joekes et al. 2010)
. A subsequent randomized, double-blind trial that assigned patients to have maintenance on heroin (N = 102) or hydromorphone (N = 100) for a 6month period also reported equivalent retention and illicit drug outcomes for the two groups (Oviedo-Joekes et al. 2016). ...
... X-axis represents baseline (BL) and minutes post-dose, Y-axis represents mean peak rating averaged across subjects monetary values to the two drugs on the Drug versus Money Questionnaire, suggesting that the subjectivelydetected differences in drug effects were not of sufficient value to influence ratings of drug abuse liability. These results are in contrast to hydromorphonemaintenance trials, wherein patients who were randomized to heroin or hydromorphone maintenance were unable to accurately identify which medication they had received (Oviedo-Joekes et al. 2010
. The fact that subjects in those studies were physically-dependent, with higher tolerance levels than those in the current study, and were not rewarded for correct drug identification likely contributed to these differences. ...
Characterizing the subjective, observer-rated, and physiological effects of hydromorphone relative to heroin in a human laboratory study Article Full-text available
Apr 2018 PSYCHOPHARMACOLOGY
Kelly E Dunn Bruna Brands George E. Bigelow David C Marsh
Background
This study compared the effects of the several doses of the opioid agonists heroin and hydromorphone across two routes of administration in humans. The goal was to guide development of human laboratory studies of opioid effects and inform subsequent injection pharmacotherapy trials of hydromorphone-assisted treatment. MethodsA within-subject (N = 16), double-blind, double-dummy, placebo-controlled, evaluation of acute doses of heroin and hydromorphone was completed at four dose levels (placebo, low, medium, high) across two routes of administration (intravenous, subcutaneous) in non-physically dependent, opioid-experienced individuals. Subject and observer ratings, as well as physiological outcomes, were assessed. ResultsWithin each route of administration, heroin and hydromorphone produced effects that were qualitatively similar on most variables across the doses examined. All effects were dose-dependent. The drugs produced different effects on VAS ratings of “Feels Like Heroin,” a Heroin Identification Test, observer agonist ratings, and oxygen saturation levels. Drug-dependent differences emerged at the highest doses in all cases. Few significant main effects of Route were identified and their pattern was not uniform. Relative potency calculations across all subject, observer, and physiological outcomes that met analysis criteria revealed similar profiles and resulted in mean heroin:hydromorphone potencies of 3.35:1 and 2.88:1 for the intravenous and subcutaneous routes, respectively, and intravenous:subcutaneous potencies of 0.47:1 and 0.49:1 for heroin and hydromorphone, respectively. Conclusions
Hydromorphone produced similar subjective and physiological effects as heroin, but was more potent than heroin. The current findings support the use of hydromorphone as a model for heroin in human laboratory and clinical treatment studies, and help identify appropriate hydromorphone dose conversion ratios to produce effects qualitatively similar to heroin.
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... This treatment regimen is in accordance with provincial clinical guidance for iOAT and has been described in other recent case reports among people who use fentanyl [22][23][24][25]. Several randomized trials (such as the North American Opiate Medication Initiative (NAOMI) [26] and the Study to Assess Longer-term Opioid Medication Effectiveness (SALOME) [27]) have shown that iOAT is feasible, safe, and effective when treating individuals with long-term chronic injection opioid use and for whom the available medications for OUD have not been effective [28][29] [30]
. In addition, flexible doses of oral OAT for management of OUD are typically provided to patients receiving iOAT, as long-acting opioid such as SROM can help to reduce iOAT dose, frequency of daily injections, and reduce the severity of withdrawal symptoms by providing background 24-h opioid receptor saturation [22,23]. ...
Case report: acute care management of severe opioid withdrawal with IV fentanyl Article Full-text available
Dec 2022
Pouya Azar Jean Westenberg Martha J. Ignaszewski Michael Krausz
Background
An increasing number of individuals who use drugs in North America are preferentially consuming fentanyl over other opioids. This has significant consequences on the treatment and management of opioid use disorder (OUD) and its concurrent disorders, especially in acute care if opioid requirements are not met.
Case presentation
We present a patient with severe OUD and daily injection of fentanyl, admitted to hospital for management of acute physical health issues. Due to high opioid requirements and history of patient-initiated discharge, intravenous fentanyl was administered for treatment of opioid withdrawal, and management of pain, which supported continued hospitalization for acute care treatment and aligned with substance use treatment goals.
Conclusion
This case demonstrates that intravenous fentanyl for management of OUD in hospital can be a feasible approach to meet opioid requirements and avoid fentanyl withdrawal among patients with severe OUD and daily fentanyl use, thereby promoting adherence to medical treatment and reducing the risk of patient-initiated discharge. There is an urgent need to tailor current treatment strategies for individuals who primarily use fentanyl. Carefully designed research is needed to further explore the use of IV fentanyl for acute care management of severe opioid withdrawal in a hospital setting.
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... L'effi cacité du traitement par agonistes opioïdes injectable a été démontrée dans le cadre de plusieurs essais contrôlés randomisés dans six pays (Suisse, Pays-Bas, Espagne, Allemagne, Canada, Royaume-Uni) en termes de rétention en traitement, de réduction de la consommation d'héroïne, de diminution de la criminalité et d'une possible réduction de la mortalité (Demaret et al., 2010;Ferri et al., 2010;Strang et al., 2012; Oviedo-Joekes et al., 2010a)
. À l'heure actuelle, le TAO injectable a été rendu dans le cadre de recherches ou de programmes dans huit pays, tel qu'en témoigne la carte ci-dessous. ...
Vers une offre de traitement par agonistes opioïdes (TAO) injectable au Québec ? Disponible sur le site du colloque TDO6: https://tdo6.ca/vers-une-offre-de-traitement-par-agonistes-opioides-tao-injectable-au-quebec/ Poster
Mar 2021
Léonie Archambault Michel Perreault
Marie-Ève Goyer
View
... There are only two randomized controlled trials on hydromorphone. Findings are promising, suggesting that outcomes are no different from HAT in treating long-term OUD (Oviedo-Joekes et al., 2016; Oviedo-Joekes et al., 2010)
. There also have been some studies suggesting that extended-release morphine could be beneficial for some OUD patients (Wells and Jones, 2017). ...
The Future of Fentanyl and Other Synthetic Opioids
Book
Jan 2019
Bryce Pardo Jirka Taylor Jonathan Caulkins Bradley Stein
View
... From these findings emerged a new treatment modality, now available in Canada and some European countries: heroinassisted treatment (HAT). Injected hydromorphone has also been trialed and appears to be of similar efficacy as injected heroin (61)
. ...
Medication Treatment of Opioid Use Disorder
Article
Jul 2019 BIOL PSYCHIAT
James R Bell John Strang
Opioid use disorder (OUD) is a chronic, relapsing condition, often associated with legal, interpersonal, and employment problems. Medications demonstrated to be effective for OUD are methadone (a full opioid agonist), buprenorphine (a partial agonist), and naltrexone (an opioid antagonist). Methadone and buprenorphine act by suppressing opioid withdrawal symptoms and attenuating the effects of other opioids. Naltrexone blocks the effects of opioid agonists. Oral methadone has the strongest evidence for effectiveness. Longer duration of treatment allows restoration of social connections and is associated with better outcomes. Treatments for OUD may be limited by poor adherence to treatment recommendations and by high rates of relapse and increased risk of overdose after leaving treatment. Treatment with methadone and buprenorphine has the additional risk of diversion and misuse of medication. New depot and implant formulations of buprenorphine and naltrexone have been developed to address issues of safety and problems of poor treatment adherence. For people with OUD who do not respond to these treatments, there is accumulating evidence for supervised injectable opioid treatment (prescribing pharmaceutical heroin). Another medication mode of minimizing risk of overdose is take-home naloxone. Naloxone is an opioid antagonist used to reverse opioid overdose, and take-home naloxone programs aim to prevent fatal overdose. All medication-assisted treatment is limited by lack of access and by stigma. In seeking to stem the rising toll from OUD, expanding access to approved treatment such as methadone, for which there remains the best evidence of efficacy, may be the most useful approach.
View Show abstract
... Two studies comparing supervised injectable heroin to other injectable opioids found insignificant differences for treatment retention. The NAOMI trial had a small double-blind pilot arm comparing supervised injectable heroin to supervised injectable hydromorphone
(Oviedo-Joekes et al., 2010b)
. Retention rates at 12-months were 88% for both groups. ...
Evidence on the Effectiveness of Heroin-Assisted Treatment
Book
Jan 2018
Rosanna Smart
View
... Also, an already registered medication will likely not attract the kinds of negative publicity that prescription of (pharmaceutical) heroin did. Yet, while studies have demonstrated that participants were unable to distinguish between injectable diacetylmorphine and hydromorphone
(Oviedo-Joekes, Guh et al., 2010)
, and hydromorphone has yielded comparable results to injectable diacetylmorphine (Oviedo-Joekes et al., 2016), no study has examined provision of open-label hydromorphone so far. It would be interesting to assess whether participants are equally attracted to hydromorphone and retained in treatment as they were in the Canadian RCT (Oviedo-Joekes et al., 2016) when there was a 50% probability of receiving diacetylmorphine. ...
Learning from the past, looking to the future - Is there a place for injectable opioid treatment among Australia’s responses to opioid misuse? Article
Apr 2019 INT J DRUG POLICY
Allison M Salmon Marianne Jauncey
Vendula Belackova James R Bell
In the 1990s, a trial of prescribing pharmaceutical heroin for people with opioid-dependence had support from Australian State Health Ministers. However, in 1997 the proposal was vetoed by the federal Prime Minister in face of a negative tabloid media campaign. The debate then shifted to abstinence-orientated treatments. Later on, reduced heroin availability took opioid-related harms away from public sight. In this commentary, we aimed to explore the current need and the options to implement such program, lately referred to as supervised injectable opioid treatment (SIOT), in Australia. We argue that with the aging populations of opioid-dependent people who have not benefited from existing treatment options, increased misuse of prescription opioids, rising overdose rates, and the risk of unfolding overdose crisis, it seems timely to pilot SIOT here. Since the 1990s, seven RCTs as summarised in two systematic literature reviews, demonstrated that SIOT is effective for treatment-resistant opioid dependence. A sustainable SIOT model should, however, respond to key concerns related to its delivery, such as the lack of a patient exit strategy and the high cost of indefinite treatment. Evidence from long-term studies seem to support the notion that SIOT could be provided as a medium duration treatment (as opposed to short-term or indefinite), with the clear aim to stabilise patients, gradually wean them off injectable medication and transfer to opioid assisted treatment (OAT). Also, SIOT could be integrated into the existing public OAT clinics in Australia. This would reduce costs, but also provide a more patient-centred response to opioid dependence and further improve the acceptability and efficiency of OAT. The controversy that developed in the past should be mitigated by advances in research since the first Australian enquiry, use of a registered medication (open-label hydromorphone) rather than pharmaceutical heroin, and setting up clear treatment aims.
View Show abstract
... Published data from this pilot study revealed higher levels of overall user satisfaction, suggesting that both pharmaceutical heroin and injectable hydromorphone (i.e. Dilaudid © ) can 'effectively treat and retain opioid-dependent individuals currently outside the addiction treatment system' [94]
. The institutionalization of heroin-assisted treatment (HAT) thus represents a second clear recommendation from this research [4,34]. ...
Playing (Un)Dead: Interrogating Invocations of 'Monster' Metaphors in (Post-)MMT Service User Narratives of Methadone, Maintenance and Treatment Article Full-text available
Aug 2018
Christopher B. R. Smith
Background: From social productivity to social costs to clinical stability, traditional outcome measurements employed in methadone maintenance treatment (MMT) serve to reinforce binary oppositions between sickness and health, ‘dirty’ and ‘clean’, stable and chaotic, life and death. Such binaries thus position the (post-)MMT service user according to a series of fixed axes that are in turn reproduced in popular and professional discourse. Destabilizing these binaries, ‘monster’ - and particularly zombie or ‘undead’- metaphors have been a persistent feature of MMT culture since its inception in the 1960s. This paper thus argues that metaphorical invocations of zombies in (post-)MMT service user discourse functions as a regenerative trope, eroding the binary foundations of MMT. Methods: Based on a comparative, qualitative, ethnographic analysis of two high-volume methadone clinics - one in Toronto, Canada and the second in Philadelphia, Pennsylvania (U.S.A.), this paper draws from qualitative interviews with 20 (post-)MMT service users, broadly defined as individuals with experience of methadone tapering or treatment discontinuation. Results: Analysis reveals three primary contextual deployments of zombie metaphors in (post-)MMT service user discourse, functioning as (1) A tactic of boundary negotiation; (2) A tool of critique; and (3) A means of articulating post-treatment ‘after-lives’. Conclusion: ‘Undead’ and/or monster metaphors in (post-)MMT service user narratives represent both a product of – and a destabilizing threat to – the binary foundations of traditional MMT discourse. Revealing a range of liminal subject positions in the reductive ‘life and death’ stakes of methadone treatment, findings reveal how undead metaphors embody a reflexive space through which users re-negotiate identity, agency and autonomy. Exhuming users’ agency and ‘political pharmacology’, analysis demonstrates three interrelated themes characterizing users’ tactical discursive deployments of the undead: (1) Relapse as resistance; (2) Recovery as radical reassertion of autonomy; and (3) Harm reduction as anarchist practice.
View Show abstract
... Canadian investigators undertook a double-blind RCT (the SALOME trial) comparing SIOT with DAM and with hydromorphone [39]. The study persuasively confirmed a previous finding [66]
that experienced heroin users randomised to hydromorphone could not tell they were not receiving DAM. In terms of the primary outcome, hydromorphone did not meet the criterion for non-inferiority, as the DAM group reported slightly lower days of street heroin use; 5.50 days (95% CI 3.81-7.34), ...
Supervised Injectable Opioid Treatment for the Management of Opioid Dependence Article
Aug 2018
James R Bell Vendula Belackova
Nicholas Lintzeris
Since the 1990s, there have been seven clinical trials, and considerable clinical experience, in supervised injectable opioid treatment (SIOT) for individuals who, despite previous treatments, continue to inject illicit heroin and experience harmful health and social consequences. Most studies prescribed pharmaceutical heroin (diacetyl morphine, or DAM). This paper critically reviews randomised trials, long-term follow-up studies and qualitative reports of SIOT, and briefly reviews evidence regarding other medications used in injectable treatment as an alternative to DAM. It seeks to identify critical, unresolved issues regarding this treatment. Randomised trials comparing DAM with oral methadone (OM) report that while in treatment, participants randomised to DAM used less street heroin; reported spending less money on drugs, committed fewer crimes, and experienced improved health. Similar findings pertain to SIOT with hydromorphone. Because of the risks of overdose, diversion, and misuse, all recent trials of injected DAM involved supervised administration. This contributes to treatment being expensive to deliver. There is conflicting evidence regarding societal cost effectiveness, with some studies estimating that the reduction in crime more than compensates for the expense of the treatment. The critical, unresolved issues concerning this modality of treatment relate to the way in which it is approached—either as a medium-term, intensive intervention where other treatment has failed, designed to bring people into conventional opioid agonist treatment (OAT); or an indefinite support aimed at reducing social and personal harm. The former seems in line with the available findings on long-term effectiveness of SIOT and might be more acceptable given its rather moderate cost.
View Show abstract
... However, this finding should not discourage the careful use of such medications in patients with refractory OUD. [25]
[26][27] A key limitation of this review is that it only considered randomized controlled trials, which limited both the number of studies and types of interventions that could be reviewed. For example, we did not identify trials that primarily investigated nonpharmacological strategies, such as psychotherapies and harm reduction intervention. ...
Opioids on Trial: A Systematic Review of Interventions for the Treatment and Prevention of Opioid Overdose Article Full-text available
Mar 2018
Anees Bahji Neeraj Bajaj
Background: Canada is in the midst of an opioid epidemic. In 2016, there were more than 2800 apparent opioid-related deaths. Although improved access to naloxone has saved countless lives, it is unclear if there are other effective pharmacological or nonpharmacological interventions for the treatment and prevention of opioid overdose. In this systematic review, we aim to synthesize published findings on such interventions. Methods: We searched 5 electronic databases for randomized controlled studies using either pharmacological or nonpharmacological interventions to treat or prevent opioid overdose, and subsequently extracted and synthesized data from appropriate studies. Results: Twelve studies met our inclusion criteria. Naloxone, nalmefene, and physostigmine were effective in reversing opioid overdose, whereas naltrexone was effective in preventing opioid overdose. Opioid agonists, including methadone, buprenorphine, and diacetylmorphine, were effective in improving secondary outcomes with variable effects on overdose prevention. No trials using primarily nonpharmacological interventions were identified. Conclusions: In this systematic review, naloxone, nalmefene, and physostigmine emerged as effective in treating opioid overdose, whereas naltrexone showed evidence in preventing opioid overdose. Opioid agonists were found to be effective in improving retention in treatment and in reducing illicit opioid use. Pharmacological interventions play a key role in addressing the opioid epidemic; however, evidence for a multidisciplinary approach involving harm reduction and addressing psychosocial barriers could be the topic of subsequent literature reviews.
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... de (M. Gahr) (heroin) (Ferri, Davoli, & Perucci, 2011), (dihydro-)codeine (Hall & Mattick, 2007), hydromorphone
(Oviedo-Joekes et al., 2010)
, naltrexone (an antagonist at μ-, κ-, and σ-opioid receptors) (Krupitsky et al., 2011) and slow-release oral morphine (Beck et al., 2014) are also in use for ORT or studied for this indication. However, methadone (respectively levomethadone in Europe) is by far the most frequently used agent in ORT (Bell, 2014), followed by buprenorphine formulations (Nguyen et al., 2013). ...
Drug safety and adverse drug reaction reporting behavior related to outpatient opioid replacement therapy: Results from a survey among physicians Article
Dec 2016 J SUBST ABUSE TREAT
Maximilian Gahr J. Eller Maurice Cabanis
Carlos Schönfeldt-Lecuona
To study drug safety and the reporting behavior of adverse drug reactions (ADR) related to agents used for opioid replacement therapy (ORT) we conducted a cross-sectional questionnaire-based telephone survey among physicians who provide outpatient ORT in Germany (n = 176; response rate = 55.7%). Most respondents (n = 97/55.1%) reported that they observe ADR related to buprenorphine, (dihydro)codeine, and (levo)methdone rarely (n = 38/21.6%), very rarely (n = 39/22.2%) or never (n = 20/11.4%). Methadone was reported to be most frequently associated with the occurrence of ADR (n = 82/46.6%), followed by levomethadone (n = 33/18.8%), buprenorphine (n = 6/3.4%), and dihydrocodeine (n = 3/1.7%). Frequently observed ADR related to these agents were gastrointestinal, nervous system/psychiatric disorders, and hyperhidrosis. Methadone and levomethadone (not buprenorphine) were frequently associated with fatigue, weight gain, and sexual dysfunction. Hundred twenty nine participants (73.3%) stated that they never report ADR related to ORT; n = 19 (10.8%) did so when referring to ADR related to their complete medical practice (X² = 141.070; df = 1; p < 0.001). Similar patterns of ADR related to outpatient ORT as those reported in the product information or in pain therapy were found. Motivation to report ADR related to ORT may be reduced compared to ADR related to the general medical practice.
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... For example, retention and response rates for the HDM group were 88% and 64% respectively compared to 87.8% and 67%.0 in the DAM group. Regarding the use of illicit heroin in the prior month, from baseline to the end of the study, it decreased from 26.6 to 5.3 days in the DAM group and from 26.3 to 5.2 days in the HDM group 60
. ...
Hydromorphone Compared With Diacetylmorphine for Long-term Opioid Dependence: A Randomized Clinical Trial Article
Apr 2016
MSc1 Daphne Guh MD3 Suzanne Brissette
Eugenia Oviedo-Joekes Martin T Schechter
Importance:
Diacetylmorphine hydrochloride (the active ingredient in heroin), delivered under supervision, is effective for the treatment of severe opioid use disorder. However, owing to political and regulatory barriers, it is not available in many settings around the world, which limits the options for many long-term street opioid injectors not attracted into or retained in available treatments.
Objective:
To test if injectable hydromorphone hydrochloride is noninferior to injectable diacetylmorphine in reducing illicit heroin use for chronic injection opioid users after 6 months of intervention.
Design, setting, and participants:
The Study to Assess Longer-term Opioid Medication Effectiveness (SALOME) was a phase 3, double-blind, noninferiority trial. The study randomized 202 long-term street opioid injectors in Vancouver, British Columbia, Canada. Eligible participants were recruited between December 19, 2011, and December 18, 2013. Both intent-to-treat (ITT) and per-protocol (PP) analyses were conducted.
Interventions:
Participants were randomly assigned to receive injectable diacetylmorphine or hydromorphone (up to 3 times daily) for 6 months under supervision.
Main outcomes and measures:
Primary and coprimary efficacy outcomes were self-reported days of street heroin use (primary), days of any street-acquired opioids in the prior 30 days (noninferiority margin, 4 days), and the proportion of urinalyses positive for street heroin markers (margin, 10% of the observed rate in the diacetylmorphine group). The mean differences between diacetylmorphine and hydromorphone for the ITT and PP analyses were reported.
Results:
The study included 202 participants; 100 randomized to receive hydromorphone and 102 to diacetylmorphine. Their mean (SD) age was 44.33 (9.63) years, and 30.7% (62 of 202) were women. Noninferiority of hydromorphone was confirmed in the PP analysis (-1.44; 90% CI, -3.22 to 0.27) for street heroin use, although the margin of 4 days was not excluded in the ITT analysis (-2.34; 90% CI, -4.14 to -0.52). Noninferiority was confirmed for any street opioids in the ITT analysis (-0.85; 90% CI, -2.97 to 1.25) and the PP analysis (-0.15; 90% CI, -2.09 to 1.76), as well as for the urinalyses (0.09; 90% CI, -0.02 to 0.19 for the ITT analysis and 0.13; 90% CI, 0.02-0.24 for the PP analysis). There were 29 SAEs considered to have some relationship with the injection medication, 5 in the hydromorphone group and 24 in the diacetylmorphine group (rate ratio, 0.21; 95% CI, 0.06-0.69). Seizures and overdoses accounted for 25 of the 29 related SAEs.
Conclusions and relevance:
This study provides evidence to suggest noninferiority of injectable hydromorphone relative to diacetylmorphine for long-term opioid dependence. In jurisdictions where diacetylmorphine is currently not available or for patients in whom it is contraindicated or unsuccessful, hydromorphone could be offered as an alternative.
Trial registration:
clinicaltrials.gov Identifier: NCT01447212.
View Show abstract
... Metha- don wurde zwar im Rahmen der schweizerischen Kohorten- studie PROVE bereits in den 90er Jahren untersucht ( Steffen et al. 1999), bei allerdings nicht darauf ausgerichteter Me- thodik. Hydromorphon war für PatientInnen in einer ver- blindeten Studie nicht von Diacetylmorphin zu unterschei- den (
Oviedo-Joekes et al. 2010
). Auch andere Substanzen sollten in ihrer Wirksamkeit überprüft werden. ...
The future of heroin assisted treatment from a clinical point of view
Article
Jan 2013
Johannes Strasser Marc Vogel
Heroin assisted treatment (HAT) of patients with severe opioid dependence is scientifically and politically established in Switzerland. However, further development is necessary in order to meet the challenges of the future. We begin our article with a discussion of recent emerging problems. Foremost, the aging cohort will lead to complex psychiatric, medical and ethical questions. The management of chronic disease is related to this development. Furthermore, we describe the need for an expansion of pharmaceutical forms and opioid agonists in opioid maintenance treatment. Already, oral diacetylmorphine is prescribed to more than a third of Swiss patients in HAT. We discuss the need for research on characteristics and effectiveness of other maintenance substances in order to enable an individualized treatment. Lastly, we argue that the HAT setting could be expanded for research on maintenance treatment of other substance use disorders such as severe cocaine or stimulant dependence, in the sense of a "Treatment with substances with rapid onset of action". © ecomed Medizin, Verlagsgruppe Hüthig Jehle Rehm GmbH, Landsberg.
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... 36 Six-month MAT retention rates were also comparable (48%) for patients with chronic non-malignant pain who received either methadone or buprenorphine/naloxone. 37 High 12-month retention rates (88%) were found among treatment-refractory patients treated with either diacetylmorphine (the active ingredient of heroin) or hydromorphone (a semisynthetic opioid analgesic). 38
In another study, patients' 1-month retention in MAT did not differ according to whether they received direct or indirect induction of buprenorphine/naloxone. 39 Several studies failed to find significant effects on MAT retention for medications provided in addition to a primary opiate medication. In one, 3-month retention among patients receiving oral naltrexone did not differ according to whether they received varying doses of Memantine (a dementia drug) or a placebo (retention rates of ≥19%). ...
Retention in Medication-Assisted Treatment for Opiate Dependence: A Systematic Review Article Full-text available
Oct 2015 J ADDICT DIS
Christine Timko Nicole R Schultz
Michael A. Cucciare Christina Garrison-Diehn
Retention in medication-assisted treatment (MAT) among opiate-dependent patients is associated with better outcomes. This systematic review (55 articles, 2010-2014) found wide variability in retention rates (i.e., 19%-94% at 3-month, 46%-92% at 4-month, 3%-88% at 6-month, and 37%-91% at 12-month follow-ups in randomized controlled trials), and identified medication and behavioral therapy factors associated with retention. As expected, patients who received naltrexone or buprenorphine had better retention rates than patients who received placebo or no medication. Consistent with prior research, methadone was associated with better retention than buprenorphine/naloxone. And, heroin-assisted treatment was associated with better retention than methadone among treatment-refractory patients. Only a single study examined retention in MAT for longer than one year, and studies of behavioral therapies may have lacked statistical power; thus, studies with longer-term follow-ups and larger samples are needed. Contingency Management showed promise to increase retention, but other behavioral therapies to increase retention, such as supervision of medication consumption, or additional counseling, education, or support, failed to find differences between intervention and control conditions. Promising behavioral therapies to increase retention have yet to be identified.
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... Finally, while various research -including secondary findings from the present study -has demonstrated the protective effect of methadone maintenance treatment on overdose (Brugal et al., 2005;Caplehorn et al., 1996;Kerr et al., 2007;Schwartz et al., 2013), retention in methadone treatment has long been a challenge among opioid users in British Columbia (Anderson and Warren, 2004). While methadone is the dominant opioid substitution therapy (OST) in this setting, promising second-line therapies such as diacetylmorphine (Oviedo-Joekes et al., 2009;Strang et al., 2010), hydromorphone
(Oviedo-Joekes et al., 2010)
, and morphine (Hammig et al., 2014) have the potential to reduce overdose rates through improving treatment engagement and retention; however, widespread implementation of these programs has not received adequate political attention . Further research is required to understand how engagement and retention rates for different OST programs may differ across groups of people who inject POs (both primarily and occasionally) and those who use heroin in this type of population. ...
The Effect Of Prescription Opioid Injection On The Risk Of Non-Fatal Overdose Among People Who Inject Drugs Article
Sep 2015
Stephanie Lake Kanna Hayashi
Jane Buxton Thomas Kerr
Objectives:
Prescription opioid (PO) use by people who inject drugs (PWID) is a growing public health concern. Non-fatal overdose remains a leading source of morbidity among PWID, however, little is known about the relationship between PO injection and non-fatal overdose in this population. In this study we sought to examine the impact of PO injection on non-fatal overdose among PWID from Vancouver, Canada.
Methods:
Data were derived from two open prospective cohorts of PWID for the period of December, 2005 to May, 2014. Multivariable generalized estimating equations were used to examine the odds of overdose among those who injected: POs; heroin; and POs and heroin.
Results:
In total, 1660 PWID (33.7% women) participated in this study. In multivariable analyses, in comparison to those who were injecting non-opioid drugs, exclusive PO injection was not significantly associated with non-fatal overdose (adjusted odds ratio [AOR]: 1.17, 95% confidence interval [CI]: 0.74-1.86). The odds of non-fatal overdose were elevated for heroin injection (AOR: 1.72, 95% CI: 1.31-2.27), but were greatest for those who injected both heroin and POs (AOR: 2.46, 95% CI: 1.83-3.30).
Discussion:
Compared to injecting non-opioids, injecting POs exclusively did not increase risk of non-fatal overdose; however, injecting both POs and heroin doubled the risk. This may reflect consistencies in drug potency and composition when POs are used, as well as unique characteristics of exclusive PO injectors. Our findings call for the continued scale-up of evidence-based overdose prevention interventions for people who inject opioids, including POs.
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... There is a clear need for alternative treatments as effective as injectable DAM that health care systems could adopt to attract and retain long-term street opioid injectors into treatment. One such alternative could be HDM [5]
and the SALOME (Study to Assess Long-term Opioid Medication Effectiveness) study was designed to test this. SALOME is a randomized double blind controlled trial testing if injectable HDM (a licenced pain medication) is as effective as DAM for the treatment of long-term opioid-dependent individuals who are not benefitting sufficiently from conventional treatments, and if a transition to the oral equivalent of HDM and DAM after six-months is as effective as the injection form. ...
The SALOME study: Recruitment experiences in a clinical trial offering injectable diacetylmorphine and hydromorphone for opioid dependency Article Full-text available
Jan 2015 SUBST ABUSE TREAT PR
Kurt Lock Eugenia Oviedo-Joekes
Kirsten Marchand Martin T Schechter
The Study to Assess Long-term Opioid Medication Effectiveness (SALOME) is a two-stage phase III, single site (Vancouver, Canada), randomized, double blind controlled trial designed to test if hydromorphone is as effective as diacetylmorphine for the treatment of long-term illicit opioid injection. Recruiting participants for clinical trials continues to be a challenge in medical and addiction research, with many studies not being able to reach the planned sample size in a timely manner. The aim of this study is to describe the recruitment strategies in SALOME, which offered appealing treatments but had limited clinic capacity and no guaranteed post-trial continuation of the treatments.
SALOME included chronic opioid-dependent, current illicit injection opioid users who had at least one previous episode of opioid maintenance treatment. Regulatory approvals were received in June 2011 and recruitment strategies were implemented over the next 5 months. Recruitment strategies included ongoing open communication with the community, a consistent and accessible team and participant-centered screening. All applicants completed a pre-screening checklist to assess prerequisites. Applicants meeting these prerequisites were later contacted to commence the screening process.
A total of 598 applications were received over the two-year recruitment period; 130 were received on the first day of recruitment. Of these applicants, 485 met prerequisites; however, many could not be found or were not reached before recruitment ended. For the 253 candidates who initiated the screening process, the average time lapse between application and screening date was 8.3 months (standard deviation [SD] = 4.44) and for the 202 randomized to the study, the average processing time from initial screen to randomization was 25.9 days (SD = 37.48; Median = 15.0).
As in prior trials offering injectable diacetylmorphine within a supervised model, recruiting participants for this study took longer than planned. The recruitment challenges overcome in SALOME were due to the high number of applicants compared with the limited number that could be randomized and treated. Our study emphasizes the value of integrating these strategies into clinical addiction research to overcome study-specific barriers.Trial registration: ClinicalTrials.gov: NCT01447212.
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... These medications have shown efficacy only in clinical trials. Other treatment paradigms shown in pilot clinical trials include the use of slow-release oral morphine (Substitol ® ) [44], hydromorphone and diacetylmorphine [45]
. Heroin-assisted treatment programs have been studied in Austria, Belgium, Canada, France, Germany, Spain, Switzerland, the United Kingdom and the Netherlands [46]. ...
International Expansion of the Use of Pharmacotherapies for the Treatment of Opioid Dependence Article Full-text available
Jan 2012
Thomas F Kresina
Until recently, the global availability and consumption of opioid agonists and psychotropic medications have been below the levels needed for research to demonstrate local efficacy and to develop local evidence-based best medical practices. In addition, the global availability and use of opioid agonists and psychotropic medications have not been sufficient to implement the well documented efficacy shown for the treatment of opioid dependence that has been developed by research over the last 40 years. This strong research base has resulted in the development of evidence-based medical practices, such as Medication Assisted Treatment (MAT) for opioid dependence. The recognition of MAT as an effective medical treatment for opioid abuse and dependence has resulted in a substantial global increase in the medical use of opioid agonists and psychotropic medications to address opioid dependence. This increase is particularly evident in the initiation of new MAT programs in regions of Europe, North America, Africa, Asia and Oceania. While in other regions of the world, the medical use of opioid agonists and psychotropic medications have not substantially increased, the implementation of MAT programs have begun as part of the global effort to reduce HIV/AIDS. These HIV prevention programs have utilized MAT as an element of programs that target injection drug users to reduce their risk of both acquiring and transmitting HIV infection. Thus, this article documents the recent international expansion of the use of MAT for opioid dependence as a result of efforts to increase access and availability of evidence based treatments for opioid dependence as well as efforts to reduce the spread of infectious diseases, such as HIV/AIDS.
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... Methadon wurde zwar im Rahmen der schweizerischen Kohortenstudie PROVE bereits in den 90er Jahren untersucht ( Steffen et al. 1999), bei allerdings nicht darauf ausgerichteter Methodik. Hydromorphon war für PatientInnen in einer verblindeten Studie nicht von Diacetylmorphin zu unterscheiden (
Oviedo-Joekes et al. 2010
). Auch andere Substanzen sollten in ihrer Wirksamkeit überprüft werden. ...
Die Zukunft der heroingestützten Behandlung aus klinischer Sicht in der Schweiz [The future of heroin assisted treatment from a clinical point of view] Article
Jan 2013
Johannes Strasser Marc Vogel
View
... Data from participants randomized to either injectable diacetylmorphine or hydromorphone were combined, based on similar outcomes during the active treatment study period [18]
. These participants were then divided into three groups: 1) 'voluntary transition' (n = 16) were those who voluntarily stopped receiving injectable medications and transitioned to oral methadone before the 12 month time-point; 2) 'involuntary transition' (n = 95) were those who were still receiving injectables at 12 months but were discontinued and offered other treatments because their study period ended; and 3) 'withdrawal/drop outs' (n = 28) were those who dropped out or were discontinued from the injectable medications before 12 months (various reasons: e.g., attempted to divert the study medications, violent behaviour, etc.). ...
Differential long-term outcomes for voluntary and involuntary transition from injection to oral opioid maintenance treatment Article Full-text available
Jun 2014 SUBST ABUSE TREAT PR
Kirsten Marchand Eugenia Oviedo-Joekes Daphne Guh Martin T Schechter
Background:
The most widely used maintenance treatment for opioid dependency is substitution with long-acting oral opioids. Treatment with injectable diacetylmorphine provides an opportunity for patients to stabilize and possibly transition to oral treatment, if clinically indicated. The aim of this study was to explore outcomes of individuals that received injectable diacetylmorphine and voluntarily transitioned to oral methadone.
Design and methods:
The North American Opiate Medication Initiative was a randomized controlled trial that compared the effectiveness of injectable diacetylmorphine (or hydromorphone) to oral methadone for long-term opioid-dependency. Treatment was provided for 12-months with an additional 3 months for transition and weaning. Participants were followed until 24-months from randomization. Among the participants randomized to injectable treatments, a sub-group voluntarily chose to transition to oral methadone (n = 16) during the treatment period. Illicit heroin use and treatment retention were assessed at 24-months for those voluntarily and involuntarily transitioning (n = 95) to oral methadone.
Results:
At 24-months, the group that voluntarily transitioned to oral methadone had higher odds of treatment retention (adjusted odds ratio = 5.55; 95% confidence interval [CI] = 1.11, 27.81; Chi-square = 4.33, df = 1, p-value = 0.037) than the involuntary transition group. At 24-months, the adjusted mean difference in prior 30 days of illicit heroin use for the voluntary, compared to the involuntary group was -5.58 (95% CI = -11.62, 0.47; t-value = -1.83, df = 97.4, p-value = 0.070).
Conclusions:
Although the results of this study were based on small groups of self-selected (i.e., non-randomized) participants, our data underlines the critical importance of voluntary and patient-centered decision making. If we had continued offering treatment with diacetylmorphine, those retained to injectable medication may have sustained the achieved improvements in the first 12 months. Diversified opioid treatment should be available so patients and physicians can flexibly choose the best treatment at the time.
Trial registration:
Clinical trial registration:
NCT00175357.
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... 4 27 When heroin is not available, other medications, such as hydromorphone, have been studied for such patients. 28
Methadone and buprenorphine are now available in 73 countries, and the evidence for effectiveness and cost effectiveness is far stronger than for all other treatments for severe heroin dependence. ...
THERAPEUTICS Maintenance drugs to treat opioid dependence
Article
May 2012 Br Med J
Michael Farrell Alex Wodak Linda Gowing
View
... Participants were randomized to receive oral methadone (n = 111) or injected diacetylmorphine (n = 115). A small subgroup of participants (n = 25) was randomized to receive injected hydromorphone only for the purpose of a validation sub-study on self-reported illicit heroin use
(Oviedo-Joekes et al., 2010)
. Oral methadone was dispensed daily; the injection medications were self-administered under supervision in the treatment clinics up to three times daily. ...
Effectiveness of diacetylmorphine versus methadone for the treatment of opioid dependence in women Article
Sep 2010
Eugenia Oviedo-Joekes Daphne Guh
Suzanne Brissette Martin T Schechter
There is consistent evidence showing women access treatment with more severe substance-related profiles relative to men; however, treatment outcome evaluation shows inconclusive results regarding gender differences. Furthermore, few studies evaluate response by gender.
The present analyses were performed using data from the NAOMI study, an open-label, phase III randomized controlled trial, carried out between 2005 and 2008 in Vancouver and Montreal, Canada. A total of 226 long-term treatment-refractory opioid dependent individuals were randomized to receive injectable diacetylmorphine or oral methadone for 12 months. Patients in both treatment groups were offered psychosocial and primary care services. Main outcomes were retention in addiction treatment at 12 months. Drug use, health, psychosocial adjustment and health-related quality of life were examined at baseline and during treatment, using the European Addiction Severity Index, Maudsley Addiction Profile, SF-6D and EuroQol EQ-5D.
A total of 88 (38.9%) females and 138 (61.1%) males were included in the present analysis. Retention rates among female participants in the diacetylmorphine group were significantly higher than oral methadone (83.3% vs. 47.8%). Males receiving diacetylmorphine improved significantly more than females in physical health, health-related quality of life, and family relations but female participants in the diacetylmorphine group had significantly greater improvements in illicit drug use scores and psychological health compared to females allocated to oral methadone.
Among long-term opioid dependent women who have not benefited sufficiently from available treatments, medically prescribed diacetylmorphine is more effective than oral methadone. Men receiving diacetylmorphine showed more improvements than women.
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Iteration is not solving the opioid crisis, it's time for transformation
Article
Mar 2023 AM J DRUG ALCOHOL AB
Kelly E. Dunn
Opioid use disorder (OUD) produces exceedingly high rates of morbidity and mortality in the United States and throughout the world. Almost 90% of persons qualifying for treatment do not enter treatment and 72% of those who initiate treatment leave within 60 days. This Perspective posits that over the past decade our OUD treatment system has produced only small iterative gains in treatment access because, in part, it is founded in a series of top-down regulatory policies dating back more than 100 years. These policies prioritized restricting persons with OUD from having access to opioid agonists over empirical discovery of treatment best practice. It further suggests that for persons who are not already responding positively to our existing treatments, we may need to fundamentally transform care to enact true, meaningful change. Four potential considerations are outlined: expanding beyond long-acting opioids for treatment, embracing safe use as a viable therapeutic target, ending closed medication distribution systems, and partnering with our patients. The overarching aim of this discussion is to motivate broader thinking about new solutions for the patients for whom the existing strategies are not working and who may benefit from more transformative approaches. Though efforts to-date to expand existing treatment systems and find new ways to promote existing MOUDs have been important, these efforts have represented iterative changes. For us to meet our goal of substantially reducing opioid-related harms, it may be time to consider strategies that represent true transformation.
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Hydromorphone and the risk of infective endocarditis among people who inject drugs: a population-based, retrospective cohort study Article
Jan 2020 LANCET INFECT DIS
Michael S Silverman Justin Slater
Racquel Jandoc Matthew A. Weir
Background:
The incidence of infective endocarditis related to injection drug use is increasing. On the basis of clinical practice and epidemiological and in-vitro data, we postulated that exposure to controlled-release hydromorphone is associated with an increased risk of infective endocarditis among people who inject drugs.
Methods:
We used linked health administrative databases in Ontario, Canada, to assemble a retrospective cohort of adults (aged 18-55 years) who inject drugs for the period of April 1, 2006, to Sept 30, 2015. Cases of infective endocarditis among this cohort were identified using International Classification of Diseases 10 codes. We estimated exposure to hydromorphone and risk of infective endocarditis among this cohort in two ways. First, in a population-level analysis, we identified patients living in regions with high (≥25%) and low (≤15%) hydromorphone prescription rates and, after matching 1:1 on various baseline characteristics, compared their frequency of infective endocarditis. Second, in a patient-level analysis including only those with prescription drug data, we identified those who had filled prescriptions (ie, received the drug from the pharmacy) for controlled-release or immediate-release hydromorphone and, after matching 1:1 on various baseline characteristics, compared their frequency of infective endocarditis with that of patients who had filled prescriptions for other opioids.
Results:
Between April 1, 2006, and Sept 30, 2015, 60 529 patients had evidence of injection drug use, 733 (1·2%, 95% CI 1·1-1·3) of whom had infective endocarditis. In the population-level analysis of 32 576 matched patients, we identified 254 (1·6%) admissions with infective endocarditis in regions with high hydromorphone use and 113 (0·7%) admissions in regions with low use (adjusted odds ratio [OR] 2·2, 95% CI 1·8-2·8, p<0·0001). In the patient-level analysis of 3884 matched patients, the frequency of infective endocarditis was higher among patients who filled prescriptions for hydromorphone than among those who filled prescriptions for non-hydromorphone opioids (2·8% [109 patients] vs 1·1% [41 patients]; adjusted OR 2·5, 95% CI 1·8-3·7, p<0·0001). This significant association was seen for controlled-release hydromorphone (3·9% [73 of 1895 patients] vs 1·1% [20 of 1895]; adjusted OR 3·3, 95% CI 2·1-5·6, p<0·0001), but not for immediate-release hydromorphone (1·8% [36 of 1989] vs 1·1% [21 of 1989]; 1·7, 0·9-3·6, p=0·072.
Interpretation:
Among people who inject drugs, the risk of infective endocarditis is significantly higher for those exposed to controlled-release hydromorphone than to other opioids. This association might be mediated by the controlled-release mechanism and should be the subject of further investigation.
Funding:
Ontario Ministry of Health and Long-Term Care, Academic Medical Organization of Southwestern Ontario, Schulich School of Medicine and Dentistry (Western University), and Lawson Health Research Institute.
View Show abstract
Playing (un)dead: Interrogating invocations of 'monster' metaphors in drug/service user narratives of methadone, maintenance and treatment Working Paper
Mar 2017
Christopher B R Smith
View
Heroin-assisted treatment - From efficacy to effectiveness and long-term outcome Thesis Full-text available
Feb 2011
Peter Blanken
View
Heroin assisted treatment in Switzerland
Article Full-text available
Jan 2012
Ambros Uchtenhagen
View
Heroin on trial: Systematic review and meta-analysis of randomised trials of diamorphine-prescribing as treatment for refractory heroin addiction Article Full-text available
Jul 2015
John Strang Teodora Groshkova
Ambros Uchtenhagen Nicola Metrebian
Background
Supervised injectable heroin (SIH) treatment has emerged over the past 15 years as an intensive treatment for entrenched heroin users who have not responded to standard treatments such as oral methadone maintenance treatment (MMT) or residential rehabilitation.AimsTo synthesise published findings for treatment with SIH for refractory heroin-dependence through systematic review and meta-analysis, and to examine the political and scientific response to these findings.Method
Randomised controlled trials (RCTs) of SIH treatment were identified through database searching, and random effects pooled efficacy was estimated for SIH treatment. Methodological quality was assessed according to criteria set out by the Cochrane Collaboration.ResultsSix RCTs met the inclusion criteria for analysis. Across the trials, SIH treatment improved treatment outcome, i.e. greater reduction in the use of illicit 'street' heroin in patients receiving SIH treatment compared with control groups (most often receiving MMT).ConclusionsSIH is found to be an effective way of treating heroin dependence refractory to standard treatment. SIH may be less safe than MMT and therefore requires more clinical attention to manage greater safety issues. This intensive intervention is for a patient population previously considered unresponsive to treatment. Inclusion of this low-volume, high-intensity treatment can now improve the impact of comprehensive healthcare provision.
© The Royal College of Psychiatrists 2015.
View Show abstract
Harm Reduction: Front Line Public Health
Article
Jun 2015 J ADDICT DIS
Sharon Stancliff Benjamin W Phillips
Nazlee Maghsoudi Herman Joseph
Drug use is public health problem associated with high mortality and morbidity, and is often accompanied by suboptimal engagement in health care. Harm reduction is a pragmatic public health approach encompassing all goals of public health: improving health, social well-being and quality of life. Harm reduction prioritizes improving the lives of people who use drugs in partnership with those served without a narrow focus on abstinence from drugs. Evidence has shown that harm reduction oriented practice can reduce transmission of blood-borne illnesses, and other injection related infections as well as preventing fatal overdose. (Word Count: 93).
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Predictors of non-use of illicit heroin in opioid injection maintenance treatment of long-term heroin dependence Article Full-text available
Oct 2014 ADDICT BEHAV
Luis Sordo Eugenia Oviedo-Joekes
Daphne Guh Martin T Schechter
Aims
To investigate baseline and concurrent predictors of non-use of illicit heroin among participants randomized to injectable opioids in the North American Opiate Medication Initiative (NAOMI) clinical trial.
Methods
NAOMI was an open-label randomized controlled trial comparing the effectiveness of injectable diacetylmorphine and hydromorphone for long-term opioid-dependency. Outcomes were assessed at baseline and during treatment (3, 6, 9, 12 months). Days of non-use of illicit heroin in the prior month at each follow-up visit were divided into three categories: Non-use; Low use (1 to 7 days) and High use (8 days or more). Tested covariates were: Sociodemographics, Health, Treatment, Drug use and illegal activities. Mixed-effect proportional odds models with random intercept for longitudinal ordinal outcomes were used to assess the predictors of the non-use of illicit heroin.
Results
139 participants were included in the present analysis. At each follow-up visit, those with non-use of illicit heroin represented 47.5% to 54.0% of the sample. Fewer days of cocaine use (p = 0.074), fewer days engaged in Illegal activities at baseline (p < 0.01) and at each visit (p < 0.01), less money spent on drugs (p < 0.001), days with injection opioid or oral methadone treatment (p < 0.001) and total mg of injectable opioids taken (p < 0.001), independently predicted lower use of illicit heroin.
Conclusions
The independent effect of several concurrent factors besides the injection opioid dose suggests benefits from the clinic that go beyond the provision of the medication alone. Thus, this supervised model of care presents an opportunity to maximize the beneficial impact of medical and psychosocial components of the treatment on improving outcomes associated with non-use of illicit heroin.
View Show abstract
A Call For Evidence-Based Medical Treatment Of Opioid Dependence In The United States And Canada Article
Aug 2013 HEALTH AFFAIR
Bohdan Nosyk M. Douglas Anglin Julio S G Montaner Suzanne Brissette
Despite decades of experience treating heroin or prescription opioid dependence with methadone or buprenorphine-two forms of opioid substitution therapy-gaps remain between current practices and evidence-based standards in both Canada and the United States. This is largely because of regulatory constraints and pervasive suboptimal clinical practices. Fewer than 10 percent of all people dependent on opioids in the United States are receiving substitution treatment, although the proportion may increase with expanded health insurance coverage as a result of the Affordable Care Act. In light of the accumulated evidence, we recommend eliminating restrictions on office-based methadone prescribing in the United States; reducing financial barriers to treatment, such as varying levels of copayment in Canada and the United States; reducing reliance on less effective and potentially unsafe opioid detoxification; and evaluating and creating mechanisms to integrate emerging treatments. Taking these steps can greatly reduce the harms of opioid dependence by maximizing the individual and public health benefits of treatment.
View Show abstract
[Social Integration after 4 Years of Heroin-Assisted Treatment.]
Article
Dec 2012 Rehabilitation
Uwe Verthein Ingo Schäfer Peter Degkwitz
Hintergrund:
Studien aus mehreren Ländern konnten mittlerweile die größere Wirksamkeit der Diamorphin- im Vergleich zur Methadonbehandlung bei Opiatabhängigen belegen. Jedoch sind nur wenige langfristige Ergebnisse sowie insbesondere jene zur sozialen Integration der Patienten bekannt.
Ziel:
Es wird der Frage nachgegangen, wie sich der soziale Integrationsprozess unter den Patienten des bundesdeutschen Modellprojekts nach 4 Jahren Behandlungsdauer entwickelt.
Methode:
Bei Patienten, die mindestens 4 Jahre mit Diamorphin behandelt wurden (n=156), werden die sich im Verlauf ergebenden Veränderungen in den Bereichen Gesundheit, Drogenkonsum sowie schwerpunktmäßig der sozialen Integration anhand von Messwiederholungsanalysen auf Signifikanz geprüft. Dabei wird auf die Instrumente der OTI-Gesundheitsskala und der Symptom-Checkliste SCL-90-R, auf ärztliche Beurteilungen, Urinkontrollen zum Drogenkonsum sowie auf Variablen des European Addiction Severity Index und dessen Composite-Scores zurückgegriffen.
Ergebnisse:
In allen Bereichen ergeben sich signifikante Verbesserungen im Zeitverlauf. Der Anteil an Patienten, die aktuell arbeiten, hat sich mit knapp 40% nach 4 Jahren Diamorphinbehandlung mehr als verdreifacht. Auch in der Wohnsituation sowie im Freizeitverhalten zeigen sich Verbesserungen, und die Delinquenz geht erheblich zurück. Haupteinflussfaktor auf eine gelungene soziale Integration nach 4 Jahren Behandlung ist die Arbeitsfähigkeit.
Schlussfolgerung:
Die Diamorphinbehandlung erweist sich hinsichtlich der Verbesserung des Gesundheitszustands, der Verringerung des Konsums harter Drogen sowie der verbesserten sozialen Integration langfristig als ausgesprochen erfolgreiche Therapie schwerstabhängiger Heroinkonsumenten. Die Ergebnisse zeigen ferner, dass soziale (Re-)Integrationsprozesse bei Drogenabhängigen Zeit benötigen.
View Show abstract
Endogenous opiates and behavior: 2011
Article
Oct 2012
Richard J Bodnar
This paper is the thirty-fourth consecutive installment of the annual review of research concerning the endogenous opioid system. It summarizes papers published during 2011 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides, opioid receptors, opioid agonists and opioid antagonists. The particular topics that continue to be covered include the molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors related to behavior (Section 2), and the roles of these opioid peptides and receptors in pain and analgesia (Section 3); stress and social status (Section 4); tolerance and dependence (Section 5); learning and memory (Section 6); eating and drinking (Section 7); alcohol and drugs of abuse (Section 8); sexual activity and hormones, pregnancy, development and endocrinology (Section 9); mental illness and mood (Section 10); seizures and neurologic disorders (Section 11); electrical-related activity and neurophysiology (Section 12); general activity and locomotion (Section 13); gastrointestinal, renal and hepatic functions (Section 14); cardiovascular responses (Section 15); respiration (Section 16); and immunological responses (Section 17).
View Show abstract
BAP updated guidelines: Evidence-based guidelines for the pharmacological management of substance abuse, harmful use, addiction and comorbidity: Recommendations from BAP Article Full-text available
May 2012
Anne R Lingford-Hughes S Welch L Peters
David J Nutt
The British Association for Psychopharmacology guidelines for the treatment of substance abuse, harmful use, addiction and comorbidity with psychiatric
disorders primarily focus on their pharmacological management. They are based explicitly on the available evidence and presented as recommendations
to aid clinical decision making for practitioners alongside a detailed review of the evidence. A consensus meeting, involving experts in the treatment of
these disorders, reviewed key areas and considered the strength of the evidence and clinical implications. The guidelines were drawn up after feedback
from participants. The guidelines primarily cover the pharmacological management of withdrawal, short- and long-term substitution, maintenance of
abstinence and prevention of complications, where appropriate, for substance abuse or harmful use or addiction as well management in pregnancy,
comorbidity with psychiatric disorders and in younger and older people.
View Show abstract
Potency ratio of hydromorphone and diacetylmorphine in substitution treatment for long-term opioid dependency Article
Sep 2011
David C Marsh Eugenia Oviedo-Joekes Daphne Guh Martin T Schechter
Data on conversion ratios for switching opioids in substitution treatment are limited.
Data were obtained from a randomized controlled trial among long-term opioid-dependent patients conducted in Vancouver and Montreal, Canada. Patients received diacetylmorphine (n = 115) or hydromorphone (n = 25) on a double-blind basis, on a 1:3 potency ratio with individually adjusted dosage, both injectable.
Average daily dosages of hydromorphone and diacetylmorphine prescribed were 212.6 mg and 454.0 mg, respectively; potency ratio was 1:2.0-2.2 at different dose ranges.
Studies using hydromorphone as a diacetylmorphine equivalent should consider the ratio found in this study to achieve equipotency and maintain the blinding.
View Show abstract
Prescription Opioid Misuse Characteristics of Earliest and Most Recent Memory of Hydromorphone Use Article
Nov 2011
Heather G Fulton Sean P Barrett
Sherry H Stewart Cindy Macisaac
: Prescription opioid use is highly prevalent and a major physician concern. However, little is known about how individuals initiate into use of these medications or how they use them later in life. Hydromorphone is a medication of particular interest given its subjective similarities to heroin and tendency to be misused by illicit opioid users. The purpose of this study was to evaluate the characteristics of initial, and more recent, hydromorphone use occasions as remembered by a population of individuals in treatment for their opioid use.
: Seventy-eight clients enrolled in low-threshold methadone maintenance treatment were interviewed regarding their earliest and most recent uses of hydromorphone.
: Hydromorphone was first used after trying many different substances (eg, tobacco, alcohol, hallucinogens, powder cocaine). Two-thirds of the sample reported initially using hydromorphone without a prescription. Participants who initially used hydromorphone without a prescription reported using for different reasons (ie, to get high, curiosity vs manage pain), via different routes of administration (ie, injection vs orally), and were more likely to co-use other substances, than those whose earliest hydromorphone use was prescribed. However, these 2 subgroups did not differ greatly during their most recent use occasion (ie, the majority reported using to avoid withdrawal, via injection; almost 50% reported co-use with other substances).
: There was considerable variability in characteristics of hydromorphone use initiation among individuals enrolled in low-threshold methadone maintenance treatment. However, later use of hydromorphone was remarkably consistent across individuals and shares many characteristics previously documented for heroin use. Additional investigations into hydromorphone are warranted, particularly given previous findings regarding the prevalence of nonmedical use of this drug and its similarities to heroin.
View Show abstract
[Efficacy diacetylmorphine (pharmaceutical heroin) for heroin treatment ] Article
Dec 2010 Rev Med Liege
Isabelle Demaret Andre LEMAITRE M Ansseau
Before implementing the TADAM project in Belgium (a heroin-assisted treatment trial), our research team studied the trials in other countries. Since 1994, six randomised controlled trials have been developed using the same treatment model of heroin-assisted treatment (HAT). Each trial concluded that HAT had more efficacy than methadone treatment. We analysed those trials in order to find on which levels patients in a HAT treatment are expected to improve. Improvements appeared after at least six months on the level of street heroin use, (physical and mental) health and criminal behaviour. In the longer term, the continuation of treatment had positive but limited effects on the social level. Due to his higher cost, this treatment should remain a second-line treatment for this special target group: severe heroin addicts, using continuously street heroin in spite of a methadone treatment.
View Show abstract
The North American Opiate Medication Initiative (NAOMI): Profile of Participants in North America’s First Trial of Heroin-Assisted Treatment Article Full-text available Nov 2008 Eugenia Oviedo-Joekes Bohdan Nosyk Suzanne Brissette Martin T Schechter The North American Opiate Medication Initiative (NAOMI) is a randomized controlled trial evaluating the feasibility and effectiveness
of heroin-assisted treatment (HAT) in the Canadian context. Our objective is to analyze the profile of the NAOMI participant
cohort in the context of illicit opioid use in Canada and to evaluate its comparability with patient profiles of European
HAT studies. Recruitment began in February 2005 and ended in March 2007. Inclusion criteria included opioid dependence, 5
or more years of opioid use, regular opioid injection, and at least two previous opiate addiction treatment attempts. Standardized
assessment instruments such as the European Addiction Severity Index and the Maudsley Addiction Profile were employed. A total
of 251 individuals were randomized from Vancouver, BC (192, 76.5%), and Montreal, Quebec (59, 23.5%); 38.5% were female, the
mean age was 39.7years (SD:8.6), and participants had injected drugs for 16.5years (SD:9.9), on average. In the prior month,
heroin was used a mean of 26.5days (SD:7.4) and cocaine 16days (SD;12.6). Vancouver had significantly more patients residing
in unstable housing (88.5 vs. 22%; p < 0.001) and higher use of smoked crack cocaine (16.9days vs. 2.3days in the prior month; p < 0.001), while a significantly higher proportion of Montreal participants reported needle sharing in the prior 6months
(25% vs. 3.7%; p < 0.001). In many respects, the patient cohort was similar to the European trials; however, NAOMI had a higher proportion
of female participants and participants residing in unstable housing. This study suggests that the NAOMI study successfully
recruited participants with a profile indicated for HAT. It also raises concern about the high levels of crack cocaine use
and social marginalization. View Show abstract Diacetylmorphine versus Methadone for the Treatment of Opioid Addiction Article Full-text available Aug 2009 NEW ENGL J MED Eugenia Oviedo-Joekes Suzanne Brissette David C Marsh Martin T Schechter Studies in Europe have suggested that injectable diacetylmorphine, the active ingredient in heroin, can be an effective adjunctive treatment for chronic, relapsing opioid dependence.
In an open-label, phase 3, randomized, controlled trial in Canada, we compared injectable diacetylmorphine with oral methadone maintenance therapy in patients with opioid dependence that was refractory to treatment. Long-term users of injectable heroin who had not benefited from at least two previous attempts at treatment for addiction (including at least one methadone treatment) were randomly assigned to receive methadone (111 patients) or diacetylmorphine (115 patients). The primary outcomes, assessed at 12 months, were retention in addiction treatment or drug-free status and a reduction in illicit-drug use or other illegal activity according to the European Addiction Severity Index.
The primary outcomes were determined in 95.2% of the participants. On the basis of an intention-to-treat analysis, the rate of retention in addiction treatment in the diacetylmorphine group was 87.8%, as compared with 54.1% in the methadone group (rate ratio for retention, 1.62; 95% confidence interval [CI], 1.35 to 1.95; P<0.001). The reduction in rates of illicit-drug use or other illegal activity was 67.0% in the diacetylmorphine group and 47.7% in the methadone group (rate ratio, 1.40; 95% CI, 1.11 to 1.77; P=0.004). The most common serious adverse events associated with diacetylmorphine injections were overdoses (in 10 patients) and seizures (in 6 patients).
Injectable diacetylmorphine was more effective than oral methadone. Because of a risk of overdoses and seizures, diacetylmorphine maintenance therapy should be delivered in settings where prompt medical intervention is available. (ClinicalTrials.gov number, NCT00175357.) View Show abstract Medical prescription of heroin to treatment resistant heroin addicts: Two randomised controlled trials Article Full-text available Sep 2003 Br Med J Wim van den Brink Vincent Hendriks Peter Blanken Jan M. van Ree To determine whether supervised medical prescription of heroin can successfully treat addicts who do not sufficiently benefit from methadone maintenance treatment.
Two open label randomised controlled trials.
Methadone maintenance programmes in six cities in the Netherlands.
549 heroin addicts.
Inhalable heroin (n = 375) or injectable heroin (n = 174) prescribed over 12 months. Heroin (maximum 1000 mg per day) plus methadone (maximum 150 mg per day) compared with methadone alone (maximum 150 mg per day). Psychosocial treatment was offered throughout.
Dichotomous, multidomain response index, including validated indicators of physical health, mental status, and social functioning.
Adherence was excellent with 12 month outcome data available for 94% of the randomised participants. With intention to treat analysis, 12 month treatment with heroin plus methadone was significantly more effective than treatment with methadone alone in the trial of inhalable heroin (response rate 49.7% v 26.9%; difference 22.8%, 95% confidence interval 11.0% to 34.6%) and in the trial of injectable heroin (55.5% v 31.2%; difference 24.3%, 9.6% to 39.0%). Discontinuation of the coprescribed heroin resulted in a rapid deterioration in 82% (94/115) of those who responded to the coprescribed heroin. The incidence of serious adverse events was similar across treatment conditions.
Supervised coprescription of heroin is feasible, more effective, and probably as safe as methadone alone in reducing the many physical, mental, and social problems of treatment resistant heroin addicts. View Show abstract Controlled trial of prescribed heroin in the treatment of opioid addiction Article Full-text available Sep 2006 J SUBST ABUSE TREAT Joan Carles March Eugenia Oviedo-Joekes Emilio Perea-Milla Francisco Carrasco This study aimed to assess the efficacy of the prescription of intravenous diacetylmorphine (DAM) versus oral methadone with medical and psychosocial support, with a view of improving physical and mental health as well as social integration among socially excluded, opioid-dependent individuals for whom standard treatments have failed.
This study used an open, randomized controlled trial.
This study took place in Granada, Spain.
Sixty-two opioid-dependent participants were randomized, 31 in each treatment group, and 50 of them were analyzed. The participants were recruited directly from the streets, through peer outreach, in well-known meeting places for drug-addicted individuals.
Participants in the experimental group received injected DAM, twice a day, plus oral methadone, once a day, for 9 months. The control group received only oral methadone, once a day. The two groups received an equivalent opioid dosage. The average DAM dosage was 274.5 mg/day (range: 15-600 mg), and an average methadone dosage was 42.6 mg/day (range: 18-124 mg). The daily methadone dosage in the control group was 105 mg/day (range: 40-180 mg). Comprehensive clinical, psychological, social, and legal support was given to both groups.
The following were measured in this study: general health, quality of life, drug-addiction-related problems, nonmedical use of heroin, risk behavior for HIV and HCV, and psychological, family, and social status.
Both groups improved with respect to the total domain assessed. Those in the experimental group showed greater improvement in terms of physical health (the improvement was 2.5 times higher; p = .034) and risk behavior for HIV infection (the improvement was 1.6 times higher; p = .012). In addition, this group decreased its street heroin use from 25 days/month to 8 days/month as seen on the Addiction Severity Index (p = .020), as well as the number of days free from drug-related problems (the improvement was 2.1 times higher; p = .004) or involvement in crime (from 11 days/month to <1 day/month; p = .096 between groups).
These findings support the hypothesis that, under the same conditions, DAM could be safely delivered, in our context. Also, in physical health, HIV risk behavior, street heroin use, and days involved in crime, DAM plus methadone was more efficacious than methadone alone. This implies that this treatment could provide an effective alternative for the treatment of socially excluded, opioid-dependent patients with severe physical and mental health problems because of drug addiction, when all available previous treatments have failed. View Show abstract Comparison of heroin and hydromorphone in opioid users Article Feb 2004 Bruna Brands David C Marsh Usoa E Busto A. MacDonald Hydromorphone (HM) is a potential alternative to heroin (H) in opioid dependence prescription trials. A within-subject study of 8 casual injection heroin-users compared acute intravenous (iv) and subcutaneous (sc) H and HM effects over a range of 4 doses to determine if they are pharmacologically distinguishable. Subjective, physiological, and behavioral measures were assessed before and for 3 hours after administration. Comparing baseline-corrected peak values (highest doses, HM 2.5 mg iv (A) vs H 10 mg iv (B) and HM 5 mg sc (C) vs H 20 mg sc (D)), pupil diameter mean reductions (mm) were |[minus]|3.19 (A) vs |[minus]|3.34 (B) & |[minus]|3.30 (C) vs |[minus]|3.35 (D). Decreases in mean % oxygen saturation levels were |[minus]|2.4 for iv doses (A & B) & for sc doses |[minus]|1.6 (C) vs |[minus]|2.1 (D). Visual analog scales ratings (0-100) for a |[ldquo]|Drug Effect|[rdquo]| were 66.8 (A) vs 66.9 (B) & 70.5 (C) vs 63.8 (D), and for a |[ldquo]|Rush|[rdquo]| were 70.8 (A) vs 65.6 (B) & 52.6 (C) vs 58.5 (D). Opiate adjective scores of weighted Fraser scale agonist effects were 8.1 (A) vs 9.4 (B) & 12.4 (C) vs 13.8 (D). H and HM produced similar effects, had similar time courses, peak effect times, onsets of action, and approximately parallel dose response curves on most measures, with HM being 3-4 fold more potent than H. Subjects only subjectively distinguished the effects of iv H from iv HM: heroin identifications (mean % correct responses/session, all doses) are 70.3% vs 69.5% (iv) (NS) & 54.7% vs 78.1% (sc) (p<.001). HM may be a suitable surrogate for heroin. View Show abstract EuropASI: European Adaptation of a Multidimensional Assessment Instrument for Drug and Alcohol Dependence Article Jan 1995 EUR ADDICT RES A. Kokkevi C. Hartgers View Clinical analgesic assay of repeated and single doses of heroin and hydromorphone Article May 1990 Stanley L. Wallenstein Raymond W. Houde Russell K. Portenoy Kathleen maher Foley A direct comparison of the analgesic activities of heroin and hydromorphone was carried out in cancer patients with postsurgical pain. Intramuscular doses of 5 and 10 mg of heroin were compared with 1 and 2 mg of hydromorphone in a randomized, double-blind, 4-point parallel group assay. Design innovations in the study provided that about half the patients would receive prior repeated doses of the same drug as the test medication and half would receive the alternate medication. Both test drugs were found to be potent, relatively short acting analgesics with similar profiles of action. Hydromorphone was about 5 times as potent as heroin on a milligram basis. The comparison of those patients who had repeated doses of the same treatment prior to the test dose and those who had repeated doses of the alternate drug demonstrated no significant effect on the relative potency estimates. Side effect occurrence was similar for both drugs, with sleepiness the most prominent effect. The study supports the view that hydromorphone and heroin produce similar clinical effects and that either drug may adequately substitute for the other. Covariate analysis indicated that time since last analgesic was positively related to analgesia and amount of prior opioid had a negative relationship. To a lesser extent, increase in patient age was associated with an increase in analgesic scores. Taking these covariates into account served to increase the sensitivity of the analysis. View Show abstract Diagnostic and Statistical Manual of Mental Disorders DSM-IV Book Jan 2000 A.P American Psychiatric Association View Mortality among clients of a state-wide opioid pharmacotherapy program over 20 years: Risk factors and lives saved Article Aug 2009 Louisa Degenhardt Deborah A Randall Wayne Hall Lucy Burns The small size of previous studies of mortality in opioid dependent people has prevented an assessment of the extent to which elevated mortality risks are consistent across time, clinical and/or patient groups. The current study examines reductions in mortality related to treatment in an entire treatment population.
Data from the New South Wales (NSW) Pharmaceutical Drugs of Addiction System, recording every "authority to dispense" methadone or buprenorphine as opioid replacement therapy, 1985-2006, was linked with data from the National Deaths Index, a record of all deaths in Australia. Crude mortality rates and standardized mortality ratios were calculated according to age, sex, calendar year, period in- or out-of-treatment, medication type, previous treatment exposure and cause of death.
Mortality among 42,676 people entering opioid pharmacotherapy was elevated compared to age and sex peers. Drug overdose and trauma were the major contributors. Mortality was higher out of treatment, particularly during the first weeks, and it was elevated during induction onto methadone but not buprenorphine. Mortality during these risky periods changed across time and treatment episodes. Overall, mortality was similarly reduced (compared to out-of-treatment) whether patients were receiving methadone or buprenorphine. It was estimated that the program produced a 29% reduction in mortality across the entire cohort.
Mortality among treatment-seeking opioid-dependent persons is dynamic across time, patient and treatment variables. The comparative reduction in mortality during buprenorphine induction may be offset by the increased risk of longer out-of-treatment time periods. Despite periods of elevated risk, this large-scale provision of pharmacotherapy is estimated to have resulted in significant reductions in mortality. View Show abstract Scientific and political challenges in North America's first randomized controlled trial of heroin-assisted treatment for severe heroin addiction: Rationale and design of the NAOMI Study Article Jul 2009 Eugenia Oviedo-Joekes Bohdan Nosyk David C Marsh Martin T Schechter Heroin addiction is a chronic relapsing disease, best treated with opioid-agonist substitution therapy such as methadone maintenance. However, a subset of the most severely affected individuals do not benefit sufficiently from this treatment. The North American Opiate Medication Initiative (NAOMI) is a randomized clinical trial (RCT) to evaluate the hypothesis that pharmaceutical-grade heroin, diacetylmorphine (DAM) is more effective in retaining patients and improving their outcomes than Methadone Maintenance Treatment (MMT) among those with chronic, refractory injection opioid dependence.
The study aimed at randomizing 253 participants to two intervention arms: (1) MMT alone or (2) injectable opioids (DAM or hydromorphone) plus adjunctive MMT if deemed appropriate. The planned study duration was 3 years, with a 1-year intake period, 1 year of treatment, and an additional year of follow-up. The NAOMI trial was initiated in March 2005 at two Canadian sites (Vancouver and Montreal). This was the first multicenter RCT in North America to compare the relative efficacy of these different therapeutic strategies. We discuss the rationale behind the NAOMI study design, as well as the scientific and political issues and methodological challenges arising from the conduct of a trial that involves the prescription of a controlled substance to individuals with dependence on that substance.
Restrictive entry criteria led to the exclusion of many otherwise eligible participants, slowing recruitment into the study. Inability to offer DAM treatment beyond 12 months led to artificial boundary effects in the trial.
Addiction treatment research navigates between science and politics, and evidence-based medicine is many times confronted by moral beliefs. Political considerations influence study design to a further degree than in RCTs treating less-stigmatized disorders with more-reputable medications. View Show abstract Effects of agonist-antagonist opioids in humans trained in a hydromorphone/not hydromorphone discrimination Article Nov 2000 Kenzie L Preston George E. Bigelow The purpose of this study was to examine the discrimination of agonist-antagonist opioids in humans trained in a two-choice hydromorphone/not hydromorphone discrimination. Eight adult male volunteers with histories of opioid abuse who were not currently physically dependent were trained to discriminate the mu receptor agonist hydromorphone (3 mg/70 kg, i.m.) ("Drug A") from a "Not Drug A" training condition (saline placebo). Volunteers received financial reinforcement for correct responses. After training, generalization dose-effect curves for hydromorphone, butorphanol, pentazocine, nalbuphine, and buprenorphine were determined. Other subjective, behavioral, and physiological measures were concurrently collected in all sessions. In generalization testing hydromorphone and buprenorphine produced dose-related increases in hydromorphone-appropriate responses. Pentazocine produced an inverted U-shaped dose-response curve with complete substitution at 32 mg/70 kg but not at 64 mg/70 kg. Butorphanol and nalbuphine did not completely substitute for hydromorphone at any dose tested. These results differ from an earlier two-choice, Drug A versus Drug B (hydromorphone/saline) discrimination study. After Drug/Not Drug instructions the behavioral discriminations of agonist-antagonist opioids were more consistent with their putative agonist activities at the mu opioid receptor and with their subjective effects profiles than was the case after Drug A versus Drug B instructions. These results suggest that instructions are an important factor in the outcome of human drug discrimination studies. View Show abstract Feasibility, safety, and efficacy of injectable heroin prescription for refractory opioid addicts: A follow-up study Article Nov 2001 Jurgen Rehm Patrick Gschwend Thomas Steffen Ambros Uchtenhagen Heroin-assisted substitution treatment for severely opioid-dependent drug users has been available in Switzerland since 1994. Our aim was to ascertain the feasibility, safety, and efficacy of this treatment.
We did a cohort study in 21 community outpatient treatment centres. We assessed 1969 opioid-dependent drug users, who began heroin-assisted substitution treatment between January, 1994, and December, 2000, to ascertain admission and discharge patterns, and patient characteristics. We also followed up a subset of 237 patients who began treatment between Jan 1, 1994, and March 31, 1995, and who stayed with the programme for at least 18 months. We used questionnaires, interviews, and medical examinations done at entry and after 6, 12, and 18 months to assess somatic and mental health, social integration, and treatment outcomes.
More than 70% (1378) of patients remained in treatment for more than a year. Treatment showed positive effects with respect to health and social outcomes. A long stay in treatment was related to a higher chance of starting abstinence-oriented therapy than a short stay.
Heroin-assisted substitution treatment might be an effective option for chronically addicted patients for whom other treatments have failed. View Show abstract Blockade of hydromorphone effects by buprenorphine/naloxone and buprenorphine Article Feb 2002 Eric Strain Sharon L Walsh George E. Bigelow Buprenorphine is an opioid agonist-antagonist used in the treatment of opioid dependence. Naloxone has been combined with buprenorphine to decrease the parenteral abuse potential of buprenorphine. This addition of naloxone may also confer further opioid blockade efficacy.
To test the opioid blockade efficacy of sublingual buprenorphine/naloxone versus buprenorphine alone and determine whether: (1) the blockade efficacy of buprenorphine/naloxone varies between the time of expected maximal and minimal effects of naloxone, (2) the blockade efficacy of buprenorphine/naloxone and buprenorphine varies as a function of maintenance dose level, and (3) there are adaptive changes over time associated with repeated daily dosing of buprenorphine/naloxone and buprenorphine.
Residential subjects ( n=6) were maintained on different double-blind dose levels of buprenorphine/naloxone (4/1, 8/2, 16/4, 32/8 mg) and buprenorphine (32 mg) for 6-day periods and challenged with parenteral doses of hydromorphone (12 mg) in laboratory sessions.
There was no evidence of additional opioid blockade efficacy conferred by combining naloxone with buprenorphine. Higher doses of buprenorphine/naloxone provided greater blockade of hydromorphone effects. Changes over time associated with repeated daily dosing of buprenorphine/naloxone and buprenorphine were minimal.
The addition of naloxone to buprenorphine may deter the parenteral abuse of buprenorphine/naloxone, but it does not enhance the therapeutic efficacy of buprenorphine. The blockade efficacy of buprenorphine/naloxone is dose related; however, doses up to 32/8 mg buprenorphine/naloxone provide only partial blockade when subjects receive a high dose of an opioid agonist. View Show abstract Breaking the deadlock over an Australian trial of injectable opioid maintenance Article Feb 2002 Wayne Hall Jo Kimber Richard P Mattick View A Systematic Review of Hydromorphone in Acute and Chronic Pain Article Mar 2003 J PAIN SYMPTOM MANAG Columba Quigley Phil Wiffen While morphine is historically the gold standard for the management of severe cancer pain, some patients either do not achieve adequate analgesia, or suffer intolerable side effects from this drug. For these patients, alternatives such as hydromorphone are recommended. This review explores the evidence for the efficacy of hydromorphone in the management of pain. A systematic search, from 1966 to 2000, of published and unpublished randomized trials that involved the administration of hydromorphone for both acute and chronic pain conditions in adults and children, was conducted. Forty-three studies were included in the review; 11 involved chronic cancer pain and 32 acute pain. Approximately half the studies received a low quality score. In addition, the heterogeneity of the studies precluded combination of data and results. Overall, hydromorphone appears to be a potent analgesic. The limited number of studies available suggests that there is little difference between hydromorphone and other opioids in terms of analgesic efficacy, adverse effect profile and patient preference. However, most studies involved small numbers of patients and wide ranges in equianalgesic dose ratios, making it difficult to determine real differences between interventions. View Show abstract Substitution treatment of injecting opioid users for prevention of HIV infection Article Feb 2004 Linda Gowing Michael Farrell Reinhard Bornemann Robert Leonard Ali Oral substitution treatment for injecting opioid users reduces drug-related behaviours with a high risk of HIV transmission, but has little effect on sex-related risk behaviours. Injecting drug users are vulnerable to infection with HIV and other blood borne viruses as a result of collective use of injecting equipment as well as sexual behaviour. This review looks at original studies that reported the frequency or prevalence of risk behaviours, or the prevalence of HIV infection related to substitution treatment of opioid dependence to assess the extent to which oral substitution treatment prevents the transmission of HIV infection. It was not possible to accurately estimate the extent of reduction, but it is clear that oral substitution treatment reduces risk behaviours and also actual cases of HIV infection amongst injecting drug users in substitution treatment. View Show abstract Behavioral economic analysis of opioid consumption in heroin-dependent individuals: Effects of unit price and pre-session drug supply Article Nov 2006 DRUG ALCOHOL DEPEN Mark K Greenwald Steven R Hursh Behavioral economic analysis has been used to investigate factors underlying drug consumption in laboratory animals and, increasingly, in human drug abusers. However, there are few studies in heroin abusers, especially those who are not in treatment; such studies may be valuable for understanding the mechanisms of persistent drug use. This study investigated effects of unit price (UP) and pre-session supply of hydromorphone (HYD) on choice and consumption of HYD. Heroin-dependent research volunteers (n=13) stabilized on buprenorphine 8 mg/day completed this eight-session inpatient study. In sessions 1-2, participants sampled two total HYD doses (12 and 24 mg IM) that could be earned in later sessions. In each of the final six sessions, volunteers were given access to a 12-trial choice progressive ratio schedule lasting 3h. On each trial, volunteers could earn a HYD unit dose (1 or 2 mg, for a maximum of 12 or 24 mg, respectively) or money (US dollars 2, for a maximum of US dollars 24). Fixed ratio requirements increased exponentially, generating 24 unit prices for behavioral economic analysis. Before some choice sessions, volunteers could choose (FR 1) to receive extra HYD (12 or 24 mg; at 0915), whereas on other days no supplement was available. HYD choice and peak responding (breakpoint, O(max)) measures increased with unit dose, decreased with pre-session supplements, and were greater among volunteers who used cocaine prior to the experiment. Taking pre-session supplements decreased P(max) and made group-percent HYD consumption more demand-elastic. Consumption was functionally equivalent at differing FR/unit dose combinations. Thus, opioid demand in heroin-dependent individuals not in treatment is a function of drug supply, unit price, and cocaine use. View Show abstract Heroin-assisted treatment for opioid dependence - Randomised controlled trial Article Aug 2007 Christian Haasen Uwe Verthein Peter Degkwitz Dieter Naber Heroin-assisted treatment has been found to be effective for people with severe opioid dependence who are not interested in or do poorly on methadone maintenance.
To study heroin-assisted treatment in people on methadone who continue intravenous heroin and in those who are heroin dependent but currently not in treatment.
In an open-label multicentre randomised controlled trial, 1015 people with heroin dependence received a variable dose of injectable heroin (n=515) or oral methadone (n=500) for 12 months. Two response criteria, improvement of physical and/or mental health and decrease in illicit drug use, were evaluated in an intent-to-treat analysis.
Retention was higher in the heroin (67.2%) than in the methadone group (40.0%) and the heroin group showed a significantly greater response on both primary outcome measures. More serious adverse events were found in the heroin group, and were mainly associated with intravenous use.
Heroin-assisted treatment is more effective for people with opioid dependence who continue intravenous heroin while on methadone maintenance or who are not enrolled in treatment. Despite a higher risk, it should be considered for treatment resistance under medical supervision. View Show abstract Buprenorphine and methadone maintenance treatment of heroin addicts preserves immune function Article Jun 2008 BRAIN BEHAV IMMUN Paola Sacerdote Silvia Franchi Gilberto Gerra Lorenzo Somaini Opiate addiction influences many physiological functions including immune responses. The objective of this study was to investigate the immune system function in heroin addicted patients submitted to methadone or buprenorphine maintenance treatment compared to untreated heroin addicts and healthy controls. Four groups were studied: group A included nine heroin addicted subjects, who were still injecting heroin; groups B and C were composed of 12 patients previously addicted to heroin, being treated with methadone (mean dosage 58+/-12.7 mg/day) or buprenorphine (mean dose 9.3+/-2.3mg/day) since at least 6 months; group D was composed of 15 sex and age matched healthy controls. Lymphoproliferation and peripheral mononuclear cell cultures production of the Th1 cytokines IL-2 and IFN-gamma, the Th2 cytokine IL-4, and of the pro-inflammatory cytokine TNF-alpha were evaluated in all the patients and controls. PHA-lymphoproliferation was lower in untreated heroin addicts than in controls, while it was normal in methadone and buprenorphine treated patients. An altered Th1/Th2 balance, characterized by reduced IL-4, IFN-gamma and TNF-alpha but normal IL-2 levels, was present in untreated heroin addicted subjects, while the Th1/Th2 balance was well conserved in the methadone and buprenorphine groups. These findings suggest that the immune system abnormalities in heroin addicted patients can be restored to almost normal values by controlled treatment with methadone and buprenorphine. View Show abstract Substitution treatment of injecting opioid users for prevention of HIV infection (Review) Article Feb 2008 Linda Gowing Michael Farrell Reinhard Bornemann Robert Leonard Ali Injecting drug users are vulnerable to infection with HIV and other blood borne viruses as a result of collective use of injecting equipment as well as sexual behaviour.
To assess the effect of oral substitution treatment for opioid dependent injecting drug users on rates of HIV infections, and high risk behaviours.
We searched the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE and PsycINFO to March 2007. We also searched reference lists of articles, reviews and conference abstracts
Studies were required to consider the incidence of risk behaviours, or the incidence of HIV infection related to substitution treatment of opioid dependence. All types of original studies were considered. Two reviewers independently assessed studies for inclusion.
One reviewer extracted data from included studies, assessed quality and confirmed decisions by consulting with all other reviewers.
Thirty-three studies, involving 10,400 participants, were included. The majority were not randomised controlled studies and there were problems of confounding and bias. The studies varied in several aspects limiting the extent of quantitative analysis. Studies consistently show that oral substitution treatment for opioid-dependent injecting drug users is associated with statistically significant reductions in illicit opioid use, injecting use and sharing of injecting equipment. It is also associated with reductions in the proportion of injecting drug users reporting multiple sex partners or exchanges of sex for drugs or money, but has little effect on condom use. It appears that the reductions in risk behaviours related to drug use do translate into reductions in cases of HIV infection.
Oral substitution treatment for injecting opioid users reduces drug-related behaviours with a high risk of HIV transmission, but has less effect on sex-related risk behaviours. The lack of data from randomised controlled studies limits the strength of the evidence presented in this review. View Show abstract
Blockade of hydromorphone effects by buprenorphine/naloxone and buprenorphine Medical prescription of heroin to treatment resistant heroin addicts: Two randomised controlled trials Jan 2002 310 E C Strain S L Walsh G E W Bigelow V M Hendriks P Blanken M W Koeter B J Van Zwieten J M Van Ree
Strain, E. C., Walsh, S. L., & Bigelow, G. E. (2002). Blockade of
hydromorphone effects by buprenorphine/naloxone and buprenorphine.
Psychopharmacology (Berl), 159, 161−166.
van den Brink, W., Hendriks, V. M., Blanken, P., Koeter, M. W., van
Zwieten, B. J., & van Ree, J. M. (2003). Medical prescription of heroin
to treatment resistant heroin addicts: Two randomised controlled trials.
British Medical Journal, 327, 310.
Guideline for good clinical practice. EMEA. ICH Harmonised Tripartite Guideline
ICH Harmonised Tripartite Guideline. (2002). Guideline for good clinical
practice. EMEA.
Best practices in methadone maintenance treatment. Health Canada
Health Canada. (2002). Best practices in methadone maintenance treatment.
Ontario, Canada: Minister of Public Works and Government Services
Canada.
Report into the feasibility of trialling hydromorphone as a treatment for heroin dependence in the Australian Capital Territory. Bammer G. Dance P. McDonald D.
Bammer, G., Dance, P., & McDonald, D. (2004). Report into the feasibility
of trialling hydromorphone as a treatment for heroin dependence in the
Australian Capital Territory. Australian National University.
Hydromorphone, product monograph Jan 1996
Pharmascience Inc. (1996). Hydromorphone, product monograph.
Recommendations
Discover more about: Pilot Projects
Article
Donny EC, Walsh SL, Bigelow GE, Eissenberg T, Stitzer ML. High-dose methadone produces superior opio...
June 2002
· Psychopharmacology
Sharon L Walsh George E. Bigelow
Eric C Donny [...] Maxine L. Stitzer
The efficacy of methadone for treating heroin dependence derives, in part, from suppression of opiate withdrawal and attenuation of the effects of heroin.
The purpose of this double-blind, within-subject, inpatient study was to determine whether larger doses of methadone, which are more effective in the treatment of opioid dependence, produce greater or longer-lasting blockade of the effects of
... [Show full abstract]
heroin in addition to adequate withdrawal suppression.
Participants were maintained on 30, 60, and 120 mg methadone (ascending order) for approximately 3 weeks at each dose. During each maintenance period, heroin challenges were administered at 4, 28, and 52 h after the last methadone dose. Opioid agonist effects and opioid withdrawal symptoms were assessed prior to heroin challenge. Challenge sessions consisted of three doses of heroin (0, 10, and 20 mg/70 kg; ascending order) 45 min apart.
All three methadone maintenance doses produced similar agonist effects. Participants tested 4 h after receiving 120 mg methadone showed complete suppression of withdrawal symptoms and full attenuation of the effects of heroin. Thirty and 60 mg methadone suppressed withdrawal for up to 52 h, but failed to block completely the effects of heroin. The effects of heroin increased slightly at longer post-methadone intervals.
Heroin use may persist during methadone treatment because low to moderate doses of methadone suppress withdrawal, but fail to eliminate the effects of heroin. These results provide a mechanism for the clinical observation that higher methadone doses are more effective at reducing heroin use.
Read more
Article Full-text available
Methadone versus buprenorphine for the treatment of heroin-dependent outpatients
May 2003
· Journal of Substance Abuse Treatment
Jamshid Ahmadi
The aim of this study was to assess the efficacy of methadone compared with buprenorphine maintenance therapy in heroin-dependent patients over a treatment period of 18 weeks. Subjects were randomized to receive either methadone or buprenorphine in a comparative double-blind study and consisted of 164 heroin-dependent male patients who met the DSM-IV criteria for heroin dependence and were
... [Show full abstract]
seeking treatment. The 164 subjects included 41 patients in 1-mg, 41 patients in 3-mg, and 41 patients in 8-mg dosage group of buprenorphine, and also 41 patients in the 30-mg dosage group of methadone. The mean age was 31.4 years for total buprenorphine group and 33.7 years for methadone group (the mean age differences in 4 groups were not statistically significant). Subjects received buprenorphine at a dose of 1, 3, or 8 mg per day or methadone at a dose of 30 mg per day and were treated in an urban outpatient clinic, offering a 1-hour weekly individual counseling session. Days retained in treatment were measured. Completion rates by buprenorphine dosage group were 29.3% for the 1-mg dose group, 46.3% for the 3-mg dose group, 68.3% for the 8-mg dose group, and 61% for the 30-mg methadone dose group. Retention in the 8-mg dose group was significantly better than in the 1-mg dose group (p=.00041) and in the 3-mg dose group (p=.045); other comparison (1 mg dose with 3 mg dose) was not significant. Methadone group was significantly better than 1mg buprenorphine dose group (p=.004), but was not significantly different from 3 mg buprenorphine dose group (p=.18) or 8 mg buprenorphine dose group (p=.49). The results support the efficacy of buprenorphine for outpatient treatment of heroin dependence and seem to indicate that the highest dose (8 mg) of buprenorphine was the best of the three doses of buprenorphine, and also support the superiority of 30 mg of methadone compared to 1 mg dose of buprenorphine for Iranian heroin-dependent patients to increase their retention in treatment.
View full-text
Article Full-text available
Effects of a Single 50% Extra Dose of Methadone on Heroin Craving and Mood in Lower- Versus Higher-D...
August 2010
· Journal of Clinical Psychopharmacology
Johannes Strasser Gerhard A Wiesbeck Natalie Meier [...]
Kenneth Dürsteler-MacFarland
Some patients on steady-state methadone occasionally crave for extra opioids for different reasons (eg, cue-elicited craving, stress). This study examined the acute-on-chronic effects on heroin craving, mood, and opioid-like symptoms of a single, extra half-dose on top of the patient's prescribed daily methadone dosage. A randomized, double-blind, placebo-controlled, counterbalanced crossover
... [Show full abstract]
design was used to test the safety of this practice and the hypotheses that extra methadone would reduce heroin craving and improve mood, with greater responses in lower-dose (20-60 mg/d) as compared with higher-dose patients (80-120 mg/d). Fourteen stabilized methadone-maintained volunteers of each dose group were examined predrug and postdrug on 2 separate days using a range of self-report measures (Heroin Craving Questionnaire, visual analogs, Befindlichkeits-Skala, Short Opiate Withdrawal Scale, and Opioid Agonist Scale). Additionally, patients' expectations and guesses regarding treatment were assessed predrug and postdrug, respectively. No adverse effects occurred after extra methadone. Participants could not reliably distinguish between extra methadone and placebo. Repeated-measures analyses of variance showed no effects of extra methadone on heroin craving and opioid agonist effects. However, extra methadone improved mood on the Befindlichkeits-Skala (F1/24 = 4.71, P = 0.04), with marginally greater effects in lower-dose patients ((F1/24 = 2.94, P = 0.099). A single 50% extra methadone dose is most likely safe in patients on stable methadone doses of 20 to 120 mg/d and may improve patients' mood. Extra methadone may constitute an important factor in the attractiveness of maintenance treatment and may enhance treatment outcome.
View full-text
Article
Exposure to opioid maintenance treatment reduces long-term mortality
April 2008
· Addiction
Louisa Degenhardt Richard P Mattick Amy Gibson [...] Susannah O'Brien
To (i) examine the predictors of mortality in a randomized study of methadone versus buprenorphine maintenance treatment; (ii) compare the survival experience of the randomized subject groups; and (iii) describe the causes of death.
Ten-year longitudinal follow-up of mortality among participants in a randomized trial of methadone versus buprenorphine maintenance treatment.
Recruitment through ... [Show full abstract]
three clinics for a randomized trial of buprenorphine versus methadone maintenance.
A total of 405 heroin-dependent (DSM-IV) participants aged 18 years and above who consented to participate in original study.
Baseline data from original randomized study; dates and causes of death through data linkage with Births, Deaths and Marriages registries; and longitudinal treatment exposure via State health departments. Predictors of mortality examined through survival analysis.
There was an overall mortality rate of 8.84 deaths per 1000 person-years of follow-up and causes of death were comparable with the literature. Increased exposure to episodes of opioid treatment longer than 7 days reduced the risk of mortality; there was no differential mortality among methadone versus buprenorphine participants. More dependent, heavier users of heroin at baseline had a lower risk of death, and also higher exposure to opioid treatment. Older participants randomized to buprenorphine treatment had significantly improved survival. Aboriginal or Torres Strait Islander participants had a higher risk of death.
Increased exposure to opioid maintenance treatment reduces the risk of death in opioid-dependent people. There was no differential reduction between buprenorphine and methadone. Previous studies suggesting differential effects may have been affected by biases in patient selection.
Read more
Last Updated: 26 Mar 2023
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21
14
6.5
1.3
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20
14
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18
16
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19
15
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15
17
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18
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11
23
8.0
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8
26
11.0
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13
--
2.0
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15
1.0
0.1
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16
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16
17
3.5
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26
12.0
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23
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1.1
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17
17
6.0
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16
18
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19
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20
14
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15
1.5
0.3
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17
16
2.5
1.3
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14
19
5.5
-0.4
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10
24
10.0
-0.6
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20
14
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1.3
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18
16
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Including Insects in Organic Poultry Diets | eOrganic
Including Insects in Organic Poultry Diets
NOTE: Before using any feed ingredient make sure that the ingredient is listed your Organic System Plan and approved by your certifier.
Introduction
Eggs from chickens on range have been found to be higher in total fat content than those in a cage production environment (Anderson, 2011). A drop in the total fat content of eggs may be observed when the hens are 74 weeks old, generally corresponding to the winter months when fat intake from insects is at its lowest. It has been observed that the consumption of insects results in the increased fat content of eggs from hens on pasture. The nutrient content of poultry meat or eggs may differ due to the type of insects attracted to the pasture crops.
Bambara and Watson (2011) reported that several insect species could be present on forages and pastures in North Carolina. This includes alfalfa weevil ( Hypera postica), potato leafhopper ( Empoasca fabae), true armyworm ( Pseudaletia unipuncta), fall armyworm ( Spodoptera frugipenda), cutworms ( Agrotisand Feltia), green june beetle ( Cotinis nitida), meadow spittlebug ( Philaenus spumarius), and clover root curculia ( Sitona hispidulus), as well as aphids, grasshoppers, and crickets.
Composition
A variety of insects have been used as a food source for both animals and humans. As a result, reports on their nutrient content are published in a variety of different journals ranging from anthropology to zoology. Finke (2008) completed an extensive review of the published literature related to the nutrient content of insects commonly used as food for humans or animals, including poultry. In this review, it was found that the moisture content of raw, whole insects varied from 55% to 85%. The insects with the lowest moisture content generally had a high fat content. On a dry matter basis, protein is a major component of raw, whole insects with values ranging from 21% to 80%. Feeding trials with different insects have suggested that the quality of insect protein is similar to that of fishmeal or soybean meal. The other major component of most raw, whole insects is fat—ranging from 2.2% to 60%. Based on the limited data available Finke (2008) concluded that, in general, female insects contain more fat than male insects.
Insects have a protein-rich exoskeleton rather than a calcified skeleton, so the mineral content of most insects is relatively low (Finke, 2008). All insects, however, are reported to contain a high level of phosphorous and a low level of calcium. The result is a calcium to phosphorus ratio of less than one. While the phosphorus availability in plant sources is low, the phosphorus found in insects is almost 100% available. Most insects are a good source of trace minerals including iron, zinc, copper, manganese and selenium. Finke (2008) concluded, however, that the mineral composition is mainly a reflection of the material that the insects were feeding on. Studies with wild insects have shown seasonal variation in mineral content, corresponding with differences in material available to the insects.
While some researchers have reported that soft-bodied insects contain less fiber than those with a hard exoskeleton, a critical evaluation of the literature by Finke (2008) suggests this may not be so clear-cut. The content of the gastrointestinal tract may be the reason for the high fiber values reported for some insect species.
Feeding Insects to Poultry
For poultry raised on pasture, the type of insects available to them depends on the type and quantity that are attracted to the forage. Insects can also be grown commercially, and different insect meals are available for use in poultry diets.
Recent research in China (Sun et al., 2012) indicated that meat from chickens raised on pastures with a heavy grasshopper population had more antioxidant potential and a longer storage life.
References and Citations
Anderson, K. E. 2011. Comparison of fatty acid, cholesterol, and vitamin A and E composition in eggs from hens housed in conventional cage and range production facilities. Poultry Science 90:1600–1608. (Available online at: http://dx.doi.org/10.3382/ps.2010-01289 ) (verified 19 Oct 2013)
Banjo, A. D., O. A. Lawal, and E. A. Songonuga. 2006. The nutritional value of fourteen species of edible insects in southwestern Nigeria. African Journal of Biotechnology 5:298–301. (Available online at: http://hdl.handle.net/1807/6678 ) (verified 19 Oct 2013)
Bambara, S., and W. Watson. 2003. Insects found in forage and pasture. In Chamblee, D. S, and J. T. Green (eds.) Chapter 13 revision, beneficial and pest insects in forage crops, production and utilization of pastures and forages in North Carolina. 1995. NC Agricultural Research Service, NC State University, Raleigh, NC. Technical Bulletin 305. (Available online at: http://www.ces.ncsu.edu/depts/ent/notes/forage/past&for/past&for.html ) (verified 19 Oct 2013)
Finke, M. D. 2002. Complete nutrient composition of commercially raised invertebrates used as food for insectivores. Zoo Biology 21:269–285. (Available online at: http://dx.doi.org/10.1002/zoo.10031 ) (verified 19 Oct 2013)
Finke, M. D. 2008. Nutrient content of insects. p. 2687–2710. In J. L. Capineira (ed.) Encyclopedia of entomology, 2nd edition. Springer Netherlands.
Khusro, M., N. R. Andrews, and A. Nicholas. 2012. Insects as poultry feed: A scoping study for poultry production systems in Australia. World's Poultry Science Journal 68:435–446. (Available online at: http://dx.doi.org/10.1017/S0043933912000554 ) (verified 19 Oct 2013)
Sun, T., R. J. Long, Z. Y. Liu, W. R. Ding, and Y. Zhang. 2012. Aspects of lipid oxidation of meat from free-range broilers consuming a diet containing grasshoppers on alpine steppe of the Tibetan plateau. Poultry Science 91:224–231. (Available online at: http://dx.doi.org/10.3382/ps.2011-01598 ) (verified 19 Oct 2013)
Wang, D., S. W. Zhai, C. X. Zhang, Y. Y. Bai, S. H. An, and Y. N. Xu. 2005. Evaluation on nutritional value of field crickets as a poultry feedstuff. Asian-Australasian Journal of Animal Sciences 18:667–670. (PDF Available online at: http://ajas.info/upload/pdf/18_104.pdf ) (verified 19 Oct 2013)
| https://eorganic.org/node/8148 |
Thermodynamic Preservation of Carbon in Anoxic Environments - Environmental System Science Program Environmental System Science Program
Thermodynamic Preservation of Carbon in Anoxic Environments
Novel mechanism shifts understanding of the reactivity of carbon in subsurface stocks.
The Science
A new study provides important insights into why carbon persists in waterlogged soil and subsurface sediments. Energetic constraints prevent microbial respiration of certain organic carbon compounds, leaving a pool of water-soluble carbon that is susceptible to oxidation or export and subsequent decomposition in downstream, aerated environments.
The Impact
Terrestrial, anoxic environments hold large stocks of carbon, and knowledge of the dynamics of these stocks is insufficient. Thermodynamic limitations on organic carbon decomposition operate differently than better-recognized kinetic and spatial constraints, and this must be accounted for in models predicting carbon cycling rates. The new findings imply that organic carbon stocks respond differently than previously thought to changes in sediment water saturation. Moreover, carbon exported from anoxic environments has the potential to drive nutrient, contaminant, and carbon cycles in downstream aquatic ecosystems. The study also demonstrates the benefits of combining X-ray absorption spectroscopy (XAS) at the Stanford Synchrotron Radiation Lightsource (SSRL) with Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR-MS) at the Environmental Molecular Sciences Laboratory (EMSL).
Summary
It is well recognized that carbon persists in environments where the oxygen levels are low. Carbon stocks existing in floodplains, wetlands, and subsurface sediments, which often are suboxic to anoxic, comprise a considerable portion of the global dynamic carbon inventory. In spite of the importance to accurately represent the dynamics of these carbon stocks in global, regional, and local carbon models, the mechanisms responsible for carbon preservation in anoxic conditions are unclear. The degradation of organic matter takes place through multiple steps, involving enzymatic and metabolic processes carried out by many different types of microorganisms. However, the last step, the oxidation of organic molecules to carbon dioxide through microbial respiration, requires the molecules to be water-soluble and small enough to enter the microbial cell. In addition to this, the oxidation of carbon must generate enough energy to support microbial growth. With oxygen present the respiratory oxidation of any carbon compound is thermodynamically viable; it provides sufficient energy to sustain growth. But without oxygen, some carbon compounds, mostly belonging to the chemical classes of lipids and proteins, become thermodynamically unviable for oxidation, in spite of being dissolved and small enough to enter the microbial cell. This changes the chemical composition of the water-soluble carbon in environments where this thermodynamic preservation mechanism is operational.
In a Stanford University and SSRL-based study, Boye et al.(2017), utilized the shift in water soluble–carbon chemistry to demonstrate the relevance of thermodynamic limitations for preserving carbon in field samples from anoxic floodplain sediments from four sites across the upper Colorado River Basin. X-ray absorption spectroscopy at SSRL was used to identify sediments containing sulfides produced by microbial respiration in the absence of oxygen. The water-soluble carbon from these sediments was then analyzed by FT-ICR-MS at EMSL and compared to that from oxic sediment samples. The results reveal a clear difference in carbon chemistry consistent with theoretically calculated thermodynamic thresholds and provide unprecedented field-based evidence for thermodynamic preservation of carbon in anoxic conditions. This is important because it illuminates a mechanism previously unrepresented in carbon cycling models and further highlights that water-soluble, and thus readily exported, carbon from anoxic environments is highly susceptible to rapid decomposition upon exposure to oxygen. The downstream implications of this reactive carbon source are currently not fully understood, but are likely substantial.
Principal Investigator
John BargarSLAC National Accelerator [email protected]
Program Manager
Paul BayerU.S. Department of Energy, Biological and Environmental Research (SC-33)Environmental System [email protected]
Funding
Funding was provided by the Subsurface Biogeochemistry Research (SBR) program of the Office of Biological and Environmental Research (BER), within the U.S. Department of Energy (DOE) Office of Science, to the SLAC Scientific Focus Area (SFA) under contract DE-AC02-76SF00515 to SLAC and to Scott Fendorf through BER’s Terrestrial Ecosystem Science (TES) program under Award Number DE-FG02-13ER65542. Use of the Stanford Synchrotron Radiation Lightsource (SSRL) is supported by the Office of Basic Energy Sciences, within the DOE Office of Science. A portion of the research was conducted at the Environmental Molecular Sciences Laboratory (EMSL), a DOE Office of Science user facility sponsored by BER and located at Pacific Northwest National Laboratory. Field operations were supported through Lawrence Berkeley National Laboratory’s Sustainable Systems SFA (DOE BER, contract DE-AC02-05CH11231) and through the DOE Office of Legacy Management (DOE-LM). Research described in this paper was performed at beamline 11ID-1 at the Canadian Light Source (CLS), which is supported by the following Canadian entities: Natural Sciences and Engineering Research Council of Canada (NSERC), Canadian Institutes of Health Research (CIHR), National Research Council (NRC), Western Economic Development Canada (WEDC), the University of Saskatchewan, and the Province of Saskatchewan.
References
Boye, K., V. Noël, M. M. Tfaily, and S. E. Bone, et al.
"Thermodynamically controlled preservation of organic carbon in floodplains." Nature Geoscience10415–419
(2017).https://doi.org/10.1038/ngeo2940.
| https://ess.science.energy.gov/highlight/thermodynamic-preservation-of-carbon-in-anoxic-environments/ |
PART V
PART V.
PROCEDURE AND DECREE
§571-41 Procedure in children's cases.(a) Cases of children in proceedings under section 571-11(1) and (2) shall be
heard by the court separate from hearings of adult cases and without a jury.
Stenographic notes or mechanical recordings shall be required as in other civil
cases in the circuit courts, unless the parties waive the right of such record
or the court so orders. The hearings may be conducted in an informal manner
and may be adjourned from time to time.
(b) Except as provided in section 571-84.6,
the general public shall be excluded and only such persons admitted whose
presence is requested by the parent or guardian or as the judge or district
family judge finds to have a direct interest in the case, from the standpoint
of the best interests of the child involved, or in the work of the court;
provided that:
(1) Upon request by a party, hearings initiated
pursuant to chapter 587A may be opened to the public if a judge determines that
doing so would be in the best interests of the child;
(2) Parties involved in hearings initiated pursuant
to chapter 587A shall be allowed to be accompanied by an adult advocate to
provide support, unless the court finds that the presence of the advocate would
not be in the best interests of the child. The advocate need not be a licensed
attorney. The State shall not be required to pay, directly or through
reimbursement, for any fees, costs, or expenses related to the advocate. No
person shall act as an advocate who has an interest in the matter beyond the
protection of the child and the healing and rehabilitation of the family; and
(3) The victim of the alleged violation and all other
witnesses who are younger than eighteen years of age shall be entitled to have
parents, guardians, or one other adult and may have an attorney present while
testifying at or otherwise attending a hearing initiated pursuant to section
571-11(1) or 571-11(2).
Prior to the start of a hearing, the parents,
guardian, or legal custodian, and, when appropriate, the child, the child
victim, or witness shall be notified of the right to be represented by counsel
and the right to remain silent.
(c) Findings of fact by the judge or district
family judge of the validity of the allegations in the petition shall be based
upon a preponderance of evidence admissible in the trial of civil cases except
for petitions alleging the court's jurisdiction under section 571-11(1) which
shall require proof beyond a reasonable doubt in accordance with rules of
evidence applicable to criminal cases; provided that no child who is before the
court under section 571-11(1) shall have admitted against the child any
evidence in violation of the child's rights secured under the constitution of
the United States or the State of Hawaii. In the discretion of the judge or
district family judge the child may be excluded from the hearing at any time.
When more than one child is alleged to have been involved in the same act, the
hearing may be held jointly for the purpose of making a finding as to the
allegations in the petition and then shall be heard separately for the purpose
of disposition except in cases where the children involved have one common
parent.
(d) In the disposition part of the hearing any
relevant and material information, including that contained in a written
report, study, or examination, shall be admissible, and may be relied upon to
the extent of its probative value; provided that the maker of the written
report, study, or examination shall be subject to both direct and
cross-examination upon demand and when the maker is reasonably available. The
disposition shall be based only upon the admitted evidence, and findings
adverse to the child as to disputed issues of fact shall be based upon a
preponderance of such evidence.
(e) Upon a final adverse disposition, if the
parent or guardian is without counsel the court shall inform the parent or
guardian of the parent's or guardian's right to appeal as provided for in
section 571-54.
(f) The judge, or the senior judge if there is
more than one, may by order confer concurrent jurisdiction on a district court
created under chapter 604 to hear and dispose of cases of violation of traffic
laws or ordinances by children, provision to the contrary in section 571-11 or
elsewhere notwithstanding. The exercise of jurisdiction over children by
district courts shall, nevertheless, be considered noncriminal in procedure and
result in the same manner as though the matter had been adjudicated and
disposed of by a family court. [L 1965, c 232, pt of §1; Supp, §333-19; HRS
§571-41; am L 1973, c 211, §1(e) and c 219, §2; am L 1976, c 85, §9; am L 1980,
c 262, §1; am L 1983, c 199, §1; gen ch 1985; am L 1997, c 317, §3; am L 2004,
c 211, §1; am L 2010, c 135, §7]
Rules of Court
Juvenile proceedings, see Hawaii Family Court Rules, part D.
Evidence; proof, see HFCR rule 143.
Findings by court, see HFCR rule 52.
Transcripts, see HFCR rule 80.
Case Notes
Preponderance of evidence standard applies only to
adjudicatory and post-adjudicatory proceedings. 61 H. 48, 594 P.2d 1084.
Probation revocation hearing, procedural requirements. 62 H.
70, 610 P.2d 509.
Provision relating to admissibility of evidence at the
dispositional phase of hearing is consistent with due process. 62 H. 70, 610
P.2d 509.
Right to counsel; waiver. 63 H. 162, 623 P.2d 86.
District court has concurrent jurisdiction with family court
in DUI cases where defendant is a minor. 69 H. 455, 746 P.2d 82.
District court may not impose a sentence of imprisonment for
a traffic offense. 70 H. 328, 770 P.2d 418.
Because subsection (c) lacks any express standards governing
the exercise of the court's discretion to join cases or to account for
situations where joinder may result in unfair prejudice to one of the minors,
family court's use of HRPP rules 8, 13, and 14, in and of itself, did not
conflict with subsection (c) and thus, was not reversible error. 79 H. 265
(App.), 900 P.2d 1332.
<table><tbody><tr><td> Previous</td><td> Vol12_Ch0501-0588</td><td> Next</td></tr></tbody></table>
| https://www.capitol.hawaii.gov/hrsarchive/hrs2010/Vol12_Ch0501-0588/HRS0571/HRS_0571-0041.htm |
Drones | Free Full-Text | Estimating Wildlife Tag Location Errors from a VHF Receiver Mounted on a Drone
Recent studies have demonstrated the high potential of drones as tools to facilitate wildlife radio-tracking in rugged, difficult-to-access terrain. Without estimates of accuracy, however, data obtained from receivers attached to drones will be of limited use. We estimated transmitter location errors from a drone-borne VHF (very high frequency) receiver in a hilly and dense boreal forest in southern Québec, Canada. Transmitters and the drone-borne receiver were part of the Motus radio-tracking system, a collaborative network designed to study animal movements at local to continental scales. We placed five transmitters at fixed locations, 1–2 m above ground, and flew a quadrotor drone over them along linear segments, at distances to transmitters ranging from 20 m to 534 m. Signal strength was highest with transmitters with antennae pointing upwards, and lowest with transmitters with horizontal antennae. Based on drone positions with maximum signal strength, mean location error was 134 m (range 44–278 m, n = 17). Estimating peak signal strength against drone GPS coordinates with quadratic, least-squares regressions led to lower location error (mean = 94 m, range 15–275 m, n = 10) but with frequent loss of data due to statistical estimation problems. We conclude that accuracy in this system was insufficient for high-precision purposes such as finding nests. However, in the absence of a dense array of fixed receivers, the use of drone-borne Motus receivers may be a cost-effective way to augment the quantity and quality of data, relative to deploying personnel in difficult-to-access terrain.
Estimating Wildlife Tag Location Errors from a VHF Receiver Mounted on a Drone
by André Desrochers 1,* , Junior A. Tremblay 2 , Yves Aubry 3 , Dominique Chabot 4 , Paul Pace 5 and David M. Bird 6
5
Defense Research and Development Canada, 3701 Carling Avenue, Ottawa, ON K1A 0Z4, Canada
6
Avian Science and Conservation Centre of McGill University, c/o 10980 Dunne Road, North Saanich, BC V8L 5J1, Canada
*
Author to whom correspondence should be addressed.
Drones 2018 , 2 (4), 44; https://doi.org/10.3390/drones2040044
Received: 9 November 2018 / Revised: 3 December 2018 / Accepted: 7 December 2018 / Published: 11 December 2018
(This article belongs to the Special Issue Drones for Biodiversity Conservation and Ecological Monitoring )
Abstract
Recent studies have demonstrated the high potential of drones as tools to facilitate wildlife radio-tracking in rugged, difficult-to-access terrain. Without estimates of accuracy, however, data obtained from receivers attached to drones will be of limited use. We estimated transmitter location errors from a drone-borne VHF (very high frequency) receiver in a hilly and dense boreal forest in southern Québec, Canada. Transmitters and the drone-borne receiver were part of the Motus radio-tracking system, a collaborative network designed to study animal movements at local to continental scales. We placed five transmitters at fixed locations, 1–2 m above ground, and flew a quadrotor drone over them along linear segments, at distances to transmitters ranging from 20 m to 534 m. Signal strength was highest with transmitters with antennae pointing upwards, and lowest with transmitters with horizontal antennae. Based on drone positions with maximum signal strength, mean location error was 134 m (range 44–278 m, n = 17). Estimating peak signal strength against drone GPS coordinates with quadratic, least-squares regressions led to lower location error (mean = 94 m, range 15–275 m, n = 10) but with frequent loss of data due to statistical estimation problems. We conclude that accuracy in this system was insufficient for high-precision purposes such as finding nests. However, in the absence of a dense array of fixed receivers, the use of drone-borne Motus receivers may be a cost-effective way to augment the quantity and quality of data, relative to deploying personnel in difficult-to-access terrain.
Keywords:
radio-tracking
;
Motus
;
drone
;
boreal forest
;
precision
;
accuracy
;
response surface
;
forêt Montmorency
Graphical Abstract
1. Introduction
For several decades, radio-tracking has proven itself as a valuable tool for the investigation of animal movements at a wide range of temporal and spatial scales [
1
]. The advent of the Global Positioning System (GPS) and similar satellite-based systems has revolutionized wildlife tracking by transmitting precise coordinates directly from tagged animals. However, GPS transmitters remain costly and too heavy for small animals. As a result, conventional, non-GPS, transmitters remain the predominantly used tracking technology in studies of small songbirds and many other terrestrial applications. With the exception of light-sensitive geolocators, which require recaptures to retrieve data stored in memory [
2
], the location of non-GPS transmitters usually has to be inferred from signal detection, signal strength, compass direction or combinations of those.
To get precise estimates of the location of animals fitted with non-GPS transmitters, field biologists will often resort to triangulation or homing, i.e., getting progressively closer to the focal animal [
3
]. In rugged, difficult-to-access terrain, the latter two approaches are labor-intensive and may be well outside research budgets, not to mention ever-increasing concerns about safety [
4
]. For species ranging over kilometers or more, the use of conventional aircraft such as Cessna planes is often the only way to obtain sufficient amounts of data, but such campaigns also pose a safety risk, with aviation accidents determined to be the leading cause of mortality among wildlife workers in the United States from 1937–2000 [
5
].
The advent of drones in the civil sector may offer immense potential for combining affordability, safety, and accuracy in the effort to document movements of animals fitted with non-GPS transmitters. Chabot and Bird [ 6 ] provide a review of recent advances in the use of drones for wildlife applications. They point out that despite its potential, drone-borne wildlife radio-tracking remains underdeveloped, possibly due to enduring skepticism about its potential and/or technological and operational barriers. To this day, the published literature suggests that, with few exceptions, the subject continues to be largely approached as an engineering curiosity more so than an endeavor by those who stand to benefit from its development: wildlife researchers and managers [ 7 , 8 , 9 , 10 ].
One of the concerns that needs to be addressed to promote the effective use of drones in wildlife radio-tracking is accuracy. Signal power density is proportional to the inverse square of the distance between the transmitter and the receiver. In principle thus, knowing the strength and direction of a transmitter signal from two locations, sufficiently distinct in space and sufficiently close in time, should yield highly accurate positions. However, transmitter signals are dampened by trees, rocks, etc., to varying extents, and may exhibit multi-path effects, making it practically impossible to infer transmitter locations from two locations with intervening obstacles.
We estimated transmitter location errors with fixed-location ”test” transmitters and a drone-borne receiver in a hilly and dense forest composed mostly of balsam fir (
Abies balsamea
). We used a simple quadratic, two-dimensional response surface of signal strength against Latitude and Longitude.
2. Materials and Methods
We conducted this study in September 2016 at Forêt Montmorency (47.4 N, 71.1 W), a teaching and research forest located north of Québec City, Québec, Canada. The study area is a dense balsam fir/white birch (
Betula papyrifera
) boreal forest landscape with altitudes ranging from 750 to 1000 m, covered by a dense network of forestry roads (for details see [
11
]). We conducted seven flights, within two sectors each covering ~0.2 km
2
, each composed of a matrix of old, mid-successional, and early-successional balsam fir stands resulting from clearcutting (
Figure 1
). Tree height in the study site varied from ~4 m to 12 m, with ~2500–10,000 stems/ha.
Figure 1. Flight transects and test transmitter locations, in yellow. Takeoff times are indicated.
Each flight was performed by a custom-built heavy-lift quadrotor drone based on a Gryphon Dynamics airframe (Daegu, South Korea) and a Pixhawk flight controller (3D Robotics, Berkeley, CA, USA), with a payload capacity of about 4 kg including the battery. The drone was programmed to fly at a fixed altitude of 50 m above the ground at the location where it was launched and a forward speed of 5 m/s. We automated flights from takeoff to landing, and monitored them from the ground using a tablet computer. We mounted a radio receiver system on the ground-facing side of the drone. The radio receiver system was composed of a hanging omnidirectional dipole antenna attached to a weight at the bottom end, and coupled to a Funcube Pro+ dongle. The dongle was connected to a BeagleBone computer programmed to monitor and record signals simultaneously from multiple transmitters (for details see [
12
]).
Before each flight, we deployed five radio-transmitters at distances ranging from 18 m to 507 m from one another ( Figure 1 ). We placed each transmitter in a tree at ca. 1.3 m above ground, with the antenna pointing up, down or horizontal. Transmitters were avian nanotags model NTQB-4-2, Lotek Wireless Inc., Newmarket, ON, Canada). Each nanotag had a unique set of pulses delivered each 5 s at a frequency of 166.38 MHz (VHF; very high frequency), a standard used by the Motus Wildlife Tracking System [ 12 , 13 ].
After the completion of each flight, we downloaded data from two sources: the telemetry receiver and the drone navigation log. Timestamps from the two sources were synchronized, allowing us to match each signal reception from test transmitters to the exact location of the drone and in turn, the distance between the transmitters and the receiver.
As pointed out earlier, several factors may influence signal reception and strength. However, on average, signal strength should provide an unbiased estimate of the distance between the transmitter and the receiver. Thus, a two-dimensional array, i.e., a map of signal strengths, should inform us about the true location of the transmitter. We estimated the location errors with two methods. First, we retained the drone location at which the signal was strongest, and calculated the Euclidean distance between the drone XY coordinates, and the XY coordinates of the source. Second, we modelled signal strength as a function of the drone’s XY coordinates in meters from a Modified Transverse Mercator map projection (Easting and Northing) using two quadratic functions:
Easting: Dbm ~ β 0 + β 1 (Easting) + β 2 (Easting 2 ) + ε
(1)
Northing: Dbm ~ β 0 + β 1 (Northing) + β 2 (Northing 2 ) + ε
(2)
where Dbm is the signal’s strength,
β
i
regression estimates, and
ε
a vector of model residuals. The formulas yielded a peak signal strength when the regression estimate for the quadratic term was negative. Note that in the presence of a peak signal strength both on X and Y coordinates, only
relative
signal strength will be required to estimate transmitter locations. Differences in signal strength among transmitters, whether because of manufacturing or placement in the forest, are measured by the models’ intercept (
β
0
). We obtained Easting and Northing estimates by:
E ^ , N ^ = − β 1 2 · β 2
(3)
We conducted all analyses with the statistical software R version 3.5.0 [ 14 ].
3. Results
We obtained 669 detections of the test transmitters from the combined drone flights. Signal strength decreased significantly with increasing distance to drone, with the furthest detection at 534 m ( Figure 2 , F 1,646 = 181.7, p < 0.001). The orientation of the transmitter’s antenna also had a significant effect on signal strength ( F 2,646 = 62.6, p < 0.001), with antennae pointing upward performing best.
Figure 2. Signal strength in response to the distance between the drone and the transmitter.
Given that we conducted seven flights, each with five test transmitters deployed, we obtained 35 detection sets. Five to 42 detections were obtained for each detection set (mean = 19.9). Based solely on drone locations when signal strength was greatest, mean location error was 132.3 m (range: 28.8–294.2 m, n = 35). The reliability of the maximum strength method is questionable when the strongest signal is on the periphery of the drone route, because in those cases the transmitter was likely outside of the range covered by the drone. To prevent this, we removed all detection sets where the strongest signal came from a drone location on the periphery of the convex hull enclosing the detection set. The resulting subset of data yielded a mean location error of 134.0 m (range: 43.9–278.0 m, n = 17).
Nearest distances to transmitters yielded strongest signals in only two of the 35 detection sets. Furthermore, signal strength did not always increase nearer transmitters ( Figure 3 ), leading to only seven cases where quadratic regression coefficients of signal strength against X or Y coordinates were negative, i.e., leading to a maximum estimated signal strength as required for position estimation.
Figure 3. Left: best case scenario, with signal strength, depicted by cross size, roughly increasing toward the location of the test transmitter (blue dot). Right, worst case scenario, with signal strength showing no obvious relationship with distance to transmitter.
Of the seven cases with estimable positions, we dropped one case with an estimate error (3034 m) greater than the maximum known distance between the drone and the transmitter (534 m). Figure 4 illustrates the remaining six cases where quadratic curve-fitting yielded estimable positions.
Figure 4. Transmitter location errors from quadratic regression estimation, based on signal strength. Test transmitter locations in yellow, estimated locations in red.
The mean location error from the quadratic method was 69.9 m (range 20.8–161.3 m).
4. Discussion
The main outcome of this study was that drones offer an alternative to the more labor-intensive, traditional approaches for radio-tracking small birds, amphibians, or small mammals in rugged terrain. All five transmitters were detected on each of the seven flights, thus for the purposes of simple detection at a range of a few hundred meters, a drone appears highly effective. However, the precision of the detection-by-drone method is likely insufficient for finer-scale applications such as finding nests or dens or documenting microhabitat use. We explored two ways to estimate source locations, based on observed vs. modeled maximum signal strength. Observed maximum signal strength has the benefit of being simple and easily obtainable (larger sample), but it wastes the bulk of the information obtained by the drone. Furthermore, it is overly sensitive to outliers. The estimation method based on quadratic estimation has the advantage of combining a comprehensive use of the data with computational simplicity. In the present study, the quadratic method yielded disappointing results. However, we believe that this method should be assessed more thoroughly with denser flight paths, and a less variable elevation of the drone above ground, than in the present study. Additionally, field trials should be conducted over open areas such as fields to evaluate the statistical noise, and possible bias, caused by dense canopy. Our results were possibly influenced by the proximity of test transmitters to road edges, so future field trials could be more reliable if transmitters were placed at more varying distances from roads.
Given the aims of this study, it was natural to design the drone search pattern so that it would fly directly over the transmitters. Of course, in real searches for animals wearing transmitters, search patterns would result from a tradeoff between high density, e.g., the mean distance between flight segments, and extent. Maximum detection distance should set a lower limit to search pattern density. We found that signal strength decreased approximately linearly with increasing distance between the source and the drone. Given that we were able to detect few signals at distances further than 500 m, we believe that drones should always fly within 500 m of locations where animals wearing tags are expected, or test transmitters were placed, in the case of calibration studies such as the present one.
Even in cases where drones would be flown in a dense search pattern over large extents, locating tags carried by animals in motion will be more challenging than locating stationary tags. The proximity of an animal body is known to amplify signals [
15
], but fortunately this effect should not influence location estimation, which is based on
relative
signal strength from one drone location to another. Animals moving fast on the horizontal plane, e.g., birds in flight, would undoubtedly pose the greatest challenge. However, even animals remaining in fixed locations may prove more difficult to locate than fixed tags, if they move (e.g., foraging), because signal strength depends on tag angle relative to the drone, as we found here.
Over the past several years, there has been a dramatic increase in the use of drones to survey and monitor birds by means of optical imaging, including breeding colonies [ 16 , 17 , 18 ], wintering and migrating waterbirds [ 19 , 20 , 21 ], and individual nest inspections [ 22 , 23 , 24 ]. Rapid uptake of these applications has been made possible by the relative maturity, simplicity and accessibility of the requisite technologies, namely sophisticated and user-friendly drone flight control systems combined with compact and very high-resolution digital cameras. However, the applicability of these approaches remains limited to relatively large and/or unconcealed birds, whereas a considerable proportion of species under study or management are small and challenging to locate or directly observe [ 25 ]. Thus, it is of continuing interest to develop drone-based solutions to monitor and track birds using alternative sensing methods that do not rely on direct visual observation of subjects, including acoustic sensors [ 26 ] and radio telemetry. Such developments would help in addressing more elaborate questions, such as habitat selection. This also extends to non-avian species: Chabot and Bird [ 6 ] identified a range of wildlife taxa whose study and monitoring could potentially benefit from drone-based radio-tracking, such as small- to medium-sized mammals including primates, mustelids, rodents and bats, as well as lizards, snakes, land turtles and amphibians.
We believe that the lack of breakthrough in drone-based radio-tracking in the last decade results in part from a focus on more appealing, but more challenging, solutions. One of those is based on an “active” localization system whereby multiple antennas mounted on a drone would enable real-time, onboard triangulation of an animal’s location, which in turn automatically adjusts the drone’s heading to fly towards the animal and pinpoint its position [
6
]. Indeed, the complexities involved in bringing this idea to fruition have proven exacting, and the best working prototypes to date still require a human operator at the drone’s ground control station to manually determine and transmit flight path adjustments based on real-time feedback from the onboard antenna-triangulation system [
7
]. In contrast, the approach detailed in our study and explored by few others [
27
] consists of a “passive” localization system whereby the drone executes a preprogrammed flight path over an area potentially containing one or more radio-tagged animals. The varying signal strength of a given transmitter received by a single antenna on the drone at multiple locations along its flight path is analyzed post hoc to estimate the animal’s location. Although not as compelling a solution as active localization, this passive approach can be much more readily implemented using existing technology (i.e., a drone capable of autonomous waypoint navigation and a simple antenna–receiver–logger system) without needing to develop and integrate sophisticated new gadgetry.
Continuing technological and operational advancements of drones are likely to improve their effectiveness for wildlife radio-tracking going forward. Already, “terrain following” capabilities have now been integrated into most popular drone flight control systems, enabling the aircraft to maintain a constant altitude above ground level in areas of varying relief, and consequently better normalization of the strength of radio signals received from the ground. The flight range of drones is also currently limited both by battery capacity and, often more significantly, airspace regulations that predominantly restrict drone operation to within visual line of sight of operators on the ground [
28
,
29
]. This restriction tends to be especially crippling in forests, where tall and dense trees, and hilly topography surrounding ground operators cause them to quickly lose sight of the drone as it flies away. It is therefore promising that regulatory agencies in several countries have recently undertaken more serious considerations of allowing drone operations beyond visual line of sight (BVLOS) under certain conditions, and even begun granting BVLOS approvals in limited cases. Regarding flight endurance, fixed-wing drones can typically remain airborne significantly longer (upwards of an hour) than rotary-wing drones (typically <30 min), but the takeoff and landing space requirements of the former tend to prohibit their use in areas such as forests, whereas the latter feature more versatile vertical takeoff and landing (VTOL). However, a growing number of hybrid VTOL fixed-wing drones have recently begun to enter the commercial market.
5. Conclusions
Despite the limited number and extent of drone flights in this study, we were able to obtain detection sets with enough detail to provide an operational assessment of transmitter location errors. We conclude that accuracy in this system was insufficient for high-precision purposes such as finding nests. However, in the absence of a dense array of telemetry towers, the use of drone-borne receivers may be a cost-effective way to enhance the quantity and quality of data, relative to deploying personnel in difficult-to-access terrain.
The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.
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Figure 1. Flight transects and test transmitter locations, in yellow. Takeoff times are indicated.
Figure 2. Signal strength in response to the distance between the drone and the transmitter.
Figure 3. Left: best case scenario, with signal strength, depicted by cross size, roughly increasing toward the location of the test transmitter (blue dot). Right, worst case scenario, with signal strength showing no obvious relationship with distance to transmitter.
Figure 4. Transmitter location errors from quadratic regression estimation, based on signal strength. Test transmitter locations in yellow, estimated locations in red.
Chicago/Turabian Style
Desrochers, André, Junior A. Tremblay, Yves Aubry, Dominique Chabot, Paul Pace, and David M. Bird. 2018. "Estimating Wildlife Tag Location Errors from a VHF Receiver Mounted on a Drone" Drones2, no. 4: 44.
https://doi.org/10.3390/drones2040044
Article Metrics
MDPI and ACS Style
Desrochers, A.; Tremblay, J.A.; Aubry, Y.; Chabot, D.; Pace, P.; Bird, D.M. Estimating Wildlife Tag Location Errors from a VHF Receiver Mounted on a Drone. Drones 2018, 2, 44.
https://doi.org/10.3390/drones2040044
AMA Style
Desrochers A, Tremblay JA, Aubry Y, Chabot D, Pace P, Bird DM. Estimating Wildlife Tag Location Errors from a VHF Receiver Mounted on a Drone. Drones. 2018; 2(4):44.
https://doi.org/10.3390/drones2040044
Chicago/Turabian Style
Desrochers, André, Junior A. Tremblay, Yves Aubry, Dominique Chabot, Paul Pace, and David M. Bird. 2018. "Estimating Wildlife Tag Location Errors from a VHF Receiver Mounted on a Drone" Drones2, no. 4: 44.
https://doi.org/10.3390/drones2040044
| https://www.mdpi.com/2504-446X/2/4/44/htm |
Ordinance of Georgia Appointing Benjamin Franklin Agent, 11 Ap …
Ordinance of Georgia Appointing Benjamin Franklin Agent, 11 April 1768
Ordinance of Georgia Appointing Benjamin Franklin Agent, 11 April 1768
Ordinance of Georgia Appointing Benjamin Franklin Agent
In November, 1765, Georgia dismissed William Knox6as its agent because of his support of the Stamp Act. For two and a half years thereafter the question of the agency was a political football: the House of Assembly attempted to have Charles Garth7appointed to succeed Knox; the Council refused, and Governor Wright8used his influence in London to prevent Garth’s being recognized as agent. In January, 1768, after the Council had again rejected Garth, the Assembly gave way and suggested Franklin instead. This recommendation the Council unenthusiastically accepted.9
An Ordinance
Appointing Benjamin Franklin Esquire Agent to Solicit the affairs of this Province in Great Britain.
WhereasThere are many important affairs necessary to be represented Solicited and Transacted in Great Britain which cannotbe Effectually done without having an Agent there And WhereasThe General Assembly of this Province have thought Benjamin Franklin Esquire a proper person to be appointed for the purposes aforesaid Be It Therefore Ordainedand it is hereby Ordained by His Excellency James Wright Esquire Capitain General and Governor in Chief of His Majestys Province of Georgia by and with the advice and Consent of the Honourable Council and Commons House of Assembly of the said Province in General Assembly met and by the Authority of the same That the said Benjamin Franklin be, and he is hereby declared nominated and appointed Agent to represent solicit and transact the affairs of this Province in Great Britain And Be It Further Ordainedthat the said Benjamin Franklin shall be and he is hereby fully Authorized and impowered to follow and pursue all such Instructions as he shall from time to time receive from the General assembly of this province or from the Committee hereinafter appointed to correspond with him.
And Be It Further OrdainedThat the Honourable James Habersham, Noble Jones James Edward Powell Lewis Johnson and Clement Martin Esquires The Honourable Alexander Wylly Esquire John Mullryne, John Smith Noble Wimberly Jones, John Milledge, John Simpson, Archibald Bullock, William Ewen and Joseph Gibbons Esquire1untill Others shall be appointed or anyseven of them two of which to be of the Council Provided nevertheless that if after being summoned in consequence of An Order from any of the Committee by the Clerk or Other person appointed by them for that purpose to meet the Committee they shall refuse or neglect to Attend then any seven of the persons before named shall be and they are hereby nominated and appointed a Committee to Correspond with the said Benjamin Franklin and give him such Orders and instructions from time to time as they shall Judge to be for the service of this Province.
And Be It Further Ordainedthat there shall be Allowed and paid unto the said Benjamin Franklin for his Agency the sum of One Hundred pounds Sterling money of Great Britain2over and above his reasonable Charges and disbursements on his application to the several offices and Boards in Negotiating the affairs of this Province.
And Be It Further Ordainedthat the said Benjamin Franklin shall be and Continue Agent for this Province for One whole year to Commence the first day of June next in the year of Our Lord One Thousand seven hundred and Sixty Eight.
Council Chamber By Order of the Commons House of Assembly
11 April 1768 Alex Wylly Speaker
Assented to By Order of the upper House of Assembly
Ja Wright N Jones exd
An Ordinance
Appointing Benjamin Franklin Esquire Agent to Solicit the affairs of this Province in Great Britain
Commons House of Assembly
1st Time 15th
Read
2d Time 24thMarch 1768
3d Time 25th
And Passed Henry KeallCDC
Upper House of Assembly
3Time 5 April
And Passed C. WatsonCGA
GeorgiaSecretarys Office A true Copy taken from the Original in this Office Examined and Certified by Thos Moodie2d Secry.
[Note numbering follows the Franklin Papers source.]
5 .The ordinance is printed in Candler, ed., Ga. Col. Recs., XIX, 12–14.
6 .William Knox (1732–1810) had lived in Georgia, 1757–61, and fancied himself as a colonial expert. He was a voluminous pamphleteer, but his principal claim to fame is as Undersecretary of State for the American Colonies during the lifetime of that department; he served successively under Hillsborough, Dartmouth, and Germain, and had a real if undefinable influence upon the formulation of American policy. DNB.
7 .The agent for South Carolina and M.P., for whom see above, XII, 30 n.
8 .James Wright (1716–85) was a native Carolinian, son of the provincial chief justice, and served successively as attorney general, lieutenant governor, and governor from 1761 to 1776 and again, after a two-year exile, from 1779 to 1782. In 1772 he was created a baronet. DNB.
9 .See William W. Abbot, The Royal Governors of Georgia, 1754–1775(Chapel Hill, [1959]), pp. 109, 136–8, 140, 142–3; Alfred O. Aldridge, “Benjamin Franklin as Georgia Agent,” The Georgia Review, VI(1952), 163–4.
1 .For James Habersham, secretary of the province, see above, III, 72 n. Noble Jones ( c.1700–75), James Edward Powell, Dr. Lewis Johnson (or Johnston), and Clement Martin were all councilors and political moderates. Jones was one of the original settlers; he had been a carpenter, surveyor, and physician, and at this time was a judge and the provincial treasurer. Powell, the captain of Fort George, was also a judge of the admiralty court. Johnson had formerly represented Savannah, and later became treasurer on Jones’s death in 1775. Alexander Wylly, speaker of the Commons House of Assembly, was moderate except when he supported the Massachusetts circular letter in 1768. John Mullryne, of Bonaventure, represented Wilmington, Tybee, Skidaway, and Green Island; he became a loyalist, and helped rescue Gov. Wright in 1776. John Smith, assemblyman from Medway and St. John’s Parish, later went the other way, becoming a member of the Council of Safety and the provincial Congress in 1775. Dr. Noble Wimberly Jones ( c.1724–1805), a representative from Savannah and the son of Noble Jones, was elected to succeed Wylly as speaker in Nov., 1768, was rejected in 1772 by Habersham, then acting governor, and subsequently served in the Continental Congress. John Simpson was an assemblyman from Frederica and St. James’s and another political moderate. Archibald Bullock (or Bulloch), a representative from Savannah, became speaker after Jones’s ouster in 1772, and later served as first president of the provincial Congress and delegate to the Continental Congress. William Ewen, an early settler and former basket-maker, represented Ebenezer, and in 1775 became president of the Council of Safety; he was then also a member of the provincial Congress, as was Joseph Gibbons, an assemblyman from St. John’s. John Milledge (1721–81), a Savannah representative, became a staunch adherent of independence.
These biographical details are collected from the following sources: Jack N. Averitt, Georgia’s Coastal Plain(3 vols., New York, etc., [1964]), I, 132; E. Merton Coulter, Wormsloe: Two Centuries of a Georgia Family(Athens, Ga., [1955]), pp. 1–107, 115–17, 131; Warren Grice, Georgia through Two Centuries, ed. E. Merton Coulter (3 vols., New York, etc., [1965]), I, 63, 71, 80, 348, 389, 397, 640–1, 645; Charles C. Jones, Jr., The History of Georgia(2 vols., Boston, 1884), I, 462; II, 103–5, 123–5, 142–3, 207; William B. Stevens, A History of Georgia… (2 vols., New York and Philadelphia, 1847–59), I, 392; II, 73, 101, 104–8; Sarah B. G. Temple and Jenneth Coleman, Georgia Journeys… (Athens, Ga., 1961), pp. 12, 211, 267–91.
2 .Another £50 was added later, but no salary was paid after 1773; BFwas eventually compensated with a grant of land. Kammen, Rope of Sand, p. 177.
Title
Moodie, Thomas
Date
11 April 1768
Reference
Cite as
“Ordinance of Georgia Appointing Benjamin Franklin Agent, 11 April 1768,” Founders Online, National Archives, https://founders.archives.gov/documents/Franklin/01-15-02-0056. [Original source: The Papers of Benjamin Franklin, vol. 15, January 1 through December 31, 1768 , ed. William B. Willcox. New Haven and London: Yale University Press, 1972, pp. 94–97.]
| https://founders.archives.gov/documents/Franklin/01-15-02-0056 |
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The Dark Side of Fungal Competition and Resource Capture in Wood: Zone Line Spalting from Science to Application - DocsLib
Materials and Design 201 (2021) 109480 Contents lists available at ScienceDirect Materials and Design journal homepage:
Materials and Design 201 (2021) 109480
Contents lists available at ScienceDirect
Materials and Design
journal homepage: www.elsevier.com/locate/matdes
The dark side of fungal competition and resource capture inwood: Zone linespaltingfrom science to application
Hugh Morris a,b,⁎, Kevin T. Smith c, Seri C. Robinson d, Maximilian Göttelmann e, Siegfried Fink e, Francis W.M.R. Schwarze a a Laboratory for Cellulose & Wood Materials, Empa-Swiss Federal Laboratories for Materials Science and Technology, Lerchenfeldstrasse 5, CH-9014 St. Gallen, Switzerland b Institute of Botany, BOKU Vienna, Vienna, Austria c United States Department of Agriculture Forest Service, Northern Research Station, 271 Mast Road, Durham, NH 03824, USA d Department of Wood Science and Engineering, Oregon State University, 119 Richardson, Corvallis, OR 97331, USA e Chair of Forest Botany, University of Freiburg, Bertoldstr. 17, 79085 Freiburg, Germany
HIGHLIGHTS GRAPHICAL ABSTRACT
• Spalted wood is a highly sought after speciality wood product in niche furni- ture and construction markets. • Spalting is a term specifically designated to any pattern in wood as a result of competition between decay-fungi. • By manipulating fungi, the operator can create unique patterns in wood called zone lines. • Zone lines are formed of melanin, the same pigment humans produce in their skin. • We review a method to standardise the treatment of wood using specific fungi and how we can upscale the process.
article info abstract
Article history: On wood surfaces and in planar section, zones lines appear as narrow and sharply delineated dark lines within Received 28 November 2020 wood visibly altered (“spalted”) by the decay process. In intact wood, zone lines define an irregular volume of Received in revised form 6 January 2021 decaying wood. They are primarily aggregations of melanised hyphae that enclose wood being decayed by a sin- Accepted 11 January 2021 gle genetic individual of a wood decayfungus. In the industry for speciality wood products, zone lines are highly Available online 20 January 2021 valued, especially for decorative pieces produced from wood turnery. While zone lines are commonly found in naturally infected wood, they can also be induced under controlled conditions. Although with great economic po- Keywords: Decay-fungi tential for application, there is currently no spalting process to produce zone lines on a commercial scale for niche Melanin furniture and construction markets. Successfully spalting wood in a defined timeframe that meets industry ex- Secondary xylem pectations requires a knowledge of fungal species, wood colonisation strategies, fungal decay processes along Soft rot fungi with wood behaviour (i.e. its hygroscopicity), anatomy and wood mechanical properties in relation to fungal Spalting decay. This review identifies current limitations of zone-line spalting and looks at a novel approach to inducing Zone line wood by combining genetic individuals from the same fungal species, enabling the operator to homogenise the spalting method. © 2021 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
⁎ Corresponding author at: Institute of Botany, BOKU Vienna, Vienna, Austria. E-mail addresses:[email protected](H. Morris),[email protected](K.T. Smith),[email protected](S.C. Robinson),[email protected](M. Göttelmann), siegfried.fi[email protected](S. Fink),[email protected](F.W.M.R. Schwarze).
https://doi.org/10.1016/j.matdes.2021.109480 0264-1275/© 2021 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). H. Morris, K.T. Smith, S.C. Robinson et al. Materials and Design 201 (2021) 109480
Contents
1. Introduction...... 2 2. Biologyandcategorisationofspaltingfungi...... 2 2.1. Taxonomyofspaltingfungi...... 2 2.2. Spaltingoverview...... 2 2.3. Formationandecologyofzonelines...... 3 3. Zone-lineformationandmelaninsynthesis...... 5 3.1. Zone-lineformationandresourcecaptureinwood...... 5 3.2. 3-dimensionalzonelinesversusmelaniseddiscoloration...... 5 3.3. Zone-linespatialarrangement...... 5 3.4. Melaninstructure,evolutionandbiosynthesis...... 5 4. Currentzone-linespaltingmethods...... 8 5. Standardisingthespaltingmethodforcommercial-scaleapplications...... 8 5.1. Zonelines,woodmechanicalproperties,pHandwoodmoisturecontent...... 8 5.2. Decayfungiandmechanicalproperties...... 8 5.3. Softrotfungiandmechanicalproperties...... 9 5.4.Kretzschmariadeusta andzone-lineformation...... 9 5.5. Incipientversusadvanceddecayandmechanicalproperties...... 11 5.6. EffectsofpHandtemperatureonzone-lineformationanddecay-fungi...... 11 5.7. Currentresearchonzonelineformation...... 11 5.8. Futuremarketingpotentialofspaltedwood...... 11 6. Discussionandfutureoutlook...... 12 DeclarationofCompetingInterest...... 12 Acknowledgements...... 12 AppendixA. Supplementarydata...... 12 References...... 12
1. Introduction (Robinson, 2016). Recent advances have improved laboratory proce- dures to screen for suitable fungal and wood species, to manipulate The biotechnological prospects for wood decay fungi are numerous moisture content and mass loss, and for digital colour analysis of zone and diverse with potential to deliver huge economic dividends, especially lines [20,57,59,75]. However, the majority of recent advances in induc- inthegreensectorwherefungicanmakeasignificant contribution to the ing spalting have focused on pigmentation and direct application of fun- circular economy and climate mitigation ([2]; Meyer et al. [9,40]). Wood gal stains to wood [48,54,61] with less emphasis on zone-line decomposing fungi also harbour huge potential for novel applications, production. A reliable, time-efficient method to produce zone lines is such as in the development of fungal-induced bow instruments (i.e. the necessary to meet the potential demands for decorative furniture, floor- ‘biotech Stradivarius’;[65]) and wood products with artistic appeal. Visi- ing and millwork. ble indicators of wood decay such as zone lines (also known as demarca- In this review, we focus on the biology and biochemistry of zone-line tion lines) and wood discoloration induced by fungi are collectively production and cultural methods to reliably induce spalting to meet the referred to as spalting or spalted wood [58]. From the timber commodity demands for specialty wood stock for high-value products. perspective, spalting is a defect and a source of lost economic value. How- ever, for specialty craft and artisanal products, spalting has aesthetic ap- 2. Biology and categorisation of spalting fungi peal and can greatly increase the economic value of wood for artistic expression. For the forest product industry, the ability to reliably induce 2.1.Taxonomyof spalting fungi zone-line formation would provide a means to enhance the economic value of otherwise low-value timber products. The fungi associated with spalting can be categorised by fungal tax- An understanding of wood anatomy and wood decay strategies is onomy, colonisation strategy, and the biochemistry of the decay pro- key to artificially produce zone-line spalting, with a history now span- cess. Within mycological systematics [31], the fungi responsible for ning a half-century of practice. The German forest pathologist Robert wood decay are all members of theBasidiomycota(class Hartig [23] first described zone lines as sharply defined black linesAgaricomycetesincluding members of theHymenochaetaceae, that accompanied decay of Larix decidua wood by Armillaria mellea.InFomitopsidaceae,Polyporaceae) andAscomycota(produces a soft rot microscopic view, Hartig described zone lines as bladder-like hyphae decay and from familyXylariaceae, primarily). To understand zone- within 3–4 rows of tracheids, resembling tyloses (Fig. 1;[23]). Later re- line formation and to choose suitable fungi to maximise potential for search by Campbell [10–12] concluded that zone lines were the result of zone-line spalting, knowledge of the biological differences between competition between decay-fungi. Melvin Lindquist, a pioneer of the the taxonomic groups is important (See Fig. 2 and Table 1 for definition American woodturning craft, made zone-lined wood into an art form of terms and table Supplementary Information Table 1 for fungi known in the 1960s, thus establishing the spalting industry [36,58]. Mark to form zone lines). Lindquist (son of Melvin) was a pioneer of producing zone lines in wood through burial of unspalted wood with wood shavings previously 2.2. Spalting overview infected with fungi (e.g. Armillaria andXylariaspp.) capable of produc- ing zone lines [58]. In the late 1970s, students of Mark Lindquist Zone-line formation is one of three types of spalting, which also in- attempted but failed to induce spalting under laboratory conditions clude both formation and removal of pigment (fungal staining and
2 H. Morris, K.T. Smith, S.C. Robinson et al. Materials and Design 201 (2021) 109480
White rot spalting appears as localized or extensive bleaching in wood, especially when confined to specific regions where the contrast with the surrounding darker wood creates a strong visual effect (Fig. 2F, G, J, K, L). Also, the bleached region is usually not a standalone spalting type and is often separated from surrounding wood by zone lines, also produced by white rot fungi (e.g.Trametesversicolor)orin many cases, soft rot fungi (Fig. 2G, L). The high contrast between white rot, wood discoloration and the surrounding darker border (zone lines) is often referred to as ‘marble rot’ owing to the marbled ap- pearance [77]. Zone-line spalting is spatially defined pigmentation by melanin and other secondary metabolites (e.g. metabolites responsible for orange-red zone lines of somewoods, Fig. 2C, D, E). Zone lines occur more frequently in wood of angiospermstreesthanconifersdue to the more frequent occurrence of white rot fungi in the former [32]. There is little to no evidence of brown rot fungi producing black melanised zone lines in wood, which may be related to the life history of this fungal group. Brown rot fungi evolved at least seven times in thePolyporalesthrough reduction or complete loss of class II peroxi- dases, an efficient non-enzymatic strategy in conifers known as the Fenton reaction (Flouas et al. [18]; [32]). White rot fungi use laccase and other enzymes (including peroxidases) to synthesize melanin from catechol, which are absent in brown rot fungi [49]. The loss or re- duction of class II peroxidases and laccase in brown rot fungi likely re- sulted in the inhibition of melanin, although this needs to be experimentally tested on a range of brown rot fungi to show that zone lines do not occur or extremely rarely as shown inFomitopsisbetulina. Strains of the latter brown rot fungus produced only faint brown zone lines lacking the dark pigmentation associated with melanin [1]. How- ever, this could be owing to melanin derivatives associated with re- duced phenoloxidases, e.g. class II peroxidases and laccase, tyrosinase, Fig. 1. An original illustration by the German forest pathologist R. Hartig [23] showing a transverse section of larch wood (Larix decidua) with a single black zone line induced by etc., rather than their complete loss during the evolutionary transition the basidiomycete Armillaria mellea. The zone line is up to four wood cells wide, where from white rot to brown rot fungi [34,63]. tracheid-to-tracheid torus-margo pit membranes reveal entrance points for fungal hyphae prior to melanin synthesis and accumulation. RP, ray parenchyma; Tr,tracheid; PM, pit membrane. Scale bar = 50 μm. Copyright permission obtained from Alamy Ltd. 2.3. Formation and ecology of zone lines (https://www.alamy.com/terms/uk.aspx). Zone lines most frequently result from the interaction of fungal hy- phae produced by different genetic individuals. In wood of living trees, zone lines occur within compartments “walled off” from the functional bleaching, respectively) (Table 1). Fungal staining of wood normally sapwood symplast, the interconnected network of living cells. This causes economic loss for timber products (e.g. lumber and wood compartmentalisation process in response to injury and infection resists pulp). The most familiar type of product stain is caused by “blue stain the loss of wood function and the spread of infection by wood decay fungi”, a polyphyletic assemblage of perithecial ascomycetes (primarily fungi and other microorganisms through boundary setting (MorrisgenusCeratocystis, in a broad sense) (Kirk 2008). The blue stain fungi do et al. 2016, [9,69]). Compartmentalisation boundaries include both con- not decay wood but do consume nutrients including nonstructural car- stitutive features and induced changes in wood anatomy and physiol- bohydrates (i.e. starch and simple sugars) contained in sapwood of both ogy including visible reaction zones. Reaction zones are produced as a conifers and angiosperm trees and in freshly-cut logs and lumber. The response to injury and infection and consist of a narrow layer of sap- blue stain colour is from melanin, a group of water-insoluble pigments wood parenchyma and that have undergone a physiological shift to pro- that are brown to black in colour and biosynthesised from the amino duce waterproofing and antimicrobial secondary metabolites [42]. acid tyrosine. Melanin confers protection from UV exposure as well as Successful compartmentalisation maintains function in remaining, ap- environmental extremes in pH, temperature, salinity and radioactivity parently uninfected sapwood. Effective compartmentalisation results [15,71]. In blue stain, the melanin is bound to hyphal cell walls, making in the co-existence of potentially large and old trees with wood decay the infected wood in reflected light to appear blue to grey in colour. Al- fungi. Compartmentalisation boundaries can be confused with zone ternatively, extracellular secretions from the brown rot fungus Fistulina lines and other spalting features (e.g. [79]; Table 1). Also, another hepatica are apparently responsible for the desirable “brownoak” pig- sought after artisan wood product very similar in appearance to spalted mentation in heartwood of English oak, which commands a high price wood is termed marblewood (i.e. Zygia racemosa: Fabaceae) on account in the market (Fig. 4F; [13,22]). Although there is general consensus of the high contrast between the yellow body of the heartwood and the that hyphae of F. hepatica deposits a ‘brown material’ into parenchyma, dark streaks that run through it. While both spalted wood and other factors may also contribute to the prized staining, such as the re- marblewood command a high price in niche timber markets, the streaks lease of phenols (e.g. tannins, etc.) during the decay process. Other soft in marblewood are not caused by fungi but occur naturally and the term rot fungi responsible for blue-green spalting in wood belong to should not be confused with ‘marble rot’. Chlorociboria (i.e. C. aerigenascens and C. aeruginosa). Chlorociboria give Within a zone line, the fungal hyphae are highly melanised and are a range of angiosperm woods a blue-green coloration deriving from sec- viewed microscopically as aggregated masses that plug the lumina of ondary metabolites (e.g. xylindein) that are released by the fungi during wood cells in radial, tangential and axial directions, forming resource capture in wood (Fig. 2 B, D) [78]. 3-dimensional self-isolating compartments of xylem space [10,11,68].
3 H. Morris, K.T. Smith, S.C. Robinson et al. Materials and Design 201 (2021) 109480
Fig. 2. Macrographs of a range of naturally and artificially infected woods showing zone lines and pigmentation combinations. (A) Spaltedaspen(Populus spp.) bowl by Seri Robinson. Zone lines induced by Xylaria polymorpha (white arrows); pigments from Scytalidium cuboideum appliedtozone-linedregions.(B)Spaltedredmaple(Acer rubrum)bowlbySeriRobinson.Zone lines induced by Xylaria polymorpha (white arrows), and application of blue-green stain by Chlorociboria aeruginascens. (C) Orange zone lines onbeechwood (Fagus sylvatica)inTriglav National Park, Slovenia; fungus unknown. (D) Wood of F. sylvatica displaying combination of blue stain from Chlorociboria spp. and orange zone lines of probably Mucidula mucida. (E) Orange zone lines on unknown tropical wood from the Peruvian Amazon rainforest; fungus unknown. (F) Longitudinal section of bleached wood from F. sylvatica. Zone lines associated with multiple strains ofKretzschmaria deustaand Trametes versicolor (G) close-up of image (F), showing zone lines (white arrow) and bleaching effect from T. versicolor (black arrow). (H) Brown zone lines (white arrows) that accompany white rot of white oak (Quercus alba) sapwood, extending into heartwood; causal fungus unknown. (I) Zone lines in sapwood of white oak (Q. alba); a cavity formed by a wood-boring insect (white arrows) is lined with mycelium of an unidentified fungus. (J) Black zone lines (white arrows) in heartwood of white oak (Q. alba). (K) Zone lines (black arrows) and bleaching within a compartmentalised decay column associated with a stem wound of yellowbirch(Betula alleghaniensis); fungus unknown. (L) Close-up of image (F). (M) Melanised surface discoloration byFomes fomentarius(white arrow) and mycelial spread causing cracking along rays (black arrow).
4 H. Morris, K.T. Smith, S.C. Robinson et al. Materials and Design 201 (2021) 109480
Table 1 3. Zone-line formation and melanin synthesis Overview of key terms related to wood spalting.
Terms Meaning and references 3.1. Zone-line formation and resource capture in wood
5 H. Morris, K.T. Smith, S.C. Robinson et al. Materials and Design 201 (2021) 109480
Fig. 3. Micrographs in transverse view of a range of angiosperm species artificially inoculated at Empa, St. Gallen, showing zone-line formations. (A) Processed wood of F. sylvatica showing a single zone line after artificial incubation, pairing Kretzschmaria deusta with Trametes pubescens,withthe‘black’ line being formed by the former (black arrows). (B) Fraxinus excelsior (Oleaceae) wood incubated with K. deusta and T. pubescens where the zone line five cells wide (black arrow) runs diagonally, traversing ray parenchyma between vessels. (C) Close-up of image (B) showing the melanised zone lines circumventing and partially entering a vessel group. Hyphae can be seen emerging from pseudosclerotia (black arrow). (D) Double zone lines induced after pairing two strains of K. deusta in processed wood of Acer pseudoplatanus (Sapindaceae), with each strain forming a single 3-dimensional line. Aggregated pseudosclerotial masses occlude a vessel group, similar to tyloses in appearance (black arrow, right). (E) Double zone lines radially oriented through a growth ring, vessels and ray parenchyma, as image (D). (F) Fluorescent image of (E, D) with bright green fluorescence in vessels indicating phenolic composition of melanin (white arrows).
6 H. Morris, K.T. Smith, S.C. Robinson et al. Materials and Design 201 (2021) 109480
7 H. Morris, K.T. Smith, S.C. Robinson et al. Materials and Design 201 (2021) 109480 the oxidative polymerisation of the phenolic compounds catechol or greater success for aspen (Populus tremuloides), sugarmaple(Acer 1,8-dihydroxynaphtalene (DHN), resulting in allomelanin and saccharum), birch (Betula spp.), and basswood (Tiliaamericana). The lat- pyomelanin. Basidiomycetes (e.g. Armillaria spp.) form melanin through ter are all diffuse-porous hardwood species. The chemical and anatom- 4, 3,4-dihydroxyphenylalanine (DOPA, resulting in eumelanin) and ical characteristics that favour zone line formation without a fungal cysteinyl-DOPA (resulting in pheomelanin) [53,73,74]. Extracellular se- antagonist have not been identified. cretion of melanin minimises degradation of plant cells and supports Although the techniques described can produce spalted wood structural integrity of zone lines and fungus survivability [4,76]. The more quickly than through natural colonisation, those methods are melanin appears to fill pit membranes and the lumina of adjoining unreliable and too slow to meet industry requirements for speed cells where it helps form a complete and continuous almost impenetra- and volume of production (Fig. 5). Significant loss in mechanical ble closely packed barrier (e.g. Armillaria ostoyae in Picea abies, Fig. 4C, strength is a particular concern for traditional approaches to spalting. D). The stability of melanin pigmentation in spalted wood exposed to Long incubation periods, especially with white rot fungi, gives the indoor lighting has not been broadly established but is essential to de- craftsman little control over the spalting process and the loss of termine indoor applications (e.g. decorative partitioning, furniture, ta- wood mechanical strength and stability. Improvements in methods bles, etc.). As far as we know, melanin stability has not been will likely come from laboratory screening and testing of small investigated thus far for indoor use but can be tested through a number wood samples with various fungi, alone and in combination. Then, of ways, for example with a Xenon-arc lamp fitted with a 3 mm window techniques can be successfully adjusted for larger samples with the glass filter (to simulate spalted wood products indoors) or a Chroma goal to spalt table-top sized wood stock. Mater CR-200 (KONICA MINOLTA) [21]. An alternative approach is to artificially induce zone lines formation with a single fungus exposed to highly localized chemical stress. In tests with X. polymorpha, the fungus was grown on wood in culture. Copper 4. Current zone-line spalting methods sulphate (a fungicide) was locally applied to the infected wood to effec- tively ‘draw’ zone lines on the wood surface [56]. Although effective and Although there is an increasing demand for natural wood material reliable in two spatial dimensions, copper sulphate treatment does not with aesthetic character [58,67], the common methods to produce result in the desirable highly defined 3-dimensional display that results zone lines are slow (many months to years) and inadequate to produce from direct fungal competition (Fig. 4 A-C). the volume to meet commerical demands, particularly for large-scale projects in the premium furniture market. There is no standard scien- tific method to produce wood with zone lines in large commercial 5. Standardising the spalting method for commercial-scale large com quantities nor the basis to predict the patterns and fungal be- applications haviour under controlled conditions. Historically, spalting has been car- ried out by workers from the wood craft industry with techniques based 5.1. Zone lines, wood mechanical properties, pH and wood moisture content on anecdote and lacking in scientific rigour. The primary technique at- tempts to mimic the natural process through burial of wood stock in Wood decay-fungi naturally degrade and depolymerise wood con- the forest floor and natural colonisation by extant fungi, providing un- stituents with associated reductions of tensile strength, elasticity and predictable results. During natural colonisation, both interspecific and stiffness [80,86]. For successful wood colonisation, most wood decay- intraspecific competition between basidiomycetes and ascomycetes is fungi generally require a wood moisture content above bound water ca- at play with a diverse range of fungal species and strains of a single spe- pacity (approx. 30% moisture content on a dry-weight basis, [62]) as cies. In temperate world regions, the spalting fungi that colonise dead water must be freely available for wood decay to occur. However, as wood piles include the white rot basidiomycetes Trametes spp., these fungi are aerobic, mycelial growth and wood decay ceases as Bjerkandera adusta, Armillaria spp., and ascomycetes Kretzschmaria moisture increases towards the wood saturation. The following chapter deusta, Daldinia concentrica and Xylaria spp., etc. ([52]; Cooke and describes bound water capacity (formerly fibre saturation point) in Rayner, 1985; [8]). more detail with respect to soft rot decay fungi. More sophisticated methods to induce zone line formation have in- cluded incubation of stacked piles of wood in a warehouse with impre- 5.2. Decay fungi and mechanical properties cise controls of temperature and wood moisture levels (moisture content of the wood at circa 30%). The most scientific approach to- The ideal fungal species to produce zone lines on a commercial scale date also takes 3–4 months with wood stacked in opaque plastic tubs would result in the desired spalting with no marked alteration of me- containing 3 cm of water or moistened vermiculate. Spalting fungi are chanical properties. Mechanical properties of wood used for load bear- applied using various approaches (e.g. plugs, sprays, etc). The wood ing applications must meet industry standards (e.g. BS EN 1534 [9]). stacks are incubated in a heated space and maintained at a moisture For spalted wood in the high-end furniture industry, mechanical wood content <35% [58]. Different successful combinations of white rot basid- values, which differ between wood species, should not be reduced by iomycetes have been used to form zone lines, including the white rot more than 10% for stiffness measurements or below 25% for Brinell sur- fungi Bjerkandera adusta and Lentinus brumalis when paired separately face hardness measurements [80]. with Trametes versicolor in both agar and sugar maple (Acer saccharum) Fungi used for spalting wood differ widely in their impact on the [47,59]. The ascomycete Xylaria polymorpha has been used extensively wood mechanical properties. White rot fungi degrade lignin, cellulose to form zone lines without a fungal antagonist [55,60]. For commercial and hemicellulose at usually equal rates, secreting specialised enzymes zone line production with X. polymorpha, Robinson and Laks [55] had that degrade all constituents of a lignified cell wall [35,51,63]. Decay
Fig. 4. Micrographs to-scale of tangential sections (A-E) of both artificially induced zone lines (A, B) and naturally infected wood (C-E). F-H reproduced by Francis Schwarze. (A) Tangential view of F. sylvatica a single zone line diagonally traversing fibre-tracheids and vessels from pairing K. deusta strains (white arrows); scale bar = 10 μm). (B) Close-up of (A) showing completely occluded cell lumina of fibre-tracheids; scale bar = 10 μm. (C) Tangential image of a zone line with melanin deposits occluding both tracheids and unicellular rays in Picea abies (Pinaceae) naturally infected with Armillaria solidipes; scale bar = 100 μm. (D) Close-up of image (A) showing the route for mycelia into adjoining cells through pits (white arrow, ray-tracheid half-bordered pits occluded with melaninised mycelia); scale bar = 10 μm. (E) Tangential image of naturally infected Q. robur with the simultaneous white rot Ganoderma pfeifferi. Revealing diffusion of extracellular melanin deposits (black arrows); scale bar = 50 μm. (F) Brown rot spalting of naturally infected Q. robur heartwood by Fistulina hepatica caused from the degradation of tannin compounds by hydrolytic tanninases; scale bar = 10 μm. (G) Soft rot decay of F. sylvatica naturally infected by K. deusta with rhomboid cavities evident in the secondary cell walls (black arrows) while the middle lamella remains intact (white arrows); scale bar = 10 μm. (H) Wood of F. sylvatica naturally infected by K. deusta (hyphae: black pointers), with advanced decay evident from the brittle lignin skeleton; as shown in (G), the middle lamella (black arrows) that binds surrounding cells remains undecayed; scale bar = 20 μm. Fr, fibre; Tr, tracheid, V, vessel; RP, ray parenchyma.
8 H. Morris, K.T. Smith, S.C. Robinson et al. Materials and Design 201 (2021) 109480
Fig. 5. Diagram of variables affecting zone-line formation in wood, showing the contrast in variables (environmental variability, mechanical properties and fungal control) between naturally infected wood (in blue) and laboratory controlled tests (in green). Arrows pointing upwards or downwards indicate an increase or decrease in a particular variable, ultimately resulting in faster or slower zone-line formation. associated with simultaneous white rot often results in a rapid loss of for reaction zone development) in processed timber, members of the wood mechanical strength, the level of which varies depending on the Xylariaceae and in particular K. deusta, can form zone lines without ob- fungus, the tree species and the wood conditions at time of infection. struction from reaction zones during the inoculation process, a key ad- For instance, Bjerkandera adusta and Trametes versicolor can cause ex- vantage when using these fungal species to spalt wood. tensive decay followed by a rapid loss of mechanical stiffness and strength through degradation of the cell walls of all cell types including vessels, fibres and parenchyma [3]. Considering the extent of the decay 5.4. Kretzschmaria deusta and zone-line formation and the speed at which it occurs, a short incubation period to induce zone lines is essential. Robinson et al. [59] showed that wood blocks of In preliminary trials at the bio-engineered wood laboratory, Empa, Acer saccharum (sugar maple) treated with L. brumalis and T. versicolor Switzerland, we found K. deusta to be exceptional as a spalting fungus incubated for 10 weeks produced spalting without a significant loss of owing to the retention of wood mechanical strength and form, even at fi wood mechanical strength, which is an acceptable timeframe for large advanced stages of decay [64]. K. deusta preferentially degrades bres – commercial upscaling. and the S2 layer of the secondary wall (Figs. 3A H, M, 6), which has a high concentration of syringyl units, whereas cell types (vessels, tra- cheids, fibres) and cell wall layers (compound middle lamella) that 5.3. Soft rot fungi and mechanical properties are rich in guaiacyl units persist even at advanced stages of decay (Fig. 4G, H; [63,64]). K. deusta also performs better in artificial culture Soft rot fungi (e.g. Daldinia concentrica, Xylaria polymorpha and media, demonstrating much faster growth rates than X. polymorpha,
K. deusta) preferentially form cavities in the S2 secondary wall layer of likely enabling the former to spalt wood at a faster rate. In naturally in- wood cells, resulting in a slow loss of mechanical strength. All wood fected trees, K. deusta causes extensive decay in large volumes of wood components except the compound middle lamella are subject to soft- by switching from a soft rot to a white rot, leaving a pattern of very fine rot decay (Schwarze et al., 2007). The persistence of lignin-rich regions zone lines [81–84]. of the wood matrix in trees decayed by K. deusta is not only due to their Also, for survival in dry wood, xylariaceous species like K. deusta are initially high high lignin content per se, but also to their high percentage exceptional; their hyphae grow in the cell wall thus accessing bound of guaiacyl lignin. Members of the Xylariaceae have relatively poor water unavailable to most decay-fungi (in engineering, classified as lignolytic ability, mainly confined to the decomposition of syringyl lig- moisture contents <30%). However, it must be made clear that moisture nin (Nilsson et al. [44]). There are also key differences in the life cycles content % at the interface between cell wall saturation (bound water ca- of the two zone-line producing soft rots, K. deusta and X. polymorpha. pacity) and capillary water in cell lumina (a prerequisite for decay prop- The former is a facultative-parasite (saprotroph-necrotroph spectrum) agation) is arbitrary and not scientifically accurate. Bound water penetrating functional sapwood ([46]; Deflorio et al. [17]), while the lat- capacity is more accurately defined as a gradual transition (i.e. phase ter is a saprotroph surviving only on dead tissue. In functional sapwood, boundary) rather than a fixed moisture content, as shown by low field K. deusta can only slowly pass or breach reaction zones laid down by the nuclear magnetic resonance studies [19,85]. Traditionally, wood is host (Morris et al. [9,41]); pits become encrusted with polyphenols, ini- kept at a minimum of 30% moisture content for successful inoculation tially blocking hyphal entrance points for the fungus (Fig. 2Ain[42]). as this is a preference for most decay fungi. Some zone line forming However, due to the absence of living parenchyma cells (responsible white rot decay fungi, such asInonotushispidus and Polyporus
9 H. Morris, K.T. Smith, S.C. Robinson et al. Materials and Design 201 (2021) 109480
10 H. Morris, K.T. Smith, S.C. Robinson et al. Materials and Design 201 (2021) 109480 squamosus produce maximum pigmentation at wood moisture contents Along with pH and wood moisture content, species of wood decay- from 35 to 55%, a range that depends on the fungus and the wood spe- fungi vary in temperature optima [26], which should be considered dur- cies [75]. However, if the wood moisture content is too high, oxygen ing the incubation process. Water activity tests (aw, 0–1; the relative availability, which is essential for the decay process, is reduced [5]. A vapour pressure of a substrate) enable us to discover which species key objective in producing zone lines in wood for furniture and paneling work best at a given temperature or even strains within a species is to develop a process that allows the treatment of wood of a low mois- where small temperature differences can help determine the success ture content (15–25%) below bound water capacity. Such a method of zone-line formation. For instance, Fomes fomentarius (Fig. 2)hasan might be deemed favourable as the low wood moisture content lowers optimum temperature from 27 to 30 °C, Armillaria mellea prefers it the risk of contamination, requires less energy for wood drying after slightly lower at 25–26 °C while Trametes versicolor has a broader opti- treatment and provides wood with higher dimensional stability free mum range of 24–33 °C [62]. As zone lines are produced by the fungus from defects and deformations. Zone line induction at a lower moisture under the duress of stress, artificially inducing stress by manipulating content would greatly reduce financial and environment costs when ap- temperature and moisture might result in higher melanin production plied on a commercial scale. but at the expense of growth; this is an area of research that requires further attention.
5.5. Incipient versus advanced decay and mechanical properties 5.7. Current research on zone line formation A critical point is that zone lines appear to be associated with incip- ient decay, meaning they occur during the early stages of decay when From our trials at Empa, successful zone line formation in common mechanical properties have not yet been altered to a significant degree beech (Fagus sylvatica), ash (Fraxinus excelsior) and maple wood (Acer [29,68]. Evidence of the early development of zone lines is also provided pseudoplatanus)treatedwithK. deusta and Trametes pubescens occurred by Lopez-Real [37] stating that pigmentation, which follows hyphal at 22 °C, 70% relative humidity and in wood of a moisture content be- swelling and hyphal aggregation, occurs in as few as five-days after in- tween 15 and 25%. Moreover, wood was never in direct contact with oculation for A. mellea and seven-days for Stereum hirsutum.Knowledge water, which ensured that wood moisture content remained low of the latter is of high importance during the application process, as de- enough for K. deusta infection while maintaining plentiful oxygen sup- termining the length of time required before stopping the spalting pro- ply for wood decay. The time required to produce 3-dimensional zone cess is critical to provide zone-lined wood products that maintain strong lines from paired antagonists (or more) both between fungal species mechanical properties. Determining the length of time for zone-line and between strains of K. deusta ranged from 5 to 8 weeks depending production also prevents the need to brace the wood, a common proce- on the size of the wood piece being tested (Fig. 6). Of interest, we dure in spalting when wood is left to decay for too long [16]. The timing found that the degree and competition and intensity of zone line forma- of zone-line development will have to be considered during the tion varied greatly between fungal species and also between strains. upscaling process, as large pieces of wood will take longer to spalt. How- Consequently, successful fungal pairing requires time and advanced ever, workers have not, to our knowledge, investigated whether or not screening beginning with antagonism tests in culture media before ap- fungi at an advanced decay stage produce zone lines. plications to wood.
5.6. Effects of pH and temperature on zone-line formation and decay-fungi 5.8. Future marketing potential of spalted wood
The pH of the wood substrate can vary within the tree along and The future potential of spalted wood is moving beyond wood turn- across the stem, influencing the enzymatic activity of wood-degrading ery (unique fruit bowls, cups, etc), where the concept is now being fungi and affecting decay rates [46,62]. While basidiomycetes prefer a adopted by furnishers of high design [45,67]. The furnisher can also tai- slightly acidic environment, ascomycetes can tolerate a more alkaline lor the product to the taste of the customer through control of patterns habitat [30]. All these aspects of pH variation are reflected in fungal di- created by the fungi and by giving the products a unique identification versity and distribution of species succession in wood, where a knowl- number or GPS location from where the tree was felled, marketing edge of this is critically important to enable the operator to maximise that emphasises place and story. There is a growing shift towards spalting potential. The ability to manipulate fungal reactions through wood in construction in general, which is linked to global climate moisture content and pH changes in wood may offer a chance to en- change and sustainability. For example, wooden skyscrapers are being hance the pigmentation intensity and patterns currently available constructed around the world and could replace steel and concrete in with spalted woods. However, as a number of decay fungi (e.g. the future as a more viable alternative ([72]; Ramage and Scherman Armillaria spp., Trametes spp.) have the ability to adjust their own pH [50]; [33]). To make office spaces distinct from each other within and moisture content to favour their growth and nutrient assimilation, wood-framed skyscrapers, spalted partitions dividing office space this makes these parameters difficult to control when producing zone could add appeal to the work space along with spalted interior wall lines [14,28,38,39,70]. cladding for inspiration, further opening new market potential.
Fig. 6. Macrographs showing zone-line formation on artificially treated processed wood from Empa, St. Gallen after a five-week incubation period of three common European tree species with varying combination of different strains of Kretzschmaria deusta, Trametes pubescens and T. versicolor. Patterns can be both controlled random depending on how the wood is inoc- ulated. (A) Beech wood (Fagus sylvatica) showing zone-line formation from two strains of K. deusta and one strain of T. pubescens. (B) Beech wood with patterned double zone-line for- mations from pairing two K. deusta strains. (C) Maple wood (Acer pseudoplatanus) showing the bleached affect (‘Eisbuche’)frompairingK. deusta with T. trametes.(D)Asinglestraight zone line in beech wood from pairing a K. deusta strain with T. pubescens. (E) Maple wood with alternate pattern of T. pubescens - K. deusta (strain 1) - K. Deusta (Strain 2) - T. pubescens - K. deusta. The double zone line between K. deusta have merged to appear as a single wide black line, and the wood is bleached due to the enzyme laccase from T. pubescens. (F) Beech wood alternating pattern of T. pubescens - K. deusta – T. pubescens giving two single zone line running with the grain. (G) Wood of common ash (Fraxinus excelsior) showing single zone line compartments separated by alternating T. pubescens and K. deusta (single strain) down and across the wood grain. (H) Maple wood showing zone-lined com- partments using same method as (G). (I) Beech wood with single bleached zone-lined compartment. (J) Beech wood after inoculation with two strains of K. deusta revealing two straight double zone line running with the wood grain. (K) Bleached maple wood with random zone line formations from T. pubescens, T. versicolor and K. deusta. (L) Beech wood with a double zone-line compartment after inoculation with alternating strains of K. deusta. (M) Maple wood zone-lined bleached compartments through down and across alternating of T. pubescens with K. deusta. (N) Maple wood with zone-lined bleached compartments as (M). (O) Beech wood with a single straight double zone line from pairing two K. deusta strains along the grain in the centre of wood sample.
11 H. Morris, K.T. Smith, S.C. Robinson et al. Materials and Design 201 (2021) 109480
6. Discussion and future outlook Declaration of Competing Interest
Inducing spalting involves applying the scientific method to meet ar- The authors declare that they have no known competing financial tistic ends with the aim of providing decorative wood products to niche interests or personal relationships that could have appeared to influ- markets. A successful approach to spalting wood on a large commercial ence the work reported in this paper. scale should involve careful collaboration between wood scientists and industrial partners. The challenge is to develop a reliable and well- Acknowledgements defined method to produce spalted wood of consistent high quality in a suitable time-frame while maintaining mechanical properties. Con- The authors are grateful for the financial support by the KTI/ trolling the outcome, e.g. making zone lines that are curved, circular, InnoSuisse Project No. 26083.1. Authors are in the order of contribution rectangular, in zig-zag patterns, straight lines or double zone lines, made. We thank Koster AG Holzwelten, Arnegg, Switzerland for etc., gives choice to the customer rather than leaving the process to ran- assisting in the preparation of wood samples and for their technical sup- dom chance (Fig. 6). We should be able to guarantee the customer a port. We sincerely thank Kenneth Dudzik (USDA FS) for providing im- minimalist design with few zone lines or a baroque pattern with ages Fig. 2H, I, J. many zone lines, accounting for the great variation in people's artistic senses. Also, retaining mechanical properties (i.e. stiffness and hard- Author contributions ness) to meet industry regulations we need to assess a range of woods using different fungi to understand fungal growth under different tem- Hugh Morris and Francis W.M.R. Schwarze: Conceptualization, perature and pH regimes between and within species. Hugh Morris: Writing - Original draft preparation: Hugh Morris, Kevin An important approach to optimise and homogenise the spalting T. Smith, Francis W.M.R. Schwarze, Seri C. Robinson, Maximilian method is to screen and select competitive strains of a single fungal spe- Göttelmann, Siegfried Fink: Writing - Reviewing and Editing. Hugh cies alongside developing a carrier system to easily and reliably apply Morris, Kevin T. Smith, Francis W.M.R. Schwarze, Seri C. Robinson, fungi to wood. In a climate chamber, the operator can control the pa- Maximilian Göttelmann, Siegfried Fink: Visualization. rameters such as temperature and humidity. Using glass windows, it is easier to investigate precisely when interaction zone lines occur with Appendix A. Supplementary data the knowledge that they form during incipient decay just prior to ad- vanced wood decay. The latter observational studies can significantly Supplementary data to this article can be found online at https://doi. reduce the timeframe from 6 months down to between 5 and org/10.1016/j.matdes.2021.109480. 8 weeks, depending on the fungi and wood used. Soft rot fungi such as K. deusta may have advantages of being able to inoculate wood of low References moisture contents thereby reducing opportunity for contamination [1] T.J.H. Adams, N.K. Todd, A.D.M. Rayner, Antagonism between dikaryons of while maintaining wood stability. However, white rot fungi (e.g.Piptoporusbetulinus, Trans. Br. Mycol. Soc. 76 (1981) 510–513, https://doi.org/10. Trametes spp.) should not be overlooked in furniture applications, as 1016/S0007-1536(81)80085-X. they provide the bleaching effect that complements the zone line, [2] F.V.W. Appels, S. Camere, M. Montalti, E. Karana, K.M.B. Jansen, J. Dijksterhuis, P. fl known as “Eisbuche” in the German spalting industry (Fig. 6C). As an Krijgsheld, H.A.B. 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Bley, Zone line formation on artifi- Scherman, The wood from the trees: the use of timber in construction, Renew. cial media and in hardwoods by basidiomycetes for production of spalted wood, Sust. Energ. Rev. 68 (2017) 333–359, https://doi.org/10.1016/j.rser.2016.09.107. Holzforschung 71 (2017) 833–841, https://doi.org/10.1515/hf-2016-0222. [51] A.D.M. Rayner, L. Boddy, Fungal Decomposition of Wood: Its Biology and Ecology, [21] H. Guo, D. Klose, Y. Hou, G. Jeschke, I. Burgert, Highly efficient UV protection of the John Wiley & Sons, Chichester, 1988. biomaterial wood by A transparent TiO2/Ce Xerogel, ACS Appl. Mater. Interfaces 8 [52] A.D.M. Rayner, N.K. Todd, Intraspecific antagonism in natural populations of wood- (2017) 39040–39047, https://doi.org/10.1021/acsami.7b12574. decaying basidiomycetes, J. Gen. Microbiol. 103 (1977) 85–90, https://doi.org/10. [22] P. Groom, ‘Brown oak’ anditsorigin,Ann.Bot.29(1915)393–408, https://doi.org/ 1099/00221287-103-1-85. 10.1093/oxfordjournals.aob.a089554. [53] J. Ribera, G. Panzarasa, A. Stobbe, A. Osypova, P. Rupper, D. Klose, F.W.M.R. Schwarze, [23] R. Hartig, Wichtige Krankheiten der Waldbäume: Beiträge zur Mykologie und Scalable biosynthesis of melanin by the basidiomycete Armillaria cepistipes,J.Agric. Phytopathologie für Botaniker und Forstmänner, Springer-Berlin, 1874. Food Chem. 67 (2019) 132–139, https://doi.org/10.1021/acs.jafc.8b05071. [24] J. Heilmann-Clausen, A gradient analysis of communities of macrofungi and slime [54] S.C. Robinson, Developing fungal pigments for “painting” vascular plants, Appl. moulds on decaying beech logs, Mycol. Res. 105 (2001) 575–596, https://doi.org/ Microbiol. Biotechnol. 93 (2012) 1389–1394, https://doi.org/10.1007/s00253-011- 10.1017/S0953756201003665. 3858-2. [25] J. Hiscox, L. Boddy, Armed and dangerous - chemical warfare in wood decay com- [55] S.C. Robinson, P.E. Laks, Culture age and wood species affect zone line production of munities, Fungal Biol. Rev. 31 (2017) 169–184, https://doi.org/10.1016/j.fbr.2017. Xylaria polymorpha, Open Mycol. J. 4 (2010) 18–21, https://doi.org/10.2174/ 07.001. 1874437001004010018. [26] J. Hiscox, G. Clarkson, M. Savoury, G. Powell, I. Savva, M. Lloyd, J. Shipcott, A. [56] S.C. Robinson, P.E. Laks, D.L. Richter, Stimulating spalting in sugar maple using sub- Choimes, X.A. Cumbriu, L. Boddy, Effects of pre-colonisation and temperature on in- lethal doses of copper, Eur. J. Wood Prod. 69 (2011) 527–532, https://doi.org/10. terspecific fungal interactions in wood, Fungal Ecol. 21 (2016) 32–42, https://doi. 1007/s00107-010-0479-x. org/10.1016/j.funeco.2016.01.011. [57] S.C. Robinson, P.E. Laks, E.J. Turnquist, A method for digital color analysis of spalted [27] J. Hiscox, J. O'Leary, L. Boddy, Fungus wars: basidiomycete battles in wood decay, wood using Scion image software, Materials 2 (2009) 62–75, https://doi.org/10. Stud. Mycol. 89 (2018) 117–124, https://doi.org/10.1016/j.simyco.2018.02.003. 3390/ma2010062. [28] J. Hiscox, M. Savoury, C.T. Müller, B.D. Lindahl, H.J. Rogers, L. Boddy, Priority effects [58] S.C. Robinson, H. Michaelsen, J.C. Robinson, Spalted Wood: The History, Science, and during fungal community establishment in beech wood, ISME J. 9 (2015) Art of a Unique Material, Schiffer Publishing, Ltd., Atglen, PA, USA, 2016. 2246–2260, https://doi.org/10.1038/ismej.2015.38. [59] S.C. Robinson, D.L. Richter, P.E. Laks, Colonization of sugar maple by spalting fungi, [29] E.E. Hubert, The diagnosis of decay in wood, J. Agric. Res. 29 (1924) 523–567. For. Prod. J. 57 (2007) 24–32. [30] M. Humar, M. Petric, F. Pohleven, Changes of the pH value of impregnated wood [60] S.C. Robinson, D. Tudor, G. MacDonald, Y. Mansourian, P.A. Cooper, Repurposing during exposure to wood-rotting fungi, Holz Roh-Werkstoff 59 (2001) 288–293, mountain pine beetle blue wood for art through additional fungal colonization, https://doi.org/10.1007/s001070100207. Int. Biodeterior. Biodegradation 85 (2013) 372–374, https://doi.org/10.1016/j. [31] P.M. Kirk, P. Cannon, D.W. Minter, J. Stalpers, Ainsworth & Bisby’sDictionaryofthe ibiod.2013.08.021. Fungi, CABI Pub, New York, 2008. [61] S.C. Robinson, G. Weber, E. Hinsch, S.M. Vega Gutierrez, L. Pittis, S. Freitas, Utilizing [32] F.S. Krah, C. Bässler, C. Heibl, J. Soghigian, H. Schaefer, D.S. Hibbett, Evolutionary dy- extracted fungal pigments for wood spalting: A comparison of induced fungal pig- namics of host specialization in wood-decay fungi, BMC Evol. Biol. 18 (2018) 119, mentation to fungal dyeing, J. Coat. 2014 (2014) 1–8, https://doi.org/10.1155/ https://doi.org/10.1186/s12862-018-1229-7. 2014/759073. [33] D. Lazarevic, P. Kautto, R. Antikainen, Finland's wood-frame multi-storey construc- [62] O. Schmidt, Wood and Tree Fungi: Biology, Damage, Protection, and Use, Springer- tion innovation system: Analysing motors of creative destruction, Forest Policy Verlag, Berlin, 2006. Econ. 110 (2020), 101861, https://doi.org/10.1016/j.forpol.2019.01.006. [63] F.W.M.R. Schwarze, Wood decay under the microscope, Fungal Biol. Rev. 21 (2007) [34] C.T. Li, Phenoloxidase and peroxidase activities in zone lines ofPhellinusweirii, 133–170, https://doi.org/10.1016/j.fbr.2007.09.001. Mycologia 73 (1981) 811–821, https://doi.org/10.1080/00275514.1981.12021412. [64] F.W.M.R. Schwarze, D. Lonsdale, C. Mattheck, Detectability of wood decay caused by [35] W. Liese, The action of fungi and bacteria during wood deterioration, Rec. Ann. Conv. Ustulina deusta in comparison with other tree decay fungi, Eur. J. Plant Pathol. 25 Br. Wood Pres. Assoc. 4 (1970) 1–4. (1995) 327–341, https://doi.org/10.1111/j.1439-0329.1995.tb01348.x. [36] M. 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Schwarze, Using B. Hebecker, M. da Glória Teixeira Sousa, C. Cunha, Y. Liu, T. Feizi, A.A. Brakhage, the CODIT model to explain secondary metabolites of the xylem in defence systems K.J. Kwon-Chung, N.A.R. Gow, M. Zanda, M. Piras, C. Zanato, M. Jaeger, M.G. Netea, of temperate trees to decay fungi, Ann. Bot. 125 (2020) 701–720, https://doi.org/10. F.L. van de Veerdonk, J.F. Lacerda, A. Campos, A. Carvalho, J.A. Willment, J.P. Latgé, 1093/aob/mcz138. G.D. Brown, Recognition of DHN-melanin by a C-type lectin receptor is required [43] E.E. Nelson, Survival of Poria weirii in wood buried in urea-amended forest soil, Phy- for immunity to Aspergillus, Nature 555 (2018) 382–386, https://doi.org/10.1038/ topathology 65 (1975) 501–502, https://doi.org/10.1094/Phyto-65-501. nature25974.
13 H. Morris, K.T. Smith, S.C. Robinson et al. Materials and Design 201 (2021) 109480
| https://docslib.org/doc/8619656/the-dark-side-of-fungal-competition-and-resource-capture-in-wood-zone-line-spalting-from-science-to-application |
1 Chronicles 11 Expositor's Greek Testament
Expositor's Greek Testament
1 Chronicles 11:1
Then all Israel gathered themselves to David unto Hebron, saying, Behold, we are thy bone and thy flesh.
1 Chronicles 11:2
And moreover in time past, even when Saul was king, thou wast he that leddest out and broughtest in Israel: and the LORD thy God said unto thee, Thou shalt feed my people Israel, and thou shalt be ruler over my people Israel.
1 Chronicles 11:3
Therefore came all the elders of Israel to the king to Hebron; and David made a covenant with them in Hebron before the LORD; and they anointed David king over Israel, according to the word of the LORD by Samuel.
1 Chronicles 11:4
And David and all Israel went to Jerusalem, which is Jebus; where the Jebusites were , the inhabitants of the land.
1 Chronicles 11:5
And the inhabitants of Jebus said to David, Thou shalt not come hither. Nevertheless David took the castle of Zion, which is the city of David.
1 Chronicles 11:6
And David said, Whosoever smiteth the Jebusites first shall be chief and captain. So Joab the son of Zeruiah went first up, and was chief.
1 Chronicles 11:7
And David dwelt in the castle; therefore they called it the city of David.
1 Chronicles 11:8
And he built the city round about, even from Millo round about: and Joab repaired the rest of the city.
1 Chronicles 11:9
So David waxed greater and greater: for the LORD of hosts was with him.
1 Chronicles 11:10
These also are the chief of the mighty men whom David had, who strengthened themselves with him in his kingdom, and with all Israel, to make him king, according to the word of the LORD concerning Israel.
1 Chronicles 11:11
And this is the number of the mighty men whom David had; Jashobeam, an Hachmonite, the chief of the captains: he lifted up his spear against three hundred slain by him at one time.
1 Chronicles 11:12
And after him was Eleazar the son of Dodo, the Ahohite, who was one of the three mighties.
1 Chronicles 11:13
He was with David at Pasdammim, and there the Philistines were gathered together to battle, where was a parcel of ground full of barley; and the people fled from before the Philistines.
1 Chronicles 11:14
And they set themselves in the midst of that parcel, and delivered it, and slew the Philistines; and the LORD saved them by a great deliverance.
1 Chronicles 11:15
Now three of the thirty captains went down to the rock to David, into the cave of Adullam; and the host of the Philistines encamped in the valley of Rephaim.
1 Chronicles 11:16
And David was then in the hold, and the Philistines' garrison was then at Bethlehem.
1 Chronicles 11:17
And David longed, and said, Oh that one would give me drink of the water of the well of Bethlehem, that is at the gate!
1 Chronicles 11:18
And the three brake through the host of the Philistines, and drew water out of the well of Bethlehem, that was by the gate, and took it , and brought it to David: but David would not drink of it, but poured it out to the LORD,
1 Chronicles 11:19
And said, My God forbid it me, that I should do this thing: shall I drink the blood of these men that have put their lives in jeopardy? for with the jeopardy of their lives they brought it. Therefore he would not drink it. These things did these three mightiest.
1 Chronicles 11:20
And Abishai the brother of Joab, he was chief of the three: for lifting up his spear against three hundred, he slew them , and had a name among the three.
1 Chronicles 11:21
Of the three, he was more honourable than the two; for he was their captain: howbeit he attained not to the first three.
1 Chronicles 11:22
Benaiah the son of Jehoiada, the son of a valiant man of Kabzeel, who had done many acts; he slew two lionlike men of Moab: also he went down and slew a lion in a pit in a snowy day.
1 Chronicles 11:23
And he slew an Egyptian, a man of great stature, five cubits high; and in the Egyptian's hand was a spear like a weaver's beam; and he went down to him with a staff, and plucked the spear out of the Egyptian's hand, and slew him with his own spear.
1 Chronicles 11:24
These things did Benaiah the son of Jehoiada, and had the name among the three mighties.
1 Chronicles 11:25
Behold, he was honourable among the thirty, but attained not to the first three: and David set him over his guard.
1 Chronicles 11:26
Also the valiant men of the armies were , Asahel the brother of Joab, Elhanan the son of Dodo of Bethlehem,
1 Chronicles 11:27
Shammoth the Harorite, Helez the Pelonite,
1 Chronicles 11:28
Ira the son of Ikkesh the Tekoite, Abiezer the Antothite,
1 Chronicles 11:29
Sibbecai the Hushathite, Ilai the Ahohite,
1 Chronicles 11:30
Maharai the Netophathite, Heled the son of Baanah the Netophathite,
1 Chronicles 11:31
Ithai the son of Ribai of Gibeah, that pertained to the children of Benjamin, Benaiah the Pirathonite,
1 Chronicles 11:32
Hurai of the brooks of Gaash, Abiel the Arbathite,
1 Chronicles 11:33
Azmaveth the Baharumite, Eliahba the Shaalbonite,
1 Chronicles 11:34
The sons of Hashem the Gizonite, Jonathan the son of Shage the Hararite,
1 Chronicles 11:35
Ahiam the son of Sacar the Hararite, Eliphal the son of Ur,
1 Chronicles 11:36
Hepher the Mecherathite, Ahijah the Pelonite,
1 Chronicles 11:37
Hezro the Carmelite, Naarai the son of Ezbai,
1 Chronicles 11:38
Joel the brother of Nathan, Mibhar the son of Haggeri,
1 Chronicles 11:39
Zelek the Ammonite, Naharai the Berothite, the armourbearer of Joab the son of Zeruiah,
1 Chronicles 11:40
Ira the Ithrite, Gareb the Ithrite,
1 Chronicles 11:41
Uriah the Hittite, Zabad the son of Ahlai,
1 Chronicles 11:42
Adina the son of Shiza the Reubenite, a captain of the Reubenites, and thirty with him,
1 Chronicles 11:43
Hanan the son of Maachah, and Joshaphat the Mithnite,
1 Chronicles 11:44
Uzzia the Ashterathite, Shama and Jehiel the sons of Hothan the Aroerite,
1 Chronicles 11:45
Jediael the son of Shimri, and Joha his brother, the Tizite,
1 Chronicles 11:46
Eliel the Mahavite, and Jeribai, and Joshaviah, the sons of Elnaam, and Ithmah the Moabite,
1 Chronicles 11:47
Eliel, and Obed, and Jasiel the Mesobaite.
The Expositor's Greek Testament - Nicoll Text Courtesy of BibleSupport.com . Used by Permission. Bible Hub
| https://biblehub.com/commentaries/egt/1_chronicles/11.htm |
Indoor IPM Plan
Indoor Integrated Pest Management (IPM) Plan
36 Middlesex Trpk
Bedford, MA 01730-1404
IPM Coordinator
Thomas Markham
Primary Contact
Thomas Markham, 617-738-5600 , [email protected]
This School has a contract with
Gary Weisberg of A-1 Exterminators, 781-592-2731.
By signing the end of this indoor IPM plan, the IPM coordinator, Thomas Markham, of this School and the Pest Management Professionals described above acknowledge, and agree to the terms of this INDOOR integrated pest management plan.
A .INTRODUCTION
In compliance with the Act Protecting Children and Families from Harmful Pesticides, Edco Collaborative on 11/27/2018 10:13:00 AM has prepared the following indoor IPM plan. By centralizing all of the information about this facility’s pest management practices the plan serves as a guide to direct this facility’s IPM coordinator, Thomas Markham , about pest control and pesticide use.This plan describes the pest management practices for indoor areas of the Edco Collaborative and clearly states it’s pesticide use policies.A copy of the plan has been filed with the Massachusetts Department of Agricultural Resources (MDAR), and at least one printed copy must be kept on site and made available to the public upon request. ObjectivesThe objectives of the integrated pest management program conducted at the Edco Collaborative are listed below. Reduce children’s exposure to pesticides and pesticide residues whenever possible. Manage pests that may occur on facilities to prevent interference with the learning environment of the students. Provide the safest playing or athletic surfaces possible.In light of these objectives, the Edco Collaborative has selected the following as it’s IPM policy statement:
B.POLICY STATEMENT
Structural and landscape pests can pose significant problems for people and property. Pesticides can pose risks to people, property, and the environment. It is therefore the policy of this school to incorporate Integrated Pest Management (IPM) procedures for control of structural and landscape pests. The objective of this program is to provide necessary pest control while minimizing pesticide use.
C.IPM COMMITTEE
The tasks set before an IPM committee are to:
Develop an IPM plan. The IPM plan is in essence, a document that describes the organization and implementation of IPM on school grounds. Evaluate progress of the IPM program. Communicate about IPM - Facilitate communication within the school about IPM practices. Assist in development of contract specifications. Provide notification to parents about pesticide use.
The INDOOR committee members selected for the Edco Collaborative are listed below:1) Thomas Markham (Indoor IPM Coordinator)2) Curtis Eckelkamp
D. COMMUNICATING IPM WITHIN THE FACILITY
The Pest Management Professional communicates with the IPM coordinator of the facility. The IPM coordinator then passes this information onto an administrative assistant who decides how the information will be distributed throughout the facility.
Staff/Students communicate with their supervisors or teachers who then pass information onto the IPM coordinator.
E. EDUCATION AND TRAINING OF FACILITY OCCUPANTS & STAFF
Training Maintenance and Housekeeping, Waste Disposal Contractor and Kitchen Staff.
Training Content will focus on Pest reduction strategies correcting people''s behavior such as, over watering plants and eating at desks, which contribute to pest problems.
Training programs will be held annually. It will be the facility''s responsibility to schedule the meetings with the pest control provider.
A designated pest control professional will present training annually and will provide pamphlet and fact sheets at the time of training.
Staff, teachers and students will be instructed on how to log pest complaints and be given a brief overview on pest identification and the conditions that promote the pests.
F. INDOOR MONITORING
The IPM committee will evaluate the plan annually.
When pests are present
, Edco Collaborative has chosen an
INDOOR monitoring schedule that consists of monthly inspections
.
When pests are absent
the
INDOOR monitoring schedule will consist of monthly inspections
.
The following technique will be used to monitor for pests: The facility’s contracted Pest Management Professional would conduct regular pest inspections and would then instruct the IPM coordinator as to the proper course of action.
G. COURSE OF ACTION TAKEN FOR INDOOR PESTS
The following pests have historically and/or currently been a problem at Edco Collaborative: Ants
The School's IPM approach to managing the indoor pests includes the following actions: SCHOOL PEST DESCRIPTION small brown pavement ants SCHOOL PEST LOCATION DETAILS kitchen SCHOOL PEST ACTIVITY low to moderate MONITORING/INSPECTION Visual inspections are provided monthly. Monitoring traps are used to detect insect and/or rodent activity. Any pest issues will be treated accordingly. ELIMINATING ACCESS Our pest control provider will inform us accordingly of preventative measures that should be taken. ELIMINATING SOURCES OF FOOD AND WATER Our facility is cleaned on a regular basis to prevent food and water access to pests. Our pest control provider will inform us if any changes should be made. ELIMINATION OF SHELTER AND HARBORAGE Our facility is cleaned on a regular basis to prevent shelter and harborage. Our pest control provider will inform us if any changes should be made. NON-CHEMICAL CONTROLS Sticky traps and/or mechanical traps will be used for prevention. Our pest control provider will treat any pest issues accordingly using IPM approved baits if necessary. CHEMICAL CONTROLS PESTICIDE USE ATTESTATION: Pesticides are only applied by a certified and/or licensed applicator. Pesticides are used only when monitoring has shown that pests are present and when the use of the pesticide is justified or in the case of an emergency situation. Only pesticides allowed under the Children's and Families' Protection Act are used indoors.
H. RECORD KEEPING
In the case of Edco Collaborative, INDOOOR monitoring records will be maintained through the following technique: The use of forms which will be filled out by the person monitoring the facility
I. EVALUATING THE PROGRAM
The IPM committee will evaluate the plan annually .
J. IN THE EVENT OF A HEALTH EMERGENCY
During the creation of this IPM plan, Thomas Markham has assigned committee member Thomas Markham with the responsibility of applying for an emergency waiver.
K. LIST OF PESTICIDES TO BE USED INSIDE THE FACILITY
The following list includes all the pesticides that will be used inside the Edco Collaborative. This list includes all herbicides, fungicides, and insecticides that will be used in the event that chemical is required. Pesticide Name Active Ingredient EPA Registration # Target Pest Rationale for use Advanced 360 Dual Choice Stations abamectin b 499-496 ants pest elimination Gourment Ant Gel Disodium,Octaborate 73766-1 ants pest elimination maxforce fc killer ant gel Fipronil 432-1264 Ants pest elimination Tempo dust 1% Cyfluthrin 432-1372 insecticide pest elimination Vendetta abamectin 1021-1828 roaches pest elimination Vendetta Plus abamectin/nylar 1021-2593 roaches pest elimination mother earth diatomaceous earth 499-509 insecticide pest elimination final all weather brodifacoum 12455-89 rodents pest elimination Maxforce FC Roach Bait Fipronil 432-1259 Roaches Pest Elimination Final Soft Bait brodifacoum 12455-139 rodents Pest Elimination
I attest, to the best of my knowledge, that the above information is complete, accurate and true
________________________________________________ __/______/___ IPM Coordinator Signature Date ________________________________________________ __/______/___ Administrator, Director, or Principal Date
Indoor IPM Plan originally submitted on: 11/27/2018 10:13:00 AM Plan updated by Thomas F Markham III on: 11/27/2018 10:13:00 AM
| https://massnrc.org/data/ipm/Edco_Collaborative_in_2_2018_9429.htm |
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'FLYING SAUCER' FINANCIAL PROBLEMS VIEWED
'FlyingSaucer' Financial Problems Viewed Full Text Supersone of Message 1 //((Article by IZVESTIYA ... writer Viktor Litovkin: "'FlyingSaucers' Made in Saratov")) 2 ((Text)) ((begin ... but simply put it is a "flyingsaucer." It is made at the Saratov Aircraft Plant.((end bold)) ...
SIGHTINGS OF UNIDENTIFIED FLYING OBJECTS
Marocaloe, 5 Jul 54 Since PAY 1954, mysterious objects, described as "flyingsaucers... people elm* report having seen two "flyingsaucers' over Schleswig between 2200 sad 2315 hours. ...SAUCERS' OVUI BC7MIS GERMANY-- low York, 5.1, Btaats-Zeitueg uod Rerold, 25 Aug 54 Two "flying...
DANISH DEFENSE LEADERS TAKE SERIOUS VIEW OF FLYING SAUCERS
aircraft].NIBS DEFENSE LEADERS TAKE SERIOUS VIEW OFFLYINGSAUCERS13 Juli 1953. The leading Copenhagen dailies, ... a serious view of the problem offlyingsaucers. The military experts are of the opinion that although ... most of the observations Lofflyingsaucers] have turned out to be astronomical phenomena, there remain the reports ...
FLYING SAUCERS' THEORIES AND EXPERIMENTS
by the periodical indicates that the French Air Force admits the existence of "flyingsaucers... describing the experimental construction of "flyingsaucers" carried out by him from 1941 to 1945. ... Klein stated that be was present when, in 1945, the first piloted "fly- ingsaucer" took ...
REPORTS OF UNCONVENTIONAL AIRCRAFT IN FRENCH AFRICA, CORSICA, AND WESTERN EUROPE
of the Algerian weather bvreav stated recently that the "fly- ingsaucers" seen recently over Algiers ... (Department of Term, Prance) reported wit- sensing a "flyingsaucer" formation kst about 1600 bows ... % The first patent for a "flyingsaucer" was recently applied for in West Ger- many by Rudolf ...
UNIDENTIFIED FLYING OBJECTS OVER MOROCCO AND FRENCH WEST AFRICA
of an eyewitness who?claim$ to have observed aflyingsaucerabove Dakar at 0608 hours on 3 July 1952. According ... fros.Mecbra bel Esiri that on 12 July 1952, twoflyingsaucerswere seen by two policemen on night duty ... OF.. INFORMATION 1952 SUBJECT Military- Unidentified aircraft ETEHI7FE3S REPORTSSAUCEROVER DAXAB-- ...
FLYING SAUCERS IN SPAIN AND NORTH AFRICA
nor Sabadell airport ad- ' itted any knowledge of the object), and unlike the so-calledflyingsaucers... Jun 52 Two witnesses reportid aflying.saucersppearla~ shove Meknes &$'23W hours an 7 yune ... as indicated.!!. GSAUCERSIII SPAIN AND NORTB AFBTCA.'fr SMDNE-'iSAILiN OBJECT OUR BSA-- Tangier, ...
SIGHTINGS OF UNIDENTIFIED FLYING OBJECTS OVER SPAIN AND AFRICA, JULY-OCTOBER 1952
From several points of the Marrakech rrgien, lminous disks were seen On I4 July,flyingsaucersbad been seen ... According to the witnesses, the apparatus, which bid no resemblance to aflyingsaucer, emitted ... in its barest de- tails to provide another item for L'!t:udy of theflyingsaucerphenomenon. ...
GOVERNMENT TO PATENT NEW 'FLYING SAUCER' AIRLINER
1200 GMT 9 Mar 93 SUBJ Government To Patent New 'FlyingSaucer' Airliner Full Text Superzone ... of Message 1 [Text] Russia intends to patent a new airliner, dubbed by air designers aflyingsaucer... of theflyingsaucerwill be provided. Its carrying capacity ranges from 20 to 2,000 passengers. No special ...
SIGHTINGS OF UNIDENTIFIED FLYING OBJECTS, 31 JULY-20 SEPTEMBER 1954
OUR=, 31 JULY-20 "FLYINGSAUCER' SIGHTED OVER 31 GE71?L-- Vienna, Rena Viener Tageszeitung, 21 ... a "flyingsaucer" at about 2045 hours or. 19 August. A carpenter nsm*J Fessler, his sou-in-lav, ... seen by a farmer in Thaan, also in Calvados Department. RELIEVE 'FLYINGSAUCER" Pa.O'IS ...
SARATOV PLANT'S SUCCESSES, FUTURE PLANS REPORTED
"flyingsaucer"] There is no doubt about it, the our entire camera crew was very eager to see ... and film the Saratov Aviation Plant's most unusual design-- the "flyingsaucer... ." The "flyingsaucer" needs no airfield. It can take off and land with the help of an air cushion on land, ...
(EST PUB DATE) CIA'S ROLE IN THE STUDY OF UFO'S, 1947-90, BY GERALD K. HAINES
report ofa-flyingsaucer" over the United States came on 24 June 1947, when Kenneth Arnold, ... or not the Air Force investiga- tion offlyingsaucerswas sufficiently objective and how much more money ... and manpower would be necessary to determine the cause of the small per- centage of unexplainedflyingsaucers...
REPORT ON BOOK ENTITLED "FLYING SAUCERS FROM OUTER SPACE"
1$$3 MOM: Chief, Operations Staff, 0/SI suo)scra F.dport on Book Entitled "FlyingSaucers... with particular roterance to possible security violations concerning CIA's part in theflyingsaucer... the Atv. Fares to put out a report debun:inx thesaucers, tell'the public the project was ended ...
NON-ORBIT SIGHTINGS OF UNIDENTIFIED FLYING OBJECTS, 10 DECEMBER 1953-2 MARCH 1954
Presse de Tunisia, 16 Jv%r: 54 At 1030 hours on 12 January 1954, a 'flyingsaucer' crossed ... The object grew larger, 000015476 d0-W-30339 "FLY31RiSAUCER" OVER I()NTEVM]RO-- Fes, Le Courrier ... a "flyingsaucer," a sort of metallic disk emitting yellavieb reflections. It remained stationary ...
NOTHING BUT THE FACTS ON UFOS OR WHICH NOVOSTI WRITER DO YOU READ? (WITH 2 ARTICLES ATTACHED)
and clubs. Are these "flyingsaucers" just imagination or reality/. Thousands of recorded ... Only" Kenneth Arnold, an American pilot, is the "godfather" offlyingsaucers. /t ... encounter withsaucershad a tragic outcome. In January 1948, an immenseflyingsaucerappeared over the Mos ...
FLYING SAUCERS (WITH MEMO ATTACHED DATED 520924, SUBJECT: FLYING SAUCERS)
Intel- ligence advise the:rational Security Council of the bplications of thn "flyingsaucer... Assistant:Director,:Offico of Scientific Intelligence SU3J-- nsaucers1. PROM r''==,c=deter?si ies ... `?{a)-r.hether_or_not there are national, security. implications in the problem of "unidentifiedflyingobi ...
ARE FLYING SAUCERS A MYTH?
(Science eoseentator IZT'w: Areflyingsaucersa nyth? for AFIr) 50UCCB: Pravda. Ukrainy...'uo. ... tencion distracted from politics or economics, re 1 appearflyingsaucers, Inch!tees ncnsters,or Enaunen. ... 40,;l1 Fab 68; p. 4, cols. 2-7 /?' TOPIC 'FAG: s.. p34a~p,rcrusr.saan, unidtntificdflying...
ENGINEER CLAIMS 'SAUCER' PLANS ARE IN SOVIET HANDS; SIGHTINGS IN AFRICA, IRAN, SYRIA
~ranslit-. Atheffi, I Yrndyni, 13.~Y 53 "Flyingsaucers"..Bare-been lmarn:`to be.in actuality since ...saucer:" During the eYperiment,.yICLeia reported, the "flyingsaucer" raeched an al- titude ... The Damnscua newspaper A1~ reports that`"flyingsaucers" were recently above the city of Homs,.Syria ...
SENSATION: FLIGHT TO ALPHA-CENTAURUS
T88T OF ARTICLE: 1. [Article by Vladimir Lagovskiy] 2. [Text]...On "FlyingSaucer" 3. ... in "flyingsaucers" are justified. I am looking at a document. It is entitled, " A Protocol ... of the Test Results of an ExploratoryFlyingVehicle Motion Method." At the top,_-- as- i~t-should ...
SIGHTINGS OF UNIDENTIFIED FLYING OBJECTS
of a "flyingsaucer." The object made a bole in the field about 3.5 meters deep and 25 centimeters ... a skywriter of his firm at the time, called the object a "flyingsaucer" and stated ... OR RADIO BROADCASTS CD NO.-- COUNTRY Non-Orbit SUBJECT Military- Ub1 entifiedflyingobjects HOW PUBLISHED ...
| https://www.cia.gov/readingroom/search/site/Flying%20saucer?f%5B0%5D=dm_field_release_date%3A%5B2011-01-01T00%3A00%3A00Z%20TO%202012-01-01T00%3A00%3A00Z%5D |
Sensors and Sensor Systems for Guidance and Navigation II | (1992) | Publications | Spie
PROCEEDINGS VOLUME 1694
Sensors and Sensor Systems for Guidance and Navigation II
Editor(s): Sharon S. Welch
Volume Details
Volume Number: 1694 Date Published: 1 July 1992
Table of Contents
Application of new GPS aircraft control/display system to topographic mapping of the Greenland ice cap
Author(s):
Wayne Wright
A facet of the NASA Greenland Ice Sheet mapping experiment is the requirement for precise navigation and positioning of the aircraft. In order to establish baseline elevational measurements it is necessary to reoccupy ifight tracks several times to ensure the validity of the survey. The Airborne Oceanographic Lidar1 (AOL) was operated in a scanning mode from an a!titude of 400 m so the survey swath width is '200m thus the real-time navigational requirement is +1-50 m to provide for at least a 50% swath overlap on repeated passes. We developed the GPS Flight Management System (GFMS) using the Global Positioning System (GPS). The GFMS inputs GPS position data to a PC which generates _ aircraft automatic pilot steering commands and a cockpit display including 1) course deviation indicators for cross-track error and altitude, 2) flight plan and waypoint map overlay oriented to the aircraft and 3) other mission pertinent numerical data.
Application of advanced guidance and navigation systems to flight control of aircraft and future space vehicles
Author(s):
Clint C. Browning;
Kevin W. Braden
A joint NASA-Langley/Honeywell flight test project evaluating a differential Global Positioning System (GPS)Ilnertial Navigation System (INS) as an approach/landing aid was completed in November 1990. The test objective was to acquire a system performance data base and to demonstrate automatic landing using an integrated differential GPS/INS with radar altimeter aiding for vertical axis guidance. A NASA Boeing 737 testbed was used to evaluate the differential GPSIINS performance which included real-time comparison against MLS-derived position. This paper presents an overview and summary of the results from that flight test and discusses the application and benefits of the integrated INS/GPS to future space vehicles.
Aircraft collision avoidance using statistical decision theory
Author(s):
Patrick R. Williams
Collision avoidance involves the detection of impending collisions of an aircraft with either another aircraft or the ground from radar data and the timely alert of the danger to the pilot or air-traffic controller. The challenge is to provide sufficient warning (timely detections) with minimal false alarms. Radar measurement uncertainties degrade collision detection performance and must be accounted for in the algorithm design. This paper describes a method which uses statistical decision theory to control both missed or late detections and false alarms. The key to the technique is the mathematical description of the aircraft corridor uncertainty region. The corridor uncertainty region is derived from the position and velocity confidence ellipsoid associated with the aircraft radar track via a mapping from six dimensional space to three. By careful choice of the mapping, the minimum volume corridor uncertainty region is derived. This allows for the definition of the optimal collision avoidance decision rule. Since the method is based solely on the statistical properties of an aircraft's position and velocity track, it may be adapted to a variety of collision avoidance or guidance problems involving a radar or beacon-type sensors such as Mode C or Mode S.
Progress in low-cost interferometric fiber optic gyros
Author(s):
James N. Blake;
Bogdan Szafraniec;
John R. Feth;
K. Diamond
Low cost interferometric fiber optic gyros (both polarization maintaining and depolarized types) having bias drift less than one degree/hr over wide temperature ranges are reported. The depolarized fiber gyros exhibit significantly lower sensitivity to temperature transients than the polarization maintaining fiber gyros.
Pulsed diode ring laser gyroscope
Author(s):
William R. Christian;
Mark J. Rosker;
Ian C. McMichael
We have demonstrated a novel solid-state ring laser gyroscope by actively modelocking a pair of InGaAsP diodes in an external ring cavity. We observe no evidence of gain competition or frequency locking between the counterpropagating optical pulse trains circulating in the cavity to within the limit of our experimental resolution.
Integrated microgyroscope
Author(s):
Timothy J. Hawkey;
Richard P. Torti
A feasibility study was conducted of a prototype electrostatically suspended micromechanical two-axis gyroscope on a microchip, which is expected to find many applications in commercial, aerospace, and military sectors. Particular attention is given to the microfabrication techniques used for this device, the specifications and the configuration of the gyroscope, the configurations of the motor and the sensor, the electromechanical design, and the control and electronics design. Results of the feasibility study were very promising.
Proposed mechanism for lock-in growth in ring laser gyros
Author(s):
Sven G. Roden;
David A. Andrews;
Christopher Knipe;
Terence A. King
A model is developed which explains the lock-in growth phenomenon in ring laser gyros (RLGs), based on the concept of a 'burn-in' reflection grating proposed by Chao et al. (1984). It is suggested that a 'burn-in grating' is produced by the photoinduced refractive index modulation of the dielectric mirror stack. Experimental results supporting the burn-in grating model are presented, including lock-in growth and recovery measurements, second-order optical nonlinear activity measurements confirming electrooptic activity, and high- and low-intensity laser-induced damage measurements.
Star sensor simulation for astroinertial guidance and navigation
Author(s):
John M. Kennel;
Steven A. Havstad
;
Dave D. Hood
A star sensor simulator was developed, which models the characteristics of the star, the background, the sensor's windows, the telescope, the detector, the electronics, and the environment, generating data which are similar to data received from a real star sensor. The simulated data are then processed to reveal the star sensing capability. The paper discusses the requirements of the star sensor simulator, the models used, and the simulator design and presents representative simulations.
Microgravity monitoring instrument development and application to vernier guidance, navigation, and vehicle control
Author(s):
Joseph J. Howell
The fact that a spacecraft traveling through the 'vacuum' of space conforms to the classical Keplerian ellipse has recently been disproven. It is now well known that such a vehicle is acted on by many external forces such as drag in the rarefied particle atmosphere, solar wind and particle impact. This paper discusses the development of sensors and sensor systems to measure these minute forces of acceleration/deceleration. Four systems will be discussed: a 10 exp -4 g system, a 10 exp -6 g system, a 10 exp -(6-8) g system and a 10 exp -9 g system. The design of each system will be explained along with the advantages/disadvantages of each. Various applications unique to each system will be discussed. Configurations, design schemes, test plans and calibration procedures, both in the ground laboratory and inflight, will be presented. The current design/development/operational status of each system will be examined and future plans discussed. Application to aerodynamic studies and vernier guidance, navigation, and vehicle control will also be examined.
Autonomous millimeter-wave radar guidance systems
Author(s):
Kevin S. Schweiker
Hercules Defense Electronics Systems, Incorporated has applied millimeter wave technologies to a variety of guidance and control problems. This presentation documents the development and integration of an autonomous millimeter wave seeker to the AGM-65(D) (Maverick) air- to-ground missile. The resulting system was successfully demonstrated to search a large area for potential targets, prioritize detections, and guide the missile to the target during recent free-flight tests.
Performance of a 1-um 1-joule coherent launch site atmospheric wind sounder
Author(s):
James G. Hawley
;
Russell Targ;
Richard S. Bruner;
Sammy W. Henderson
;
Charley P. Hale
;
Steven Vetorino;
Robert W. Lee;
Scott Harper;
Tayyab Khan
The paper describes the design and performance of the Coherent Launch Site Atmospheric Wind Sounder (CLAWS), which is a test and demonstration program designed for monitoring winds with a solid-state lidar in real time for the launch site vehicle guidance and control application. Analyses were conducted to trade off CO2 (9.11- and 10.6-microns), Ho:YAG (2.09 microns), and Nd:YAG (1.06-micron) laser-based lidars. The measurements set a new altitude record (26 km) for coherent wind measurements in the stratosphere.
1.32 micron, long-range, solid-state, imaging LADAR
Author(s):
Clarence Clifton Andressen
The design of a newly designed ladar system (called LADAR) using a diode-pumped Q-switched Nd:YLF laser operating at 1.32 micron is described, and images obtained with the LADAR are presented together with the performance results of signal processing algorithms. It is shown that the system is able to obtain a range image of a target at 2 km, obtain intensity image information, and implement target detection and identification algorithms.
Microfabricated magnetometer using Young's modulus changes in magnetoelastic materials
Author(s):
Ralph C. Fenn;
Michael J. Gerver;
Richard L. Hockney;
Bruce G. Johnson;
John L. Wallace
Recent advances in tunneling-tip technology, magnetic materials, and microfabrication techniques allow development of a new class of improved magnetometers. The sensor utilizes changes in Young's modulus of amorphous magnetic alloys resulting from their excellent magnetoelastic properties. Changes in applied magnetic field cause resonant frequency changes of a sputtered, electrostatically excited Metglass cantilever. Resonant cantilever position is measured by a second, electrostatically controlled cantilever holding a tunneling-tip that tracks the Metglas cantilever. The phase relationship between the exciting signal and the position is fed back to maintain the excitation frequency at the moving resonant peak. In this way the resonant frequency is measured, and the field is inferred from the frequency. The 'Q' of the Metglas cantilever is increased to very high levels using closed loop control of cantilever dynamics, producing extraordinary resolution.
Space microguidance and control: applications and architectures
Author(s):
Edward Mettler
;
Fred Y. Hadaegh
The features and the components of a new microscale guidance, navigation, and control (GN&C) system for future space systems are discussed. An approach is described for the utilization of new microengineering technologies for achieving major reductions in the GN&C system's mass, size, power, and costs. The micro-GN&C system and the component concepts include microactuated adaptive optics, micromachined inertial sensors, fiberoptic data nets with light-power transmission, and VLSI microcomputers. The GN&C system will be applied in microspacecraft, microlanders, microrovers, remote sensing platforms, interferometers, and deployable reflectors.
Fabrication and testing of metal micromechanisms with rotational and translational motion
Author(s):
Henry Guckel;
Todd R. Christenson;
Kenneth J. Skrobis
Microactuators ideally produce large output forces per unit chip area. This requires processing procedures which lend themselves to structures with large structural heights. Processing which also produces large edge acuities is required for low friction, low wear sliding bearing surfaces. Both attributes are accommodated in a processing sequence which uses thick photoresist technology, X-ray exposure, and metal plating together with a surface micromachined sacrificial layer. The end results are thick precision metal structures which can be assembled to achieve submicron tolerances in sliding bearing surfaces. The process has been used to fabricate rotational planar magnetic micromotors with low friction. Linear reluctance drives with spring returns have also been achieved and are in the testing phase.
Novel position sensor technologies for microaccelerometers
Author(s):
Thomas R. VanZandt;
Thomas W. Kenny;
William J. Kaiser
An important new approach for vehicle guidance and control is based on the use of compact, low-mass, low-cost sensors integrated with the vehicle structure. Many advantages of this approach lead to new capabilities. However, the development of compact guidance and control sensors leads to a variety of fundamental physical problems associated with sensor sensitivity and noise. For example, as sensor size is reduced, it becomes necessary to improve the sensitivity of the sensor signal detection mechanism. These challenges to sensor development will be described. Recent developments at JPL, based on new position sensor principles such as electron tunneling, have produced a series of novel, ultra-high sensitivity micro-sensors and micro-instruments. Included among the applications demonstrated, are a high sensitivity micro-accelerometer and micro-seismometer. In this paper, the fundamental limits of conventional position sensors will be discussed and a new position sensor for advanced accelerometers will be described.
Ferroelectric thin film materials, structures, and microsensors
Author(s):
Dennis L. Polla
;
T. Tamagawa;
Chian-Ping Ye;
P. J. Schiller;
Linda Pham
;
Cuong Y. Tu
The paper describes the integration of sol-gel ferroelectric thin films into micromachined sensors and optical detectors, devices which are based on the piezoelectric and pyroelectric effects in Pb(Zr(x)Ti(1-x))O3 and PbTiO3 thin films, respectively. The ferroelectric and surface-micromachining technologies are described, which are compatible with 3-micron CMOS technology. At 297 K and a chopping frequency of 50 Hz, the measured blackbody voltage responsivity of a pyroelectric element with an active area of 7 x 10 exp -4 sq cm was 4.2 x 10 exp 4 V/W and the measured normalized detectivity was 1.0 x 10 exp 9 cm sq-rt Hz/W.
Thin film diamond temperature sensor array for harsh aerospace environment
Author(s):
Mohammad Aslam;
Ashraf Masood;
Ronald J. Fredricks;
Mike A. Tamor
The feasibility of using polycrystalline CVD diamond films as temperature sensors in harsh aerospace environment associated with hypersonic flights was tested using patterned diamond resistors, fabricated on flat or curved oxidized Si surfaces, as temperature sensors at temperatures between 20 and 1000 C. In this temperature range, the measured resistance was found to vary over 3 orders of magnitude and the temperature coefficient of resistance to change from 0.017/K to 0.003/K. After an annealing treatment, the resistance change was reproducible within 1 percent on the entire temperature range for short measuring times.
Effects of display configuration on attentional sampling performance
Author(s):
Jay L. Brand
An empirical study was conducted to determine the ability of naive subjects to sample information from different display configurations. Simple line drawings circumscribed areas shaped like squares, rectangles, `Ts,' `Ls,' and `+,' among others. Each such `area' was presented for one second followed after a brief interstimulus interval (ISI) by a 12-letter (3 X 4) matrix. The subjects' task was to report all the letters that would have been surrounded by the area, if the line drawing of the area were superimposd on the letter matrix. The effects of display configuration on attentional sampling performance were thus assessed for an arbitrary set of 36 configurations. The results indicated that single, spatially contiguous areas could be monitored better than separate areas, and simple configurations were better than more complex ones. These results have implications for Heads-up Displays (HUDs) and for the optimal spatial configuration of salient gauges and instruments within a vehicle or airplane cockpit.
Applications of thin film trielectrode electroluminescent display devices for automotive vehicles
Author(s):
Zbigniew W. Porada
Generally, dashboard information display devices can be divided into active and passive ones, i.e., emitting or modulating light. The thin film electroluminescent display devices belong to the former category. The new concept electroluminescent dashboard information display devices conceived by the author are presented in this paper. In this case, a DC and an AC power supply voltage are simultaneously applied. As a result, the DC voltage is essentially reduced to about 25 V DC. The electroluminescent information display device was prepared by vacuum methods on a glass substrate in the form of tri-electrode structure.
New cathode ray tube gun interconnection assembly
Author(s):
David M. McCormick
A novel interconnection assembly method was developed for the electron gun of airborne CRTs, which makes it possible for the connectors to be connected and disconnected repeatedly (as opposed to soldering as in the conventional method) to provide access to the tube and its interconnecting cable harness. Environmental tests were conducted on one series of CRTs, which included electrical and environmental conditions which would be experienced in a worst-case aircraft cabin environment, including the altitude, humidity, thermal shock, vibration, and mechanical shock.
Tactical cockpits: the coming revolution
Author(s):
Eugene C. Adam
A cockpit revolution is in the making. Many of the much ballyhooed, much promised, but little delivered technologies of the 70s and 80s will finally come of age in the 90s, just in time to complement the data explosion coming from sensor and processing advances. Technologies such as helmet systems, large flat panel displays, speech recognition, color graphics, decision aiding, and stereopsis are simultaneously reaching technology maturities that promise big payoffs for the third generation cockpit and beyond. The first generation cockpit used round dials to help the pilot keep the airplane flying right side up. The second generation cockpits used multifunction displays and the HUD to interface the pilot with sensors and weapons. What might the third generation cockpit look like? How might it integrate many of these technologies to simplify the pilot's life and most of all: what is the payoff? This paper examines tactical cockpit problems, the technologies needed to solve them, and recommends three generations of solutions.
Advanced airborne 3D computer image generation systems technologies for the year 2000
Author(s):
Alan L. Bridges
An airborne 3-D computer image generation system (CIGS) is a modular avionics box that receives commands from and sends status information to other avionics units. The CIGS maintains a large amount of data in secondary storage systems and simultaneously drives several display units. Emerging requirements for CIGS include: advanced avionics system architecture requirements and BIT/fault tolerance; real-time operating systems and graphic interface languages in Ada; and geometric/pixel processing functions, rendering system, and frame buffers/display controllers for pictorial displays. In addition, podded sensors (FLIR, LLTV, radar, etc.) will require multiplexing of high-resolution sensor video with graphics overlays. A combination of head-down AMLCD flat panels, helmet-mounted display (HMD), and Head-Up Display (HUD) will require highly parallel graphics generation technology. Generation of high-resolution, real-time 2-D/3-D displays with anti-aliasing, transparency, shading, and motion, however, emphasizes compute-intensive processing. High-performance graphics engines, powerful floating point processors, and parallel architectures are needed to increase the rendering speed, functionality and reliability, while reducing power, space requirements, and cost. The CIGS of the future will feature special high speed busses geared toward real-time graphics processing. The CIG system will be multi-channel, will have a high addressable resolution to drive HUD, 3-D displays in 4-pi-steradian virtual space, and 3-D panoramic displays; and will include fiber optics video distribution between CIG and display units. The head-down display (HDD) is by far the most complex display in that both background and overlay display elements are required. The background is usually generated from terrain/cultural features data. Terrain data is used to generate 2-D map backgrounds or 3-D perspective views duplicating or substituting for the pilot's out-the-window view. Performance of 150,000 to 500,000 3-D triangles/second is needed. Gouraud shading, ambient-diffuse lighting models, and anti-aliasing are required. For the year 2000, a single large and very high-resolution display surface covering the entire instrument panel is required.
Self-scanned polysilicon active-matrix liquid crystal displays
Author(s):
Alan L. Bridges
The paper describes the structure and technology of active matrix liquid crystal displays (AMLCDs) and discusses the advantages of the AMLCD technology ocmpared with CRT technology. AMLCDs use microelectronic thin film transistors (TFTs) to produce bright, full-color images equal to those of CRTs in clarity and resolution. At the same time, color AMLSDs alleviate many problems associated with color CRTs, such as poor reliability in a severe environment, modest color performance in high ambient light, poor mean time between repair (five times less than that of AMLCDs), relatively great weight, and poor volumetric efficiency. The paper considers the AMLCD electronics and discusses the development of self-scanned poly-Si AMLCDs with integrated row and column (data and select line scanners) circuitry and 5-bit grey shade drivers. The integration of row and column and gray scale circuitry on glass will dramatically increase compactness and reliability and decrease AMLCD panel costs.
AC thin film electroluminescent display unit for cockpit control display unit application
Author(s):
Alan L. Bridges
A prototype thin film electroluminescent (TFEL) display unit (DU) for a control display unit (CDU) design and development was initiated in FY90. Features of the display include high brightness and contrast, sunlight readability, night vision goggle compatibility, light weight, low power, automatic brightness control based on ambient light conditions, modular design, ease of assembly and test, and high reliability. The display contains an integral switch and lightplate that is night vision goggle compatible. The unit was designed for cockpit CDU applications, but can be easily converted for other display needs. The scope of this task was to design and build an ANVIS-compatible, sunlight-readable TFEL CDU DU engineering evaluation unit to replace an existing cathode ray tube (CRT) DU in the V-22 CDU. In order to accomplish that task it was necessary to learn interface, drive, and improved packaging techniques. The electronics were very straight forward using large scale integration (LSI) components. The CDU is mounted in the instrument panel in standard cockpit avionics mounting rails, utilizing quarter turn captive fasteners. The CDU is cooled by natural convection. The TFEL display unit weighs 4.3 pounds compared to 7.8 pounds for the CRT version. Surface mount was a requirement for the drive card due to size constraints. Elastomeric connectors were used to interface the driver board to the glass. The approach uses as much proven design as possible, but makes use of state-of-the-art display technology to provide a low power display unit with outstanding characteristics. The TFEL CDU DU tasks completed during 1991-92 included design and development of: (1) controller and RS-170 digitizer board, (2) high voltage-switching or pre-driver board, (3) row and column driver circuitry for gray scale (double-sided surface mount using sample Supertex HV38 gray-shade column drivers and TI high-voltage row drivers); (4) high and low voltage power supplies; and bezel and packaging. Performance of the TFEL DU, functions and operation of the TFEL CDU DU and key board unit (KBU), and aircraft interfaces are described.
Precision visual guidance for agricultural applicator aircraft
Author(s):
Joseph R. Hartt;
Frank R. Bletzacker;
T. J. Forgette;
Alan A. Vetter
The in-cockpit swath centerline identifier (SCI) for aerial applicators uses differentially corrected global positioning system (GPS) signals to determine precise ground track of an aircraft and provide guidance to the pilot for flying patterns for aerial application of materials such as pesticides, herbicides, and fertilizers. Cross track distance from the swath centerline is provided by a heads up light bar display while detailed navigation, position, and status information is provided on an alphanumeric display on a panel mounted console. This system provides straight line guidance when executing a swath and turn-in guidance when proceeding from one swath to the next. It provides a record of the swaths which were sprayed and logs all of the associated navigation and operational data, including time. In addition, it provides navigation information from base to the fields, between fields, and return. The SCI eliminates the need for flaggers while providing improved accuracy of application. Reduced exposure to liability and improved quality control results as the position, altitude, time, and spray status are logged for post flight analysis. The SCI has been used in commercial agricultural applications. Demonstrations of the SCI showed better precision than anticipated.
Laser centerline localizer and laser glideslope indicator for visual guidance on approach to landing
Author(s):
David M. Shemwell;
Alan A. Vetter;
R. I. Gellert
The Laser Centerline Localizer (LCL) and the laser Glideslope Indicator (LGI) use a series of low power, but highly visible laser beams to illuminate approach corridors for carrier flight operations. By taking advantage of the ability to precisely shape and direct visible laser beams and by encoding the illuminated paths using color and temporal frequency, direct visual signals which provide a positive on course signal as well as an indication of the direction and degree of deviation from the proper approach are seen by the pilot. The LCL provides centerline guidance and the LGI provides descent guidance. This laser visual landing aid (LVLA) system provides the pilot with significantly improved visual cues to aid in the safe landing of the aircraft. The LCL and LGI units have been constructed and field tested. The ability to guide pilots from a range of over 15 miles has been demonstrated.
Scanning laser aircraft surveillance system for carrier flight operations
Author(s):
Alan A. Vetter;
David M. Shemwell;
R. I. Gellert;
J. Black
The Scanning Laser Aircraft Surveillance System (SLASS) uses two scanning infrared laser beams to illuminate retroreflectors located on aircraft landing gears and hook to determine very precisely the azimuthal, ascension, yaw, roll, and pitch angles of the aircraft in the approach corridor. The range, approach velocity, and aircraft type are also determined. Aircraft configuration is determined by the presence or absence of each return signal, and aircraft type is identified with an encoded sequence of retroreflectors on one landing gear. The position of the aircraft is determined by the time in the scan that the beam encounters the retroreflectors.
Effects of laser glare on visual search performance
Author(s):
John A. D'Andrea;
James C. Knepton;
Michael D. Reddix
In the future, aviation aircrews will likely operate in an environment that is saturated with electromagnetic energy emitted from a variety of sources. Lasers serving many applications, such as rangefinding and guidance, will be included in this environment. Eye damage from laser sources is possible, but laser irradiation below levels necessary to produce eye damage may still degrade visually guided human performance. It is important to understand how, and to what extent, visually mediated human performance is affected by low-level laser glare. To this end, we have conducted some initial laboratory studies in which we have systematically varied level of glare and cockpit windscreen characteristics while subjects, who were seated in a cockpit familiarization trainer, performed a visual search task. The search task required subjects to scan a complex visual scene projected on a screen and report the location of one small target disk randomly placed among larger background disks. In a series of studies, we have shown that windscreen characteristics and ambient illumination can interact with laser- induced glare to disrupt visual search performance. We have also shown that lens opacity, an opaqueness of the lens that increases with age, may interact with laser glare and degrade visual search performance more in older individuals. Laser light intensities well below the eye injury threshold may effectively disrupt visually guided performance.
Autonomous rendezvous, docking, and landing system using cruise missile technologies
Author(s):
Ruel Edwin Jones
General Dynamics has been developing an Autonomous Rendezvous Docking and Landing (ARD&L) system that utilizes cruise missile technologies. In November 1990 the Autonomous Rendezvous and Docking (AR&D) system was first demonstrated for members of NASA's Strategic Avionics Technology Working Group (SATWG). This simulation utilized prototype hardware from the Cruise Missile and Advanced Centaur Avionics systems. The objective was to show that all the accuracy, reliability, and operational requirements established for a spacecraft to dock with Space Station Freedom could be met by the proposed system. Rapid prototyping techniques were used to evaluate the proposed system in a real time, hardware in the loop simulation of the rendezvous and docking reference mission. The simulation is currently being upgraded to test an Autonomous Approach and Landing (AA&L) system. Both systems use inertial guidance and control systems supplemented by the Global Positioning System (GPS) and an Image Processing System (IPS), for target recognition and tracking. The IPS includes a general purpose multiprocessor computer and a selected suite of sensors that will provide the required relative position and orientation data. Graphic displays can provide the astronaut/operator with realtime guidance and navigation data with enhanced video or sensor imagery.
Optical processing for range and attitude determination
Author(s):
Marija Scholl
;
James W. Scholl
A rugged, miniaturized, optical cross-correlator that recognizes a single object is particularly suitable for performing a single-vision function, such as pattern recognition for semi- autonomous navigation, landing, and docking of vehicles to a pre-designated landing mark. The optical cross-correlator, with a video input from a simple imaging system and the output of the optical correlation plane processed using the standard star tracker software, produces sufficient information for a spacecraft's terminal homing navigation system to complete a docking maneuver.
History and development of coated contrast enhancement filters for cockpit displays
Author(s):
Clifford E. Sisler
The development of the coated Contrast Enhancement Filters, the coated narrow band-pass absorbing optical filters designed for P43 CRT color shadow mask displays and flat panel displays is discussed. Particular attention is given to the properties and applications of several series of Contrast Enhancement Filters, including filters designed to meet special day-night application.
| https://spie.org/Publications/Proceedings/Volume/1694 |
Molecules | Free Full-Text | Identification and Characterization of a Novel N- and O-Glycosyltransferase from Saccharopolyspora erythraea
Glycosyltransferases are important enzymes which are often used as tools to generate novel natural products. In this study, we describe the identification and characterization of an inverting N- and O-glycosyltransferase from Saccharopolyspora erythraea NRRL2338. When feeding experiments with 1,4-diaminoanthraquinone in Saccharopolyspora erythraea were performed, the formation of new compounds (U3G and U3DG) was observed by HPLC-MS. Structure elucidation by NMR revealed that U3G consists of two compounds, N1-α-glucosyl-1,4-diaminoanthraquinone and N1-β-glucosyl-1,4-diaminoanthraquinone. Based on UV and MS data, U3DG is a N1,N4-diglucosyl-1,4-diaminoanthraquinone. In order to find the responsible glycosyltransferase, gene deletion experiments were performed and we identified the glycosyltransferase Sace_3599, which belongs to the CAZy family 1. When Streptomyces albus J1074, containing the dTDP-d-glucose synthase gene oleS and the plasmid pUWL-A-sace_3599, was used as host, U3 was converted to the same compounds. Protein production in Escherichia coli and purification of Sace_3599 was carried out. The enzyme showed glycosyl hydrolase activity and was able to produce mono- and di-N-glycosylated products in vitro. When UDP-α-d-glucose was used as a sugar donor, U3 was stereoselective converted to N1-β-glucosyl-1,4-diaminoanthraquinone and N1,N4-diglucosyl-1,4-diaminoanthraquinone. The use of 1,4-dihydroxyanthraquinone as a substrate in in vitro experiments also led to the formation of mono-glucosylated and di-glucosylated products, but in lower amounts. Overall, we identified and characterized a novel glycosyltransferase which shows glycohydrolase activity and the ability to glycosylate “drug like” structures forming N- and O-glycosidic bonds.
Identification and Characterization of a Novel N - and O -Glycosyltransferase from Saccharopolyspora erythraea
Yvonne-Isolde Schmidt-Bohli 1 ,
Tina Strobel 1 ,
Danye Qiu 2 ,
Henning Jessen 2 ,
Thomas Paululat 3 and
Andreas Bechthold 1,*
1
Institute for Pharmaceutical Biology and Biotechnology, Albert-Ludwigs-University, Stefan-Meier-Straße 19, 79104 Freiburg, Germany
2
Institute of Organic Chemistry, Albert-Ludwigs-Universität, Albertstrasse 21, 79104 Freiburg, Germany
3
Organic Chemsitry II, Universität Siegen, Adolf-Reichwein-Strasse 2, 57068 Siegen, Germany
*
Author to whom correspondence should be addressed.
Molecules 2020 , 25 (15), 3400; https://doi.org/10.3390/molecules25153400
Received: 18 June 2020 / Revised: 24 July 2020 / Accepted: 24 July 2020 / Published: 27 July 2020
(This article belongs to the Section Bioorganic Chemistry )
:
Glycosyltransferases are important enzymes which are often used as tools to generate novel natural products. In this study, we describe the identification and characterization of an inverting
N
- and
O
-glycosyltransferase from
Saccharopolyspora erythraea
NRRL2338. When feeding experiments with 1,4-diaminoanthraquinone in
Saccharopolyspora erythraea
were performed, the formation of new compounds (U3G and U3DG) was observed by HPLC-MS. Structure elucidation by NMR revealed that U3G consists of two compounds,
N
1
-α-glucosyl-1,4-diaminoanthraquinone and
N
1
-β-glucosyl-1,4-diaminoanthraquinone. Based on UV and MS data, U3DG is a
N
1
,
N
4
-diglucosyl-1,4-diaminoanthraquinone. In order to find the responsible glycosyltransferase, gene deletion experiments were performed and we identified the glycosyltransferase Sace_3599, which belongs to the CAZy family 1. When
Streptomyces albus
J1074, containing the dTDP-
d
-glucose synthase gene
oleS
and the plasmid pUWL-A-
sace_3599
, was used as host, U3 was converted to the same compounds. Protein production in
Escherichia coli
and purification of Sace_3599 was carried out. The enzyme showed glycosyl hydrolase activity and was able to produce mono- and di-
N
-glycosylated products in vitro. When UDP-α-
d
-glucose was used as a sugar donor, U3 was stereoselective converted to
N
1
-β-glucosyl-1,4-diaminoanthraquinone and
N
1
,
N
4
-diglucosyl-1,4-diaminoanthraquinone. The use of 1,4-dihydroxyanthraquinone as a substrate in in vitro experiments also led to the formation of mono-glucosylated and di-glucosylated products, but in lower amounts. Overall, we identified and characterized a novel glycosyltransferase which shows glycohydrolase activity and the ability to glycosylate “drug like” structures forming
N
- and
O
-glycosidic bonds.
Keywords:
glycosyltransferase
;
glycohydrolase
;
Saccharopolyspora erythraea
;
anthraquinone
;
glycobiology
;
nucleotide-activated sugar donor
Graphical Abstract
1. Introduction
Natural products continue to serve as a key platform for drug development and it is well established that glycosylation of small molecules can dramatically influence the pharmacological properties of the parent scaffold. In glycosylated natural products, the sugar moieties are often crucial for activity and it has been shown that sugar moieties of a natural compound directly interact with the cellular targets. Today glycosylated natural products are often used as antibiotics (e.g., aminoglycosides, macrolides like erythromycin), drugs with antifungal activities (e.g., polyenes like amphotericin and nystatin) and cytotoxic drugs (e.g., angucyclines like doxorubicin) [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 ].
Catalytic modules, which degrade, modify, or create glycosidic bonds are called Carbohydrate Active enZymes and are grouped in the CAZy database ( http://www.cazy.org/ ). CAZy families are classified according to amino acid sequence similarities [ 9 ]. Enzymes belonging to the superfamily of glycosyltransferases (GTs) catalyze the transfer of sugar moieties from activated sugar donors onto acceptor molecules by forming glycosidic bonds [ 1 , 10 , 11 ]. GTs are distributed in both prokaryotes and eukaryotes, and demonstrate enormous structural and functional variety [ 12 , 13 ]. Acceptor molecules can be structurally versatile, comprising sugars, lipids, nucleic acids, steroid hormones, biogenic amines, secondary metabolites from plants and bacteria, and therapeutic drugs [ 11 ].
N -glycosylation is a ubiquitous modification that occurs mainly in proteins. This process involves the transfer of preassembled oligosaccharides from a lipid donor to asparagine side chains of polypeptides and is catalyzed by membrane-bound oligosaccharyltransferase (OST) [ 14 ]. A few nitrogen glycosylating GTs ( N -GTs) have been identified that use nucleotide-activated monosaccharides as donors to modify either asparagine residues of peptides and proteins or to introduce sugar moieties to natural products. For example, the N -GT PtmJ from Streptomyces pactum is involved in biosynthesis of the antitumor antibiotic pactamycin [ 15 ] and AaNGT from Aggregatibacter aphrophilus is able to utilize different sugar donors [ 16 ]. Further examples are Asm25, a N -GT involved in ansamitocin biosynthesis [ 17 ] and StnG that glycosylates the imine nitrogen atom of guanidine during streptothricin biosynthesis [ 18 ]. As indicated above, attachment or exchange of sugar moieties can essentially optimize the pharmacological characteristics of a drug and modify the molecular mode of action [ 19 , 20 , 21 ]. There is a vivid demand in efficient procedures to alter the glycosylation pattern of diverse chemicals and, therefore, improve therapeutic agents. GTs can be used to perform these modifications in an effective and economic way in contrast to challenging chemical synthesis [ 22 , 23 ]. GT genes have been cloned and characterised to develop in vitro and in vivo techniques to glycosylate given compounds and generate new glycosylated bioactive compounds [ 24 , 25 , 26 , 27 , 28 , 29 , 30 ]. Previously, the O -glycosylation of a range of complex natural products and drugs with the help of these potent tools has been reported [ 31 , 32 , 33 ]. While such approaches have dramatically extended the structural diversity of a range of therapeutically important natural products, they have largely been restricted to O -glycosylation and, only to a lesser extent to N -glycosylation [ 34 ].
Actinomycetes are known for their ability to glycosylate several natural products. In order to find new, unknown GTs our working group started to screen different strains performing in vivo feeding experiments.
Saccharopolyspora erythraea
NRRL2338 is a Gram-positive mycelial soil Actinomycete, producing the clinically useful broad-spectrum macrolide antibiotic erythromycin A [
35
]. In this paper, we report the identification of a
N
- and
O
-GT of the CAZy family 1 from
Saccharopolyspora erythraea
NRRL2338 which is able to convert 1,4-diaminoanthraquinone (U3) to its
N
1
-β-glycosylated,
N
1
-α-glycosylated and di-glycosylated derivatives. Moreover, it catalyzes the conversion of 1,4-dihydroxy-anthraquinone (U2) to its mono- and di-glucosylated products (U2G, U2DG).
2. Results
2.1. In Vivo Biotransformation of Anthraquinone Derivatives
To examine the biotransformation ability of
S. erythraea
, in vivo feeding experiments were performed. Therefore, 1,2-dihydroxyanthraquinone, 1,4-dihydroxyanthraquinone (U2), 1,4-diamino-anthraquinone (U3), 1,5-diaminoanthraquinone, 1-amino-2-methylanthraquinone, 1-amino-2-carboxyanthraquinone, 1-amino-2-chloroanthraquinone, and 1-amino-4-chloranthraquinone were dispensed to
S. erythraea
under whole cell feeding conditions. The crude extract of the cultures fed with U3 exhibited new natural compounds in HPLC-MS analysis at retention times of 4.2 min (U3DG) and 11.7 min (U3G) (
Figure 1
a I). In comparison to the MS spectrum of the substrate U3
m/z
= 237.1 [M − H]
−
for the new detected compound U3G MS signals of
m/z
= 399.2 [M − H]
−
,
m/z
= 435.2 [M + Cl]
−
and
m/z
= 459.2 [M + CH
3
COO]
−
were measured. For U3DG, MS signals of
m/z
= 561.2 [M − H]
−
and
m/z
= 597.2 [M + Cl]
−
were detected (
Figure 1
c). Feeding of the other anthraquinone derivatives did not result in the formation of any new compounds.
2.2. Genes Encoding for Glycosyltransferases in the Genome of S. erythraea
The whole genome of S. erythraea NRRL2338 was sequenced in 2007 [ 36 ], revealing 7198 protein-encoding sequences. Altogether 56 GT genes are present. GTs supposed to be involved in primary metabolism are responsible for cell wall synthesis and DNA formation. S. erythraea possesses also GTs participating in secondary metabolism. These enzymes generally have protein sequence homology to GTs of CAZy family 1. Three GT genes can be found in the genome of S. erythraea whose gene products show homology to Uridine diphosphate (UDP)-glucosyltransferases and N -GTs of family 1 ( sace_1884 , sace_3599 , sace_4470 ). All these GT genes are not located close to biosynthetic gene clusters, but distributed throughout the genome.
2.3. Heterologous Expression of Sace_3599 in S. albus Gluc
To identify the
N
-GT responsible for
N
-glycosylation of U3
S. albus
Gluc was generated. This strain contains
oleS
, a gene encoding a dTDP-
d
-glucose synthase, which is able to convert α-glucose 1-phosphate to dTDP-
d
-glucose as a putative sugar donor for the
N
-GT. Expression of
oleS
in the marker-free host strain
S. albus
Gluc is controlled by the constitutive
ermE*
promoter [
37
]. Plasmids containing
sace_1884
,
sace_3599
, and
sace_4470
were introduced into
S. albus
Gluc, leading to
S. albus
Gluc x pUWL-A-
sace_1884
,
S. albus
Gluc x pUWL-A-
sace_3599
, and
S. albus
Gluc x pUWL-A-
sace_4470
, respectively. The compound U3 was fed to
S. albus
WT,
S. albus
Gluc, and all mutant strains containing one of the GT-genes from
S. erythraea
. Extracts were analysed by HPLC-MS. The crude extract of
S. albus
Gluc x pUWL-A-
sace_3599
exhibited a new peak at a retention time of 11.7 min (U3G) shown in
Figure 1
a VIII, while the other generated strains did not produce any new compounds. After solid phase fractionation of the extract using an Oasis HLB column, preparative thin-layer chromatography and Sephadex LH20 column, U3DG was also detected at 4.2 min by HPLC-MS (
Figure 1
a IV).
2.4. Gene Deletion and Complementation Experiments
In order to prove that sace_3599 is the only GT of S. erythraea , responsible for the formation of the N -glucosylated derivatives of U3, gene inactivation experiments were carried out. A double-crossover mutant was generated in which sace_3599 was replaced by a spectinomycin resistance-conferring gene. S. erythraea Δ sace_3599 was not able to glucosylate U3 ( Figure 1 a V). Complementation of S. erythraea Δ sace_3599 with an unscathed copy of the gene sace_3599 restored biotransformation ability, indicating that Sace_3599 is the only N -glucosylating GT ( Figure 1 a VI).
2.5. Structure Elucidation of U3G and U3DG
U3G and U3DG were isolated from 1.5–5.l of
S. erythraea
and
S. albus
Gluc x pUWL-A-
sace_3599
, respectively, both fed with U3 and from in vitro glycosylation activity assays. Structure elucidation was performed using HPLC-MS and NMR spectroscopy. U3G consists of the
N
1
-glucosylated derivative of the substrate U3. When UDP-α-
d
-glucose was used as a sugar donor, U3 was stereoselective converted in vitro to
N
1
-β-glucosyl-1,4-diaminoanthraquinone. U3G isolated from Actinomycetes after whole-cell feeding experiments consisted of the
N
1
-α-glucosylated derivative as well as the
N
1
-β-glucosylated derivative (
Figure 2
). NMR-data are shown in
Supplementary Material (File 2)
.
The percentage ratios of α- and β-anomer in U3G varied. Both anomers could be separated by capillary electrophoresis ( Figure 3 ). Due to low amounts and purities, the structure of U3DG could not be clearly elucidated, but UV spectra, mass spectrometry and NMR data indicate, that two sugars are attached to the diaminoanthraquinone moiety via N -glycosylation. There is no evidence for an intact disaccharide moiety. Therefore, we conclude that the compound is N 1 , N 4 -diglucosyl-1,4-diaminoanthraquinone.
2.6. Production, Purification and In Vitro Activity Assay of Sace_3599
For further characterization of the identified GT Sace_3599, we decided to perform in vitro activity assays. Therefore, the gene sace_3599 was expressed in E. coli Rosetta™. Soluble protein was obtained and purified as described in Materials and Methods (see Section 4.11 ). The molecular mass of the enzyme Sace_3599 was 45.3 kDa. A SDS Gel after immobilized-metal affinity chromatography (IMAC) with Ni 2+ -NTA and a gel filtration chromatogram can be found in Supplementary Material (Figure S3) .
In in vitro activity assays, the highest conversion catalyzed by Sace_3599 was reached using TRIS buffer pH 8.8 and an incubation of 22 h at 28 °C. Although the enzyme was active without the addition of any metal ion, high activity was detected when Mn 2+ or Mg 2+ were added ( Supplementary Material, Figure S4 ). In the presence of UDP-α- d -glucose, Sace_3599 converted U3 in in vitro assays to its N 1 -β-glucosylated derivative (U3G) which was detected by HPLC-MS and shown by NMR spectroscopy. In addition, we observed the formation of the N 1 , N 4 -diglucosylated derivative (U3DG, Figure 4 a III; Figure 4 b). In negative controls without Sace_3599, only U3 and no biotransformation products were detected. The enzyme also accepted TDP-α- d -glucose as a sugar donor in small quantities ( Figure 4 a I, Figure 4 b), but not UDP-α- d -galactose ( Figure 4 a II; Figure 4 b).
Next, in order to test, whether Sace_3599 can also form
O
-glycosidic bonds, 1,4-dihydroxyanthraquinone (U2) was tested as a substrate. In the presence of UDP-α-
d
-glucose, Sace_3599 converted 1,4-dihydroxyanthraquinone (U2, at 29.3 min) to two new products at retention times of 4.2 min (U2DG) and 16.0 min (U2G,
Figure 5
b I). Due to low amounts and purities, the structure of U2G and U2DG could not be clearly elucidated, but UV spectra (
Figure 5
c) and mass spectrometry (
Figure 5
d) indicate that compound U2G is
O
1
-glucosyl-1,4-dihydroxyanthraquinone and U2DG is
O
1
,
O
4
-diglucosyl-1,4-dihydroxyanthraquinone (
Figure 5
a). For U2G, characteristic MS signals of
m/z
= 401.1 [M − H]
−
and
m/z
= 437.1 [M + Cl]
−
were detected. U2DG is less pure but characteristic MS signals of
m/z
= 563.2 [M − H]
−
,
m/z
= 599.2 [M + Cl]
−
and
m/z
= 623.3 [M + CH
3
COO]
−
were detected. In negative controls without Sace_3599, no biotransformation products of U2 were detected by HPLC-MS analysis.
In order to test whether Sace_3599 exhibits glycohydrolase activity UDP-[ 14 C]glucose was added as substrate to in vitro assays with 50 µM Sace_3599. After 1, 2 and 22 h samples of 1 µL were taken for thin layer chromatography (see Section 4.13 ). Interestingly, a lot more free [ 14 C]glucose in the assay-samples was detected than in the negative controls without enzyme ( Figure 6 ).
2.7. Genome Sequence Analysis
In silico analysis of a 10.5 kb DNA fragment containing sace_3599 revealed that the gene is enclosed by genes encoding for proteins with unknown function, named hypothetical proteins ( hp ), a transcriptional Xenobiotic Response Element regulator ( xre-reg ), a polymorphic GC-repetitive sequence ( pe-pgrs ) family protein, a methionine aminopeptidase ( meth-ap ), two aminoglycoside N3′ acetyltransferases ( ag-at ), an oxidase ( ox ), a class II aldolase ( cII-ald ), and an enolase-phosphatase ( en-phos ), respectively ( Figure 7 ).
2.8. Homologous Proteins to Sace_3599
Protein BLAST [ 38 ] showed high sequence identity of Sace_3599 to other known glycosyltransferases which are involved into antibiotic metabolism or antibiotic biosynthetic process like YjiC ( Bacillus subtilis ) [ 39 , 40 ], OleI ( Streptomyces antibioticus ) [ 41 , 42 , 43 ], TylCV ( Streptomyces fradiae ) [ 44 ], OleD ( Streptomyces antibioticus ) [ 41 , 42 , 43 ], Mgt ( Streptomyces lividans ) [ 45 ], YojK ( Bacillus subtilis ) [ 40 , 46 ] and YdhE ( Bacillus subtilis ) [ 40 , 46 , 47 ]. YjiC, an uncharacterized UDP-glucosyltransferase and OleI are the most similar GTs with 39% identical amino acids. OleI, TylCV (38% identity), OleD (34% identity) and Mgt (34% identity) are Macrolide glycosyltransferases. Sequence alignment is shown in Figure 8 . Similar amino acids are highlighted in grey, amino acids binding the sugar donor in OleI are marked with blue arrows, while amino acids binding the acceptor substrate in OleI are marked with turquoise arrows [ 42 ]. All homologous GTs belong to CAZy family 1. This family mainly consists of inverting GTs belonging to GT-B superfamily [ 9 ]. In contrast to GTs belonging to GT-A superfamily, GT-B-GTs do not contain a conserved DxD motif for coordination of divalent metal ions (usually Mg 2+ or Mn 2+ ) [ 11 ].
3. Discussion
Anthraquinones and their derivatives have diverse physiological and pharmacological properties including antibiotic, antifungal [ 48 ] and anticancer activities [ 49 , 50 ]. Saccharide moieties are, in many cases, essential for the biological activity of glycosylated secondary metabolites. Conjunctions of sugars usually result in improved activities or properties as, for example, better solubility, increased polarity, and improved chemical stability [ 51 ]. GTs, which catalyze the conjunction of a sugar moiety with an aglycon, are main enzymes for generating novel compounds with changed glycosylation patterns.
We aimed to find GTs that catalyze exceptional sugar attachment reactions. Therefore, we became interested in
Saccharopolyspora erythraea
. After feeding experiments with various types of anthraquinones, in silico analysis and knockout experiments, we identified Sace_3599 to be an
N
-GT from CAZy family 1. Further biotransformation experiments in
S. erythraea
, heterologous expression in
S. albus
Gluc and in vitro glycosylation assays pointed out that Sace_3599 catalyzes the formation of mono- and di-glucosylated derivatives of 1,4-Diaminoanthraquinone (U3). When U3 together with UDP-α-
d
-glucose as a sugar donor was used in in vitro experiments, the formation of
N
1
-β-glucosyl-1,4-diaminoanthraquinone was detected by UV spectra, mass spectrometry, and NMR data. This result indicates that Sace_3599 may be a GT with an inverting reaction mechanism as published by Lairson et al. [
11
], which was already proposed by CAZy database [
9
].
In vitro assays have also shown that Sace_3599 is more active at higher pH values and that the GT shows high selectivity towards the sugar donor. This was shown for GTs like OleD ( Streptomyces antibioticus ), Mgt ( Streptomyces lividans ) and others before [ 42 , 45 , 52 ]. When no divalent cations as cofactors were added, Sace_3599 was still active, which supports the assignment to the GT-B superfamily through the CAZy database [ 9 ]. When 1,4-Dihydroxyanthraquinone (U2) was used as substrate, two new, more hydrophilic peaks at retention times of 16.0 min (U2G) and 4.2 min (U2DG) appeared in HPLC/MS analysis which were not present in negative controls without Sace_3599. UV spectra and mass spectrometry indicated, that U2G is the mono-glucoside and U2DG is the di-glucoside of U2. This result leads to the assumption, that Sace_3599 is quite flexible towards the acceptor substrate and that Sace_3599 also functions as an O -GT. Other GTs have been published, which are also able to form different glycosidic bonds. This property makes them quite attractive for both research and industry. One example is the GT UGT71E5 from Carthamus tinctorius , which catalyzes the formation of N -, O - and S -glycosidic bonds [ 53 ]. To test the S -glycosylation activity of Sace_3599, in vitro assays with acceptor substrates like 7-Mercapto-4-methylcoumarin or 3,4-dichlorothiophenol could be carried out.
In order to test the glycohydrolase activity of Sace_3599, in vitro activity assays with UDP-[ 14 C]glucose were carried out following a protocol by Levanova et al. [ 54 ]. Since a lot more of free [ 14 C]glucose was detected in the assay-samples compared to the negative controls, Sace_3599 seems to have some glycohydrolase activity in addition to the glycosyltransferase activity. Although this result is not surprising it is worth mentioning that there are other GTs like lymphocyte surface or ecto-GTs which do not hydrolase the nucleotide sugars [ 55 ].
After feeding the “drug like” structure 1,4-U3 to bacterial strains expressing
sace_3599
, we interestingly observed the formation of the
N
1
-α-glucosylated derivative and the
N
1
-β-glucosylated derivative. The percentage ratios of the anomers varied, probably depending on the growth stages of the strains. Since there was no glycosylated U3 in biotransformation experiments with
S. erythraea
Δ
sace_3599
or
S. albus
Gluc detectable, Sace_3599 is the only GT in our Actinomycetes which glycosylates U3. Mutarotation, known from glucose, might be a reason for the difference in the configuration of the anomeric centre. As mutarotation cannot occur in nucleotide sugars such as UDP-
d
-glucose, the only possibility where mutarotation could take place would be in the products. Mutarotation of secondary amines has been reported before [
56
]. During our study, we could not observe epimerization of C-1 in the sugars in these compounds even after prolonged storage. Moreover, both ROESY- and EXSY-NMR show no exchange signals between the two components. Even at different temperatures (25–80 °C), the ratio between the two components did not change (
Supplementary Material, File 5
). These results lead us to the assumption that the α- and β-glucosylated derivatives are stable without the occurrence of mutarotation. Another explanation for the formation of both anomers might be the existence of an epimerase in both bacterial strains, that catalyzes the epimerization of the mono-glucosylated product (U3G) or, we believe, Sace_3599 might show substrate flexibility towards the sugar donor substrate and accept UDP-α-
d
-glucose as well as UDP-β-
d
-glucose.
4. Materials and Methods
4.1. Bacterial Strains and Growth Conditions
Saccharopolyspora erythraea NRRL 2338 [ 57 ], Streptomyces albus J1074 [ 58 ], and their mutants were cultivated on mannitol soya flour agar plates [ 59 ] containing 10 mM MgCl 2 or tryptic soya agar plates [ 60 ] at 28 °C for at least 48 h. The cultivation was carried out in tryptic soya broth (TSB) in double-baffled Erlenmeyer flasks with stainless steel spring at 28 °C and 180 rpm on a rotary shaking incubator for at least 48 h. For selection the medium was supplied with apramycin and spectinomycin to final concentrations of 100 µg/mL each. Escherichia coli Turbo was used for cloning, the strain ET12567 x pUZ8002 was used for the intergeneric conjugal transfer of non-methylated plasmid DNA from E. coli to the actinomycete recipient, and Rosetta™ 2 cells (41402 Novagen, Darmstadt, GER) were used as host for the heterologous expression of the Sace_3599 protein applying standard protocols [ 36 , 37 , 61 ]. The E. coli strains were grown on lysogeny broth (LB-Lennox) [ 62 , 63 ] agar plates at 37 °C or in LB-Lennox liquid medium at 20 °C to 37 °C, shaking at 180 rpm in baffled Erlenmeyer flasks. The media contained the appropriate selection antibiotic at a final concentration of 30 µg/mL kanamycin and 34 µg/mL chloramphenicol accordingly.
4.2. Plasmid Construction
Plasmids used in this study are listed in Table 1 . Primer sequences and cloning protocols for the generation of the plasmids are delineated in Supplementary Material (File 1) . All plasmids were confirmed by restriction endonuclease digestion and sequencing.
4.3. Whole-Cell Feeding Experiments
In order to determine the biotransformation abilities of the
S. erythraea
NRRL2338 WT as well as the mutants
S. albus
Gluc x pUWL-A-
sace_1884
,
S. albus
Gluc x pUWL-A-
sace_3599
, and
S. albus
Gluc x pUWL-A-
sace_4470
, feeding experiments were performed. A total of 100 mL of NL111 medium [
71
], containing the appropriate antibiotics, were inoculated with 1 mL of a 24-h-preculture of the respective actinomycete strain grown in TSB in a rotary shaking incubator at 28 °C and 180 rpm. After 36 h the culture was fed with 20 µL of test compound dissolved in dimethyl sulfoxide (DMSO) (0.1 M). The feeding procedure was performed five times in total at 12 h intervals. The culture was harvested (10 min, 1000 g) 7 days after inoculation and extracted with ethyl acetate in a ratio of 1:1 after adjustment to pH 7. The solvent was removed in vacuo. The received crude extract was analysed for biotransformation products by high-pressure liquid chromatography–mass spectrometry (HPLC-MS). 1,2-dihydroxyanthraquinone, 1,4-dihydroxyanthraquinone (U2), 1,4-diamino-anthraquinone (U3), 1,5-diaminoanthraquinone, 1-amino-2-methylanthraquinone, 1-amino-2-carboxyanthraquinone, 1-amino-2-chloroanthraquinone, and 1-amino-4-chloranthraquinone were used as test compounds.
4.4. Heterologous Test System
The plasmid pTOS-Gluc, containing the dTDP- d -glucose synthase gene oleS , was integrated into the genome of S. albus . Recombinant clones were isolated and used as host for transformation with pUWL-Dre capable of expressing the recombinase gene dre [ 61 ]. Expression of dre led to the marker-free mutant S. albus Gluc. This strain was used as host for transformation with sace_1884 , sace_3599 or sace_4470 , which have been cloned into pUWL-A before.
4.5. Inactivation of Sace_3599 in the Genome of S. erythraea
The GT gene
sace_3599
was inactivated by the insertion of a resistance-conferring gene via homologous recombination. For that reason, two homologous regions of approximately 1.7 kb, including either a part of the beginning or the end of the gene, were amplified and cloned into the suicide vector pKC1132. In the middle of the gene a spectinomycin resistance-conferring gene was cloned. The plasmid pKCΔ
sace_3599
was conjugally transferred from
E. coli
ET12567 x pUZ8002 into
S. erythraea
. Single-crossover mutants were obtained overlaying the conjugation with apramycin and spectinomycin. After 10–12 passages, in liquid medium with spectinomycin single colonies were picked both on apramycin- or spectinomycin-containing agar plates. The required double-crossover mutants were screened for the loss of apramycin resistance. PCR was used to prove the successful inactivation of
sace_3599
. In order to determine the biotransformation abilities of the resulting mutant feeding experiments were performed.
4.6. Complementation of S. erythraea Δsace_3599 with an Intact Copy of Sace_3599
The plasmid pTOS(z)- sace_3599 was conjugally transferred from E. coli ET12567 x pUZ8002 into S. erythraea Δ sace_3599 . Feeding experiments were performed using the resulting spectinomycin- and apramycin-resistant mutant.
4.7. Purification of Biotransformation Products
Novel compounds were isolated from the crude extracts for structure elucidation. After fractionation of the extracts using Oasis HLB columns (Waters, Eschborn, Germany) applying a methanol/water gradient, preparative thin-layer chromatography (silica gel 60 F 254 , Macherey-Nagel, Düren, Germany) was developed using acetonitrile-water-acetic acid (89.4:10.5:0.1) or dichloromethane-methanol-acetic acid (89.9:10.0:0.1) as solvent. In the last step, the biotransformation products were purified by gelfiltration on Sephadex LH20 column (GE Healthcare, Solingen, Germany) with methanol. After each purification step, the solvent was removed in vacuo.
4.8. Sample Analysis by HPLC-MS
For analysis the dried samples were dissolved in methanol. HPLC-MS analysis was performed using an Agilent 1100 series LC/MS system (Agilent Technologies, Santa Clara, USA) with electrospray ionization (ESI) and detection in positive and negative modes. The LC system contained a Zorbax Eclipse XDB-C8 column (5 µm particle size; 150 mm × 4.6 mm; Agilent Technologies, Santa Clara, CA, USA) and a Zorbax XDB-C8 precolumn (5 µm particle size; 12.5 mm × 4.6 mm; Agilent Technologies, Santa Clara, CA, USA), kept at 18 °C. Detection wavelengths/reference wavelengths of the diode array were 254/360, 480/800, 300/450, 430/600 and 550/700 nm. Solvent A (acetonitrile) and solvent B (acetic acid (0.5 %
v/v
) in water) were used in the following gradient: 80 to 67% solvent B (0 to 9 min), 67 to 50% solvent B (9 to 16 min), 50 to 30% solvent B (16 to 20 min), 30 to 5% solvent B (20 to 24 min), a hold at 5% solvent B (24 to 30 min) and a hold at 80% solvent B (30 to 35 min) at a flow rate of 0.5 mL/min.
4.9. Structure Elucidation Using NMR Spectroscopy
Nuclear Magnetic Resonance spectra (NMR) of U3G and U3DG isolated from in vitro experiments with Sace_3599 and in vivo feeding experiments with S. erythraea and S. albus Gluc x pUWL-A- sace_3599 were measured using a Varian VNMR-S 600MHz spectrometer equipped with 3 mm triple resonance inverse and 3 mm dual broadband probes. Pulse sequences were taken from Varian pulse sequence library. Spectra were recorded in 150 µL DMSO-d 6 at 35 °C. Variable temperature experiments were measured at 25, 35, 50, 65 and 80 °C in DMSO-d 6 . EXSY spectra were recorded using the NOESY pulse sequence with a mixing time of 3 s.
4.10. Separation of Mono-Glucosylated Products Using Capillary Electrophoresis
Capillary electrophoresis (CE) with U3G of extracts from S. erythraea and S. albus Gluc x pUWL-A- sace_3599 and the products of the in vitro reactions were performed. Therefore, a fused silica capillary with 40 cm effective length and 50 μm inner diameter was used. Running buffer consisted of 20 mM Borate, pH 9.3 with 50 mM SDS. Samples were injected at 100 mbar for 5 s. Separation voltage of 15 kV, temperature of 20 °C and UV detection at 254 nm were used.
4.11. Expression of Sace_3599 in E. coli and Purification of the Protein
For heterologous expression of
sace_3599
the plasmid pET28a-
sace_3599
-N-his
6
was constructed. Rosetta™ 2 cells (Novagen, Darmstadt, Germany) were used as host for the heterologous expression. For cells cultivated in lysogeny broth medium at 20 °C with shaking at 180 rpm in baffled Erlenmeyer flasks, optimal protein synthesis conditions were achieved. At an optical density of OD
600
= 0.5–0.7, overexpression of
sace_3599
was induced by addition of 0.1 mM isopropyl-β-
d
-thiogalactopyranoside (IPTG). The cells were cultivated at 20 °C for 20 h and harvested by centrifugation at 14,500×
g
for 20 min.
Rosetta™ 2 cells containing the plasmid pET28a-
sace_3599
-N-his
6
were resuspended in elution buffer A (50 mM TRIS-HCl pH 8.0, 300 mM NaCl, 10 mM MgCl
2
, 10 mM imidazole) and incubated with lysozyme and DNase I on ice for 30 min. The cells were mechanically disrupted using a French press (Thermo Spectronic, Rochester, NY, USA). Subsequently, the cytosolic fraction was cleared of cellular debris by centrifugation (18,500×
g
, 20 min, 4 °C) and the protein Sace_3599 was purified by immobilized-metal affinity chromatography (IMAC) with nickel-nitrilotriacetic acid (Ni
2+
-NTA). Therefore, a 5 mL HisTrap FF column (GE Healthcare, Solingen, Germany), pre-equilibrated with elution buffer A, was loaded with the supernatant. Following extensive washing with 15% elution buffer B (50 mM TRIS-HCl pH 8.0, 300 mM NaCl, 10 mM MgCl
2
, 500 mM imidazole), 50% elution buffer B was used for the elution of the protein. Fractions containing Sace_3599 were collected and instantly concentrated to a final volume of 2.0 mL by centrifugation using a Vivaspin 20 concentrator (Sartorius Stedim Biotech, Göttingen, Germany) with a molecular mass cut-off size of 30 kDa. As a last purification step, gel filtration was performed on a size exclusion Superdex 200 10/300 GL column (GE Healthcare, Solingen, Germany), pre-equilibrated with gelfiltration buffer (25 mM TRIS-HCl pH 8.0, 300 mM NaCl, 10% [mass/vol] glycerol). Fractions containing Sace_3599 were collected, concentrated and instantly used for in vitro assays. The protein concentration was determined by measurement of the UV absorption at 280 nm.
4.12. In Vitro Glycosylation Activity Assay
The enzyme assays used for
N
- and
O
-Glycosyltransferase activity determination are based upon the transfer of the glucose moiety of an activated sugar donor to an acceptor catalyzed by recombinant Sace_3599 and resulting in glycosylated products. In vitro activity assays, with a final volume of 50–500 µL, were conducted at different temperatures and incubation times. Therefore, 50 µM of Sace_3599 was added to the incubation mixture containing an anthraquinone as substrate (0.1 mM), buffer (0.25 M), BSA (0.5 mg/mL), metal ions (5 mM), and a sugar donor (2 mM). A negative control without enzyme was included. After a defined incubation time and temperature, the reaction was stopped by addition of an equal volume of ethyl acetate twice. The organic phases were subsequently removed. Phases from the same reaction tubes were combined and dried in vacuo. The synthesised derivatives were analysed by HPLC-MS (see
Section 4.8
) and/or NMR spectroscopy (see
Section 4.9
).
4.12.1. Variation of Time and Temperature
In vitro activity assays with U3, TRIS buffer (0.25 M; pH 8.8), MgCl 2 (5 mM), UDP-α- d -glucose (2 mM) and a final volume of 50 µL were conducted at 20, 28 or 37 °C. After 1, 1.5, 2, 3 and 22 h reaction was stopped and the extracts were analysed as described in Section 4.12 .
4.12.2. Variation of Sugar Donor
In vitro activity assays with U3, TRIS buffer (0.25 M; pH 8.8), MgCl 2 (5 mM), either UDP-α- d -glucose (2 mM) or UDP-α- d -galactose (2 mM) or TDP-α- d -glucose (2 mM) and a final volume of 50 µL were conducted at 28 °C for 22 h. The reaction was stopped and the extracts were analysed as described in Section 4.12 .
4.12.3. Variation of Buffer
In vitro activity assays with U3, either Citric Acid (0.25 M; pH 5.0) or PBS buffer (0.25 M; pH 6.2 or pH 6.7 or pH 7.2 or pH 7.7 or pH 8.2) or HEPES buffer (0.25 M; pH 7.0) or TRIS buffer (0.25 M; pH 7.0) or TRIS buffer (0.25 M; pH 8.8), MgCl 2 (5 mM), UDP-α- d -glucose (2 mM) and a final volume of 50 µL were conducted at 28 °C for 22 h. The reaction was stopped and the extracts were analysed as described in Section 4.12 .
4.12.4. Variation of Metal Ions as Putative Cofactors
Before using the purified Sace_3599 the enzyme solution was treated with 10 mM EDTA for 1 h at room temperature. Afterwards EDTA was removed by PD-10-columns (GE-Healthcare, Solingen, Germany). In vitro activity assays with U3, TRIS buffer (0.5 M; pH 8.8), either CaCl 2 (5 mM) or CoCl 2 (5 mM) or MgCl 2 (5 mM) or MnCl 2 (5 mM), or ZnCl 2 (5 mM) or no metal ion, UDP-α- d -glucose (2 mM) and a final volume of 50 µL were conducted at 28 °C for 22 h. The reaction was stopped and the extracts were analysed as described in Section 4.12 .
4.12.5. Variation of Substrate
In vitro activity assays with either U2 or U3, TRIS buffer (0.25 M; pH 8.8), MgCl 2 (5 mM), UDP-α- d -glucose (2 mM) and a final volume of 50 µL were conducted at 28 °C. After 22 h reaction was stopped and the extracts were analysed as described in Section 4.12 .
4.12.6. Calculation of Conversion of Substrate to Glucosylated Product
Peaks of the mono-glucosylated products (
UG
), di-glucosylated products (
UDG
) and the substrate (
U
) of the HPLC-chromatograms of the crude extracts at detection wavelengths of 254/360 nm (wavelength/reference) were integrated. The percentage of conversion of
U
to
UG
was calculated with the help of the areas under curve (
AUC
) and the following formula:
U
G
[
%
]
=
A
U
C
[
U
G
]
×
(1)
The percentage of conversion of
U
to
UDG
was calculated with the following formula:
U
D
G
[
%
]
=
A
U
C
[
U
D
G
]
C
4.13. In Vitro Glycohydrolase Assay
To monitor hydrolysis of UDP-glucose by Sace_3599, different in vitro assays with a final volume of 10 µL have been performed. Sace_3599 (50 µM) was incubated at 28 °C with 10 µM UDP-[ 14 C]glucose in PBS buffer (0.25 M; pH 8.2) for up to 22 h. After 1, 2 and 22 h samples of 1 µL were subjected to PEI (polyethyleneimine)-cellulose thin layer chromatography (Merck, Darmstadt, GER). LiCl (0.2 mM) was used as mobile phase to separate the hydrolysed [ 14 C]glucose from the intact UDP-[ 14 C]glucose. After running the samples for 12 min, the plates were dried and analysed with phosphorimager (Typhoon FLA 7000, GE Healthcare Europe, Freiburg, Germany). Quantification was performed using Multi Gauge V3.0 software.
5. Conclusions
We identified the new, very flexible GT Sace_3599 of Saccharopolyspora erythraea NRRL2338 which, in biotransformation experiments, led to α- and β-glucosylated derivatives. We showed that Sace_3599, which belongs to the inverting glycosyltransferases, is able to glucosylate aromatic amines and aromatic alcohols.
Supplementary Materials
The following are available online: File 1: Construction of plasmids, File 2: NMR data for structure elucidation of U3G, Table S1: NMR data of U3G
1
(600/150 MHz (DMSO-d
6
. 35 °C), Figure S1:
1
H NMR spectrum of U3G
1
(600 MHz, DMSO-d
6
, 35 °C), Figure S2:
13
C NMR spectrum of U3G
1
, 35 °C), Figure S3: COSY NMR spectrum of U3G
1
(600 MHz, DMSO-d
6
, 35 °C), Figure S4: HSQC NMR spectrum of U3G
1
(600 MHz, DMSO-d
6
, 35 °C), Figure S5: HMBC NMR spectrum of U3G
1
(600 MHz, DMSO-d
6
, 35 °C), Figure S6: TOCSY NMR spectrum of U3G
1
(600 MHz, DMSO-d
6
, 35 °C), Figure S7: 1D TOCSY NMR spectrum of U3G
1
(600 MHz, DMSO-d
6
, 35 °C, sel. excitation of 1′-H), Figure S8: ROESY NMR spectrum of U3G
1
6
, 35 °C, sel. excitation of 1′-H), Table S2: NMR data of U3G
2
(600/150 MHz (DMSO-d
6
. 35 °C), Figure S9:
1
H NMR spectrum of U3G
2
(600 MHz, DMSO-d
6
, 35 °C), Figure S10:
13
C NMR spectrum of U3G
2
(150 MHz, DMSO-d
6
, 35 °C), Figure S11: COSY NMR spectrum of U3G
2
(600 MHz, DMSO-d
6
, 35 °C), Figure S12: HSQC NMR spectrum of U3G
2
(600 MHz, DMSO-d
6
, 35 °C), Figure S13: HMBC NMR spectrum of U3G
2
(600 MHz, DMSO-d
6
, 35 °C), Figure S14: TOCSY NMR spectrum of U3G
2
(600 MHz, DMSO-d
6
, 35 °C), Figure S15: 1D TOCSY NMR spectrum of U3G
2
(600 MHz, DMSO-d
6
, 35 °C, sel. excitation of 1′-H), Figure S16: ROESY NMR spectrum of U3G
2
(600 MHz, DMSO-d
6
, 35 °C), File 3: Protein purification of Sace_3599, Figure S17: Protein purification, File 4: Factors affecting the biotransformation activity of Sace_3599, Figure S18: Factors affecting the biotransformation activity, File 5: NMR-data eliminating mutarotation/epimerization in U3G, Figure S19: Expansion of NH region of
1
H spectra NMR of U3G
1
(600 MHz, DMSO-d
6
) at different temperatures, Figure S20: Expansion of NH region of
1
H spectra NMR of U3G
1
after sample preparation and 4 weeks later (600 MHz, DMSO-d
6
), Figure S21: Expansion of NH region of
1
H spectra NMR of U3G
2
(600 MHz, DMSO-d
6
) at different temperatures, Figure S22: Expansion of NH region of
1
H spectra NMR of U3G
2
after sample preparation and 4 weeks later (600 MHz, DMSO-d
6
), Figure S23: EXSY NMR of U3G
2
(600MHz, DMSO-d
6
, 35 °C).
Author Contributions
Conceptualization, F.G., Y.-I.S.-B. and A.B.; methodology, F.G., Y.-I.S.-B., T.S., D.Q. and T.P.; software, F.G. and Y.-I.S.-B.; investigation, F.G., Y.-I.S.-B., T.S., D.Q., T.P.; resources, T.P., H.J. and A.B.; writing—original draft preparation, F.G. and A.B.; writing—review and editing, F.G. and A.B.; project administration, A.B.; funding acquisition, A.B. All authors have read and agreed to the published version of the manuscript.
Funding
This research was supported by the Deutsche Forschungsgemeinschaft (DFG)-RTG 1976 (Functional Diversity of Cofactors in Enzymes)/235777276.
Acknowledgments
We thank Mohamed A. Marahiel from the Philipps University in Marburg for providing the Saccharopolyspora erythraea NRRL2338 strain.
Conflicts of Interest
The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds are available from the authors.
Figure 1. ( a ) HPLC chromatograms (λ = 254 nm) of ( I ) crude extract of S. erythraea fed with U3; ( II ) U3; ( III ) purified biotransformation products U3G and ( IV ) U3DG; ( V ) crude extract of S. erythraea Δ sace_3599 fed with U3; ( VI ) crude extract of S. erythraea Δ sace_3599 x pTOS(z)- sace_3599 fed with U3; ( VII ) crude extract of S. albus Gluc fed with U3; ( VIII ) crude extract of S. albus Gluc x pUWL-A- sace_3599 fed with U3. ( b ) UV-spectra of U3 (grey); U3G (turquoise) and U3DG (blue). ( c ) Mass spectra (ESI-) of U3G at 11.7 min retention time and U3DG at 4.2 min.
Figure 1. ( a ) HPLC chromatograms (λ = 254 nm) of ( I ) crude extract of S. erythraea fed with U3; ( II ) U3; ( III ) purified biotransformation products U3G and ( IV ) U3DG; ( V ) crude extract of S. erythraea Δ sace_3599 fed with U3; ( VI ) crude extract of S. erythraea Δ sace_3599 x pTOS(z)- sace_3599 fed with U3; ( VII ) crude extract of S. albus Gluc fed with U3; ( VIII ) crude extract of S. albus Gluc x pUWL-A- sace_3599 fed with U3. ( b ) UV-spectra of U3 (grey); U3G (turquoise) and U3DG (blue). ( c ) Mass spectra (ESI-) of U3G at 11.7 min retention time and U3DG at 4.2 min.
Figure 2. Chemical structures and masses of the substrate U3 and the corresponding mono- and di-glucosylated biotransformation products U3G and U3DG. Glycosylations are catalyzed by Sace_3599.
Figure 2. Chemical structures and masses of the substrate U3 and the corresponding mono- and di-glucosylated biotransformation products U3G and U3DG. Glycosylations are catalyzed by Sace_3599.
Figure 3. Capillary electrophoresis of U3G with separated α- and β-anomer.
Figure 3. Capillary electrophoresis of U3G with separated α- and β-anomer.
Figure 4. ( a ) HPLC chromatograms (λ = 254 nm) of the in vitro glycosylation activity assay with U3 and either ( I ) TDP-α- d -glucose; ( II ) UDP-α- d -galactose or ( III ) UDP-α- d -glucose used as a sugar donor. ( b ) Corresponding percentages of U3 and glycosylated products U3G and U3DG after 22 h at 28 °C. Mean values and standard deviations of three independent experiments are indicated.
Figure 4. ( a ) HPLC chromatograms (λ = 254 nm) of the in vitro glycosylation activity assay with U3 and either ( I ) TDP-α- d -glucose; ( II ) UDP-α- d -galactose or ( III ) UDP-α- d -glucose used as a sugar donor. ( b ) Corresponding percentages of U3 and glycosylated products U3G and U3DG after 22 h at 28 °C. Mean values and standard deviations of three independent experiments are indicated.
Figure 5. ( a ) Chemical structures and masses of the substrate U2 and the corresponding mono- and di-glucosylated biotransformation products U2G and U2DG. The glycosylations are catalyzed by Sace_3599. ( b ) HPLC chromatogram (λ = 254 nm) of the in vitro glycosylation activity assay ( I ) with U2 and UDP-α- d -glucose in comparison to negative control ( II ) without Sace_3599. ( c ) UV-spectra of U2 at retention time of 29.3 min (grey); U2G at 16.0 min (turquoise) and U2DG at 4.2 min (blue). ( d ) Mass spectra (ESI-) of U2G at 16.0 min retention time and U2DG at 4.2 min.
Figure 5. ( a ) Chemical structures and masses of the substrate U2 and the corresponding mono- and di-glucosylated biotransformation products U2G and U2DG. The glycosylations are catalyzed by Sace_3599. ( b ) HPLC chromatogram (λ = 254 nm) of the in vitro glycosylation activity assay ( I ) with U2 and UDP-α- d -glucose in comparison to negative control ( II ) without Sace_3599. ( c ) UV-spectra of U2 at retention time of 29.3 min (grey); U2G at 16.0 min (turquoise) and U2DG at 4.2 min (blue). ( d ) Mass spectra (ESI-) of U2G at 16.0 min retention time and U2DG at 4.2 min.
Figure 6. Phosphorimager picture of thin layer chromatography plate of glycohydrolase assays with Sace_3599 after 1, 2 and 22 h in contrast to negative controls (nc) without Sace_3599. A lot more free [ 14 C]glucose was detected in assay-samples with Sace_3599 than in nc.
Figure 6. Phosphorimager picture of thin layer chromatography plate of glycohydrolase assays with Sace_3599 after 1, 2 and 22 h in contrast to negative controls (nc) without Sace_3599. A lot more free [ 14 C]glucose was detected in assay-samples with Sace_3599 than in nc.
Figure 7. Region around the glycosyltransferase gene sace_3599 in the genome of S. erythraea : ag-at , aminoglycoside N3′ acetyltransferase genes; cII-ald , gene encoding for class II aldolase; en-phos , gene encoding for an enolase phosphatase; hp , genes encoding for hypothetical proteins; meth-ap , methionine aminopeptidase gene; ox , oxidase gene; pe-pgrs , gene encoding a polymorphic GC-repetitive sequence family protein; xre-reg , gene encoding for transcriptional Xenobiotic Response Element regulator; sace_3599 , gene encoding for glycosyltransferase.
Figure 7. Region around the glycosyltransferase gene sace_3599 in the genome of S. erythraea : ag-at , aminoglycoside N3′ acetyltransferase genes; cII-ald , gene encoding for class II aldolase; en-phos , gene encoding for an enolase phosphatase; hp , genes encoding for hypothetical proteins; meth-ap , methionine aminopeptidase gene; ox , oxidase gene; pe-pgrs , gene encoding a polymorphic GC-repetitive sequence family protein; xre-reg , gene encoding for transcriptional Xenobiotic Response Element regulator; sace_3599 , gene encoding for glycosyltransferase.
Figure 8. Sequence alignment of Sace_3599 and homologous proteins with similar amino acids colored in grey. Sugar donor binding amino acids (blue) and acceptor substrate binding amino acids (turquoise) of OleI are marked with arrows [ 42 ].
Figure 8. Sequence alignment of Sace_3599 and homologous proteins with similar amino acids colored in grey. Sugar donor binding amino acids (blue) and acceptor substrate binding amino acids (turquoise) of OleI are marked with arrows [ 42 ].
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HOTEL AUDRESSELLES : Hotels near Audresselles 62164 France
HOTEL AUDRESSELLES : Find the best hotel among all the hotels near Audresselles and BOOK NOW for your trip in France ! 62164 Pas-de-Calais
Hotel Audresselles
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Hotel Audresselles
Hotel Audresselles
Audresselles
Here is the list of the hotels near Audresselles. Book your hotel near Audresselles today, Monday 26 June for the best price, reservation and cancellation free of charge thanks to our partner Booking.com, leader in on-line hotels reservation. To help you find available hotels, you can follow these links to check the list of hotels in nearby towns of Audresselles : - hotels of Ambleteuse (62164) : town located at 1.85 km - hotels of Audinghen (62179) : town located at 3.38 km - hotels of Bazinghen (62250) : town located at 4.79 km - hotels of Tardinghen (62179) : town located at 5.42 km - hotels of Beuvrequen (62250) : town located at 5.57 km - hotels of Wimereux (62930) : town located at 6.23 km - hotels of Wacquinghen (62250) : town located at 6.84 km - hotels of Wimille (62126) : town located at 7.30 km - hotels of Marquise (62250) : town located at 8.05 km - hotels of Audembert (62250) : town located at 8.09 km - hotels of Maninghen-Henne (62250) : town located at 8.16 km To help you choose your destination as well as the place of the hotel here is: - pictures of Audresselles : photo Audresselles - the map of Audresselles : map Audresselles - the road map of Audresselles : road map Audresselles Below here is the list the 50 closest hotels of Audresselles, sortable according your criteria. You will find the position of these accommodations on the Audresselles hotels map . Share the hotels list of Audresselles ! Search Hotels Book now, Best Price Guaranteed ! Where ? Audresselles Check-in date 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 June 2023 July 2023 August 2023 September 2023 October 2023 November 2023 December 2023 January 2024 February 2024 March 2024 April 2024 May 2024 _link_ Check-out date 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 June 2023 July 2023 August 2023 September 2023 October 2023 November 2023 December 2023 January 2024 February 2024 March 2024 April 2024 May 2024 _link_ on I have no specific dates Search
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Villa Audresselles Guest accommodation Ambleteuse
Guest accommodation Audresselles :
134 Rue Edouard Quenu (Audresselles) 62164 Ambleteuse
Address :
1250 Hameau d'Haringzelle 62179 Audinghen
Distance on map, Hotel - Audresselles : 1.54 kilometers
Number of room :
3
SOURIRE D'AVRIL Guest accommodation Ambleteuse
Situated in Ambleteuse in the Nord-Pas-de-Calais region, SOURIRE D'AVRIL features a terrace. The accommodation is 50 km from Le Touquet-Paris-Plage. Offering direct access to a balcony with sea views, the holiday home consists of 4 bedrooms and a fully equipped kitchen. A flat-screen TV with cable channels is featured. Calais is 29 km from the holiday home, while Boulogne-sur-Mer is 13 km away. The nearest airport is Le Touquet Opal Coast Airport, 47 km from SOURIRE D'AVRIL.
Guest accommodation Audresselles :
Location :
rue de Lille 44 62164 Ambleteuse
Route on map, Hotel - Audresselles : 1.80 kilometer
Number of rooms :
1
La marine D'opale Apartment Ambleteuse
Set in Ambleteuse, La marine D'opale features free WiFi and units equipped with a kitchen, terrace and seating area. All units are equipped with a microwave, toaster, a coffee machine, a fridge and kettle. Some units include a dining area and/or a balcony. The property has a fitness centre. If you would like to discover the area, fishing is possible in the surroundings. Le Touquet-Paris-Plage is 49 km from the apartment, while Calais is 29 km from the property. The nearest airport is Le Touquet Opal Coast Airport, 46 km from the property.
Price :
from
49.00 €
to
125.00 €
Apartment Audresselles :
Address :
2 rue marechal foch 62164 Ambleteuse
Distance on map between hotel and center of Audresselles : 1.81 km
Room in hotel :
12
Villa Beau Sejour Guest accommodation Ambleteuse
Featuring a garden, VILLA BEAU SEJOUR is a semi-detached holiday home situated in Ambleteuse. The unit is 32 km from Le Touquet-Paris-Plage, and guests benefit from free WiFi and private parking available on site. A dishwasher, an oven and a microwave can be found in the kitchen. A flat-screen TV is provided. Other facilities at VILLA BEAU SEJOUR include a barbecue. The area is popular for golfing and horse riding. Calais is 24 km from VILLA BEAU SEJOUR, while Boulogne-sur-Mer is 9 km from the property. The area is popular for fishing and hiking.
Prices :
from
150.00 €
Guest accommodation Audresselles :
Location :
32 Boulevard de la Liberte 62164 Ambleteuse
Distance between hotel and center of Audresselles : 1.84 kms
Rooms in hotel :
1
Aparthotel Des 2 Caps Apartment Ambleteuse
Aparthotel Des 2 Caps is located in Ambleteuse, 32 km from Le Touquet-Paris-Plage. Calais is 24 km away. Free WiFi is offered . All units include a seating area. There is also a kitchen, equipped with a microwave, toaster and fridge. A stovetop is also available, as well as a coffee machine and a kettle. There is a private bathroom with a shower and free toiletries in every unit. Towels and bed linen are provided. Aparthotel Des 2 Caps also includes a sun terrace. Guests can enjoy a meal at the on-site restaurant. Boulogne-sur-Mer is 9 km from Aparthotel Des 2 Caps, while Dover is 41 km from the property. Free private parking is available on site.
Rate :
from
89.00 €
to
125.00 €
Apartment Audresselles :
Address :
2 Rue Marechal Foch 62164 Ambleteuse
Distance on map, Hotel - Audresselles : 1.85 kilometers
Number of room :
3
Chez Jules Apartment Ambleteuse
Located in the village of Ambleteuse Chez Jules offers accommodation with panoramic views of the sea and free WiFi throughout the property. The 2-bedroomed apartment features a dining area and a fully-equipped kitchen complete with a dishwasher, oven and microwave. The lounge includes a flat-screen TV, DVD player and board games for guests' use. There is a private bathroom with a shower. Calais is 25 km from Chez Jules, while Boulogne-sur-Mer is 9 km away. Guests can enjoy various activities in the surroundings, including cycling and fishing.
Apartment Audresselles :
Location :
2 RUE JEANNE D'ARC 62164 Ambleteuse
Route on map, Hotel - Audresselles : 1.86 kilometer
Number of rooms :
1
Hôtel Des Argousiers Hotel Ambleteuse
The hotel features contemporary and nature-friendly design and offers cosy accommodation in quiet surroundings only a kilometre away from Ambleteuse’s beach. Located right in the centre of the Opal Coast, which stretches from Berck to the edge of the Belgian Flanders, Hôtel Des Argousiers is close to the sea and near some of the typical coastal scenery of the Channel. Hôtel Des Argousiers welcomes you all year round in the Pas-de-Calais natural park.
Prices :
from
79.00 €
to
89.00 €
Hotel Audresselles :
Address :
28 Rue Clémenceau 62164 Ambleteuse
Distance on map between hotel and center of Audresselles : 1.89 km
Room in hotel :
15
665 rue principale 62179 Audinghen
Route on map, Hotel - Audresselles : 3.61 kilometer
Number of rooms :
gites de Warincthun Guest accommodation Audinghen
Price :
63.25 €
172.50 €
Guest accommodation of Audresselles or nearby towns :
Address :
hameau de warincthun 62179 Audinghen
Distance on map between hotel and center of Audresselles : 4.29 km
Room in hotel :
Les Dunes Guest accommodation Wimereux
Les Dunes is located in Wimereux. This holiday home offers accommodation with a terrace. This holiday home comes with 1 bedroom, a TV, and a kitchen with a dishwasher. The holiday home offers a barbecue. A children's playground is available for guests at Les Dunes Wimereux to use. Le Touquet-Paris-Plage is 45 km from the accommodation, while Calais is 32 km away. Le Touquet Opal Coast Airport is 42 km from the property.
Guest accommodation of Audresselles or nearby municipalities :
Location :
62930 Wimereux
Distance between hotel and center of Audresselles : 4.65 kms
Rooms in hotel :
Hameau 504 Guest accommodation Wimereux
Hameau 504 is situated in Wimereux and offers water sports facilities and barbecue facilities. The accommodation features free WiFi. This holiday home comes with a seating area, a kitchen with an oven, and a TV. The holiday home offers a terrace. Guests at this property can enjoy horse riding nearby, or make the most of the garden. Le Touquet-Paris-Plage is 45 km from Hameau 504. Le Touquet Opal Coast Airport is 42 km away.
Guest accommodation of Audresselles or nearby towns :
Address :
62930 Wimereux
Distance on map, Hotel - Audresselles : 4.82 kilometers
Domaine de la Ronville Bed and Breakfast Wimereux
15 rue George Guynemer 62930 Wimereux
Distance on map between hotel and center of Audresselles : 5.14 km
Room in hotel :
Cap Gris Nez face mer appartement Apartment Audinghen
Apartment of Audresselles or nearby municipalities :
Location :
379 Route de la Plage 62179 Audinghen
Distance between hotel and center of Audresselles : 5.17 kms
Rooms in hotel :
L'inattendu Bed and Breakfast Wimereux
Bed and Breakfast of Audresselles or nearby towns :
Address :
57 rue jean moulin 62930 Wimereux
Distance on map, Hotel - Audresselles : 5.42 kilometers
Les Toiles de Mer Apartment Wimereux
Set in Wimereux, Les Toiles de Mer features accommodation with a seating area and flat-screen TV. All units include a fully equipped kitchen, allowing guests to prepare their own meals. An oven and coffee machine are also provided. Le Touquet-Paris-Plage is 44 km from the apartment, while Calais is 32 km away. The nearest airport is Le Touquet Opal Coast Airport, 41 km from Les Toiles de Mer.
Apartment of Audresselles or nearby towns :
Address :
3 rue du stade 62930 Wimereux
Distance on map between hotel and center of Audresselles : 5.77 km
Room in hotel :
Maison cozy Wimereux Guest accommodation Wimereux
Guest accommodation of Audresselles or nearby municipalities :
Location :
62 Rue René Cassin 62930 Wimereux
Distance between hotel and center of Audresselles : 5.80 kms
Gite Opaline Guest accommodation Wimereux
Situated in Wimereux in the Nord-Pas-de-Calais Region, this holiday home is just 300 metres from the beach. You can enjoy the south-facing terrace and Le Touquet-Paris-Plage is just 29 km away. With a contemporary décor, the 2-bedroom house is set on 2 levels. It features a living room with open-plan kitchen and dining area. The property is 26 km from Calais and free private parking is available. Boulogne-sur-Mer is 6 km from Gite Opaline, while Dover is 46 km away.
Guest accommodation of Audresselles or nearby towns :
Address :
6 Allée Alfred Capillier - Cottage C6 62930 Wimereux
Distance on map, Hotel - Audresselles : 5.91 kilometers
Le Réservoir Guest accommodation Wimereux
Le Réservoir is situated in Wimereux, just 1 km from Wimille Wimereux Train Station and 6 km from Boulogne-sur-Mer. This holiday home provides a wooden terrace as well as free WiFi. This 2-bedroom holiday home comes with a kitchen, a seating area, and a cable flat-screen TV. If you would like to discover the area, cycling is possible in the surroundings. Le Touquet-Paris-Plage is 42 km from Le Réservoir. The nearest airport is Le Touquet Opal Coast Airport, 41 km from the accommodation.
Guest accommodation of Audresselles or nearby municipalities :
One-Bedroom Apartment in Wimereux Apartment Wimereux
One-Bedroom Apartment in Wimereux is situated in Wimereux. The apartment features sea views and is 44 km from Le Touquet-Paris-Plage. The apartment has a TV and 1 bedroom. A dishwasher, a fridge and a stovetop can be found in the kitchen. Calais is 32 km from the apartment, while Boulogne-sur-Mer is 7 km from the property. The nearest airport is Le Touquet Opal Coast Airport, 40 km from One-Bedroom Apartment in Wimereux.
Apartment of Audresselles or nearby towns :
Address :
62930 Wimereux
Distance on map between hotel and center of Audresselles : 5.95 km
Location Wimereux Apartment Wimereux
Gîte 1908 Guest accommodation Wimereux
les pieds dans l'eau Apartment Wimereux
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Caldas C, Hahn SA, Hruban RH, Redston MS, Yeo CJ, Kern SEDetection of K-ras mutations in the stool of patients with pancreatic adenocarcinoma and pancreatic ductal hyperplasia. Cancer Res 54: 3568-3573 | Request PDF
Request PDF | Caldas C, Hahn SA, Hruban RH, Redston MS, Yeo CJ, Kern SEDetection of K-ras mutations in the stool of patients with pancreatic adenocarcinoma and pancreatic ductal hyperplasia. Cancer Res 54: 3568-3573 | Pancreatic adenocarcinoma is the fifth leading cause of cancer death in the United States. Mutations in the K-ras oncogene occur in 85% of... | Find, read and cite all the research you need on ResearchGate
Caldas C, Hahn SA, Hruban RH, Redston MS, Yeo CJ, Kern SEDetection of K-ras mutations in the stool of patients with pancreatic adenocarcinoma and pancreatic ductal hyperplasia. Cancer Res 54: 3568-3573
Cancer Research 54(13):3568-73
Authors:
C Caldas
C Caldas
Ruhr-Universität Bochum
R H Hruban
R H Hruban
M S Redston
M S Redston
Abstract
Pancreatic adenocarcinoma is the fifth leading cause of cancer death in the United States. Mutations in the K-ras oncogene occur in 85% of pancreatic adenocarcinomas and have also been identified in 75% of pancreatic ducts with mucinous cell hyperplasia seen in association with chronic pancreatitis. We identified K-ras mutations in 65% of duct lesions associated not only with chronic pancreatitis but also with pancreatic adenocarcinoma and distal common bile duct carcinoma (cholangiocarcinoma). These observations make K-ras a potential candidate for a gene-based diagnostic test. Indeed, K-ras mutations have been demonstrated in the pancreatic secretions of patients with pancreatic carcinoma and pancreatic intraductal neoplasia. We analyzed stool specimens for mutated K-ras sequences using a plaque hybridization assay in patients with pancreatic adenocarcinoma, cholangiocarcinoma, and chronic pancreatitis. K-ras mutations were detected in stool specimens from 6 of 11 patients with pancreatic adenocarcinoma, from 2 of 3 patients with cholangiocarcinoma, and from 1 of 3 patients with chronic pancreatitis. The K-ras mutations found in stool specimens from patients with pancreatic carcinoma were identical to those in the primary cancer in five cases. Mutations found in the stool specimens from one patient with pancreatic cancer, one patient with chronic pancreatitis, and two patients with cholangiocarcinoma were the same as those identified in pancreatic ductal mucinous cell hyperplasia lesions present in the resected pancreas specimens. Our data suggest that the K-ras mutations originating from cells of pancreatic adenocarcinomas and from cells shed by abnormal pancreatic duct epithelium can be detected in the stool. These results support the further exploration of stool K-ras analysis as a potential screening assay for the early detection of pancreatic adenocarcinoma and precursor lesions such as pancreatic ductal mucinous cell hyperplasia.
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... Researchers first detected KRAS oncogenic mutations in the blood cf-DNA of patients with pancreatic cancer in 1994 by using PCR, which was consistent with that detected in tumor tissues. In other words, the small part of cf-DNA carrying tumor-specific mutations is indeed released by tumor cells
[110]
. Thus, tumor-associated mutations in cf-DNA can serve as tumor-specific markers, and these tumor-derived cf-DNA fragments carrying tumor characteristics are referred to as ctDNA [110,111] . ...
... In other words, the small part of cf-DNA carrying tumor-specific mutations is indeed released by tumor cells [110] . Thus, tumor-associated mutations in cf-DNA can serve as tumor-specific markers, and these tumor-derived cf-DNA fragments carrying tumor characteristics are referred to as ctDNA
[110,
111] . ctDNA is DNA fragments released by apoptotic or necrotic cells into the blood vessels, and is mainly present in extracellular plasma [112] . ...
Blood-based biomarkers for early detection of esophageal squamous cell carcinoma
Article
Full-text available
Apr 2020
WORLD J GASTROENTERO
Ling-Yu Chu
Yu-Hui Peng
Xue-Fen Weng
Yi-Wei Xu
Esophageal squamous cell carcinoma (ESCC) is a common malignant tumor of the digestive system worldwide, especially in China. Due to the lack of effective early detection methods, ESCC patients often present at an advanced stage at the time of diagnosis, which seriously affects the prognosis of patients. At present, early detection of ESCC mainly depends on invasive and expensive endoscopy and histopathological biopsy. Therefore, there is an unmet need for a non-invasive method to detect ESCC in the early stages. With the emergence of a large class of non-invasive diagnostic tools, serum tumor markers have attracted much attention because of their potential for detection of early tumors. Therefore, the identification of serum tumor markers for early detection of ESCC is undoubtedly one of the most effective ways to achieve early diagnosis and treatment of ESCC. This article reviews the recent advances in the discovery of blood-based ESCC biomarkers, and discusses the origins, clinical applications, and technical challenges of clinical validation of various types of biomarkers.
... After Almoguera et al. (1988) reported a high prevalence of mutations in codon 12 of Ki-ras in EPC, about 50 reports have described Ki-ras mutations in this tumor, with prevalence ranging from 47% (Tabata et al., 1993) to 100% (Tada et al., 1990;
Caldas et al., 1994)
. The basis for such variation is unclear, and individual studies are not strictly comparable due to significant differences in strategies used to select patients, number of cases studied, type of sample analyzed, and mutation-detection techniques. ...
... Because there is currently no technique available for detecting Ki-ras mutations in situ, microdissection will be necessary to establish whether both mutations occur in the same cell population or not. Other authors have described more than one mutation in samples from the same individual with EPC (Grünewald et al., 1989;Mariyama et al., 1989;Nagata et al., 1990;Motojima et al., 1993;Schaeffer et al., 1994;
Caldas et al., 1994;
Iguchi et al., 1996), but this pattern appears to be more prevalent in our series. In this regard, it is noteworthy that a Val substitution was identified in the 5 cases with a bi-mutational pattern. ...
Ki‐ras mutations in exocrine pancreatic cancer: Association with clinico‐pathological characteristics and with tobacco and alcohol consumption
Article
Mar 1997
INT J CANCER
Núria Malats
Miquel Porta
Josep M Corominas
Francisco X. Real
The aims of this study were (i) to assess the prevalence and spectrum of codon 12 Ki‐ras mutations in patients diagnosed with exocrine pancreatic cancer (EPC) in 2 general hospitals between 1980 and 1990, (ii) to analyze the association of this genetic alteration with clinical and pathological characteristics, and (iii) to determine the association of Ki‐ras mutations with tobacco and alcohol consumption. DNA was amplified from paraffin‐embedded tissue samples and mutations in codon 12 of Ki‐ras were detected using the artificial RFLP technique. Cox proportional‐hazards regression and unconditional logistic regression were applied. Codon 12 Ki‐ras mutations were detected in 30 of 51 cases for which molecular results were available. The amino‐acid substitutions were Asp (8), Val (6), and Arg (3). A double mutation, including always a Val, was detected in 5 cases. None of the 4 non‐ductal pancreatic neoplasms were mutated. The mutation prevalence was 79% in metastases and 54% in primary tumors. The risk of a mutated tumor was 3 times higher in alcohol drinkers than in non‐drinkers, and a linear trend was apparent. When age, gender, hospital, and tobacco and alcohol consumption were taken into account, a high risk for mutations was detected in patients who only smoked and in patients who only drank, but less so in patients who both smoked and drank. These results raise novel hypotheses regarding the role of tobacco and alcohol in EPC. Int. J. Cancer, 70:661–667, 1997. © 1997 Wiley‐Liss, Inc.
... Saliva, urines, seminal fluids, tears, and stool have been analyzed to understand their correlation with cancer 36 . Stool in particular have been thoroughly evaluated in the context of gastrointestinal cancers, and proved to be a valuable source of tumoral DNA for pancreatic cancer
[37]
[38][39][40] . Stool analysis from a multiomics perspective is also able to integrate information on the role of the microbiome in cancer pathogenesis, especially in the case of colorectal cancer and pancreatic cancer, as well as in other disease entities such as inflammatory intestinal diseases [41][42][43] . ...
Liquid biopsies and cancer omics
Article
Full-text available
Dec 2020
Ivano Amelio
Riccardo Bertolo
Pierluigi Bove
Gerry Melino
The development of the sequencing technologies allowed the generation of huge amounts of molecular data from a single cancer specimen, allowing the clinical oncology to enter the era of the precision medicine. This massive amount of data is highlighting new details on cancer pathogenesis but still relies on tissue biopsies, which are unable to capture the dynamic nature of cancer through its evolution. This assumption led to the exploration of non-tissue sources of tumoral material opening the field of liquid biopsies. Blood, together with body fluids such as urines, or stool, from cancer patients, are analyzed applying the techniques used for the generation of omics data. With blood, this approach would allow to take into account tumor heterogeneity (since the circulating components such as CTCs, ctDNA, or ECVs derive from each cancer clone) in a time dependent manner, resulting in a somehow “real-time” understanding of cancer evolution. Liquid biopsies are beginning nowdays to be applied in many cancer contexts and are at the basis of many clinical trials in oncology.
... K-ras mutations were also detected in 77% o f cases in the pancreatic juice (Tenner et al, 1996) and in 63% o f cases in the duodenal juice (Iguchi et al, 1996) obtained during ERCP from patients with pancreatic cancer, and in stool from 6 o f 11 patients suffering from pancreatic carcinoma
(Caldas et al, 1994)
. In these cases mutations were found in the cancer cells shed to the gastrointestinal tract. ...
Photodynamic therapy for the treatment of cancer of the pancreas
Thesis
Jan 2001
AZ Rogowska
Cancer of the pancreas is the fifth commonest cause of cancer death and even with treatment, 80-90% of patients die within a year of diagnosis. Photodynamic therapy (PDT) is a non-thermal technique for inducing tissue necrosis. Cytotoxic oxygen species are produced from the interaction between light of a specific wavelength and a photosensitising agent in an oxygenated tissue. Experimental studies using the photosensitisers mTHPC and ALA have shown PDT to have a substantial therapeutic potential for the treatment of pancreatic cancer. mTHPC gave the largest volume of necrosis around treatment sites but clinically causes skin photosensitisation for up to a month. ALA photosensitivity only lasts 1-2 days, but clinical studies show that at the maximum tolerated dose (60mg/kg) the effect is too superficial. The aims of this thesis were: 1. To assess the safety and feasibility of interstitial PDT using mTHPC for the treatment of inoperable pancreatic cancer. To undertake animal studies to investigate a method of enhancing ALA PDT by the addition of the hydroxypyridinone iron chelator, CP94, to slow down the conversion of PPIX (the photoactive derivative of ALA) to haem. The pilot clinical study on 16 patients with localised but inoperable pancreatic cancers (2-6cm in diameter) showed that PDT could produce tumour necrosis with no treatment related mortality and a median survival of 12.5 months. Major complications included bleeding and duodenal stenosis but these were manageable. Experiments on hamsters with cancer transplanted into their pancreas showed significantly higher tissue levels of PPIX and significantly larger volumes of PDT produced tumour necrosis in those given ALA and CP94 compared with ALA alone. This thesis has shown that clinical, interstitial PDT with mTHPC for pancreatic cancer is technically feasible and could produce some survival benefit. This should now be tested in a randomised, controlled trial. The animal experiments showed that adding an iron chelator may enhance ALA PDT. This could now be tested clinically. These encouraging results justify further studies of the possible role of PDT in the management of cancer of the pancreas.
... 1 Several key somatic genetic changes that characterize pancreatic adenocarcinoma have been identified, consisting of activation of the KRAS oncogene and inactivation of the TP53, CDKN2A (encoding p16) and MADH4 (also known as SMAD4 and DPC4) tumour suppressor genes. [2]
[3]
[4][5][6][7] The nature of chromosomal rearrangements, however, is somewhat unclear. ...
Non‐random chromosomal rearrangements in pancreatic cancer cell lines identified by spectral karyotyping
Article
Feb 2001
INT J CANCER
Vorapan Sirivatanauksorn
Yongyut Sirivatanauksorn
Patricia Gorman
Nicholas R Lemoine
The molecular events involved in pancreatic cancer are becoming increasingly well characterized, with mutations in the dominant oncogene KRAS and the tumour suppressor genes TP53, CDKN2A and MADH4 being typically observed. However, other genetic abnormalities remain to be identified and molecular cytogenetics may be useful to detect chromosomal loci involved in recurrent rearrangements. We have used spectral karyotyping to characterize cytogenetic aberrations in a panel of 20 human pancreatic carcinoma cell lines and confirmed their identities by dual and triple color fluorescence in situ hybridization. The most common partial or whole‐arm gains involved 5p, 7q, 12p, 1q, 7p, 5q, 9p, 9q and 11p. The most common partial or whole‐arm losses affected 9p, 11q, 18q, 3p, 2q and 1p, as well as the short arms of the acrocentric chromosomes. Spectral karyotyping allowed us to identify a number of recurrent structural aberrations, all of them unbalanced: most frequently i(5)(p10), del(11)(q23), i(12)(p10), i(1)(q10), del(7)(q22) and del(10)(p11). Spectral karyotyping mapped the complex aberrations occurring in pancreatic cancer cell lines and identified non‐random patterns of chromosomal rearrangement. This comprehensive characterization should be useful to direct future investigation. The observation that loss at 11q and gains at 5p with i(5)(p10) and 12p with i(12)(p10) are more frequent changes than previously reported would justify more intensive investigation of these chromosomal regions. © 2001 Wiley‐Liss, Inc.
... Although KRAS gene mutations are regarded a cancer hallmark, they have also been reported in non-neoplastic tissue samples under chronic inflammatory conditions, including chronic pancreatitis and ulcerative colitis (Yanagisawa et al., 1993;
Caldas et al., 1994;
Furuya, Kawa, Akamatsu, & Furihata, 1997;Van Laethem, 1999;Lyda, Noffsinger, Belli, & Fenoglio-Preiser, 2000;Popović et al., 2007). Reactive oxygen species are one of the endogenous factors that may trigger somatic mutations (Emerit, 1994). ...
KRAS mutations in implant‐associated peripheral giant cell granuloma
Article
Nov 2019
Roberta R. Martins-Chaves
Letícia Martins Guimarães
Thaís Pereira
Ricardo S Gomez
Objectives:
To investigate the molecular pathogenesis of implant-associated peripheral giant cell granuloma (IA-PGCG).
Methods:
A convenience sample of 15 IA-PGCG cases was selected. Hotspot mutations of KRAS, FGFR1, and TRPV4 genes, previously reported in conventional giant cell lesions of the jaws, were investigated by Sanger sequencing. As these mutations could activate MAPK/ERK pathway, the expression of phospho-ERK1/2 was also evaluated by immunohistochemistry.
Results:
KRAS mutations were detected in 8/15 (53.4%) samples. Similar to conventional peripheral giant cell granuloma, the KRAS mutations most frequently occurred in codon 146 (p.A146V, n = 3), followed by codon 12 (p.G12A and p.G12D, n = 1 each) and codon 14 (p.V14L, n = 1). Variants of unknown significance (VUS) were also detected in two cases, affecting codons 37 (p.E37K) and 127 (p.T127I). All samples showed wild-type (WT) sequences for FGFR1 and TRPV4 genes. Consistent with MAPK/ERK pathway activation, all mononuclear cells of the lesion showed strong staining for phospho-ERK1/2 protein in the immunohistochemical analysis.
Conclusions:
KRAS mutations and activation of the MAPK-ERK signaling pathway occur in IA-PGCG. This is the first study to demonstrate cancer-associated gene mutations in a non-neoplastic reactive condition associated with dental implants.
... An ongoing phase II trial [NCT02399137] is studying istiratumab (MM-141), an engineered bispecific monoclonal antibody that (Figure 1). The vast majority of PDAC patients have KRAS mutations [17,
18]
. In theory, targeting this pathway may play a role in cell proliferation and tumor growth; however, a previous study showed that the presence of KRAS mutations has no impact on OS [19]. ...
Promising new treatments for pancreatic cancer in the era of targeted and immune therapies
Article
Full-text available
Sep 2019
Ahmed Elaileh
Ashish Saharia
Lucy Potter
Kirk Heyne
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer mortality among men and women in the United States. Its incidence has been on the rise, with a projected two-fold increase by 2030. PDAC carries a poor prognosis due to a lack of effective screening tools, limited understanding of pathophysiology, and ineffective treatment modalities. Recently, there has been a revolution in the world of oncology with the advent of novel treatments to combat this disease. However, the 5-year survival of PDAC remains unchanged at a dismal 8%. The aim of this review is to bring together several studies and identify various recent modalities that have been promising in treating PDAC.
... The majority of KRAS are localized in codon 12 (changing glycine to either valine, aspartic acid or arginine) involving in a constitutive and aberrant activation of the downstream KRAS signaling cascade to the cell nucleus [22]. Mutations in KRAS are an early event in PDA, and can be already observed in tissue samples from chronic pancreatitis patients
[33]
. ...
Targeting KRAS Mutant CMS3 Subtype by Metabolic Inhibitors
Chapter
Jan 2018
ADV EXP MED BIOL
Oscar Aguilera
Roberto Serna
Cancer cells rewire their metabolism in order to boost growth, survival, proliferation, and chemoresistance. The common event of this aberrant metabolism is the increased glucose uptake and fermentation of glucose to lactate. This phenomenon is observed even in the presence of O2 and completely functioning mitochondria. This is known as the “Warburg Effect” and it is a hallmark in cancer. Up to 40% of all CRC’s are known to have a mutated (abnormal) KRAS gene, found at differing frequencies in all consensus molecular subtypes (CMS). CMS3 colon cancer molecular subtype contains the so-called ‘metabolic tumours’ which represents 13% of total CR cases. These tumours display remarkable metabolic deregulation, often showing KRAS mutations (68%). Unfortunately, patients harbouring mutated KRAS are unlikely to benefit from anti-EGFR therapies. Moreover, it remains unclear that patients with KRAS wild-type CRC will definitely respond to such therapies. Although some clinically designed-strategies to modulate KRAS aberrant activation have been designed, all attempts to target KRAS have failed in the clinical assays and KRAS has been assumed to be invulnerable to chemotherapeutic attack. Quest for metabolic inhibitors with anti-tumour activity may constitute a novel and hopeful approach in order to handle KRAS dependent chemoresistance in colon cancer.
... Sampling from pancreatic juice and bile using various endoscopic methods, despite the difficulties in its acquisition, is reported to improve the sensitivity of the liquid biopsy by providing a higher concentration of tumorderived components with respect to other body fluids [27][28][29][30]. Release of the pancreatic juice into the bile duct and subsequently into the duodenum and intestine makes stool another candidate in this field
[31]
[32][33][34][35][36][37]. Although stool testing can offer non-invasive sampling, only a few investigations have been carried out to determine its potential for pancreatic cancer diagnosis, which may be partially due to low accuracy of this method [38]. ...
Liquid Biopsies for Management of Pancreatic Cancer
Preprint
Apr 2018
Mohamadmahdi Samandari
María Gil Juliá
Alistair Rice
Armando del Rio Hernandez
... Several signature mutations are involved in PDAC progression. These include mutations in K-Ras and p53 tumor suppressor genes (15)(16)
(17)
(18)(19)(20)(21), deletion of p53, p61, SMAD4/ DPC4, and deregulation of microRNA (23,24) and chromosomal aberrations (25)(26)(27). Mutations in the K-Ras gene are prevalent in PDAC and play critical, although poorly understood, roles in initiating and empowering the progression of PDAC in human and genetically engineered mouse models in the presence of mutant p53 or the absence of other tumor suppression genes (15,16,28,29). ...
Abstract 3345: MAZ is a downstream target of CCN1 and promotes aggressive behavior of pancreatic cancer cells via CRAF-ERK signaling pathway
Article
Full-text available
Jul 2018
Gargi Maity
Inamul Haque
Arnab Ghosh
Snigdha Banerjee
MAZ (Myc-associated zinc-finger protein) is a transcription factor with dual roles in transcription initiation and termination. Deregulation of MAZ expression has been shown to associate with the progression of pancreatic ductal adenocarcinoma cancer (PDAC). However, underlying mechanisms of action of MAZ in PDAC progression are largely unknown. Here we present evidence that MAZ mRNA expression and protein level were increased in human PDAC cell lines, tissue samples, subcutaneous tumor xenograft model in a nude mouse, and spontaneous cancer in the genetically engineered PDAC mouse model. We found that MAZ is predominantly expressed in pancreatic cancer stem cells. Functional analysis demonstrates that the depletion of MAZ in PDAC cells results in inhibition of invasive phenotypes such as phenotypic shift, migration, invasion, and the sphere-forming ability of PDAC cells. Mechanistically, we found no direct effect of MAZ on the expression of K-Ras mutants, but evidently MAZ increases the activity of CRAF-ERK-signaling, which is a downstream signaling target of K-Ras. Activation of CRAF-ERK-signaling by MAZ is mediated via p21-activated protein kinases (PAK) and protein kinase B (AKT/PKB) signaling cascades and promotes invasive phenotypes of PDAC cells. Moreover, a matricellular oncoprotein CCN1 regulates MAZ expression in PDAC cells. Thereby, we proposed that CCN1-induced expression of MAZ promotes invasive phenotypes of PDAC cells is not through direct K-Ras activation as presently thought but instead through the activation of CRAF-ERK signals. Collectively, these studies highlight key players that could help in clinical management, prognosis, and therapeutic strategies.
This project is funded by VA Merit Award grants (SB & SKB).
Citation Format: Gargi Maity, Inamul Haque, Arnab Ghosh, Gopal Dhar, Vijayalaxmi Gupta, Sandipto Sarkar, Imaan Azeem, Douglas McGregor, Abhishek Choudhary, Donald R Campbell, Sushanta K. Banerjee, Snigdha Banerjee. MAZ is a downstream target of CCN1 and promotes aggressive behavior of pancreatic cancer cells via CRAF-ERK signaling pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3345.
... Sampling from pancreatic juice and bile using various endoscopic methods, despite the difficulties in its acquisition, is reported to improve the sensitivity of the liquid biopsy by providing a higher concentration of tumorderived components with respect to other body fluids [27][28][29][30]. Release of the pancreatic juice into the bile duct and subsequently into the duodenum and intestine makes stool another candidate in this field
[31]
[32][33][34][35][36][37]. Although stool testing can offer non-invasive sampling, only a few investigations have been carried out to determine its potential for pancreatic cancer diagnosis, which may be partially due to low accuracy of this method [38]. ...
Liquid Biopsies for Management of Pancreatic Cancer
Article
Full-text available
Nov 2018
TRANSL RES
Mohamadmahdi Samandari
María Gil Juliá
Alistair Rice
Armando del Rio Hernandez
Pancreatic cancer is one of the main causes of cancer related deaths worldwide. It is asymptomatic at an early stage, and most diagnosis occurs when the disease is already at a late stage, by which time the tumor is non-resectable. In order to increase the overall survival of patients with pancreatic cancer, as well as to decrease the cancer burden, it is necessary to perform early diagnosis, prognosis stratifications and cancer monitoring using accurate, minimally invasive and cost-effective methods. Liquid biopsies seek to detect tumor-associated biomarkers in a variety of extractable body fluids and can help to monitor treatment response and disease progression, and even predict patient outcome. In patients with pancreatic cancer, tumor-derived materials, mainly circulating tumor DNA, circulating tumor cells and exosomes, are being studied for inclusion in the management algorithm of the disease. This review focuses on describing the biology of these biomarkers, methods for their enrichment and detection, as well as their potential for clinical applications. Moreover, we discuss the future direction of liquid biopsies and introduce how they can be exploited towards point of care personalized medicine for the management of pancreatic cancer.
... For patients with cancer, some of their cfDNA is released by tumour cells to generate circulating tumour DNA (ctDNA) and can provide a snapshot of genetic changes in the tumour itself. The tumour component of cfDNA in cancer patients was firmly established through cfDNA genomic analysis which identified canonical oncogene mutations in TP53 in patients with bladder cancer [87] and KRAS in patients with colorectal [88] and pancreatic cancer
[89]
. In a study of pancreatic cancer patients, matched tumour and cfDNA sequencing established that in each patient there was a precise match between the sequences observed in plasma cfDNA and tumour [90]. ...
Circulating Tumor Cells
Chapter
Apr 2018
Konstantinos Georgiadis
Kathryn Simpson
Mahmood Ayub
Caroline Dive
Analysis of cellular and molecular components of tumor origin detectable in the bloodstream, so-called liquid biopsies, is demonstrating potential to support management of cancer patients. Development of sensitive technologies enables detection, isolation, and downstream analysis of both circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) from the blood of patients with various malignancies, in a minimally invasive way, allowing temporal and spatial monitoring of the clinical course of the disease. This is particularly significant in cancers such as pancreas cancer, a particularly aggressive disease with limited treatment options and poor outcomes, where serial biopsy is challenging. CTC enumeration; genomic, transcriptomic, and proteomic analysis; as well as in-depth sequencing of ctDNA may define a comprehensive molecular and genetic landscape of pancreatic cancer and provide a set of novel biomarkers for screening, diagnosis, prognosis, and response assessment. A number of pilot studies have been conducted to assess the role of liquid biopsies in the setting of pancreatic cancer. Although results so far seem promising, more extensive studies are required to establish the clinical utility of CTCs and ctDNA in developing a personalized approach for the management of this malignancy. © Springer Science+Business Media, LLC, part of Springer Nature 2018.
... It has been shown more than 20 years ago that some cancer mutations can be detected noninvasively through analysis of samples including blood plasma, urine, stool and sputum [1][2][3]
[4]
[5][6]. Circulating tumor DNA (ctDNA) is believed to enter a patient's blood plasma largely through turnover of cancer cells and subsequent release of the resultant fragmented DNA into circulation. ...
Analytical validation of a next generation sequencing liquid biopsy assay for high sensitivity broad molecular profiling
Article
Full-text available
Mar 2018
PLOS ONE
Vincent Plagnol
Samuel Woodhouse
Karen Howarth
Tim Forshew
Circulating tumor DNA (ctDNA) analysis is being incorporated into cancer care; notably in profiling patients to guide treatment decisions. Responses to targeted therapies have been observed in patients with actionable mutations detected in plasma DNA at variant allele fractions (VAFs) below 0.5%. Highly sensitive methods are therefore required for optimal clinical use. To enable objective assessment of assay performance, detailed analytical validation is required. We developed the InVisionFirst™ assay, an assay based on enhanced tagged amplicon sequencing (eTAm-Seq™) technology to profile 36 genes commonly mutated in non-small cell lung cancer (NSCLC) and other cancer types for actionable genomic alterations in cell-free DNA. The assay has been developed to detect point mutations, indels, amplifications and gene fusions that commonly occur in NSCLC. For analytical validation, two 10mL blood tubes were collected from NSCLC patients and healthy volunteer donors. In addition, contrived samples were used to represent a wide spectrum of genetic aberrations and VAFs. Samples were analyzed by multiple operators, at different times and using different reagent Lots. Results were compared with digital PCR (dPCR). The InVisionFirst assay demonstrated an excellent limit of detection, with 99.48% sensitivity for SNVs present at VAF range 0.25%-0.33%, 92.46% sensitivity for indels at 0.25% VAF and a high rate of detection at lower frequencies while retaining high specificity (99.9997% per base). The assay also detected ALK and ROS1 gene fusions, and DNA amplifications in ERBB2, FGFR1, MET and EGFR with high sensitivity and specificity. Comparison between the InVisionFirst assay and dPCR in a series of cancer patients showed high concordance. This analytical validation demonstrated that the InVisionFirst assay is highly sensitive, specific and robust, and meets analytical requirements for clinical applications.
... Pancreatic adenocarcinoma is considered to be aggressive form of cancer and mostly affecting duct epithelial cells [42]. K-RAS mutation is the most frequent among the types of mutation detected at both early and chronic stage of pancreatic cancer
[43]
. Genetic studies revealed that approximately 90% of the pancreatic cancer patients carry K-RAS mutation (Table 2) [28,[44][45][46][47][48]. ...
RAS-mediated oncogenic signaling pathways in human malignancies
Article
Mar 2018
Abdul Q. Khan
Shilpa Kuttikrishnan
Kodappully Sivaraman Siveen
Shahab Uddin, Ph.D
Abnormally activated RAS proteins are the main oncogenic driver that governs the functioning of major signaling pathways involved in the initiation and development of human malignancies. Mutations in RAS genes and or its regulators, most frequent in human cancers, are the main force for incessant RAS activation and associated pathological conditions including cancer. In general, RAS is the main upstream regulator of the highly conserved signaling mechanisms associated with a plethora of important cellular activities vital for normal homeostasis. Mutated or the oncogenic RAS aberrantly activates a web of interconnected signaling pathways including mitogen-activated protein kinases (MAPK), phosphoinositide-3 kinase (PI3K)/AKT pathways, protein kinase C (PKC) and ral guanine nucleotide dissociation stimulator (RalGDS), etc., leading to uncontrolled transcriptional expression and reprogramming in the functioning of a range of nuclear and cytosolic effectors critically associated with the hallmarks of carcinogenesis. This review highlights the recent literature on how oncogenic RAS negatively use its signaling web in deregulating the expression and functioning of various effector molecules in the pathogenesis of human malignancies.
... The majority of KRAS are localized in codon 12 (changing glycine to either valine, aspartic acid or arginine) involving in a constitutive and aberrant activation of the downstream KRAS signaling cascade to the cell nucleus [22]. Mutations in KRAS are an early event in PDA, and can be already observed in tissue samples from chronic pancreatitis patients
[33]
. ...
Targeting the RAS-dependent chemoresistance: The Warburg connection
Article
Feb 2018
Roberto Serna
Marta Sanz-Alvarez
Oscar Aguilera
Jesús García-Foncillas
RAS protein family members (KRAS4A, KRAS4B, HRAS and NRAS) function as GDP–GTP-regulated on-off switches, which regulate cytoplasmic-nuclear signaling networks ruling diverse normal cellular processes. Constitutive activating mutations in RAS genes are found in up to 30% of human cancers, and remarkably, the oncogenic Ras mutations and mutations in other components of Ras/MAPK signaling pathways seem to be mutually exclusive in most tumors, pointing out that deregulation of Ras-dependent signaling is an essential requirement for tumorigenesis. Up to 30% of solid tumors are known to have a mutated (abnormal) KRAS gene. Unfortunately, patients harboring mutated KRAS CRC are unlikely to benefit from anti-EGFR therapy. Moreover, it remains unclear that patients with KRAS wild-type CRC will definitely respond to such therapies. Although some clinically designed-strategies to modulate KRAS aberrant activation have been designed, all attempts to target KRAS have failed in the clinical assays and K-RAS has been assumed to be invulnerable to chemotherapeutic attack. Recently, different encouraging publications reported that ascorbate may have a selective antitumoral effect on KRAS mutant cancer cells.
In this review we aim to describe the prevalence and importance of KRAS mutation in cancer and associated problems for the clinical handling of patients harboring these tumors. We highlight the role of mutated KRAS in boosting and keeping the tumor associated aberrant cell metabolism stating that further in-depth studies on the molecular mechanism of ascorbate to bypass mutated KRAS-related metabolic alterations may constitute a new pathway to design novel molecules in order handle tumor resistance to anti EGFR-therapies.
... Several signature mutations are involved in PDAC progression. These include mutations in K-Ras and p53 tumor suppressor genes (15)(16)
(17)
(18)(19)(20)(21), deletion of p53, p61, SMAD4/DPC4 and deregulation of microRNAs (22)(23)(24) and chromosomal aberrations (25)(26)(27). Mutations in K-Ras gene are prevalent in PDAC and play critical, although poorly understood, roles in initiating and empowering progression of PDAC in human and genetically engineered mouse models in the presence of mutant p53 or absence of other tumor suppression genes (15,16,28,29). ...
The MAZ transcription factor is a downstream target of the oncoprotein Cyr61/CCN1 and promotes pancreatic cancer cell invasion via CRAF–ERK signaling
Article
Full-text available
Feb 2018
Arnab Ghosh
Gargi Maity
Inamul Haque
Snigdha Banerjee
Myc-associated zinc-finger protein (MAZ) is a transcription factor with dual roles in transcription initiation and termination. Deregulation of MAZ expression is associated with the progression of pancreatic ductal adenocarcinoma (PDAC). However, the mechanism of action of MAZ in PDAC progression is largely unknown. Here, we present evidence that MAZ mRNA expression and protein levels are increased in human PDAC cell lines, tissue samples, a subcutaneous tumor xenograft in a nude mouse model, and spontaneous cancer in the genetically engineered PDAC mouse model. We also found that MAZ is predominantly expressed in pancreatic cancer stem cells. Functional analysis indicated that MAZ depletion in PDAC cells inhibits invasive phenotypes such as the epithelial-to-mesenchymal transition, migration, invasion, and the sphere-forming ability of PDAC cells. Mechanistically, we detected no direct effects of MAZ on the expression of K-Ras mutants, but MAZ increased the activity of CRAF-ERK signaling, a downstream signaling target of K-Ras. The MAZ-induced activation of CRAF-ERK signaling was mediated via p21-activated protein kinase (PAK) and protein kinase B (AKT/PKB) signaling cascades and promoted PDAC cell invasiveness. Moreover, we found that the matricellular oncoprotein cysteine-rich angiogenic inducer 61 (Cyr61/CCN1) regulates MAZ expression via Notch-1-sonic hedgehog signaling in PDAC cells. We propose that Cyr61/CCN1-induced expression of MAZ promotes invasive phenotypes of PDAC cells not through direct K-Ras activation, but instead through the activation of CRAF-ERK signaling. Collectively, these results highlight key molecular players in PDAC invasiveness and may help inform therapeutic strategies to improve clinical management and outcomes of PDAC.
... Mutation analysis of the present cohort of patients with operable PDAC aligns with that of prior studies reporting the presence of KRAS mutation in the majority of PDAC cases
(18,
19). Additionally, the genes of four KRAS downstream signaling pathways, including the PI3K/PDK1/AKT, RAL guanine nucle otide exchange factor, RIN1/ABL and RAF/MAPK pathways, exhibited differential expression in PDAC compared with that of the adjacent normal tissues, although no significant differences were observed in the expression of these genes between patients with KRASmutated and wildtype tumors. ...
Dysregulation of KRAS signaling in pancreatic cancer is not associated with KRAS mutations and outcome
Sep 2017
Radmila Lemstrova
Veronika Brynychova
David J Hughes
Beatrice Mohelnikova-Duchonova
Pancreatic ductal adenocarcinoma (PDAC) is a tumor with a poor prognosis, and no targeted therapy is currently available. The aim of the present study was to investigate the prognostic significance of the expression of V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS), downstream signaling pathway genes and the association with clinical characteristics in PDAC patients undergoing radical surgery. Tumors and adjacent non-neoplastic pancreatic tissues were examined in 45 patients with histologically verified PDAC. KRAS and B-Raf proto-oncogene, serine/threonine kinase (BRAF) gene mutation analysis was performed using the KRAS/BRAF/phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α array. The transcript profile of 52 KRAS downstream signaling pathway genes was assessed using quantitative-polymerase chain reaction. KRAS mutation was detected in 80% of cases. The genes of four signaling pathways downstream of KRAS, including the phosphoinositide 3-kinase/3-phosphoinositide-dependent protein kinase 1/V-akt murine thymoma viral oncogene homolog 1, RAL guanine nucleotide exchange factor, Ras and Rab interactor 1/ABL proto-oncogene-1, non-receptor tyrosine kinase, and RAF proto-oncogene serine/threonine-protein kinase/mitogen-activated protein kinase pathways, exhibited differential expression in PDAC compared with that in the adjacent normal tissues. However, no significant differences in expression were evident between patients with KRAS-mutated and wild-type tumors. The expression of KRAS downstream signaling pathways genes did not correlate with angioinvasion, perineural invasion, grade or presence of lymph node metastasis. Additionally, the presence of KRAS mutations was not associated with overall survival. Among the KRAS downstream effective signaling pathways molecules investigated, only v-raf-1 murine leukemia viral oncogene homolog 1 expression was predictive of prognosis. Overall, KRAS mutation is present in the majority of cases of PDAC, but is not associated with changes in the expression of KRAS downstream signaling pathways and the clinical outcome. This may partly explain the failure of KRAS-targeted therapies in PDAC.
... The accumulation of these genetic alterations significantly perturbs major signaling pathways, leading to the acquisition of a malignant phenotype. The most frequently altered driver genes in pancreatic ductal adenocarcinoma (the oncogene KRAS and the three tumor suppressor genes TP53, CDKN2A, SMAD4) have been thoroughly characterized in human tissue samples for some time (Table 1) [12][13]
[14]
[15] . However, recent comprehensive genomic analyses, including whole exome and whole genome sequencing studies, have provided a more detailed understanding of the complex genomic changes, orchestrated by a combination of chromosomal rearrangements, local copy number variations (CNV), and widespread single nucleotide variants (SNV) [4][5][6][7][8][9] . ...
New Developments in the Molecular Mechanisms of Pancreatic Tumorigenesis
Sep 2017
ADV ANAT PATHOL
Matthaeus Felsenstein
Laura D. Wood
Ralph H. Hruban
Pancreatic cancer is an aggressive disease with a dismal prognosis in dire need of novel diagnostic and therapeutic approaches. The past decade has witnessed an explosion of data on the genetic alterations that occur in pancreatic cancer, as comprehensive next-generation sequencing analyses have been performed on samples from large cohorts of patients. These studies have defined the genomic landscape of this disease and identified novel candidates whose mutations contribute to pancreatic tumorigenesis. They have also clarified the genetic alterations that underlie multistep tumorigenesis in precursor lesions and provided insights into clonal evolution in pancreatic neoplasia. In addition to these important insights into pancreatic cancer biology, these large scale genomic studies have also provided a foundation for the development of novel early detection strategies and targeted therapies. In this review, we discuss the results of these comprehensive sequencing studies of pancreatic neoplasms, with a particular focus on how their results will impact the clinical care of patients with pancreatic cancer.
... Besides CRC, stool tumor DNA can also be detected in other digestive system neoplasms. In 1994, Caldas demonstrated the presence of K-ras mutation in the stool of pancreatic cancer patients
[97]
. In a more recent work, Kisiel et al found a sensitivity of 67% and a specificity of 90% in detecting pancreatic cancer with a combination of stool mutated K-ras and methylated BMP3 detection [98]. ...
Non-blood circulating tumor DNA detection in cancer
Muyun Peng
Chen Chen
Alicia Hulbert
Fenglei Yu
Tumor DNA contains specific somatic alterations that are crucial for the diagnosis and treatment of cancer. Due to the spatial and temporal intra-tumor heterogeneity, multi-sampling is needed to adequately characterize the somatic alterations. Tissue biopsy, however, is limited by the restricted access to sample and the challenges to recapitulate the tumor clonal diversity. Non-blood circulating tumor DNA are tumor DNA fragments presents in non-blood body fluids, such as urine, saliva, sputum, stool, pleural fluid, and cerebrospinal fluid (CSF). Recent studies have demonstrated the presence of tumor DNA in these non-blood body fluids and their application to the diagnosis, screening, and monitoring of cancers. Non-blood circulating tumor DNA has an enormous potential for large-scale screening of local neoplasms because of its non-invasive nature, close proximity to the tumors, easiness and it is an economically viable option. It permits longitudinal assessments and allows sequential monitoring of response and progression. Enrichment of tumor DNA of local cancers in non-blood body fluids may help to archive a higher sensitivity than in plasma ctDNA. The direct contact of cancerous cells and body fluid may facilitate the detection of tumor DNA. Furthermore, normal DNA always dilutes the plasma ctDNA, which may be aggravated by inflammation and injury when very high amounts of normal DNA are released into the circulation. Altogether, our review indicate that non-blood circulating tumor DNA presents an option where the disease can be tracked in a simple and less-invasive manner, allowing for serial sampling informing of the tumor heterogeneity and response to treatment.
... 1,2 The incidence of CCA disease is greater in male than in female. 3 Jaundice is the most significant clinical presentation for diagnosis of CCA, but jaundice commonly occurs at the late stage of CCA. 4 Previous studies have suggested that various genes may be useful for diagnosis of CCA, such as CA19-9, 5 K-ras gene,
6,
7 p53, 8,9 HER-2, 10 Bcl-2 11 and DPC4. 12 Several miRNAs were upregulated in CCA, which can increase CCA proliferation and survival. ...
Identification of transcription factors (TFs) and targets involved in the cholangiocarcinoma (CCA) by integrated analysis
Nov 2016
L Yang
S Feng
Y Yang
The present study was designed to investigate the upstream transcription factors (TFs) and the signature genes in cholangiocarcinoma (CCA), providing better clues on the regulatory mechanisms and therapeutic applications. Gene expression data sets of CCA were searched in the Gene Expression Omnibus database for integrated analysis. Functional annotation of differently expressed genes (DEGs) was then conducted and the TFs were identified. Moreover, a global transcriptional regulatory network of TFs-targets was constructed. Integrated analysis of five eligible Gene Expression Omnibus data sets led to a set of 993 DEGs and 48 TFs in CCA. The constructed TFs-targets regulatory network consisted of 697 TF-target interactions between 41 TFs and 436 DEGs. The top 10 TFs covering the most downstream DEGs were NFATC2, SOX10, ARID3A, ZNF263, NR4A2, GATA3, EGR1, PLAG1, STAT3 and FOSL1, which may have important roles in the tumorigenesis of CCA. Supporting the fact that defects of cell-cycle surveillance mechanism were closely related to various cancers, we found that cell cycle was the most significantly enriched pathway. KCNN2 and ADCY6 were involved in the bile secretion. Thus, their aberrant expression may be closely related to the pathogenesis of CCA. Particularly, we found that upregulation of EZH2 in CCA is a powerful potential marker for CCA.Cancer Gene Therapy advance online publication, 18 November 2016; doi:10.1038/cgt.2016.64.
... Human pancreatic ductal adenocarcinoma (PDAC) is a common form of human pancreatic cancer (PC) with a 5-year survival rate of less than 5 % after diagnosis and treatment, indicating the dire need for improved therapy (Grote and Logsdon 2007;Han and Von Hoff 2013;Hidalgo 2010). PDAC develops through the accumulation of multiple genetic lesions, which lead to sequential, atypical, histological, preneoplastic changes, also known as pancreatic intraepithelial neoplasms (PanINs) and ultimately invasive/ metastatic PDAC (Abraham et al. 2003;Abramson et al. 2007;Aguirre et al. 2003;Aguirre et al. 2004;Banerjee et al. 2000;
Caldas et al. 1994;
Goggins 2005;Griffin et al. 1994;Keleg et al. 2003;Kern et al. 2002;Maitra et al. 2003;Maitra et al. 2002;Ottenhof et al. 2011;Reichert and Rustgi 2011;Stromnes and Greenberg 2016;Wilentz et al. 1998;Zhang et al. 1997). The earliest detectable mutations identified in precursor lesions are activating mutations of K-Ras, which is detected in~95 % of PDACs (Banerjee et al. 2000;Eser et al. 2014;Huang et al. 2014;Kanda et al. 2012). ...
Human pancreatic cancer progression: an anarchy among CCN-siblings
Aug 2016
S.K. Banerjee
Gargi Maity
Inamul Haque
Snigdha Banerjee
Decades of basic and translational studies have identified the mechanisms by which pancreatic cancer cells use molecular pathways to hijack the normal homeostasis of the pancreas, promoting pancreatic cancer initiation, progression, and metastasis, as well as drug resistance. These molecular pathways were explored to develop targeted therapies to prevent or cure this fatal disease. Regrettably, the studies found that majority of the molecular events that dictate carcinogenic growth in the pancreas are non-actionable (potential non-responder groups of targeted therapy). In this review we discuss exciting discoveries on CCN-siblings that reveal how CCN-family members contribute to the different aspects of the development of pancreatic cancer with special emphasis on therapy.
... Mutation detection was successful in 60e80% of pancreatic juice samples from PDAC patients, but collecting such sample requires uneasy endoscopic procedures (Van Laethem et al., 1998;Watanabe et al., 1999;Wilentz et al., 1998). In the stool, KRAS mutations were detected in only 20e55% of PDAC patients; this low sensitivity prevents the use as a screening or diagnostic test in clinics
(Caldas et al., 1994;
Wenger et al., 1999). Blood-based "liquid biopsies" can outperform these deceiving results, and may prove to be clinically relevant. ...
Clinical applications of circulating tumor DNA and circulating tumor cells in pancreatic cancer
Article
Jan 2016
MOL ONCOL
Francesca Riva
Oleksiy Dronov
Dmytro I. Khomenko
François-Clément Bidard
Pancreatic ductal adenocarcinoma (PDAC) is the most frequent pancreatic cancer type and is characterized by a dismal prognosis due to late diagnosis, local tumor invasion, frequent distant metastases and poor sensitivity to current therapy. In this context, circulating tumor cells and circulating tumor DNA constitute easily accessible blood-borne tumor biomarkers that may prove their clinical interest for screening, early diagnosis and metastatic risk assessment of PDAC. Moreover these markers represent a tool to assess PDAC mutational landscape. In this review, together with key biological findings, we summarize the clinical results obtained using “liquid biopsies” at the different stages of the disease, for early and metastatic diagnosis as well as monitoring during therapy.
... It has been reported that the k-ras gene at codon 12 had a high incidence of mutation in pancreatic adenocarcinoma, usually presented with CGT, GTT, and GAT styles, occasionally showed TGT, AGT ways. At present, the available methods for detecting its mutation include PCR-RMCA [1,2] , PCR-ASO
[3]
[4][5][6][7][8][9][10][11][24][25][26] , PCR-DSM [12][13][14][15][16][17] , PCR-SSP [18,31] , PCR-RFLP [17,[19][20][21][22][23][24][25][26][27]33] and PCR-SSCP [28][29][30]32] , among which PCR-SSP is the simplest and quickest one. No enzyme cut, hybridization, radioactive and non-radioactive imaging technique were needed. ...
Detection of k-ras gene point mutation in fine needle aspiration and pancreatic juice by sequence special primer method and its clinical significance
Dec 2000
WORLD J GASTROENTERO
Xun Liang Liu
The point mutation rate of k-ras gene at codon 12 in pancreatic adenocarcinoma is reported to be as high as 90%[1-30], and with no mutations in normal pancreas tissues or other pancreatic disorders. We have detected the presence of k-ras gene mutation and its mutant styles since 1994 by PCR-SSP in the FNA or pancreatic juice obtained from pancreatic adenocarcinoma tissues.
Circulating tumour DNA — looking beyond the blood
Article
Over the past decade, various liquid biopsy techniques have emerged as viable alternatives to the analysis of traditional tissue biopsy samples. Such surrogate 'biopsies' offer numerous advantages, including the relative ease of obtaining serial samples and overcoming the issues of interpreting one or more small tissue samples that might not reflect the entire tumour burden. To date, the majority of research in the area of liquid biopsies has focused on blood-based biomarkers, predominantly using plasma-derived circulating tumour DNA (ctDNA). However, ctDNA can also be obtained from various non-blood sources and these might offer unique advantages over plasma ctDNA. In this Review, we discuss advances in the analysis of ctDNA from non-blood sources, focusing on urine, cerebrospinal fluid, and pleural or peritoneal fluid, but also consider other sources of ctDNA. We discuss how these alternative sources can have a distinct yet complementary role to that of blood ctDNA analysis and consider various technical aspects of non-blood ctDNA assay development. We also reflect on the settings in which non-blood ctDNA can offer distinct advantages over plasma ctDNA and explore some of the challenges associated with translating these alternative assays from academia into clinical use.
Epithelial and Mesenchymal Features of Pancreatic Ductal Adenocarcinoma Cell Lines in Two- and Three-Dimensional Cultures
Pancreatic ductal adenocarcinoma (PDAC) is an intractable cancer that is difficult to diagnose early, and there is no cure other than surgery. PDAC is classified as an adenocarcinoma that has limited effective anticancer drug and molecular-targeted therapies compared to adenocarcinoma found in other organs. A large number of cancer cell lines have been established from patients with PDAC that have different genetic abnormalities, including four driver genes; however, little is known about the differences in biological behaviors among these cell lines. Recent studies have shown that PDAC cell lines can be divided into epithelial and mesenchymal cell lines. In 3D cultures, morphological and functional differences between epithelial and mesenchymal PDAC cell lines were observed as well as the drug effects of different anticancer drugs. These effects included gemcitabine causing an increased growth inhibition of epithelial PDAC cells, while nab-paclitaxel caused greater mesenchymal PDAC cell inhibition. Thus, examining the characteristics of epithelial or mesenchymal PDAC cells with stromal cells using a 3D co-culture may lead to the development of new anticancer drugs.
Oncogenomic Changes in Pancreatic Cancer and Their Detection in Stool
Pancreatic cancer (PC) is an aggressive malignancy with a dismal prognosis. To improve patient survival, the development of screening methods for early diagnosis is pivotal. Oncogenomic alterations present in tumor tissue are a suitable target for non-invasive screening efforts, as they can be detected in tumor-derived cells, cell-free nucleic acids, and extracellular vesicles, which are present in several body fluids. Since stool is an easily accessible source, which enables convenient and cost-effective sampling, it could be utilized for the screening of these traces. Herein, we explore the various oncogenomic changes that have been detected in PC tissue, such as chromosomal aberrations, mutations in driver genes, epigenetic alterations, and differentially expressed non-coding RNA. In addition, we briefly look into the role of altered gut microbiota in PC and their possible associations with oncogenomic changes. We also review the findings of genomic alterations in stool of PC patients, and the potentials and challenges of their future use for the development of stool screening tools, including the possible combination of genomic and microbiota markers.
Liquid biopsy at the frontier of detection, prognosis and progression monitoring in colorectal cancer
Colorectal cancer (CRC) is one of the most common cancers worldwide and a leading cause of carcinogenic death. To date, surgical resection is regarded as the gold standard by the operator for clinical decisions. Because conventional tissue biopsy is invasive and only a small sample can sometimes be obtained, it is unable to represent the heterogeneity of tumor or dynamically monitor tumor progression. Therefore, there is an urgent need to find a new minimally invasive or noninvasive diagnostic strategy to detect CRC at an early stage and monitor CRC recurrence. Over the past years, a new diagnostic concept called “liquid biopsy” has gained much attention. Liquid biopsy is noninvasive, allowing repeated analysis and real-time monitoring of tumor recurrence, metastasis or therapeutic responses. With the advanced development of new molecular techniques in CRC, circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), exosomes, and tumor-educated platelet (TEP) detection have achieved interesting and inspiring results as the most prominent liquid biopsy markers. In this review, we focused on some clinical applications of CTCs, ctDNA, exosomes and TEPs and discuss promising future applications to solve unmet clinical needs in CRC patients.
Theranostic Approach for Pancreatic Cancer. Editors: Nagaraju GP, Ahmad S (Elsevier / Academic Press)
Pancreatic cancer (PC) remains one of the deadliest malignancies worldwide and its survival prospects are projected to become worse by 2020. This negative prognosis results from the lack of significant advances in the diagnostic and therapeutic tools available for the disease, as opposed to major improvements witnessed for other cancers. Hence, there is an urgent need to develop new screening and treatment options for PC based on a molecular and targeted approach. Although our knowledge of mechanisms underlying pancreatic carcinogenesis has improved, this tumor remains
difficult to cure owing to chemoresistance. The frequently observed drug escape mechanisms characteristic of PC result from the dense stromal barrier that forms during cancer progression. This barrier results from intricate and complex interactions among the tumor microenvironment, pancreatic stellate cells, stem cells, and pancreatic cancer cells. Trends in PC research suggest that these interferences alter the signaling, molecular, and genetic landscape of PC cells, leading to various alternative chemo-evasion pathways. Hence, efficient treatment strategies for PC should focus on re-programming the immune system and stromal milieu to resensitize cells to treatment.
As this preface illustrates, acquiring increased knowledge about the mechanisms of drug resistance in PC will help design effective therapies that can overcome chemoresistance. In this book, we try to fill the current gap in the peer-reviewed scientific literature by compiling and synthesizing the latest advances in diagnostic and therapeutic approaches in PC into one book. We have merged the strategies of diagnostics and therapeutics into
the comprehensive term of “theranostics,” which promises to become the foundation of future precision medicine regimens. This book contains 16 chapters that explore the biology, pathology, and epidemiology of PC. Current findings on molecular and drug resistance mechanisms in PC are extensively discussed to provide readers with a holistic perspective on the topic. The contribution of the tumor microenvironment to these mechanisms is also examined to delineate its therapeutic and clinical potential. Novel areas of therapeutic development, such as genetic manipulation, vaccines, and small molecule-based treatments for PC are also discussed, highlighting innovative strategies undergoing evaluation. Furthermore, the anti-tumor activity of known natural compounds such as resveratrol and terpenoids is explored to illustrate their clinical significance as chemopreventive and chemosensitizing drugs. Finally, this book sheds light on the
role of the epigenome in PC development, suggesting potential therapeutic solutions that target it. It is our pleasure to present this exhaustive overview of the field to the scientific community to expand our understanding of current advances and future theranostic applications for PC. We hope that this book will motivate new research ideas, thoughts, and investigations for the ultimate benefit of PC patients and their families.
Biomarkers in the diagnosis of pancreatic cancer: Are we closer to finding the golden ticket?
Pancreatic cancer (PC) is a leading cause of cancer related mortality on a global scale. The disease itself is associated with a dismal prognosis, partly due to its silent nature resulting in patients presenting with advanced disease at the time of diagnosis. To combat this, there has been an explosion in the last decade of potential candidate biomarkers in the research setting in the hope that a diagnostic biomarker may provide a glimmer of hope in what is otherwise quite a substantial clinical dilemma. Currently, serum carbohydrate antigen 19-9 is utilized in the diagnostic work-up of patients diagnosed with PC however this biomarker lacks the sensitivity and specificity associated with a gold-standard marker. In the search for a biomarker that is both sensitive and specific for the diagnosis of PC, there has been a paradigm shift towards a focus on liquid biopsy and the use of diagnostic panels which has subsequently proved to have efficacy in the diagnosis of PC. Currently, promising developments in the field of early detection on PC using diagnostic biomarkers include the detection of microRNA (miRNA) in serum and circulating tumour cells. Both these modalities, although in their infancy and yet to be widely accepted into routine clinical practice, possess merit in the early detection of PC. We reviewed over 300 biomarkers with the aim to provide an in-depth summary of the current state-of-play regarding diagnostic biomarkers in PC (serum, urinary, salivary, faecal, pancreatic juice and biliary fluid).
An overview of genetic mutations and epigenetic signatures in the course of pancreatic cancer progression
Pancreatic cancer (PC) is assumed to be an intimidating and deadly malignancy due to being the leading cause of cancer-led mortality, predominantly affecting males of older age. The overall (5 years) survival rate of PC is less than 9% and is anticipated to be aggravated in the future due to the lack of molecular acquaintance and diagnostic tools for its early detection. Multiple factors are involved in the course of PC development, including genetics, cigarette smoking, alcohol, family history, and aberrant epigenetic signatures of the epigenome. In this review, we will mainly focus on the genetic mutations and epigenetic signature of PC. Multiple tumor suppressor and oncogene mutations are involved in PC initiation, including K-RAS, p53, CDKN2A, and SMAD4. The mutational frequency of these genes ranges from 50 to 98% in PC. The nature of mutation diagnosis is mostly homozygous deletion, point mutation, and aberrant methylation. In addition to genetic modification, epigenetic alterations particularly aberrant hypermethylation and hypomethylation also predispose patients to PC. Hypermethylation is mostly involved in the downregulation of tumor suppressor genes and leads to PC, while multiple genes also represent a hypomethylation status in PC. Several renewable drugs and detection tools have been developed to cope with this aggressive malady, but all are futile, and surgical resection remains the only choice for prolonged survival if diagnosed before metastasis. However, the available therapeutic development is insufficient to cure PC. Therefore, novel approaches are a prerequisite to elucidating the genetic and epigenetic mechanisms underlying PC progression for healthier lifelong survival.
Identification of prognostic risk factors for pancreatic cancer using bioinformatics analysis
Background
Pancreatic cancer is one of the most common malignant cancers worldwide. Currently, the pathogenesis of pancreatic cancer remains unclear; thus, it is necessary to explore its precise molecular mechanisms.
Methods
To identify candidate genes involved in the tumorigenesis and proliferation of pancreatic cancer, the microarray datasets GSE32676 , GSE15471 and GSE71989 were downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) between Pancreatic ductal adenocarcinoma (PDAC) and nonmalignant samples were screened by GEO2R. The Database for Annotation Visualization and Integrated Discovery (DAVID) online tool was used to obtain a synthetic set of functional annotation information for the DEGs. A PPI network of the DEGs was established using the Search Tool for the Retrieval of Interacting Genes (STRING) database, and a combination of more than 0.4 was considered statistically significant for the PPI. Subsequently, we visualized the PPI network using Cytoscape. Functional module analysis was then performed using Molecular Complex Detection (MCODE). Genes with a degree ≥10 were chosen as hub genes, and pathways of the hub genes were visualized using ClueGO and CluePedia. Additionally, GenCLiP 2.0 was used to explore interactions of hub genes. The Literature Mining Gene Networks module was applied to explore the cocitation of hub genes. The Cytoscape plugin iRegulon was employed to analyze transcription factors regulating the hub genes. Furthermore, the expression levels of the 13 hub genes in pancreatic cancer tissues and normal samples were validated using the Gene Expression Profiling Interactive Analysis (GEPIA) platform. Moreover, overall survival and disease-free survival analyses according to the expression of hub genes were performed using Kaplan-Meier curve analysis in the cBioPortal online platform. The relationship between expression level and tumor grade was analyzed using the online database Oncomine. Lastly, the eight snap-frozen tumorous and adjacent noncancerous adjacent tissues of pancreatic cancer patients used to detect the CDK1 and CEP55 protein levels by western blot.
Conclusions
Altogether, the DEGs and hub genes identified in this work can help uncover the molecular mechanisms underlying the tumorigenesis of pancreatic cancer and provide potential targets for the diagnosis and treatment of this disease.
Terpenoids as Potential Targeted Therapeutics of Pancreatic Cancer: Current Advances and Future Directions
MicroRNA Regulation of K-Ras in Pancreatic Cancer and Opportunities for Therapeutic Intervention
Dec 2017
Saswati Karmakar
Garima Kaushik
The Ras family of GTPases is involved in cell proliferation, cell survival, and angiogenesis. It is upregulated in several cancers, including pancreatic cancer (PC) and leads to uncontrolled growth and aggressiveness. PC is well known to be a lethal disease with poor prognosis, plagued by limited therapeutic modalities. MicroRNAs (miRNAs), which are short non-coding RNA molecules, have recently emerged as regulators of signaling networks and have shown potential to target pathway components for therapeutic use in several malignancies. K-Ras mutations are widespread in PC cases (90%), with mutations detectable as early as pancreatic intraepithelial neoplasias and in later metastatic stages alike; therefore, these mutations in K-Ras are obvious drivers and potential targets for PC therapy. Several K-Ras targeting miRNAs have lately been discovered, and many of them have shown promise in combating pancreatic tumor growth in vitro and in mouse models. However, the field of miRNA therapy is still in its infancy, and miRNA mimics or anti-miRNA oligonucleotides that target Ras pathway have thus far not been evaluated in PC patients. In this review, we summarize the role of several miRNAs that regulate oncogenic K-Ras signaling in PC, with their prospective roles as therapeutic agents for targeting K-Ras pathway.
Circulating Tumour Cells
Jan 2017
Konstantinos Georgiadis
Kathryn Simpson
Mahmood Ayub
Caroline Dive
Analysis of cellular and molecular components of tumour origin detectable in the bloodstream, so-called liquid biopsies, is demonstrating potential to support management of cancer patients. Development of sensitive technologies enables detection, isolation, and downstream analysis of both circulating tumour cells (CTCs) and circulating tumour DNA (ctDNA) from the blood of patients with various malignancies, in a minimally invasive way, allowing temporal and spatial monitoring of the clinical course of the disease. This is particularly significant in cancers such as pancreas cancer, a particularly aggressive disease with limited treatment options and poor outcomes, where serial biopsy is challenging. CTC enumeration; genomic, transcriptomic, and proteomic analysis; as well as in-depth sequencing of ctDNA may define a comprehensive molecular and genetic landscape of pancreatic cancer and provide a set of novel biomarkers for screening, diagnosis, prognosis, and response assessment. A number of pilot studies have been conducted to assess the role of liquid biopsies in the setting of pancreatic cancer. Although results so far seem promising, more extensive studies are required to establish the clinical utility of CTCs and ctDNA in developing a personalized approach for the management of this malignancy.
Genetics and Prevention of Pancreatic Cancer
Dale Vimalachandran
Paula Ghaneh
Eithne Costello
John P Neoptolemos
Background
Pancreatic cancer is an aggressive disease with a poor prognosis. Hereditary factors have been reported in up to 10% of cases of pancreatic cancer. The clinical characteristics and genetic abnormalities have been identified for a proportion of this high-risk group, and the development of preventive strategies for these individuals is now a primary goal of cancer clinicians.
Methods
A review of the current literature regarding the genetics, screening, and prevention of pancreatic cancer and its precursor lesions was undertaken.
Results
Risk factors for pancreatic cancer include smoking, chronic pancreatitis, and a genetic predisposition. The role of diabetes or a diet high in fat or meat remains unclear. The genetic mutations that accompany pancreatic cancer appear to occur in a temporal sequence, beginning in the earliest of precursor lesions. These mutations are detectable in pancreatic juice and, in conjunction with imaging, form the basis of screening programs for high-risk individuals. Not all precursor lesions will undergo malignant transformation, and testing is currently limited in its ability to determine which lesions will undergo transformation.
Conclusions
Avoiding tobacco smoking and minimizing risk factors associated with chronic pancreatitis are recommended to reduce the risk of pancreatic cancer. Individuals with a high-risk genetic background require counseling, genetic testing if appropriate (BRCA2 mutation or p16 INK4A inactivity) and secondary screening for pancreatic cancer in specialist centers. Risk stratification will improve as more genetic abnormalities causing pancreatic cancer are defined.
Liquid biopsies come of age: towards implementation of circulating tumour DNA
Feb 2017
Jonathan C M Wan
Charlie E Massie
Javier Garcia-Corbacho
Improvements in genomic and molecular methods are expanding the range of potential applications for circulating tumour DNA (ctDNA), both in a research setting and as a 'liquid biopsy' for cancer management. Proof-of-principle studies have demonstrated the translational potential of ctDNA for prognostication, molecular profiling and monitoring. The field is now in an exciting transitional period in which ctDNA analysis is beginning to be applied clinically, although there is still much to learn about the biology of cell-free DNA. This is an opportune time to appraise potential approaches to ctDNA analysis, and to consider their applications in personalized oncology and in cancer research.
Tumorbiologische und molekulargenetische Aspekte
Chapter
Jan 2010
Prof. Dr. med. G. Auer
Prof. Dr. med. H.-P. Bruch
PD Dr. Dr. med. J.K. Habermann
Durch die Fortschritte in der Molekularbiologie und deren Applikation in der Tumorforschung können die molekularen Mechanismen analysiert werden, die zu unkontrolliertem Zellwachstum führen und damit die Karzinogenese induzieren. Die Definition neuer molekularer Pathways eröffnet Möglichkeiten, neue Strategien für Diagnostik, Intervention und Behandlung von Malignomen zu entwickeln. Das molekulare Verständnis der Tumorentstehung zeigt, weshalb die Behandlung häufig hoch komplex ist. Es wird uns aber in Zukunft helfen, individuelle Diagnostik durchzuführen und eine patientenbezogene Behandlungsstrategie zu entwickeln.
Molecular Detection of Gastrointestinal Neoplasia
Sep 2016
Bradley W Anderson
David A. Ahlquist
Emerging molecular tools promise to extend the diagnostic reach of the endoscopist and open doors to population screening for gastrointestinal (GI) cancers. This review briefly addresses biological considerations in marker detection and types of markers, highlights examples of tools under development at each organ site, and appraises the possibility of universal GI cancer screening. The outlook is positive, but further technical refinement and rigorous clinical validation are needed before most of these new approaches are ready for clinical application.
Pancreas
Chapter
Jan 2002
Christine A Iacobuzio-Donahue
Michael Goggins
Ralph H. Hruban
Pancreatic cancer is one of the deadliest of all of the cancers. New approaches to detect early pancreatic cancer and pancreatic cancer precursors, and to prevent pancreatic cancer in populations at risk, are urgently needed. We believe that the revolution in our understanding of the molecular genetics of pancreatic neoplasia which has occurred in the last 10 years will provide a basis for the development of these new approaches.
Inherited Genetics of Pancreatic Cancer and Secondary Screening
Jan 2010
The process of cancer screening starts with a large population that has many more individuals who are free of cancer than there are people who have occult disease. Then by a process of risk stratification low-risk individuals are removed until a point is reached where the majority of the population (the end population) has cancer. Ideally at the end point of this process testing becomes diagnostic, but in all cases at the end point positive test results must result in an offer of treatment. In the case of pancreatic cancer, curative treatment must include surgical resection of all or part of the pancreas, a process that involves considerable morbidity. Screening must therefore give an end population where the benefits of early treatment for those with cancer outweigh the harm done to false positive individuals who will be offered unnecessary surgery. Screening can be divided into primary and secondary, primary screening being observational and secondary involving active testing. In reality there is considerable overlap and a multidisciplinary team needs to consider the entire process when deciding whether screening is justified. In the case of pancreatic cancer this requires additional quantitative as well as qualitative data on each phase of the screening process; this can only be obtained from pilot screening studies. Such studies have been initiated and are generating data on the nature of inherited predisposition and the early stages of cancer development. It is already apparent that the specificity and sensitivity of secondary screening tests need to be improved. In this chapter, the preliminary evidence from pioneering screening studies will be considered. On the basis of this there will be a discussion of which participants should be recruited into future pilot studies and how biomarkers may be combined with imaging to reduce the number of missed cancers and premature surgical interventions.
Screening for Pancreatic Cancer Using Techniques to Detect Altered Gene Products
Chapter
Jan 1998
Robb E. Wilentz
Robbert J.C. Slebos
Although cancer of the pancreas accounts for only 2% of new cancer cases in the United States, it is the fifth leading cause of cancer death (1). This is true because many patients with pancreatic cancer are not diagnosed until late in the course of the disease, when the carcinoma has already metastasized or spread locally, and is no longer curable. Although 5-yr survival for all patients with cancer of the pancreas is 3% (2), 5-yr survival after successful pancreaticoduodenectomy (Whipple procedure) approaches 20% overall, and may be as high as 40% in patients with small tumors, negative lymph nodes, and negative surgical margins (3–4). Therefore, methods that can detect pancreatic cancers earlier, when they are still surgically resectable, will improve patient outcome.
Molecular Basis of Pancreatic Cancer: Strategies for Genetic Diagnosis and Therapy
Chapter
Jan 1999
F. C. McCormick
Cancer is essentially a genetic disease, and tumour progression occurs as a multistep process with the accumulation of multiple genetic abnormalities that lead to an unstable malignant genotype. The molecular biology of pancreatic cancer is still poorly understood, though recently significant progress has been made with the identification of at least four genes involved in tumorigenesis. The genetic profile of pancreatic cancer not only involves proto-oncogene activation, and loss of tumour suppressor gene function but also derangement of the signal transduction systems for growth factors and their receptors.
Differenzierung einer Pankreas-Adenokarzinomzellinie zu polarisierten Epithelhohlkugeln: Ein in vitro Modell zum Studiurn von Vorläuferläsionen des Pankreasganges
Chapter
Jan 1999
Dipl. Biol. Lasse Lehnert
Hartwig Trost
Wolff H. Schmiegel
H Kalthoff
Maligne Erkrankungen des Pankreas sind hochagressiv und entstehen überwiegend im exokrinen Teil. Nach ihrem mikroskopischen Erscheinungsbild werden diese Tumore als duktale Adenokarzinome klassifiziert [1]. Viele molekulare Veränderungen wie z. B. Mutationen in p53- und Ki-ras-Gen sind beschrieben [2]. Dennoch ist nocht nicht viel über die Ursache der Agressivität bekannt. Hinweise gibt es aus dem kolorektalen Karzinom über den Verlust von E-Cadherin oder Mutationen von anderen Zelladhäsionsmolekülen [3]. Untersuchungen zu dreidimensionalem Wachstum von Tumorzellen ermöglichten uns die Beschreibung eines Differenzierungsmodells. Dieses besteht aus einschichtigen Epithelhohlkugeln (hollow-spheres) und wurde hinsichtlich der Proliferation, der Polarität und Modulierbarkeit durch Zytokine untersucht.
Familiäres Pankreaskarzinom
Chapter
Jan 2001
Detlef K Bartsch
Matthias Rothmund
Pankreaskarziome sind in 85–90% der Fälle duktale Adenokarzinome, d.h. Tumoren, die aus den duktalen Zellen des adulten exokrinen Pankreas entstehen. Die duktalen Pankreaskarzinome stellen in zunehmenden Maß ein öffentliches Gesundheitsproblem dar. Ihre Inzidenz nahm von 1990–1995 zu, während bei nahezu allen anderen soliden Tumoren ein Rückgang zu verzeichnen war (Koch 1996). Die Häufigkeit des duktalen Pankreaskarzinoms beläuft sich auf etwa 11000 Neuerkrankungen pro Jahr in Deutschland und die Prognose ist mit einer 5-Jahres-Überlebensrate von <5% extrem schlecht (Robert-Koch-Institut 1995). Die Letalität des duktalen Pankreaskarzinoms entspricht nahezu seiner Inzidenz, wobei jeder 6. Krebstod in Deutschland inzwischen durch ein duktales Pankreaskarzinom verursacht wird. Allerdings werden von einigen Zentren 5-Jahres-Überlebensraten von bis zu 40% beschrieben, wenn eine Tumorresektion im UICC-Stadium 1 durch-geführt werden konnte (Yeo u. Cameron 1998).
Clinical Applicability of Molecular Procedures in the Diagnosis of Pancreatic Cancer
Chapter
Jan 1997
H Friess
Pascal O Berberat
M W Büchler
Pancreatic cancer is a devastating disease with a median survival of five months after diagnosis [24, 56]. The incidence of pancreatic carcinoma in Western industrialized countries has increased significantly as the median life expectancy has been prolonged and better diagnostic options have become available. At present, approximately 10/100 000 individuals die of pancreatic cancer every year, making it the fourth to fifth most common cause of cancer-related mortality [24, 56, 69, 77].
Molecular Biology of Pancreatic Cancer
Chapter
Jan 1995
Murray Korc
The mammalian exocrine pancreas consists of acinar cells that synthesize and secrete digestive enzymes and duct cells that secrete bicarbonate rich fluid. Pancreatic exocrine function is regulated by gastrointestinal hormones, neurotransmitters, islet cell hormones such as insulin, and polypeptide growth factors. Under normal physiological conditions in the adult, there is a relatively low level of pancreatic acinar and duct cell proliferation, and proper progression through the cell cycle is assured by the presence of functioning protooncogenes and tumor suppressor genes. However, in conjunction with a variety of cellular and molecular perturbations in growth control mechanisms, the pancreas may give rise to a variety of malignancies. These malignancies may originate in any of the pancreatic cell types, leading to ductal carcinomas, acinar cell carcinomas, or islet cell tumors. Conceivably, some of these cancers may arise from a pancreatic stem cell that has the potential to acquire the characteristics of any of the above cell types. Alternatively, a given pancreatic cancer may appear to be a ductal carcinoma but may have arisen as a result of malignant transformation in another pancreatic cell which has acquired the duct cell phenotype.
Treatment of Pancreatic and Ampullary Cancer
Chapter
Jan 2002
John M. Howard
Walter Hess
With the exception of the operations by Hirschel and Tenani, no further reports on radical Surgery of pancreatic tumors were published between 1912 and 1935. It must be added that the very limited resections of pancreatic tissue performed by Kausch, Hirschel, and Tenani. were little more than ampullectomies. Thus, as the 1930s approached, history had recorded only three patients who had survived “pancreatoduodenal” resection — each for carcinoma of the ampulla. One of Kausch’s patients had survived a two-stage resection for nine months, dying of a poorly designed biliary-enteric anastomosis. No residual cancer was detected at autopsy. Hirschel’s patient survived a limited one-stage resection for approximately 12 months; death, perhaps, being the result of an inadequate reconstruction, although the surgeon, in the absence of autopsy, assumed that death was due to recurrent cancer. Tenani had performed a two-stage resection, his patient apparently being free of disease three years after resection of an ampullary carcinoma.
A case of small pancreatic cancer diagnosed by serial follow-up studies promptly by a positive K-ras point mutation in pure pancreatic juice
Koji Ochi
We report a 74-yr-old woman who was referred to our hospital because of abdominal fullness. ERP showed a questionable irregularity of the main pancreatic duct at the body. Examination of pure pancreatic juice was positive for K-ras point mutation at codon 12 and negative for cytology. Because neither US nor CT showed apparent lesions in the pancreas, we decided to follow up the patient with serial ERP and pure pancreatic juice studies at 3-month intervals. No changes had been seen up to 18 months later, when cytology was conclusive for malignancy with an apparent stenosis of the main pancreatic duct at the body. Distal pancreatectomy with splenectomy was performed. A round mass, 12 mm in diameter, was found in the body, which proved to be an adenocarcinoma at histological examination. No extrapancreatic extension and metastases were noted. Although positive K-ras point mutation has been reported in some cases of adenoma or mucinous cell hyperplasia of the pancreas and chronic pancreatitis, our case, along with previous reports, indicated the importance of testing K-ras point mutation in pure pancreatic juices for the diagnosis of pancreatic cancer at an early stage.
Molecular Genetics of Pancreatic Carcinoma
Chapter
Jan 1998
Christopher A Moskaluk
Scott E Kern
The application of modern molecular biological techniques to the study of human tumors in the past two decades has demonstrated that cancer is a genetic disease. Strucalterations in genomic DNA (point mutation, gene rearrangement, and gene deletion), which result in alterations in protein coding sequences or their expression, have been found in every human neoplasm studied. The finding of these genetic alterations in invasive cancers and in their histologically identifiable neoplastic precursor lesions, but not in the nonneoplastic tissues from which they arose, is consistent with the theory that neoplastic progression is the result of the clonal evolution of cellular populations accompanying a selection for mutations (1,2). Germ-line mutations in specific genes are also responsible for many cases in which there is a familial predisposition to cancer (3), further underscoring the genetic basis of cancer.
Pancreatic Cancer Genomics
Chapter
Jan 2013
Vincenzo Corbo
Andrea Mafficini
Eliana Amato
Aldo Scarpa
Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with the worst prognosis among all solid tumors [1]. Although surgical resection offers the only hope for cure, it is possible in only 20% of patients that present with local disease [2]. Indeed, most patients are diagnosed at an advanced stage, when the disease is inoperable. Whether dismal prognosis is a result of late diagnosis or early dissemination to distant organ is still a debate. Systemic chemotherapy provides temporary benefits in controlling advanced disease and prolonging survival in the adjuvant setting but this happens in a small proportion of patients. Several factors are supposed to contribute variably to the intrinsic chemotherapic resistance of pancreatic cancer and include: (i) the presence of a dense stromal component (termed desmoplastic reaction) that significantly reduces drug delivery [3]; (ii) the transformation of epithelial cells into a mesenchymal phenotype (referred to as epithelial to mesenchymal transition, EMT) [4]; and (iii) the presence of pancreatic cancer stem cells [5]. To complicate our understanding of chemoresistance, there is the marked molecular heterogeneity among primary tumors and metastatic deposits (discussed in details below) [6]. © 2013 Springer Science+Business Media Dordrecht. All rights are reserved.
Levi S, Urbano-Ispizua A, Gill R, Thomas DM, Gilbertson J, Foster C, Marshall CJMultiple K-ras codon 12 mutations in cholangiocarcinomas demonstrated with a sensitive polymerase chain reaction technique. Cancer Res 51: 3497-3502
Aug 1991
Sassoon Levi
A Urbano-Ispizua
R Gill
Christopher J Marshall
By using a modified polymerase chain reaction strategy, we have devised an approach to detect a K-ras oncogene mutated at codon 12 in the presence of 1000 normal alleles. This is a considerable improvement in sensitivity on previous assays. Application of this assay to 15 cholangiocarcinomas showed that all contained a K-ras mutation to codon 12 and that nine of the tumors contained two or more mutations. In 11 cases, mutations were present in less than 10% of the cells in the sample. In common with pancreatic adenocarcinomas, in which 75 to 95% of cases contain a mutation in K-ras, cholangiocarcinomas show a very high frequency of ras gene mutation, but within a tumor only a fraction of cells contain a ras mutation. The presence of multiple mutations and the low frequency of mutant alleles in the samples argue against K-ras mutations being the initiating genetic lesion in this tumor, but suggest that ras gene mutation is involved in the stepwise progression of neoplastic cells to full malignancy.
Detection of c-K-ras mutations in fine needle aspirates from human pancreas adenocarcinomas
Article
Mar 1990
Daichi Shibata
N Arnheim
Concepción Almoguera
Kathleen Forrester
Formalin-fixed paraffin-embedded tissue specimens obtained by fine needle aspiration of pancreatic masses from 47 patients were examined retrospectively for cytology and the presence of mutant c-K-ras oncogenes. Point mutations of c-K-ras in codon 12 were detected by RNA-DNA RNAse A mismatch cleavage after in vitro DNA amplification of the cellular c-K-ras sequences by the polymerase chain reaction. Of the 36 patients with pancreatic adenocarcinoma, mutant c-K-ras oncogenes were detected in 18 of 25 (72%) with malignant cytologies, 2 of 8 (25%) with atypical cytologies, and 0 of 3 with benign aspiration cytologies. The remaining 11 patients without pancreatic adenocarcinomas did not have mutant c-K-ras genes detectable by the assay. The diagnosis of pancreatic adenocarcinoma was based upon clinical follow-up. The presence of mutant c-K-ras oncogenes did not significantly affect survival in the patients studied. Mutant c-K-ras genes were found at the time of initial clinical presentation in the majority of pancreatic adenocarcinomas, suggesting an important role of the mutation in oncogenesis. In conjunction with cytology, our approach represents an application for cancer diagnosis at the molecular genetic level.
| https://www.researchgate.net/publication/15186228_Caldas_C_Hahn_SA_Hruban_RH_Redston_MS_Yeo_CJ_Kern_SEDetection_of_K-ras_mutations_in_the_stool_of_patients_with_pancreatic_adenocarcinoma_and_pancreatic_ductal_hyperplasia_Cancer_Res_54_3568-3573 |
Efficacy and Tolerability of IRL790 in Parkinson's Disease Dyskinesia - Full Text View - ClinicalTrials.gov
Efficacy and Tolerability of IRL790 in Parkinson's Disease Dyskinesia
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government.
Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT03368170 Recruitment Status :
Completed First Posted : December 11, 2017 Results First Posted : March 24, 2020 Last Update Posted : March 31, 2022
Sponsor:
The Clinical Trial Company
Information provided by (Responsible Party):
Integrative Research Laboratories AB
Study Details
Study Description
Brief Summary:
Mesdopetam (IRL790) is an experimental small molecule compound with psychomotor stabilizing properties. The primary target is the dopamine D3 receptor, a target implicated in the generation of levodopa-induced dyskinesia, a side-effect frequently occurring with long-term levodopa treatment in patients with Parkinson's disease. In experimental animals mesdopetam potently reduced levodopa-induced involuntary movement without impairing the antiparkinsonian effect of levodopa.
The primary purpose of the trial is to investigate whether mesdopetam given as adjunctive treatment can reduce levodopa induced dyskinesia in patients with Parkinson's disease. The trial will also help to establish the most optimal dosing of the compound.
Condition or disease Intervention/treatment Phase Parkinson Disease Drug: Mesdopetam (IRL790) Phase 2
Detailed Description:
METHODOLOGY:
This is a multicentre study where 74 patients with Parkinson's disease exhibiting levodopa induced dyskinesia will be randomised to receive study drug or placebo. Thirty seven patients will be randomised to mesdopetam and 37 patients to placebo (1:1 randomisation).
Patients will be screened for eligibility according to inclusion/exclusion criteria within four weeks of initiation of study treatment (Screening visit).
An outpatient study with the patients taking the study drug for four weeks at home. Mesdopetam will be taken twice daily (b.i.d.) as adjunctive treatment to the patients' regular and stable antiparkinsonian medication.
The first two weeks of treatment will allow for per patient titration of study medication to the highest tolerated predefined dose, after which patients will continue on this highest tolerated dose for an additional two weeks.
Pharmacokinetic (PK) samples will be collected for the determination of concentrations of mesdopetam and its metabolites IRL902 and IRL872 in plasma. They will be collected before and after IMP administration at two visits.
A Follow-up Visit will be performed for all patients five to eight days after last administration of IMP.
Study Design
Layout table for study information Study Type : Interventional
(Clinical Trial) Actual Enrollment : 75 participants Allocation: Randomized Intervention Model: Parallel Assignment Intervention Model Description: Double blind, placebo controlled Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor) Primary Purpose: Treatment Official Title: A Randomized, Placebo-controlled, Phase IIa Study Evaluating the Efficacy and Tolerability of IRL790 in Parkinson's Disease Dyskinesia Actual Study Start Date : April 12, 2018 Actual Primary Completion Date : June 12, 2019 Actual Study Completion Date : June 12, 2019
Resource links provided by the National Library of Medicine
MedlinePlus Genetics related topics: Parkinson disease
MedlinePlus related topics: Parkinson's Disease
U.S. FDA Resources
Arms and Interventions
Arm Intervention/treatment Experimental: Mesdopetam (IRL790) Capsule 2.5 mg, oral administration Drug: Mesdopetam (IRL790) Mesdopetam (IRL790) capsule Other Name: IRL790 Placebo Comparator: Placebo Identical capsule, oral administration Drug: Mesdopetam (IRL790) Mesdopetam (IRL790) capsule Other Name: IRL790
Outcome Measures
Unified Dyskinesia Rating Scale (UDysRS) [ Time Frame: Baseline and 4 weeks ]
The change from baseline to day 28 of treatment (Visit 4) in the sum of the items comprising the Unified Dyskinesia Rating Scale (UDysRS). The Unified Dyskinesia Rating Scale (UDysRS) is administered to assess dyskinesia. The scoring range is 0-104, where higher score means more dyskinesia.
Secondary Outcome Measures
:
Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part IV, Question 4.1 and 4.2 [ Time Frame: Baseline and 4 weeks ]
Change in MDS-UPDRS sum score of questions 4.1 (Time spent with dyskinesias) and 4.2 (Functional impact of dyskinesias) in part IV from baseline to visit 4. Minimum score is 0 and maximum score is 8. A higher score means more dyskinesia.
Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Part II and III [ Time Frame: Baseline and 4 weeks ]
Change in MDS-UPDRS sum score of parts II+III (Motor aspects of Experiences of Daily living + Motor Examination) from baseline to visit 4. Minimum value is 0 and maximum value is 124. Higher score mean a worse outcome.
Other Outcome Measures:
Change in Daily Hours Spent in ON-time With Troublesome Dyskinesia as Assessed by 24-hour Patient Diaries [ Time Frame: Run-in and 4 weeks ]
Change in ON-time with troublesome dyskinesia as assessed by patient completed 24-hour diaries, from run-in to visit 4. This is a self administered diary where patients assess their motor state every half hour during 24 hours.
The different motor states assessed: ON, ON with troublesome dyskinesia, OFF and asleep.
Eligibility Criteria
Information from the National Library of Medicine
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
Layout table for eligibility information Ages Eligible for Study: 18 Years to 79 Years (Adult, Older Adult) Sexes Eligible for Study: All Accepts Healthy Volunteers: No
Criteria
Inclusion Criteria:
Male or female ≥18 and ≤79 years of age.
Signed a current Ethics Committee approved informed consent form.
Parkinson's disease, per UK Parkinson's Disease Society (UKPDS) Brain Bank Clinical Diagnostic Criteria.
Waking day dyskinesia of ≥25% determined as a score of ≥2 as per Question 4.1 of the MDS-UPDRS.
On a stable regimen of antiparkinson medications for at least 30 days prior to screening, including a levodopa preparation administered not less than three times daily and willing to continue the same doses and regimens during study participation. Rescue medication such as Madopar dispersable and Apomorphine injections are allowed.
Taking a maximum of eight regular levodopa intakes per day, excluding bedtime and night time levodopa.
Any other current and allowed prescription/non-prescription medications and/or nutritional supplements taken regularly must have been at a stable dose and regimen for at least 30 days prior to screening and the patient must be willing to continue the same doses and regimens during study participation (this criterion does not apply to medications that are being taken pre-study only on an as-needed basis).
Patient must be willing and able to avoid direct exposure to sunlight from day 1 to day 28.
Able to complete at least one valid 24-hour patient diary at Visit 1.
Exclusion Criteria:
History of neurosurgical intervention related to Parkinson's disease (e.g. deep brain stimulation).
Treatment with pump delivered antiparkinsonian therapy (i.e. subcutaneous apomorphine or levodopa/carbidopa intestinal infusion).
History of seizures within two years prior to screening.
History of stroke or transient ischemic attack (TIA) within two years prior to screening.
History of cancer within five years prior to screening, with the following exceptions: adequately treated non-melanomatous skin cancers, localised bladder cancer, non-metastatic prostate cancer or in situ cervical cancer.
Presence of cognitive impairment, as evidenced by a Mini-Mental Status Examination (MMSE) score of less than 24 during screening.
A Hoehn and Yahr score of five when "off" as per Question 3.18 of the MDS-UPDRS, assessed during screening.
Any history of a significant heart condition or cardiac arrhythmias within the past 5 years, any repolarisation deficits or any other clinically significant abnormal ECG as judged by the Investigator
Severe or ongoing unstable medical condition including a history of poorly controlled diabetes; obesity associated with metabolic syndrome; uncontrolled hypertension; cerebrovascular disease, or any form of clinically significant cardiac disease; clinically significant symptomatic orthostatic hypotension; clinically significant hepatic disease, renal failure or abnormal renal function.
Any history of a neurological other than Parkinson's disease or a psychiatric disorder, including history of DSM IV diagnosed major depression or psychosis. Patients with illusions or hallucinations with no loss of insight will be eligible. Patients with mild depression who are well controlled on a stable dose of an antidepressant medication for at least 4 weeks before screening will be eligible.
Enrolment in any other clinical study involving medication, medical devices or surgical procedures, current or within three months prior to screening visit, or previous participation in the present study. Patients enrolled in non-interventional clinical trials will be eligible.
Drug and/or alcohol abuse.
History of severe drug allergy or hypersensitivity.
If female, is pregnant or lactating, or has a positive pregnancy test result pre-dose.
Patients unwilling to use two forms of contraception 90 days for men and 30 days for women after last IMP dose
Any planned major surgery within the duration of the study.
Any other condition or symptoms preventing the patient from entering the study, according to the Investigator's judgement.
Locations
Documents provided by Integrative Research Laboratories AB:
Study Protocol [PDF] January 14, 2019
Statistical Analysis Plan [PDF] June 13, 2019
Layout table for additonal information Responsible Party: Integrative Research Laboratories AB ClinicalTrials.gov Identifier: NCT03368170 History of Changes Other Study ID Numbers: IRL790C003 First Posted: December 11, 2017 Key Record Dates Results First Posted: March 24, 2020 Last Update Posted: March 31, 2022 Last Verified: March 2022 Individual Participant Data (IPD) Sharing Statement: Plan to Share IPD: No
Layout table for additional information Studies a U.S. FDA-regulated Drug Product: No Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Integrative Research Laboratories AB:
Levodopa induced dyskinesia
Disclaimer
| https://clinicaltrials.gov/ct2/show/NCT03368170?rank=1 |
Direct and Structural Violence Against Transgender Populations: a Comparative Legal Study - DocsLib
Florida Journal of International Law Volume 31 Issue 2 Article 2 2021 Direct and Structural Violence against Transgender Populations: A
Florida Journal ofInternational Law
Volume 31 Issue 2 Article 2
2021
Direct and Structural Violence againstTransgenderPopulations: A Comparative Legal Study
Brian Kritz
Follow this and additional works at: https://scholarship.law.ufl.edu/fjil
Part of the Civil Rights andDiscriminationCommons, International Law Commons, and the Law and Gender Commons
Recommended Citation Kritz, Brian (2021) "Direct and Structural Violence against Transgender Populations: A Comparative Legal Study,"FloridaJournal of International Law: Vol. 31 : Iss. 2 , Article 2. Available at: https://scholarship.law.ufl.edu/fjil/vol31/iss2/2
This Article is brought to you for free and open access by UF Law Scholarship Repository. It has been accepted for inclusion in Florida Journal of International Law by an authorized editor of UF Law Scholarship Repository. For more information, please [email protected]: Direct and Structural Violence against Transgender Populations: A
DIRECT AND STRUCTURAL VIOLENCE AGAINST TRANSGENDER POPULATIONS: A COMPARATIVE LEGAL STUDY
Brian Kritz*
Abstract This Article is a comparative study exploring how the law impactsTransgender rightsand Transgender access to justice. In countries where the law is hostile to Transgender rights, such law perpetuates structural violence, promotes discrimination andpersecution, causing direct violence against Transgender populations. In countries where the law is more progressive, an interesting phenomenon exists. In these countries, where Transgender lives can be more openly lived, Trans-violence rates are noticeably higher than in countries where Transgender rights are restricted. This scholarship was developed with an eye towards reforming the law in countries with problematic legal structures and continuing efforts to protect Transgender lives in more progressive countries. I hope that this Article, researched and written at the intersection of Transgender life and law, provides an engine for greater discussion on how Transgender populations can be better protected, allowing them to live freely under the letter and spirit of the Universal Declaration ofHuman Rights.
INTRODUCTION ...... 212
I. VIOLENCE AGAINST TRANSGENDER PERSONS AND COMPARATIVE LAW ...... 214 A . Trans Murder ...... 2 14 B. The Underreportingof Trans-Violence as a Constant...... 216 C. A Theory of Structural Violence ...... 218
II. DISCRIMINATORY LAW AS A FORM OF TRANS-VIOLENCE ...... 219 A . G uy an a ...... 2 19 B. Malawi...... 220 C . Saud i A rabia ...... 22 1 D . Ug a n da ...... 2 2 3
III. SUPPORTIVE LAW AND RAMPANT TRANS-VIOLENCE ...... 225 A. Argentina...... 225 B.Brazil...... 227 C . Pa k ista n ...... 2 2 8 D . In dia ...... 2 3 0 E . Nep a l ...... 2 3 3
211 Published by UF Law Scholarship Repository, 2021 1 Florida Journal of International Law, Vol. 31 [2021], Iss. 2, Art. 2
212 FLORIDA JOURNAL OF INTERNATIONAL LAW [Vol. 31
C O N C L U SIO N ...... 2 3 6
INTRODUCTION In recent years, recognition oflesbian,gay, bisexual, transgender, andqueer(LGBTQ) rights has received a vast amount of attention. Examples include aUnited NationsResolution on human rights,sexual orientationandgender identityin June 20111 and the subsequent Report of the United Nations High Commission for Human Rights on Discrimination and Violence Against Individuals Based on their Sexual Orientation and Gender Identity in 2014;2 progressive court rulings in Colombia in 2011;3 a reversal of discriminatory national legislation in Malawi in 2012;4 and the 2013 Inaugural Address and the 2014 State of the Union Address of theUnited StatesPresident Barack Obama. These examples signal the seemingly continued expansion of the protection and promotion of the basic rights of LGBTQ communities. However, the rights of Transgender persons, standing alone, often are merely lumped in with the other groups in the LGBTQ acronym, and rarely is the issue of Transgender rights, standing alone, discussed and addressed. There are moments where Transgender rights rise to the forefront, as was the case in 2014 in National Legal Services Authority v. Union of India, where the Supreme
* Brian Kritz is a Faculty Fellow in the M.A. Program in Conflict Resolution at Georgetown University. He was previously the Associate Director of the M.A. Program in Conflict Resolution at Georgetown, the Book Review Editor for Law Titles forGenocideStudies and Prevention: an International Journal, a Research Fellow in the MA Program in Conflict Resolution and a Senior Fellow at the Institute for International Law, Technology, and Global Security at Georgetown. In addition, he was a Democracy Fellow and Senior Human Rights and Rule of Law Advisor at USAID, a pro bono legal advisor to the Prosecutor General's Office for the Republic of Rwanda, and criminal prosecutor in California. His publications include articles on comparative law affecting transgender populations, the balance between national security and democracy in Rwanda, the global transgender population and the International Criminal Court (ICC), the crime of the knowing and intentional spread of HIV/AIDS and the ICC, traditional dispute resolution in Palestine, justice and reconciliation in Darfur, international legal protections for women andfemalechildren in Rwanda, and a textbook chapter on integrated peacebuilding and the rule of law. 1. Human Rights Council Res. 17/19, U.N. Doc. A/HR/RES/17/19 (July 14, 2011). 2. Human Rights Council Res. 29/23, U.N. Doc. A/HRC/29/23 (May 4, 2015). 3. Colombian Court Says Congress Must Decide on Gay Marriage, CNN WORLD, (July 27, 2011), http://www.cnn.com/2011/WORLD/americas/07/27/colombia.gay.marriage/ index.html. The Constitutional Court of Colombia ruled that "gay couples in de facto unions constitute a family" and gave the Congress two years to create legislation addressing same-sex marriages. 4. Godfrey Mapondera & David Smith, Malawi Suspends Anti-Gay Laws as MPs Debate Repeal,THE GUARDIAN(Nov. 5, 2012), http://www.guardian.co.uk/world/2012/nov/05/malawi- gay-laws-debate-repeal. In November of 2012, President Joyce Banda of Malawi announced a moratorium on sections 153 and 156 of the national penal code, which criminalizes sexual conduct between men and section 137A, which criminalizes "indecent practices betweenfemales," until Parliament decides the issue.
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2020] DIRECT AND STRUCTURAL VIOLENCE AGAINST TRANSGENDER POPULATIONS 213
Court of India provided for legal recognition of athird gender.5 But, in the aggregate, global attention to the rights of Transgender persons is greatly muted in comparison to the dialogue in support of LGBQ rights. However, Transgender persons are vulnerable in the same way that LGBQ populations are vulnerable, as the victims of both direct violence and structural violence and discrimination and persecution. For example, in March 2012, around seventy Iraqi Transgender males were murdered in and aroundBaghdad, for dressing in tight-fitting, androgynous clothing, nose rings, studded leather belts and bracelets, dyed hair, and these presumed links to non-traditional gender identity.6 Similarly, planned violent attacks on Transgender persons have occurred with increasing regularity in Russia. On August 20, 2013, in Moscow, five men ambushed a Transwoman in a public park during daylight hours. The victim was severely beaten while being dragged around the park by her attackers. Her assailants videoed the attack and posted the video on a Russian equivalent of Facebook.7 This is one example in a series of videoed attacks in Russia, and Russia is not alone in this phenomenon. Transgender persons in many countries suffer from endemic hostility, persecution, and violence.' Violence against Transgender persons also takes a less overt form. Inequality in social and legal structures exclude Transgender persons from basic rights such as the right to adequate healthcare and equal access to justice. As one report shows through case studies on Transgender rights across the globe, structural inequalities lead to poverty, marginalization, and "may also prevent Trans people from accessing health care services." 9 This lack of access to basic rights exemplifies a form of structural violence. These forms of "violence of injustice and inequity" are "embedded in ubiquitous social structures" and can become normalized by state institutions and frequent experience by Transgender
5. National Legal Services Authority v. Union of Indian and others, (2014) AIR 2014 SC 1863 (India). 6. Jack Healy, Threats and Killings Striking FearAmong YoungIraqis, Including Gays, N.Y. TIMES (Mar. 11, 2012), https://www.nytimes.com/2012/03/12/world/middleeast/killings- strike-fear-in-iraqi-gay-and-emo-youth.html. 7. James Nichols, Russian Transgender Woman Beaten In PublicPark Caught On Tape, THE HUFFINGTON POST (Aug. 20, 2013), https://www.huffpost.com/entry/russian-transgender- woman-beaten_n_3779723. 8. Mashal Shah, The Kwaja Seras: Pakistan'sEndangered Minority, THE HUFFINGTON POST (Aug. 13, 2013), http://www.huffingtonpost.com/nashal-shah/pakistans-endangered- specb_3732591.html; INT'L HIV/AIDS ALLIANCE, IMPUNITY AND VIOLENCE AGAINST TRANSGENDER WOMEN HUMAN RIGHTS DEFENDERS IN LATIN AMERICA (2012). 9. OPEN SOCIETY FOUNDATION, TRANSFORMING HEALTH: INTERNATIONAL RIGHTS-BASED ADVOCACY FOR TRANS HEALTH, https://www.opensocietyfoundations.org/uploads/29ab7all- c8c1-49dc-9c6c-ld8401905639/Transforming-health-20130213.pdf.
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communities.1, Such policies and laws can institutionalize and codify discrimination against Transgender people, leading to persecution, inciting Trans-violence, and exacting practices that compromise Transgender legal rights. While structural violence abounds and perpetrators of Trans-violence are not investigated or prosecuted such as in Guyana, Malawi,Saudi Arabia, and Uganda, a number of countries have created national laws and policies for the protection and promotion of Transgender rights and prevention of rights violations against Transgender populations. Examples of such countries include India, Nepal, and Pakistan. This Article is a comparative study exploring how domestic laws impact Transgender rights and access to justice for Transgender communities. In those countries where the law is hostile to Transgender rights and Transgender access to justice, such legal practices perpetuate structural violence, promote discrimination and persecution, and cause direct violence against Transgender populations. In other countries where the law is more progressive, an interesting phenomenon exists. In countries where Transgender lives are lived more outside of the shadows, Trans-violence rates are noticeably higher than in countries where Transgender rights are restricted. It is important to investigate domestic laws affecting Transgender populations to both demand reforms of hostile laws and to also consider the role that the international community can play in protecting Transgender rights in those countries where domestic law refuses or is incapable of doing so. Additionally, is it vital to continue efforts to protect Transgender lives in those countries whose laws are progressive, since rates of Trans-violence skyrocket as Transgender communities feel freer to live outwardly Transgender lives.
I. VIOLENCE AGAINST TRANSGENDER PERSONS AND COMPARATIVE LAW "All we want from people is to stop treating us like trash. People think that we are God's curse, so they mistreat us. How are we to blame for God's doing? If he created us this way, there must be a deeper wisdom that we as human beings are incapable of comprehending."" Laila Naz, Age 39, Lahore, Pakistan
A. Trans Murder Trans-violence, including Trans murder, is a reality for Transgender persons in many countries. The organization Transgender Europe
10. Barbara Rylko-Bauer and Paul Farmer, Structural Violence, Poverty, and Social Suffering, in OxFoRD HANDBOOKS ONLINE (David Brady and Linda M. Burton, eds., 2016); Deborah Winter and Dana C. Leighton, Structural Violence Section Introduction, IN PEACE, CONFLICT, AND VIOLENCE: PEACE PSYCHOLOGY FOR THE 21ST CENTURY at 99 (D.J. Winter, R.V. Wagner, and D.D. Winter, eds., 2001). 11. Email from Laila Naz to Mashal Shah (email record on file with author).
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(TGEU) established a "Trans Murder Monitoring Project" that releases quarterly reports of the murder count of Transgender individuals across the world.12 The March 2013 update reveals a total of 1,123 reported killings of Transgender people in fifty-seven countries worldwide from January 1, 2008 to December 31, 2012.13 The update shows a significant and constant increase in reported killings of Transgender people over the last five years. In 2008, one-hundred and forty-eight cases were reported, in 2009 two-hundred and seventeen cases, in 2010 two-hundred and twenty-nine cases, in 2011 two-hundred and sixty-two cases, and in 2012 two-hundred and sixty-seven cases.1 4 Cases have been reported from all major regions. Most reported cases were from Central and South America, which amount to eight-hundred and sixty-four reports in twenty-two countries and account for seventy- seven percent of the globally reported murders of Transgender people since January 2008.15 In Brazil, the country with the most reported killings (four-hundred and fifty-two in total), there has been a steady increase (2008: 57, 2009: 68, 2010: 99, 2011: 103, 2012: 125).16 In Mexico, one-hundred and six cases have been reported in total, showing an even more drastic yearly increase (2008: 4, 2009: 9, 2010: 14, 2011: 33, 2012: 46).17 In Colombia, sixty-five killings have been reported since 2008 (2008: 13, 2009: 13, 2010: 15, 2011: 18, 2012: 6). 18 TGEU research also shows that in the last five years: " One-hundred and five killings of Trans people have been reported in Asia (2008: 17, 2009: 17, 2010: 29, 2011: 25, 2012: 17), in fifteen countries (Afghanistan: 1, Azerbaijan: 2, Bangladesh: 1, Cambodia: 1, China: 6, India: 24, Indonesia: 7, Iran: 1,Iraq: 3, Malaysia: 6, Pakistan: 19, Philippines: 28, Republic of Korea: 1, Singapore: 1, and Thailand: 4).9 " Seventy-one killings of Trans people have been reported in Europe (2008: 13, 2009: 20, 2010: 10, 2011: 14, 2012: 14), in eleven countries (Albania: 1,
12. TRANS RESPECT VERSUSTRANSPHOBIAWORLDWIDE, TRANS MURDER MONITORING RESULTS: TMM MARCH 2013 UPDATE (2013), http://www.Transrespect-Transphobia.org/ en_US/tvt-project/tmm-results/march-2013.htm. Of course, Trans-violence encompasses more than solely Trans murder, but Trans murder may best capture the attention of the reader and the general public, thus the focus on Trans murder at this juncture. 13. Id. 14. Id. 15. Id. 16. Id. 17. Id. 18. Id. 19. Id.
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France: 2,Germany: 2,Italy: 20, Poland: 1,Portugal: 1, Russia: 2, Serbia: 1,Spain: 6, Turkey: 30, and UK: 5).20 " Seventy-one killings of Trans people have been reported in North America (2008: 19, 2009: 13, 2010: 9, 2011: 16, 2012: 14), in two countries (Canada: 2, USA: 69). " Eight killings of Trans people have been reported in Africa (2008: 2, 2009: 1, 2010: 0, 2011: 1, 2012: 4), in four countries (Algeria: 1, Mauritius: 1, Uganda: 1, South Africa: 5).21 " Four killings of Trans people have been reported in Oceania (2008: 3, 2009: 1, 2010: 0, 2011: 0, 2012: 0), in four countries (Australia: 1 Fiji: 1, New Caledonia: 1, and New Zealand: 1).2
B. The Underreportingof Trans-Violence as a Constant In many countries, Transgender life is lived with the constant danger of suffering physical violence at the hands of private citizens and police forces, and a corresponding lack of response and/or hostility from police after victimization. In fact, "[r]esearch suggests that Transgender people are one of the most victimized groups in society and are more likely to be abused by police than other members of society." 23 The combined forces of Trans-violence and a lack of police response after such violence have caused a chilling effect on the reporting of victimization. In Kuwait, for example, a 2012Human Rights Watch(HRW) report stated that interviewees "said they rarely report ... police mistreatment, abuse, and sexual assault they encounter for fear of re-arrest, retaliation, and direct threats by the perpetrators, whether civilian or police."24 HRW claims that Transgender and gay Iranians "are often the targets of harassment, abuse, blackmail, extortion, and torture because of their sexual orientation or gender identity. Yet because the law criminalizes same-sex conduct, LGBTQ Iranians cannot avail themselves of the general protections afforded under the law because they fear further
20. Id. 21. Id. 22. Id. 23. Toby Miles-Johnson, They Don't Identify With Us: PerceptionsofPolice By Australian TransgenderPeople, 16 INT'L J. OF TRANSGENDERISM 169 (2015). 24. HUMAN RIGHTS WATCH, THEY HUNT US DOWN FOR FUN: DISCRIMINATION AND POLICE VIOLENCE AGAINST TRANSGENDER WOMEN IN KUWAIT (2012), https://www.hrw.org/report/ 2012/01/1 5/they-hunt-us-down-fun/discrimination-and-police-violence-against-Transgender- women.
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discrimination and possible prosecution."2 In Kyrgyzstan, HRW documented a series of interviews with LGBTQ persons, all of whom indicated a general mistrust of the police and an unwillingness to bring complaints of violence to the police for investigation and potential prosecution. 26 In India, evidence demonstrates that Transwomen sex workers, when victimized attendant to their work, avoid taking their complaints to the police because they have engaged in homosexual sex, which is illegal under the Indian Penal Code. 7 Discussing police abuse of India's LGBTQ community and its chilling effect upon the willingness of LGBTQ victims of crime to file complaints with the police, Tripti Tandon, deputy director of the Delhi-based human rights NGO Lawyers Collective stated that "[r]ape, blackmail, violence and extortion by the police is pretty endemic. When the police are perpetrating the violence, then how do you resort to the same machinery to make a complaint?"28 Research in Australia demonstrates that "Transgender people avoid police contact and are cautious of police interaction and . . . do not trust the police or do not consider the police to be a legitimate organization."29 Finally, in the United States, in the 2011 National Transgender Discrimination Survey conducted by the National Center for Transgender Equality and the National Gay and Lesbian Taskforce, forty-six percent of respondents "reported that they were uncomfortable seeking help from police while only thirty-five percent reported that they were comfortable doing so."30 The combination of high rates of Trans-violence and low reporting rates of such violence in countries around the world demonstrates that
25. HUMAN RIGHTS WATCH, WE ARE A BURIED GENERATION: DISCRIMINATION AND VIOLENCE AGAINST SEXUAL MINORITIES IN IRAN (2010), https://www.hrw.org/report/2010/12/ 15/we-are-buried-generation/discrimination-and-violence-against-sexual-minorities. 26. HUMAN RIGHTS WATCH, THESE EVERYDAY HUMILIATIONS: VIOLENCE AGAINSTLESBIANS, BISEXUAL WOMEN, AND TRANSGENDER MEN IN KYRGYZSTAN (2008), https ://www.hrw.org/report/2008/10/06/these-everyday-humiliations/violence-against-lesbians- bisexual-women-and 27. Transgenderism in India: 'Peoplejust use us for sex,' THE GUARDIAN (July 4, 2008), http://www.theguardian.com/world/2008/jul/04/india-gender. The legality of consensual homosexual sex in India is an interesting one. Section 377 of the Indian Penal Code forbids homosexual sex. On 2 July 2009, in Naz Foundation v. Govt. of NCT of Delhi (2009), the Delhi High Court found Section 377 to be unconstitutional with respect to sex between consenting adults. On December 11, 2013, the Supreme Court of India overturned that ruling and returned the issue to the Indian Parliament for clarification. 28. Sonia Paul, Living in Fear:LGBTsin India, AL JAZEERA (Apr. 17, 2014), http://america.aljazeera.com/articles/2014/4/17/living-in-fear-lgbtsinindia.html. 29. Miles-Johnson, supra note 23, at 170. 30. JAIME M. GRANT & LISA A. MOTTET, JUSTIN TANIS, JACK HARRISON, JODY L. HERMAN, ANDMARA KEISLING, WASHINGTON: NATIONAL CENTER FOR TRANSGENDER EQUALITY AND NATIONAL GAY AND LESBIAN TASK FORCE, INJUSTICE AT EVERY TURN: A REPORT OF THE NATIONAL TRANSGENDER DISCRIMINATION SURVEY 162 (2011).
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Transgender populations are not currently being fully protected by domestic criminal law. Such a lack of protection is partially attributable to structural violence against Transgender populations.
C. A Theory of Structural Violence Violence against Transgender populations takes many forms, including structural violence. Structural violence is a broad umbrella term that includes 'a host of offensives against human dignity: extreme and relative poverty, social inequalities ranging fromracismto gender inequality, and the more spectacular forms of violence that are uncontestably human rights abuses.' The term structural violence describes the systems of institutionalized discrimination that target Transgender people in areas of everyday life, such as health care housing, employment, education, and legal identity status.3y The term structural violence was first introduced in 1969 by Johan Galtung, often considered the founder of peace and conflict resolution studies. In "Violence, Peace, and Peace Reacher," Galtung laid out definitions and models of peace and violence. Galtung discussed three types of violence-the triangle of violence-which includes direct, cultural, and structural violence. Structural violence refers to social systems embedded with injustice and exploitation. Institutionalized practices harm certain groups and perpetuate inequities in their relation to other groups. Structural violence can take on many forms, including laws that exacerbate issues of marginalization and policies or practices that prevent equal access to social institutions such as health or education for marginalized groups. 33 Structural violence is largely invisible because it is so ingrained in the fabric of society. In visualizing the triangle of violence, Galtung explains that structural violence often causes direct violence, which in turn is justified and normalized by cultural violence. 34 So while structural violence may be less apparent as a form of violence in society, when closely tied with direct violence, it gives rise to phenomena such as racial violence, state violence, gender violence, and family violence. 35
31. Paul Farmer, PATHOLOGIES OF POWER HEALTH, HUMAN RIGHTS, AND THE NEW WAR ON THE POOR (2005). 32. OPEN SOCIETY FOUNDATION, supra note 9. 33. HARVARD DIVINITY SCHOOL, RELIGIOUS LITERACY PROJECT, TYPOLOGIES OF VIOLENCE AND PEACE. https://rlp.hds.harvard.edu/our-approach/typologies-violence-and-peace. 34. William Hathaway, Varietiesof Violence: Structural, Cultural, andDirect,TRANSCEND MEDIA SERVICES (Oct. 21, 2013), https://www.Transcend.org/tms/2013/10/varieties-of-violence- structural-cultural-and-direct/. 35. James Gilligan, VIOLENCE: REFLECTIONS ON A NATIONAL EPIDEMIC 196 (1997).
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Since Galtung, scholars have expanded upon structural violence literature, including applying it to LGBTQ populations. Padilla et al., in "Globalization, Structural Violence, and LGBT Health: A Cross-Cultural Perspective," discuss how structural violence is present in societies through institutionalized discrimination that has critical implications for the livelihoods of LGBTQ populations. 36 Such institutionalized policies and laws keep structural violence against LGBTQ populations embedded in political, legal, and social structures. Below are a number of countries in which law has been used to discriminate against Transgender populations or exclude them from access to justice-a form of structural violence.
II. DISCRIMINATORY LAW AS A FORM OF TRANS-VIOLENCE
A. Guyana Section 153(1)(xlvii) of the Summary Jurisdiction (Offences) Act, Chapter 8:02 of the Laws of Guyana bans public display of Transgenderism/cross-dressing for any undefined "improper purpose." 37 Section 153(1)(xlvii) states that any person is subject to a fine if "being a man, in any public way or public place, for any improper purpose, appears in female attire; or being a woman, in any public way or public place, for any improper purpose, appears in male attire."38 In 2009, this law was challenged after seven Guyanese Transwomen were arrested and fined under this provision. 39 The seven contended that their arrest and fine was unconstitutional. 40. On September 6, 2013, the Honourable Chief Justice (Ag.) of Guyana, Mr. Ian Chang, delivered his judgment in the case. While Chief Justice Chang reversed the conviction and fine against the accused because they engaged in cross-dressing for a so-called "not-improper purpose," he found the law itself constitutional and, thus, cross-dressing in a public place is still an offense if done with a still-
36. Mark B. Padilla & Ernesto V. Del Aguila, and Richard G. Parker, Globalization, Structural Violence, and LGBT Health: A Cross-CulturalPerspective, in THE HEALTH OF SEXUAL MINORITIES 215 (Ilan Meyer & Mary Northridge eds., 2007). 37. Summary Jurisdiction (Offences) Act (Cap. 8:02) (No. 17 of 1893), § 153(1)(xlvii) (1895). 38. Id. 39. Joint Press Release, Society Against Sexual Orientation Discrimination, Guyana Trans United, Caribbean Vulnerable Communities United, Caribbean Forum for Liberation and Acceptance of Genders ad Sexualities, and the Faculty of Law University of the West Indies Rights Advocacy Project, Constitutional Court Rules Cross-Dressing is Not a Crime if Not for "Improper Purpose" (Sept. 27, 2013), http://sasod.org.gy/sasod-blog-constitutional-court-rules- cross-dressing-not-crime-if-not-%E2%80%9Cimproper-purposeE2%80%9D-rights. 40. Quincy McEwan, Seon Clarke, Joseph Fraser, Seyon Persaudand the Society Against Sexual OrientationDiscrimination (SASOD) vs. Attorney General of Guyana.
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undefined "improper purpose."4 1 While the reversal of the conviction against McEwan et al. was met with some measure of joy from the Transgender community of Guyana, Chief Justice Chang's ruling that the law itself is constitutional was met with derision. The decision is being appealed by Transgender rights advocates, who find that the law, in any form, is discriminatory based on the grounds of both sex and gender and that the term "improper" is unconstitutionally vague.42
B. Malawi In other countries, the anti-gay and anti-Transgender sentiment is passed in the form of codified law and serves as another form of structural violence. Malawi is one such case. In its recent history, Malawi passed stringent anti-gay laws that also criminalized some Transgender sexual relationships. Penal Code Cap. 7:01 of the Laws of Malawi criminalized sexual acts between two men and reads, in pertinent part, as follows: Section 153. Unnatural offences Anyone who - (a) has carnal knowledge of any person against the order of nature; or... (c) permits a male person to have carnal knowledge of him or her against the order of nature, shall be guilty of a felony and shall be liable to imprisonment for fourteen years, with or withoutcorporal punishment. Section 154. Attempt to commit unnatural offences Any person who attempts to commit any of the offences specified in the last preceding section shall be guilty of a felony and shall be liable to imprisonment for seven years, with or without corporal punishment. Section 156 Indecent practices between males Any male person who, whether in public or private, commits any act of gross indecency with another male person, or procures another male person to commit any act of gross indecency with him, or attempts to procure the commission of any such act by any male person with himself or with
41. Cynthia Miley, Guyana Judge Rules Cross-Dressing Only Criminal when Done for Improper Purposes', JURIST (Sept. 9, 2013), http://www.jurist.org/paperchase/2013/09/guyana- judge-rules-cross-dressing-only-criminal-when-done-for-improper-purposes.php. 42. Joint Press Release, Society Against Sexual Orientation Discrimination and the Faculty of Law University of the West Indies Rights Advocacy Project, Constitutional Court Reserves Judgment in Guyana Cross Dressing Case (June 6, 2013), http://sasod.blogspot.com/2013/ 06/press-release-constitutional-court.html.
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another male person, whether in public or private, shall be guilty of a felony and shall be liable to imprisonment for five years, with or without corporal punishment. 43 Similarly, Section 137(a) of the Malawian Penal Code criminalizes lesbian sex and stipulates that any woman who commits "any act of gross indecency with another female" shall receive a prison sentence of five years. 44 In 2012, then-President Joyce Banda, under significant international pressure and threat of the loss of international aid, suspended these laws. While announcing the suspension, President Banda called for a review of Malawi's anti-gay laws and proposed that they be repealed, but insisted that it be done slowly, as she felt Malawi was not ready for such immediate change. However, after significant outcry from the country's conservative religious leaders, the laws were reinstated. The laws remained virtually unenforced until 2014 when an official review was completed, and the laws were again suspended. These laws currently remain suspended, but a national debate on the topic is ongoing. The legal situation for LGBTQ persons in Malawi remains tenuous, and recent events have negatively impacted the legal landscape. On April 17, 2015, The Marriage, Divorce, and Family Relations Law (TMDFRL), signed by President Peter Mutharika, made same-sex marriages and unions illegal and also codified the immutability of gender for purposes of Malawian law. This law fixed a person's sex/gender as the one assigned to them at birth, eliminating the ability of Transgender persons to establish their preferred gender identity if it lies outside of their identified birth sex.45 Malawi's law codifying sex/gender immutability not only flies in the face of almost forty years of comparative global legal development on gender identity but, if the aforementioned anti-gay sex laws are ever reinstated in Malawi, the re-criminalization of same-sex sexual acts combined with TMDFRL's provision of immutability will criminalize some Transgender sex by not allowing legal changes to sex/gender that would establish lawful heterosexual sexual relationships.
C. Saudi Arabia Laws in other countries, while not addressing Transgender rights directly, negatively affect Transgender rights more obliquely through
43. LUCAS PAOLI & JINGSHU ZHU, INTERNATIONAL LESBIAN GAY BISEXUAL TRANS ANDINTERSEXASSOCIATION, STATE-SPONSOREDHOMOPHOBIA: A WORLD SURVEY OF LAWS: CRIMINALISATION, PROTECTION AND RECOGNITION OF SAME-SEX LOVE 4 (2014). 44. Id. 45. Aaron Morrison, Malawi Gay Rights: New MarriageLaw Further CriminalizesLGBT Relationships And Identities, Group Says, INT'L BUS. TIMES (Apr. 17, 2015), http://www.ibtimes.com/nalawi-gay-rights-new-marriage-law-further-criminalizes-lgbt- relationships-identities-1886670.
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anti-gay and lesbian laws. The Saudi Arabian Penal Code does not mention homosexual sexual relations or Transgender issues.46 Instead, Saudi Arabia applies a strict interpretation of Sharia law, whereby all forms of sodomy are criminalized. 47 If a married man commits an act of sodomy, the penalty is death by stoning.48 The penalty for an unmarried man is 100 lashes from a whip and banishment from the country for a year.49 If a non-Muslim commits sodomy with a Muslim, the penalty for the non-Muslim is death by stoning. 50 Sexual relations between women are also illegal," but enforcement of such seems less stringent. As often seems the case, the line between gay, lesbian, and Transgender is unclear when it comes to enforcement of such laws. For example, a news report from March 18, 2012, stated that forty-ninegay menwere arrested when police affiliated with the Commission for the Promotion of Virtue and the Prevention of Vice raided a party in Taif.52 The article indicates that the men arrested were gay, but also mentioned that some of the men engaged in cross-dressing.5 3 The article states that some of the men arrested "wore dresses that show most parts of their bodies . . . " while the article cites theArabiclanguage daily Sabq as reporting that the men "were caught dancing and hugging each other indecently and wearing obscene clothes . . ."54 In another example, three men were arrested and referred for prosecution in Fujairah for walking in public while dressed as women.5 5 According to the Al Khaj eel newspaper, the men confessed to "wearing cosmetics and acting feminine."56 In yet another case, a wedding in Jeddah was raided in 2005, and over 100 men were arrested for "dancing and behaving like women." 57 These men were sentenced to up to a year in prison and flogging for such behaviors, 58 which could be classified as homosexual, Transgender, or both. HRW indicated that each
46. PAOLI & ZHU, supra note 43. 47. Id. 48. Id. 49. Id. 50. Id. 51. Id. 52. 49 Gays Arrested in Saudi, EMIRATES 24/7 (Mar. 18, 2012), https://www.emirates247.com/crime/region/49-gays-arrested-in-saudi-2012-03-18-1.449008. 53. Id. 54. Id. 55. Three Men Held for Cross-dressing in Fujairah, EMIRATES 24/7 (May 1, 2011), https://www. emirate s247. com/news/emirates/three -men-held-for-cro ss-dressing-in-fuj airah- 2011-05-01-1.387355. 56. Id. 57. HUMAN RIGHTS WATCH, SAUDI ARABIA: MEN 'BEHAVING LIKE WOMEN' FACE FLOGGING (2005), https://www.hrw.org/news/2005/04/06/saudi-arabia-men-behaving-women- face-flogging. 58. Id.
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man was pardoned shortly after sentencing. 59 The same article documents yet another mass arrest of gay and Transgender persons, discussing the arrest of sixty-seven men who were arrested in Riyadh in June 2009 for wearing women's clothing.60 What seems clear from the above examples is that Transgender life in Saudi Arabia is criminalized through the application of strict Sharia law principles onhomosexualityand alleged homosexual sexual activity.
D. Uganda Uganda is another example of the victimization of Transgender persons under laws that place homosexuals and Transgender persons together. Laws prohibiting same-sex relations have existed since British Colonial Rule, with Penal Code Act of 1950: Chapter XIV-Offences against Morality Section 145. Unnatural offences. Any person who- (a) has carnal knowledge of any person against the order of nature; [or]... (c) permits a male person to have carnal knowledge of him or her against the order of nature, commits an offence and is liable to imprisonment for life.61 More recently, the virulent Anti-Homosexuality Act (AHA) was passed by the Ugandan Parliament on December 20, 2013, and was signed by President Museveni on February 24, 2014, appearing in the official Uganda Gazette on March 10, 2014, when it entered into law.6 2 Although this legislation is overtly directed towards homosexuals, it also targets the Transgender community. The lead drafter of the bill and prominent Ugandan Member of Parliament (MP), David Bahati, summarized the intentions of the bill as follows: protect the traditional family by prohibiting (i) any form of sexual relations between persons of the same sex; and (ii) the promotion or recognition of such sexual relations in public institutions and other places through or with the support of any Government entity in Uganda or any non- governmental organization inside or outside the country.
59. HUMAN RIGHTS WATCH, SAUDI ARABIA DROP 'CROSS-DRESSING' CHARGES (2009), Https://www.hrw.org/news/2009/06/24/saudi-arabia-drop-cross-dressing-charges. 60. Id. 61. Penal Code Act 1950, Cap. 120 (2000) § 145 (Uganda). 62. Anti-Homosexuality Act 2014 (2014) (repealed 2014) (Uganda).
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strengthening the nation's capacity to deal with emerging internal and external threats to the traditional heterosexual family. to protect the cherished culture of the people of Uganda, legal, religious, and traditional family values of the people of Uganda against the attempts of sexual rights activists seeking to impose their values of sexual promiscuity on the people of Uganda. protect the children and youths of Uganda who are made vulnerable to sexual abuse and deviation as a result of cultural changes, uncensored information technologies, parentless child developmental settings and increasing attempts by homosexuals to raise children in homosexual relationships through adoption, foster care, or otherwise.6 3 Fortunately for LGBTQ Ugandans, the Constitutional Court of Uganda ruled the AHA invalid-but not on substantive grounds of constitutional unfairness or human rights grounds. The Constitutional Court invalidated the law on the procedural ground that there was not the required quorum of MPs present at the time of voting on the bill.64 Despite this setback for supporters of the AHA, national sentiments towards homosexuals and gender minorities remain harsh, and the specter of the return of the AHA remains quite real. According to a HRW report, LGBTQ Ugandans "have faced a notable increase in arbitrary arrests, police abuse and extortion, loss of employment, evictions, and homelessness, and scores have fled the country" following the AHA.65 One week after President Museveni signed the AHA, a Transwoman was attacked and killed by a man she met in a bar in Kampala.66 In the aftermath of the attack, the victim's friends told HRW that they were afraid to report her murder to the police out of fear for their own safety. 67 A Ugandan Non-governmental Organization (NGO), Sexual Minorities Uganda (SMUG), reported that "the full force of the State, particularly the legislative and executive
63. The Anti-Homosexual Bill, Bill No. 18 (2009) 47 Uganda Gazette 102, Bills Supplement 13 (Uganda), https://www.wthrockmorton.com/wp-content/uploads/2012/02/ahb 2009feb2012.pdf. 64. Uganda CourtAnnulsAnti-Gay Law, BBC NEWS (Aug. 1, 2014), http://www.bbc.com/ news/world-africa-28605400. 65. HUMAN RIGHTS WATCH, UGANDA: ANTI-HOMOSEXUALITY ACT'S HEAVY TOLL (2014), https ://www.hrw.org/news/2014/05/14/uganda-anti-homosexuality-acts-heavy-toll. 66. Id. 67. Id.
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branches of government, is being used to hunt down, expose, demean and suppress Uganda's LGBTI people." 68 In these nations and others, domestic law is being used to persecute Transgender populations. In these countries, domestic law is the enemy of Transgender persons and demonstrates "the magnitude of physical and structural violence directed at Trans people." This Article will continue on a more uplifting note by discussing countries with laws that are more supportive of Transgender rights. Perversely, in these countries with more supportive laws, levels of Trans-violence systematically rise.
III. SUPPORTIVE LAW AND RAMPANT TRANS-VIOLENCE A number of countries enjoy laws that are generally respectful of Transgender life, demonstrate a deeper understanding of issues of gender identity, and the notion of gender fluidity. Unfortunately, visible Transgender communities and strong Transgender rights movements also create higher levels of Trans-violence. According to TGEU's Trans Murder Project, "[t]hroughout all six world regions, the highest absolute numbers [of Trans murders] have been found in countries with strong Trans movements and the strong visibility of Trans and gender-diverse people, and/or Trans or LGBTQ organizations that do professional monitoring: Brazil (689), Mexico (194), Colombia (85), Venezuela (85), Honduras (77), Guatemala (39), Argentina (35), and the Dominican Republic (34) in Central and South America, the USA (108) in North America, India (48) and the Philippines (35) in Asia and Turkey (37) and Italy (28) in Europe. "69 Essentially, the freedom to live outwardly Transgender lives has made those same Transgender persons easily identifiable targets for Trans-violence.
A. Argentina Argentina's law regarding gender identity rights is quite progressive. On May 8, 2012, The Argentinean Senate unanimously passed the Gender Identity Law (GIL). 70 Article 1 of the GIL reads as follows: Article 1 - Right to gender identity. All persons have the right,
68. SEXUAL MINORITIES UGANDA, FROM TORMENT TO TYRANNY ENHANCED PERSECUTION IN UGANDA FOLLOWING THE PASSAGE OF THE ANTI-HOMOSEXUALITY ACT 2014 (2014), https ://sexualminoritiesuganda.com/wp-content/uploads/2014/11/SMUG-From-Torment-to- Tyranny.pdf. 69. TRANS RESPECT VERSUS TRANSPHOBIA WORLDWIDE, TRANSGENDER EUROPE IDAHOT TMM 2015 (2015), http://Transrespect.org/en/Transgender-europe-idahot-tmm-2015/. 70. TRANSGENDER EUROPE, ENGLISH TRANSLATION OF ARGENTINA'S GENDER IDENTITY LAW AS APPROVED BY THE SENATE OF ARGENTINA ON MAY 8, 2012 (2012).
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a) To the recognition of their gender identity; b) To the free development of their person according to their gender identity; c) To be treated according to their gender identity and, particularly, to be identified in that way in the documents proving their identiti in terms of the first name/s, image, and sex recorded there.] Article 3 of the GTL grants the right to amend one's sex in accordance with their preferred gender identity, stating that "[a]ll persons can request that the recorded sex be amended, along with the changes in first name and image, whenever they do not correspond with the self-perceived gender identity." 72 Article 11 of the law grants the sweeping right to free personal development for Transgender persons, stating that: All persons older than eighteen (18) years, according to Article 1 of the current law and with the aim of ensuring the holistic enjoyment of their health, will be able to access total and partial surgical interventions and/or comprehensive hormonal treatments to adjust their bodies, including their genitalia, to their self-perceived gender identity, without requiring any judicial or administrative authorization. There will be no need to prove the will to have a total or partial reassignment surgery in order to access comprehensive hormonal treatment. The only requirement will be, in both cases, informed consent by the individual concerned.... 73 Public health officials, be they from the state, private or trade union-run health insurance systems, must guarantee in an ongoing way the rights recognized by this law. All medical procedures contemplated in this article are included in the Compulsory Medical Plan (that is, they are not subjected to additional costs for those having private or trade union-run insurance plans), or in whatever system replaces it, as decided by the enforcing authority.74 Article 12 of the law grants the right to dignified treatment of one's chosen gender identity, by mandating that the desired name of the individual be used in both the public and private sectors, while Article 13 mandates that
71. Id., at Art. 1. 72. Id., at Art. 3. 73. Id. at Art. 11. 74. Id.
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every norm, regulation or procedure must respect the human right to gender identity. No norm, regulation, or procedure must limit, restrict, exclude or annul the exercise of the right to gender identity, and all norms must always be interpreted and enforced in a manner that favors access to this right.75 However, Trans-violence remains a problem and seems to have been exacerbated by the passage of the GIL. TGEU's Trans Murder Project documented thirty-five cases of murders of Trans persons between January 2008 and December 2014.76 Similarly, 2015 was a deadly year for Argentina's Transgender population. In September 2015, a Transwoman, Marcela Estefania Chocobar, was decapitated, and her body dumped in a vacant lot in Rio Gallegos.7 7 In the same month, in Santa Fe, a Transwoman named Fernanda "Coty" Olmos was found dead in her home with multiple stab wounds, and a plastic bag pulled over her head. 78 Most prominently, Diana Sacayin, a leader of Argentina's Transgender rights movement, was stabbed to death in her Buenos Aires apartment in October 2015.79 Sacayin had previously gained national attention when President Fernandez personally presented her with her gender identity card following the passage of the GIL. 80 To date, no one has been charged with her murder.81
B. Brazil In Brazil, the reported killings of Transgender persons (452), not only represents the highest total number of Trans murders in any country in the world, but accounts for 52.31% of all Trans murders in Central and South America, and 40.25% of all reported Trans murders between these two dates.8 2 The Trans murder rate in Brazil continues to rise on a yearly basis (2008: 57, 2009: 68, 2010: 99, 2011: 103, 2012: 125),83 and the outlook shows no signs of improvement.
75. Id. at Art. 12-13. 76. TRANS RESPECT VERSUS TRANSPHOBIA WORLDWIDE, supra note 69. 77. Jonathan Gilbert, Transgender Argentines Confront Continued Murder and Discrimination, N.Y. TIMES (Nov. 28, 2015), https://www.nytimes.com/2015/11/29/world/ americas/transgender-argentines-confront-continued-murder-and-discrimination.html. 78. Id. 79. Clies Abeni, ProminentActivist Becomes ThirdTrans WomanRecently Murdered in Argentina, ADVOCATE (Oct. 15, 2015), https://www.advocate.com/transgender/2015/10/15/ prominent-activist-becomes-third-trans-woman-recently-murdered-argentina. 80. Hugh Bronstein, Outcry over the Killing of Three Transgender Women in Argentina,REUTERS(Oct. 14, 2015), https://www.reuters.com/article/argentina-Transgender/outcry-over- the-killing-of-three-Transgender-women-in-argentina-idUSL 1N12E 1XZ20151014. 81. Id. 82. Id. 83. Id.
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Brazil's leadership of the global LGBTQ rights movement stands in stark contrast to the dangerous realities of Transgender life in the country. "Brazil is a leading state in the international, domestic, and regional battle against LGBT discrimination through the Brazilian government and several active, civil society organizations. .. "84 Brazil was the catalyst for the so-called "Brazilian Resolution" in the United Nations, which called for non-discrimination relating to sexual orientation and gender identity. Brazil withdrew the resolution in the face of strong opposition from the Organization of the Islamic Conference and the Holy See, but Brazil's efforts served as the first resolution dedicated to gender identity issues and helped pave the way for the Human Rights Council's Resolution on Human Rights, Sexual Orientation and Gender Identity in 2011.85 Brazil was also a thought leader on the creation of theYogyakarta Principleswith Sonia Onufer Corr6a, Research Associate of the Brazilian Interdisciplinary AIDS Association, serving as one of the co-chairs of the process. 86 On a national level, former President Luiz Inicio Lula da Siva announced "his support of free gender-reassignment surgery to all qualified citizens as a legitimate medical procedure and a basic constitutional right for all Brazilians."87 Finally, on a regional level, Brazil presented the Human Rights, Sexual Orientation, and Gender Identity Resolution to the Organization of American States in August 2008, which was approved by the thirty-four member countries of the organization.88 Brazil is a world leader in the top-down approach to Transgender rights, and in fact, they were given a 2006 award from HRW for their progress on LGBTQ rights issues. 89 However, despite these gains, Brazil remains "the most dangerous place to be Transgender." 90
C. Pakistan Pakistan's Transgender population, called khwaja seras, or the less polite term hijras or khusras91 have a complicated relationship with the
84. Adrienne Rosenberg, The Brazilian Paradox: The Lesbian, Gay, Bisexual, and TransgenderBattlefor Human Rights 2 HUMAN RIGHTS AND HUMAN WELFARE, 16, 17-18 (2002). 85. Human Rights Council Res. 17/19, supra note 1. 86. Rosenberg, supra note 84, at 18. 87. Id. 88. Id. 89. Id. 90. Erica Hellerstein, Brazil at a Crossroadsfor LGBT Rights, THE NATION (Apr. 5, 2011), http://www.thenation.com/article/brazil-crossroads-lgbt-rights/. 91. Mashal Shah, The Kwaja Seras, HUFFINGTON POST (Aug. 13, 2013), https://www.huff post.com/entry/pakistans-endangered-spec_b_3732591?guccounter= 1&guce_referrer=aHR0cH M6Ly93d3cuZ29vZ2xiLmNvbS8&gucereferrer sig=AQAAANCaQiRNAvAZ2MmVj73bD4 3xcUW4SdDSMVLTZE9P0HNqBKKwl8PsbnCdfUb5 -BmWDgK2Egxy6yEVt2Pf0CsNh_9Y RiIyXFP iF_xkKUhEn9YPAJSuBF-dDAW2EWva3mEjXBrEnbmoehx9fr3yYGfkZCN8dzAfO Sw 1FKBuhMdTbJ2S.
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rest of Pakistani society, but they enjoy a higher range of legal freedoms and privileges than many countries, mainly facilitated by The Pakistani Supreme Court. The Chief Justice of the Supreme Court of Pakistan, Iftikhar Ahmed Chaudhry, issued a landmark judgment in 2009, recognizing the existence of Transgender as a third sex. This ruling moved beyond the male-female binary associated with the concept of a heteronormative society, Under the ruling, the Pakistan National Database and Registration Authority (NADRA) was required to introduce a third category of sex on the country's National Identity Card (NIC) through which a Transgender [person] would be able to record her biological preference. 92 As a response to the slow implementation of its ruling, Chief Justice Chaudhry ordered that election officials allow Transgender persons to register to vote as a third gender using their new identification. 93 Additionally, Chief Justice Chaudhry also ruled that Transgender persons are allowed to inherit and mandated a two-percent quota for employing Transgender persons in both the public and private sectors. 94'Out of irritation at the slow pace of implementation of his orders, Chief Justice Chaudhry has monitored the progress of compliance to his orders through a series of hearings, twenty of which had occurred by 2012.9' With these rulings, the Transgender community seems to be gaining new confidence in the Pakistani legal system. 96 There exists an overall feeling of optimism that basic protections are being secured, and some institutional discrimination is being curtailed. 97 A Washington Post interview with a Transgender activist from Rawalpindi is demonstrative of that: Police used to beat us and take money from us. It was painful for us. Now we go to the police station, and they respect us
92. USAID, SILENT NO MORE TRANSGENDER COMMUNITY IN PAKISTAN: A RESEARCH STUDY (2016), http://sxpolitics.org/wp-content/uploads/2017/01/Transgender-Comnunity-in- Pakistan6.pdf. 93. Majeed Babar & Ron Synovitz, Despite Gains, Pakistan's Transgender Community Under Attack, RADIO FREE EUROPE (Oct. 26, 2013), http://www.rferl.org/content/pakistan- Transgender-eunuchs/25148690.html. 94. Nadia Rasul, Interview: PakistaniTransgender Activist Looks to 'New Dawn' ofRights, Dignity, ASIA SOCIETY (Aug. 29, 2013), http://asiasociety.org/blog/asia/interview-pakistani- Transgender-activist-looks-new-dawn-rights-dignity; Michele Langevine Leiby, For Transgender Pakistanis, Newfound Rights, WASH. POST (Feb. 10, 2012), http://www.washingtonpo st.com/world/for-Transgender-pakistanis-newfound-rights/2012/02/ 04/gIQAM0j G4Qstory.html. 95. Michele Langevine Leiby, For Transgender Pakistanis, Newfound Rights, WASH. POST, Feb. 10, 2012. 96. Id. 97. Id.
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and they are afraid of us. They take our cases first. Now they feel we have rights.98 However, recent developments do not diminish the gaps in protection and eliminate societal marginalization that exists against Transgender Pakistanis. While the Supreme Court has been active, its reach is limited and its rulings have not been implemented through the passage of law from the Pakistani legislature. 99 It remains difficult for Transgender persons to find suitable employment and the police and society as a whole continue to marginalize Transgender persons.100 Many Transgender persons resort to begging and prostitution. 101 Access to healthcare, education, and proper housing are still major areas of concern.10 2 Legal protection for Transgender persons is growing, but there is still considerablesocial stigmaattached to being Transgender. This stigma often results in violence. One prominent example of Trans-violence was a mob campaign against a Transgender community in Peshawar in October 2013.103 A group of police officers and civilians broke into the homes of Transgender persons and set about destroying their property, harassing them, and beating some of them. 104 This attack was part of a larger campaign by local leaders to force Transgender persons from the neighborhood. 105 The Transgender community rallied together following the attacks, but the resulting protests were broken up by the police when opposition groups used the protest as another opportunity to attack Transgender protesters. 106 Another notable episode of Trans-violence occurred in 2009 in the city of Taxila, where a group of police officers attacked, robbed, and raped eight Transgender wedding dancers. 107 This episode seems to have been the catalyst for Chief Justice Chaudhry's interest in protecting Transgender rights and led to much of the legal progress in Pakistan.
D. India After conducting a fascinating historical exploration of the role of Transgender persons in Hindu mythology and other religious texts, The
98. Id. 99. Rasul, supra note 94. 100. Babar and Synovitz, supra note 93. 101. Id. 102. Rasul, supra note 94. 103. Babar and Synovitz, supra note 93. 104. Id. 105. Id. 106. Id. 107. Declan Walsh, Harassed, Intimidated, Abused: But Now Pakistan'sHyra Transgender Minority Finds Its Voice, THE GUARDIAN (Jan. 29, 2010), https://www.theguardian.com/world/ 2010/jan/29/hijra-pakistan-Transgender rights.
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Supreme Court of India, in the case of National Legal Services Authority v. Union of Indian and Others (2014), ruled that hijras and other Transgender persons must be recognized as a third gender and that non- recognition of a third gender violates the right to equality under Article 14 of the Indian Constitution and also the right to protection of life and personal liberty under Article 21.108 The Supreme Court then directed India's States to take actions to ensure full recognition of a third gender, including a third gender option on government documents, and also set quotas for Transgender persons at government jobs and universities. 109 In addition, the Supreme Court indicated that the States should take steps to guarantee medical care and social welfare to Transgender persons, both common areas of discrimination."1 0 They also asked the States to "take measures to regain their respect and place in the society which once they enjoyed in our cultural and social life."" This ruling represents a landmark moment for Transgender rights but has faced considerable resistance. The government, led by the conservative Baharatia Janata Party, asked the Supreme Court to reconsider some portions of their ruling, and also asked for clarification on some points. Colin Gonsalves, a Supreme Court lawyer and founder of the Delhi-based Human Rights Law Network, stated that "[t]he government is stonewalling. They had no intention of implementing this judgment." 112 The Attorney General, Mukul Rohatgi, responded by stating that it is not stalling, but merely seeking clarification as to the extent to which accommodations must be made for Transgender persons. 113 However, the entirety of the Indian government has not resisted the call of progress on Transgender rights. The Tamil Nadu state has been far more progressive than the rest of India.1 1 4 For example, Transgender persons are issued third gender ID cards with great regularity, and they are also eligible for special ration cards that also denote them as being third gender." 5 Also, the state government of Tamil Nadu has ordered that no Transgender persons be denied access to education or any
108. National Legal Services Authority v. Union of Indian and others, supra note 5. 109. Id. at 109-10. 110. Id. 111. Id. at 110. 112. South Asians for Human Rights, Indian Government Objects to Supreme Court Ruling on Transgender Rights, INDIA REAL TIE (Sept. 12, 2014), http://www.southasianrights.org/ indian-government-objects-to-supreme-court-ruling-on-transgender-rights/. 113. Id. 114. Anupama Sekhar, Tamil Nadu Pioneers Transgender Inclusion, INFOCHANGE (July 22, 2017), http://infochangeindia.org/agenda-issues/social-exclusion/7471-tamil-nadu-pioneers- Transgender-inclusion-.html)\. 115. Id.
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necessary counseling.116 The state's welfare has even established a special panel to directly aid the Transgender community.1 1 7 It seems that these reforms have started the process of restoring respect and place in Tamil Nadu society for Transgender persons as envisioned by the Supreme Court in NationalLegal Services Authority.1 8 As the Indian Transgender community gained the right to designate themselves as a third gender in National Legal Services Authority, Transgender rights within the four corners of Indian criminal law have moved in the opposite direction. First, Section 377 of the Indian Penal Code (IPC), established during British colonial rule in 1860, criminalizes homosexual intercourse, while also criminalizing a considerable portion of Transgender intercourse. 119 "Section 377 reads as follows: Unnatural offences.-Whoever voluntarily has carnal intercourse against the order of nature with any man, woman or animal, shall be punished with imprisonment for life, or with imprisonment of either description for a term which may extend to ten years, and shall also be liable to fine. as a 12 felony, punishable by up to a life sentence in prison. 1 In Naz Foundation (India) Trust v. Government of NCT of Delhi and Others, the petitioners challenged the constitutionality of Section 377 "on grounds of violation of right to privacy, dignity and health under Article 21, equal protection of law and non-discrimination under Articles 14 and 15 and freedom of expression under Article 19 of the Constitution."1 2 1 On July 2, 2009, The High Court of Delhi at New Delhi ruled "that Section 377 IPC, insofar it criminali[z]es consensual sexual acts of adults in private, is violative of Articles 21, 14 and 15 of the Constitution."1 22 The decision in Naz Foundation led to a rapid increase in awareness of homosexual issues in India. 123 Acceptance of homosexuals in major cities grew quickly and led to the inclusion of homosexual characters in popular culture. 124 However, the Naz Foundation decision was reversed by the Indian Supreme Court on December 11, 2013. The ruling invalidated the ruling of the High Court of Delhi, holding that only Parliament, not the
116. Id. 117. Id. 118. Id. 119. LAWYERS COLLECTIVE, LGBT SECTION 377 (2010), http://www.lawyerscollective.org/ vulnerable-comnnunities/lgbt/section-377. 120. Id. 121. Id. 122. Naz Foundation (India) Trust v. Government of NCT of Delhi and Others (2009) WP(C) No.7455/2001, § 132 (India), https://www.escr-net.org/sites/default/files/Courtdecision. pdf. 123. Paul, supra note 28. 124. Id.
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judicial branch, has the power to change a law. 125 The Naz Foundation has appealed, but, at the moment, Section 377 of the Penal Code is back in effect, criminalizing homosexual sex, as well as all portions of consensual Transgender sex that would also be considered "against the order of nature." 126 Other recent developments in Indian criminal law have proven to be detrimental to Transgender rights. On December 16, 2012, a twenty-three year-old woman was gang-raped by six men on a bus that was driving around New Delhi. 127 Thirteen days later, the woman died of injuries sustained during the assault. 128 In response, Indian civil society rose up in protest against a lack of protection under Indian criminal law for victims of sexual assault. 129 In response to the protests, the government charged a commission, led by Former Chief Justice J.S. Verma, to propose reforms to India's sex crime law. 130 Among numerous areas of reform, the commission recommended that India change its sexual assault statute which stated that only a woman could be a victim of such a crime and institute a gender-neutral sexual assault statute, allowing for any person, female, male or Transgender, to be protected. 131 However, when the Criminal Law Amendment Act was released in 2013, the final product left the law gender-specific, designating women as the only possible victims of sex crimes. Essentially, the Criminal Law Amendment Act has denied the ability to pursue criminal charges when Transgender persons who may identify as women but were not born female, or who identify as a third gender, are victims of sexual assault. 132
E. Nepal The history of Trans-violence in Nepal is well documented, and Transgender persons were often beaten by police simply because they were easy targets. Police abuse reached its peak in 2005-2006, in what
125. Deepshikha Ghosh, Supreme Court Says Gay Sex is a Criminal Offence, Activists to Seek Review, NDTV (Dec. 11, 2013), http://www.ndtv.com/india-news/supreme-court-says-gay- sex-is-a-criminal-offence-activists-to-seek-review-544125. 126. Transgender Rights in India, N.Y. TiMEs (Apr. 25, 2014), https://www.nytimes.com/ 2014/04/26/opinion/transgender-rights-in-india.html; Advocacy, NAZ INDIA, https://nazindia.org/ advocacy/. 127. Heather Timmons & Sruthi Gottipati, Woman Dies After a Gang Rape That Galvanized India, N.Y. TIMES (Dec. 28, 2012), https://www.nytimes.com/2012/12/29/world/asia/condition- worsens-for-victim-of-gang-rape-in-india.html. 128. Id. 129. Id. 130. GOI Notification No. SO (3003)E (2012), https://www.prsindia.org/report-suminmaries/ justice-verma-comnittee-report-summary. 131. Justice J.S. Verma, Justice Leila Seth, and Gopal Subramanium, Report on the Committee on Amendments to Criminal Law , Part II ¶ 3 (Jan. 23, 2013). 132. The Criminal Law (Amendment) Ordinance, 2013, No. 13 of 2013, INDIA CODE (2013).
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was described as a "sexual cleansing." 133 Amidst this process, the police beat and sexually abused Transgender persons in an effort to humiliate and intimidate them. 134 On December 28, 2005, a Transwoman was arrested and forcibly stripped by police officers, where they then ridiculed her, inspected her genitals, and threatened to cut her hair. 135 On January 3, 2006, three Transgender Nepalese in Kathmandu were beaten by four police officers. 136 One was beaten with a baton and then threatened with the officer's gun as the officer stated that these "Hijras pollute the society and must be cleaned out." 137 Four days earlier, a Transgender woman was detained by the police and beaten before escaping. 138 On March 14, 2006, the police arrested twenty-six Transgender persons in Kathmandu and held them for several days without allowing them to speak with lawyers. 139 On December 7, 2006, eleven Transgender women were arrested in a raid at a hotel and were held for multiple days before being released without charges. 140 In response to such violence, the Nepalese Supreme Court acted in Pant v. Nepal in 2007. Pant has been lauded as "arguably the single most comprehensive judgment affirming protections for gender identity anywhere in the world." 141 In Pant, the Blue Diamond Society, led by its founder Sunil Babu Pant, and three other groups sued Nepal for the recognition of the basic human rights of Nepal's LGBTQ population. 142 Pant's "demands were threefold: to recognize the civil rights of Transgender people without requiring them to renounce one gender identity for another; to create a new law preventing discrimination and violence against LGBT communities; and to require the state to make reparations to LGBT victims of state violence and/or discrimination."143
133. HUMAN RIGHTS WATCH, NEPAL: POLICE ON 'SEXUAL CLEANSING DRIVE (Jan. 14, 2006), http://www.hrw.org/news/2006/01/1 /nepal-police-sexual-cleansing-drive. 134. Id. 135. Id. 136. Id. 137. Id. 138. Id. 139. HUMAN RIGHTS WATCH, NEPAL: 'SEXUAL CLEANSING DRIVE CONTINUES (Mar. 19, 2006), http://www.hrw.org/news/2006/03/16/nepal-sexual-cleansing-drive-continues. 140. Id. 141. Kyle Knight, Nepal's Third Gender and the Recognition of Gender Identity, HUFFINGTON POST (Apr. 24, 2012), http://www.huffingtonpost.com/kyle-knight/nepal-third- gender b_1447982.html; Jenni Chang & Lisa Dazols, Nepal's Sunil PantKeeps His Country at The Forefront Of LGBT Rights, HUFFINGTON POST (Apr. 20, 2012, updated Dec. 6, 2017), https://www.huffpost.com/entry/sunil-pant_b_1427377. 142. Writ No. 917, (2064 BS) 2 Nat'l Jud. Acad. J. 262 (Nepal), https://njanepal.org.np/ index.php/research-publication/nja-law-journal?download=18:nja. 143. INTERNATIONAL GAY AND LESBIAN HUMAN RIGHTS COMMISSION, NEPAL SUPREME COURT CASE ON RELIEF FOR SEXUAL AND GENDER MINORITIES: OBSERVER'S REPORT (2007), https://outrightinternational.org/sites/default/files/111-1.pdf.
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On December 21, 2007, the Supreme Court ruled in the case, legalized same-sex marriage, and ordered that the government eliminate all laws that discriminated based on gender identity or sexual orientation. In addition, "the court took the unique approach of establishing a third- gender category." 144 According to Pant himself, the judges in this case were moved by the level of violence and discrimination suffered by LGBTQ persons in Nepal, leading up to the case and wanted to implement some sense of equality. 14 5 Pant also remarked upon the high level of empathy the judges felt for the plight of Nepal's LGBTQ populations and the extent to which the judges decided to mandate radical change. 146 The Supreme Court ruling established a committee to study and adapt same-sex marriage policy, and Nepalese citizens can now choose third gender or "other" on government documents. 147 As evidence of the impact of the Pant ruling, in its 2011 census, Nepalese were allowed to designate themselves as a third gender for the first time. 148 As Nepal established laws to allow for third gender identification, its bureaucracy had trouble catching up with the pace of legal reform. Pant himself has noted that the Supreme Court was far more open-minded than a majority of Nepalese society, meaning that implementation of new laws designed to aid the Transgender community was slow. 149 Perhaps the most apparent lapse in the transition from Supreme Court ruling to actual government policy was the delay in the issue of third gender ID cards. As of 2012, only two such ID cards had been issued in almost five years since Pant.150 Without ID cards that properly reflect their gender identity, Transgender persons continue to face many legal difficulties, such as being unable to receive loans or inherit.151 They are also subject to harassment, particularly from police, based on gender incongruence between the gender on ID cards and the physical manifestation of the gender of the actual person before the police. 152 However, progress has been made. On August 10, 2015, Monica Shahi became the first person to hold a Nepalese passport that listed the gender as "O" for other. 153 On October 24, 2015, Transgender activist Bhumika Shrestha traveled on such a passport from Nepal to Taiwan for
144. Knight, supra note 141. 145. Chang & Dazols, supra note 141. 146. Id. 147. Knight, supra note 141. 148. Id. 149. Id. 150. Id. 151. Id. 152. Id. 153. KYLE KNIGHT, HUMAN RIGHTS WATCH, DISPATCHES: NEPAL'S TRANSGENDER PASSPORT PROGRESS (2015), https://www.hrw.org/news/2015/08/10/dispatches-nepals-Transgender-pass port-progress.
Published by UF Law Scholarship Repository, 2021 25 Florida Journal of International Law, Vol. 31 [2021], Iss. 2, Art. 2
236 FLORIDA JOURNAL OF INTERNATIONAL LAW [Vol. 31
the 2015 International Lesbian and Gay Association's Asia conference.15 4 These events represent some of the progress since Pant in the realization of Transgender human rights. On September 20, 2105, the new Nepalese Constitution came into force, and Nepal became one of a small handful of countries that specifically mentions protections for LGBTQ persons in their constitution. 155 Article 12 states that citizens will be allowed to choose their preferred gender identity on their citizenship document. The choices available are male, female, or other. Article 18 states that gender and sexual minorities will not be discriminated against by the state and by the judiciary in the application of laws. It further adds that the government may make special provisions through laws to protect, empower, and advance the rights of gender and sexual minorities and other marginalized and minority groups. Article 42 lists gender and sexual minorities among the groups that have a right to participate in state mechanisms and public services to promote inclusion. 156 In these countries, national laws and policies have been adopted that better support and protect the rights of their Transgender populations. However, as mentioned earlier, the link between the existence of visible Transgender communities, strong Transgender rights movements, and high levels of Trans-violence is very real. In these nations, rising levels of Trans-violence, despite improvements in the law affecting Transgender populations, are cause for alarm and concern.
CONCLUSION Stories of Transgender persons are reaching the forefront of national and international media, and as a result, the world is becoming increasingly aware of the presence of Transgender individuals and the existence of a gender spectrum. Such awareness and attention have coincided with mounting reports of violence against Transgender persons. The combination of increased media attention and increasing violence against gender minorities necessitated an examination of the failures and successes of comparative national law affecting Transgender populations. The purpose of this Article is to explore ways that comparative domestic law protects and fails to protect Transgender
154. Kyle Knight, Nepal's Third-GenderPassports May Be the Futureof Trans Travel, THE ADVOCATE (Oct. 26, 2015), https://www.advocate.com/comnmentary/2015/10/26/third-gender- passports-may-be-future-trans-travel. 154. Id. 155.HUMAN RIGHTS CAMPAIGN, THE NEW CONSTITUTION OF NEPAL AND LGBT HUMAN RIGHTS (2015), http://hrc-assets.s3-website-us-east-1.amazonaws.com//files/documents/Nepal Constitution-LGBTRights.pdf. 156. Id.
https://scholarship.law.ufl.edu/fjil/vol31/iss2/2 26 Kritz: Direct and Structural Violence against Transgender Populations: A
2020] DIRECT AND STRUCTURAL VIOLENCE AGAINST TRANSGENDER POPULATIONS 237
communities and to recognize that law is used to discriminate and persecute. One would hope that with greater visibility of Transgender life and the corresponding increase in violence against Transgender persons, domestic laws would respond in a fair, even-handed, and just manner, protecting Transgender rights and Transgender victims of crime. In many countries, considerable progress has been made, where the law grants Transgender persons their basic rights and where criminal law responds to incidents of Trans-violence with the full force of the rule of law. In other countries, however, Transgender persons do not receive equitable treatment before the law. In these countries, neither basic rights nor legal protections are available to Transgender populations due to discrimination,bias, and inequalities inherent in the social fabric of these countries. In other countries, exclusionary or discriminatory laws and policies have been enacted and enforced, effectively sanctioning Trans discrimination and Trans-violence. It is my hope that this Article, researched at the intersection of Transgender life and comparative law, will provide an engine for greater discussion on how Transgender populations can be better protected from harm, allowing them to live freely under the letter and spirit of the Universal Declaration of Human Rights.
Published by UF Law Scholarship Repository, 2021 27 Florida Journal of International Law, Vol. 31 [2021], Iss. 2, Art. 2
https://scholarship.law.ufl.edu/fjil/vol31/iss2/2 28
| https://docslib.org/doc/11614234/direct-and-structural-violence-against-transgender-populations-a-comparative-legal-study |
StatusCode in hyper - Rust
An HTTP status code (`status-code` in RFC 7230 et al.).
Struct hyper :: StatusCode
source · [ − ]
Expand description
An HTTP status code ( status-codein RFC 7230 et al.).
Constants are provided for known status codes, including those in the IANAHTTP Status Code Registry.
Status code values in the range 100-999 (inclusive) are supported by this
type. Values in the range 100-599 are semantically classified by the most
significant digit. See StatusCode::is_success, etc. Values above 599
are unclassified but allowed for legacy compatibility, though their use is
discouraged. Applications may interpret such values as protocol errors.
Examples
use http::StatusCode ; assert_eq! ( StatusCode::from_u16 ( 200 ). unwrap (), StatusCode::OK ); assert_eq! ( StatusCode::NOT_FOUND . as_u16 (), 404 ); assert! ( StatusCode::OK . is_success ());
Implementations
impl StatusCode
pub fn from_u16 (src: u16 ) -> Result < StatusCode , InvalidStatusCode >
Converts a u16 to a status code.
The function validates the correctness of the supplied u16. It must be
greater or equal to 100 and less than 1000.
Example
use http::StatusCode ; let ok = StatusCode::from_u16 ( 200 ). unwrap (); assert_eq! ( ok , StatusCode::OK ); let err = StatusCode::from_u16 ( 99 ); assert! ( err . is_err ());
pub fn from_bytes (src: &[ u8 ] ) -> Result < StatusCode , InvalidStatusCode >
Converts a &u8to a status code
pub fn as_u16 (&self) -> u16
Returns the u16corresponding to this StatusCode.
Note
Example
let status = http::StatusCode::OK ; assert_eq! ( status . as_u16 (), 200 );
pub fn as_str (&self) -> & str
Returns a &str representation of the StatusCode
The return value only includes a numerical representation of the
status code. The canonical reason is not included.
Example
let status = http::StatusCode::OK ; assert_eq! ( status . as_str (), "200" );
pub fn canonical_reason (&self) -> Option <&'static str >
Get the standardised reason-phrasefor this status code.
This is mostly here for servers writing responses, but could potentially have application
at other times.
The reason phrase is defined as being exclusively for human readers. You should avoid
deriving any meaning from it at all costs.
Bear in mind also that in HTTP/2.0 and HTTP/3.0 the reason phrase is abolished from
transmission, and so this canonical reason phrase really is the only reason phrase you’ll
find.
Example
let status = http::StatusCode::OK ; assert_eq! ( status . canonical_reason (), Some ( "OK" ));
pub fn is_informational (&self) -> bool
Check if status is within 100-199.
pub fn is_success (&self) -> bool
pub fn is_redirection (&self) -> bool
Check if status is within 300-399.
pub fn is_client_error (&self) -> bool
Check if status is within 400-499.
pub fn is_server_error (&self) -> bool
Check if status is within 500-599.
impl StatusCode
pub const CONTINUE : StatusCode
100 Continue
[RFC7231, Section 6.2.1]
pub const SWITCHING_PROTOCOLS : StatusCode
101 Switching Protocols
[RFC7231, Section 6.2.2]
pub const PROCESSING : StatusCode
102 Processing
[RFC2518]
pub const OK : StatusCode
200 OK
[RFC7231, Section 6.3.1]
pub const CREATED : StatusCode
201 Created
[RFC7231, Section 6.3.2]
pub const ACCEPTED : StatusCode
202 Accepted
[RFC7231, Section 6.3.3]
pub const NON_AUTHORITATIVE_INFORMATION : StatusCode
203 Non-Authoritative Information
[RFC7231, Section 6.3.4]
pub const NO_CONTENT : StatusCode
204 No Content
[RFC7231, Section 6.3.5]
pub const RESET_CONTENT : StatusCode
205 Reset Content
[RFC7231, Section 6.3.6]
pub const PARTIAL_CONTENT : StatusCode
206 Partial Content
[RFC7233, Section 4.1]
pub const MULTI_STATUS : StatusCode
207 Multi-Status
[RFC4918]
pub const ALREADY_REPORTED : StatusCode
208 Already Reported
[RFC5842]
pub const IM_USED : StatusCode
226 IM Used
[RFC3229]
pub const MULTIPLE_CHOICES : StatusCode
300 Multiple Choices
[RFC7231, Section 6.4.1]
pub const MOVED_PERMANENTLY : StatusCode
301 Moved Permanently
[RFC7231, Section 6.4.2]
pub const FOUND : StatusCode
302 Found
[RFC7231, Section 6.4.3]
pub const SEE_OTHER : StatusCode
303 See Other
[RFC7231, Section 6.4.4]
pub const NOT_MODIFIED : StatusCode
304 Not Modified
[RFC7232, Section 4.1]
pub const USE_PROXY : StatusCode
305 Use Proxy
[RFC7231, Section 6.4.5]
pub const TEMPORARY_REDIRECT : StatusCode
307 Temporary Redirect
[RFC7231, Section 6.4.7]
pub const PERMANENT_REDIRECT : StatusCode
308 Permanent Redirect
[RFC7238]
pub const BAD_REQUEST : StatusCode
400 Bad Request
[RFC7231, Section 6.5.1]
pub const UNAUTHORIZED : StatusCode
401 Unauthorized
[RFC7235, Section 3.1]
pub const PAYMENT_REQUIRED : StatusCode
402 Payment Required
[RFC7231, Section 6.5.2]
pub const FORBIDDEN : StatusCode
403 Forbidden
[RFC7231, Section 6.5.3]
pub const NOT_FOUND : StatusCode
404 Not Found
[RFC7231, Section 6.5.4]
pub const METHOD_NOT_ALLOWED : StatusCode
405 Method Not Allowed
[RFC7231, Section 6.5.5]
source
pub const NOT_ACCEPTABLE : StatusCode
406 Not Acceptable
[RFC7231, Section 6.5.6]
pub const PROXY_AUTHENTICATION_REQUIRED : StatusCode
407 Proxy Authentication Required
[RFC7235, Section 3.2]
pub const REQUEST_TIMEOUT : StatusCode
408 Request Timeout
[RFC7231, Section 6.5.7]
pub const CONFLICT : StatusCode
409 Conflict
[RFC7231, Section 6.5.8]
pub const GONE : StatusCode
410 Gone
[RFC7231, Section 6.5.9]
pub const LENGTH_REQUIRED : StatusCode
411 Length Required
[RFC7231, Section 6.5.10]
pub const PRECONDITION_FAILED : StatusCode
412 Precondition Failed
[RFC7232, Section 4.2]
pub const PAYLOAD_TOO_LARGE : StatusCode
pub const URI_TOO_LONG : StatusCode
414 URI Too Long
[RFC7231, Section 6.5.12]
pub const UNSUPPORTED_MEDIA_TYPE : StatusCode
415 Unsupported Media Type
[RFC7231, Section 6.5.13]
pub const RANGE_NOT_SATISFIABLE : StatusCode
416 Range Not Satisfiable
[RFC7233, Section 4.4]
pub const EXPECTATION_FAILED : StatusCode
417 Expectation Failed
[RFC7231, Section 6.5.14]
pub const IM_A_TEAPOT : StatusCode
418 I’m a teapot
[curiously not registered by IANA butRFC2324]
pub const MISDIRECTED_REQUEST : StatusCode
421 Misdirected RequestRFC7540, Section 9.1.2
pub const UNPROCESSABLE_ENTITY : StatusCode
422 Unprocessable Entity
[RFC4918]
pub const LOCKED : StatusCode
423 Locked
[RFC4918]
pub const FAILED_DEPENDENCY : StatusCode
424 Failed Dependency
[RFC4918]
pub const UPGRADE_REQUIRED : StatusCode
426 Upgrade Required
[RFC7231, Section 6.5.15]
pub const PRECONDITION_REQUIRED : StatusCode
428 Precondition Required
[RFC6585]
pub const TOO_MANY_REQUESTS : StatusCode
429 Too Many Requests
[RFC6585]
pub const REQUEST_HEADER_FIELDS_TOO_LARGE : StatusCode
431 Request Header Fields Too Large
[RFC6585]
pub const UNAVAILABLE_FOR_LEGAL_REASONS : StatusCode
451 Unavailable For Legal Reasons
[RFC7725]
pub const INTERNAL_SERVER_ERROR : StatusCode
pub const NOT_IMPLEMENTED : StatusCode
501 Not Implemented
[RFC7231, Section 6.6.2]
pub const BAD_GATEWAY : StatusCode
502 Bad Gateway
[RFC7231, Section 6.6.3]
pub const SERVICE_UNAVAILABLE : StatusCode
503 Service Unavailable
[RFC7231, Section 6.6.4]
pub const GATEWAY_TIMEOUT : StatusCode
504 Gateway Timeout
[RFC7231, Section 6.6.5]
pub const HTTP_VERSION_NOT_SUPPORTED : StatusCode
505 HTTP Version Not Supported
[RFC7231, Section 6.6.6]
pub const VARIANT_ALSO_NEGOTIATES : StatusCode
506 Variant Also Negotiates
[RFC2295]
pub const INSUFFICIENT_STORAGE : StatusCode
507 Insufficient Storage
[RFC4918]
pub const LOOP_DETECTED : StatusCode
pub const NOT_EXTENDED : StatusCode
510 Not Extended
[RFC2774]
pub const NETWORK_AUTHENTICATION_REQUIRED : StatusCode
511 Network Authentication Required
[RFC6585]
Trait Implementations
impl Clone for StatusCode
fn clone (&self) -> StatusCode
Returns a copy of the value.Read more
1.0.0 · source
fn clone_from (&mut self, source: & Self)
Performs copy-assignment from source.Read more
impl Debug for StatusCode
fn fmt (&self, f: &mut Formatter <'_>) -> Result < () , Error >
Formats the value using the given formatter.Read more
impl Default for StatusCode
source
fn default () -> StatusCode
Returns the “default value” for a type.Read more
impl Display for StatusCode
Formats the status code, includingthe canonical reason.
Example
assert_eq! ( format! ( "{}" , StatusCode::OK ), "200 OK" );
fn fmt (&self, f: &mut Formatter <'_>) -> Result < () , Error >
Formats the value using the given formatter.Read more
impl<'a> From <&'a StatusCode > for StatusCode
fn from (t: &'a StatusCode ) -> StatusCode
Converts to this type from the input type.
impl FromStr for StatusCode
type Err = InvalidStatusCode
The associated error which can be returned from parsing.
fn from_str (s: & str ) -> Result < StatusCode , InvalidStatusCode >
Parses a string sto return a value of this type.Read more
source
impl Hash for StatusCode
fn hash <__H>(&self, state: &mut __H) where __H: Hasher ,
Feeds this value into the given Hasher.Read more
fn hash_slice <H>(data: &[Self] , state: &mut H) where H: Hasher ,
Feeds a slice of this type into the given Hasher.Read more
impl Ord for StatusCode
fn cmp (&self, other: & StatusCode ) -> Ordering
This method returns an Orderingbetween selfand other.Read more
fn max (self, other: Self) -> Self
Compares and returns the maximum of two values.Read more
fn min (self, other: Self) -> Self
Compares and returns the minimum of two values.Read more
fn clamp (self, min: Self, max: Self) -> Self
Restrict a value to a certain interval.Read more
impl PartialEq < StatusCode > for StatusCode
fn eq (&self, other: & StatusCode ) -> bool
This method tests for selfand othervalues to be equal, and is used
by ==.Read more
fn ne (&self, other: & StatusCode ) -> bool
This method tests for !=.
impl PartialEq < u16 > for StatusCode
fn eq (&self, other: & u16 ) -> bool
This method tests for selfand othervalues to be equal, and is used
by ==.Read more
1.0.0 · source
fn ne (&self, other: & Rhs) -> bool
This method tests for !=.
impl PartialOrd < StatusCode > for StatusCode
fn partial_cmp (&self, other: & StatusCode ) -> Option < Ordering >
This method returns an ordering between selfand othervalues if one exists.Read more
1.0.0 · source
fn lt (&self, other: & Rhs) -> bool
This method tests less than (for selfand other) and is used by the <operator.Read more
1.0.0 · source
fn le (&self, other: & Rhs) -> bool
This method tests less than or equal to (for selfand other) and is used by the <=operator.Read more
1.0.0 · source
fn gt (&self, other: & Rhs) -> bool
This method tests greater than (for selfand other) and is used by the >operator.Read more
1.0.0 · source
fn ge (&self, other: & Rhs) -> bool
This method tests greater than or equal to (for selfand other) and is used by the >=operator.Read more
impl<'a> TryFrom < &'a [ u8 ] > for StatusCode
type Error = InvalidStatusCode
The type returned in the event of a conversion error.
fn try_from ( t: &'a [ u8 ] ) -> Result < StatusCode , < StatusCode as TryFrom < &'a [ u8 ] >>:: Error >
Performs the conversion.
impl<'a> TryFrom <&'a str > for StatusCode
type Error = InvalidStatusCode
The type returned in the event of a conversion error.
fn try_from ( t: &'a str ) -> Result < StatusCode , < StatusCode as TryFrom <&'a str >>:: Error >
Performs the conversion.
source
impl TryFrom < u16 > for StatusCode
type Error = InvalidStatusCode
The type returned in the event of a conversion error.
fn try_from (t: u16 ) -> Result < StatusCode , < StatusCode as TryFrom < u16 >>:: Error >
Performs the conversion.
impl Copy for StatusCode
impl Eq for StatusCode
impl StructuralEq for StatusCode
impl StructuralPartialEq for StatusCode
Auto Trait Implementations
impl RefUnwindSafe for StatusCode
impl Send for StatusCode
impl Sync for StatusCode
impl Unpin for StatusCode
impl UnwindSafe for StatusCode
Blanket Implementations
impl<T> Any for T where T: 'static + ? Sized ,
fn type_id (&self) -> TypeId
impl<T> Borrow <T> for T where T: ? Sized ,
const: unstable · source
fn borrow (&self) -> & T
Immutably borrows from an owned value.Read more
impl<T> BorrowMut <T> for T where T: ? Sized ,
const: unstable · source
fn borrow_mut (&mut self) -> &mut T
Mutably borrows from an owned value.Read more
impl<T> From <T> for T
const: unstable · source
fn from (t: T) -> T
Returns the argument unchanged.
impl<T> Instrument for T
fn instrument (self, span: Span ) -> Instrumented <Self>
Instruments this type with the provided Span, returning an Instrumentedwrapper.Read more
fn in_current_span (self) -> Instrumented <Self>
Instruments this type with thecurrent Span, returning an Instrumentedwrapper.Read more
impl<T, U> Into <U> for T where U: From <T>,
const: unstable · source
fn into (self) -> U
Calls U::from(self).
That is, this conversion is whatever the implementation of From <T> for Uchooses to do.
impl<T> ToOwned for T where T: Clone ,
type Owned = T
The resulting type after obtaining ownership.
fn to_owned (&self) -> T
Creates owned data from borrowed data, usually by cloning.Read more
fn clone_into (&self, target: &mut T)
🔬 This is a nightly-only experimental API. ( toowned_clone_into )
Uses borrowed data to replace owned data, usually by cloning.Read more
impl<T> ToString for T where T: Display + ? Sized ,
source
default fn to_string (&self) -> String
Converts the given value to a String.Read more
impl<T, U> TryFrom <U> for T where U: Into <T>,
type Error = Infallible
The type returned in the event of a conversion error.
const: unstable · source
fn try_from (value: U) -> Result <T, <T as TryFrom <U>>:: Error >
Performs the conversion.
impl<T, U> TryInto <U> for T where U: TryFrom <T>,
type Error = <U as TryFrom <T>>:: Error
The type returned in the event of a conversion error.
const: unstable · source
fn try_into (self) -> Result <U, <U as TryFrom <T>>:: Error >
Performs the conversion.
impl<T> WithSubscriber for T
fn with_subscriber <S>(self, subscriber: S) -> WithDispatch <Self> where S: Into < Dispatch >,
Attaches the provided Subscriberto this type, returning a WithDispatchwrapper.Read more
| https://strawlab.org/strand-braid-api-docs/latest/hyper/struct.StatusCode.html |
European Foreign Policy and the Euro Crisis - Carnegie Europe - Carnegie Endowment for International Peace
Jan Techau
February 29, 2012
Q&A
Source: Getty
Summary:
As the euro crisis wreaks havoc on the cohesion of the European Union and the global economy, Europe faces significant foreign policy challenges, including the escalating conflict in Syria and rising tensions with Iran.
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As the euro crisis wreaks havoc on the cohesion of the European Union and the global economy, Europe faces significant foreign policy challenges, including the escalating conflict in Syria and rising tensions with Iran. In a new Q&A, Jan Techau says the euro crisis demonstrates the fundamental need for cooperation and in the long run EU member states will be drawn closer together. Techau asserts that Europe needs to become a more strategic global player to protect its own interests.
What lessons can Europe learn from the euro crisis?
Has the euro crisis impacted the EU's foreign policy efforts?
How has the euro crisis impacted the U.S.-EU relationship?
How effectively is Europe handling the concerns over Iran's nuclear program?
What are the most important issues that Europe will face in the coming year?
How can Europe be a more strategic global player?
How successful has the European External Action Service been in its first year?
What lessons can Europe learn from the euro crisis?
The fundamental lesson from the euro crisis is that Europeans will not be able to cope with their own crises or with crises around the world if they don’t stand together and act as one. The crisis has driven a deep wedge into the European Union, between the northern haves and the southern have-nots, between those who are fiscally disciplined and those who are perceived as not.
All kinds of populists have tried to cash in on these divergences but the fundamental lesson is that people are in it together—in good times and in bad. While that may sound like a given, it is a fundamental lesson because in the short run the crisis might drive Europeans away from each other. But in the long run, the crisis will most certainly drive member states closer together because there is such a fundamental need for cooperation and the last few months have been so tumultuous.
Has the euro crisis impacted the EU's foreign policy efforts?
Jan Techau
Techau was the director of Carnegie Europe, the European center of the Carnegie Endowment for International Peace. Techau works on EU integration and foreign policy, transatlantic affairs, and German foreign and security policy.
More >
@Jan_Techau
In the short term, the impact of the euro crisis on Europe’s ability to act abroad as a foreign policy power has been remarkably small. Europe reacted very swiftly to the Arab Spring. It has been able to react relatively swiftly on the Iran case, and it has been weak on all of the other issues that is has traditionally been weak on.
In the long run, how strongly the euro crisis affects Europe’s economic situation will play a major role in Europe’s ability to become a strategic power worldwide. Europe’s power relies on its economic strength and on its soft power model of integration, sovereignty, bargains, and whether nations give up sovereignty in order to regain some on the other hand. If the Europeans suffer from the euro crisis, if their economic wealth goes down, if their entire buying power goes down, if they become less influential around the world as a trading bloc, then this will inevitably also have an impact on how they are being perceived abroad, on their credibility, and on their sheer political power.
So in the short term, small impact; in the long run, a potentially very big one.
How has the euro crisis impacted the U.S.-EU relationship?
In general EU-U.S. relations are fairly boring. It’s mostly a trading relationship, despite the headlines that are all about security and burden-sharing. The bulk of transatlantic relations are in trade, economic development, and financial matters. The modus operandi of these things are fairly institutionalized.
With regard to the financial crisis, despite the frequent warnings that America is drifting away from Europe, the euro crisis has actually brought America and Europe closer together. The Obama administration, banks, and the business community in the United States clearly understand that Europe must remain stable or the ramifications for America will be horrific. They need stability in Europe, and they need Europe to tackle this crisis and to manage it well in order to survive themselves.
It’s very clear that President Obama is on the phone with Germany’s Angela Merkel and President Sarkozy of France all the time, and that the U.S.-based financial institutions have a very strong stake in the euro crisis—there is a lot of coordination going on across the Atlantic. It may not be for positive reasons that they are cooperating, but they do and that’s basically a good thing.
How effectively is Europe handling the concerns over Iran's nuclear program?
Iran is a good example of Europe acting swiftly but nobody really expecting it to. The implementation of the new round of sanctions on Iran was managed very well within Europe—everybody was on board. Europe as a trading bloc was very important in this entire construction and the business interests of specific countries that have traditionally had strong ties with Iran needed to be accommodated. But all that was done in a very effective way. Between European actions and the international sanctions regime, we are seeing a relatively impressive show of force so far.
Europeans will be less strong once the sanctions regime shows no effect and we enter a diplomatic phase that needs to be backed up by military strength. This is where EU member states will potentially be very much divided and that will be the true litmus test for European resolve on Iran. So good thus far, but potentially again there could be forces that drive the Europeans apart. We will see where that goes.
What are the most important issues that Europe will face in the coming year?
In the next twelve months, clearly the financial crisis will preoccupy Europe. It needs to find a solution to the Greece problem, which we have heard in recent weeks is getting worse not better.
Another hot issue is transatlantic burden sharing, which will take center stage at the NATO summit in May. The question is whether Europeans can find an answer to the Gates and Panetta accusations/proposals on defense.
The third important issue that will impact Europe is elections, and possible power transitions—in Russia and France this year, and in Germany in 2013. Having this many key players in Europe in political limbo always brings a certain amount of nervousness to the political scene.
Finally, perhaps less acute, is the entire question of how Europeans get their act together on the new, emerging situation in Asia. This is not something exclusively reserved for the next twelve months, but Europeans have a concern that America is shifting away from Europe in the twenty-first century—the Asian century. Europeans haven’t quite figured out how they too can get to Asia. As the thinking goes, “the Americans are going, why aren’t we going with them?” This is one of the lingering big, intellectual, and strategic questions in the foreign policy realm. It is not going to show up in the news much but it is an underlying question that Europeans have to get a lot smarter about.
How can Europe be a more strategic global player?
The most important thing that Europe can do to get its act together as a strategic player globally is to finally develop an urgent sense of the geopolitical situation that it is in. This is not just a popular phenomenon but also an elite phenomenon—Europeans are, by and large, unaware of the major tectonic shifts that are happening in the world. They are living in their cozy little niche; they are used to having outsourced their security and strategy concerns to the United States and to external players. But that old transatlantic bargain, that burden sharing across the Atlantic from the 1950s, is coming apart and is no longer an option.
Europeans have to become strategic players to protect their own interests and the most important precondition for this is an intellectual tectonic shift in European thinking and discussion—to embrace debates about their own interests, on means versus goals, and how they fit on long-term projections not just short-term management of problems. There is hope if Europe addresses these issues. If they don’t, then they have a huge foreign policy problem on their hands.
How successful has the European External Action Service been in its first year?
The entire post-Lisbon set up, coming after the Lisbon Treaty, has not really kept its promise. The new External Action Service and the other institutions that were created to streamline foreign policy in Europe and make Europe more effective and less confusing as an international player have not done that. They have created more confusion and made Europe more inward looking because the debate has focused on how the institutions function, how they work, who talks to whom, who had a fallout with whom, who has the money, and who doesn’t. It is not an output oriented debate.
Having said that, a year into the External Action Service, there are signs that the service is gaining a little bit of traction. The financial crisis has absorbed a lot of capacity in the member states to deal with international affairs. Now, they are looking at Brussels and at the relatively large External Action Service, with its capacity and its brain power, to actually give them ideas as well. It’s happening under the radar, behind this financial crisis and nobody really looks at foreign policy institutions. But this is a good sign.
End of document
Carnegie does not take institutional positions on public policy issues; the views represented herein are those of the author(s) and do not necessarily reflect the views of Carnegie, its staff, or its trustees.
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The Oxford Oratory
A sanctuary in the midst of the city
The Oxford Oratory is a vibrant centre of Catholic life. Our church is open every day: join us for Mass, pop in for some quiet prayer, or come and discover more at one of our groups. Our historic church of St Aloysius has been a key feature in the lives of the city’s Catholics for 150 years, attracting people of all ages and from every walk of life. We use beauty to raise hearts and minds to God, faithful to the traditions of St Philip Neri and St John Henry Newman.
The Sacred Heart
Love is a funny thing. Materialists will tell us that it is purely the result of a series of electro-chemical responses in the brain, and yet others will tell us that it is the result of fate, the conspiracy of the alignment of the planets or the times we find ourselves in. The heart has long been understood as the centre of a person, a place of knowledge as much as will. It makes us do unreasonable things like acts of unwarranted kindness and altruism and by the edge of its blade we can be hurt in ways that we just can’t speak about. And yet none of these express what love is in itself — only God does that.
On Friday we venerate the Heart of our Lord as the symbol of his human love in which God’s divine love is revealed to us. In most of the prayers to or the meditations on the Sacred Heart, even those very ancient prayers, the woundedness of our Lord’s heart comes to the fore. That heart pierced with a lance and bruised with outrages and blasphemies is a stark and realistic image of the extent to which Christ loves us. Christ, who is the image of the unseen God, the Icon of the Father, shows us precisely what God’s love for us looks like. And it looks like a heart pierced and bruised on account of our sins, yet burning with ardent love for you and for me. This divine love is not for softies.
The time when we celebrate this feast is very fitting. We have come to the end of the Church’s celebration of the mysteries of our redemption: the Passion, the Cross, the Resurrection, the Ascension, Pentecost, the Feast of the Blessed Trinity and Corpus Christi. But today we commemorate the divine-human love which motivated them all. In adoring the Sacred Heart, we adore the totality of Christ’s saving work — it represents the way in which God holds nothing back from us. And in order to share his divine life with us, he reaches down into the very depths of our life, even — and especially — where it is painful, difficult to speak of, hidden. By taking it all and joining it to himself, he scoops us up, he enables us to become like him. By sharing our life, and by sharing our pains, he heals us, he sanctifies us, and he strengthens us.
It is also true that his heart welcomes us precisely so that we might become like it. The whole thrust of our Christian life is that we might be conformed to our Saviour, that we might resemble him, and in this sense, in the life of faith, we should ask ourselves continually whether our heart resembles his. His Sacred Heart is both the example and the cause of our becoming like him. His love is attractive. The more we consider the love with which Jesus acted, and spoke and gave of himself for us, the more we can begin, by his grace, to imitate him — it is truly the school of Christian perfection.
And we begin in that school by prayer. When St John Henry Newman, our Cardinal, chose his motto, he looked to St Francis de Sales’ Treatise on the Love of God. The phrase he chose and paraphrased, Cor ad Cor loquiturrepresents for us the central mystery of the prayer that can begin to transform us. St Francis de Sales wrote:
Truly the chief exercise in mystical theology is to speak to God and to hear God speak in the bottom of the heart; and because this discourse passes in most secret aspirations and inspirations, we term it a silent conversing. Eyes speak to eyes, and heart to heart, and none understand what passes save those who speak.
We may be no great shakes at the spiritual life, or prayer, or we may feel that excelling in virtue is beyond us, but if we can in the simplest of ways open our poor heart to his Sacred Heart, and speak to him as to a friend, if we can entrust our lives to him and ask him devoutly and sincerely to shape us after the model of his Heart, then our Christian life will be all the more graced.
The Corpus Christi procession concluded with Benediction at the University Chaplaincy. #oxfordoratory
The procession finished at the University’s Catholic Chaplaincy. #oxfordoratory
The numbers caught the attention of the local media:
https://www.oxfordmail.co.uk/news/23582016.oxfords-catholic-congregations-take-part-corpus-christi-procession/
#oxfordoratory
Children scattered flower petals before the Blessed Sacrament all the way. #oxfordoratory
View on Instagram
Our route now passes through the city in a straight line, taking us directly through the busiest shopping areas. #oxfordoratory
The canopy was carried by members of the University of Oxford wearing their academic dress. #oxfordoratory
Fr Robert Ombres OP preached a sermon. #oxfordoratory
We paused at Blackfriars. #oxfordoratory
We were joined by local clergy and religious orders as we processed through the streets to the Dominican Priory at Blackfriars. #oxfordoratory
The processions sets off… #oxfordoratory
We had record numbers for the procession this year. There wasn’t space in church for everyone at the beginning! There were more people outside too. #oxfordoratory
The beginning of our Corpus Christi procession last Sunday.#oxfordoratory
The Oratory Prayer Book is now shipping internationally!
We’ve made it even easier to buy the Oratory Prayer Book from anywhere in the world.
And we’ve made it easier to order multiple copies too — in the UK and worldwide.
Order your copy here:https://tinyurl.com/opb-buy
If you have one, we’d love to hear what you think about it. Let us know in the comments, or tag a photo of your prayer book in the wild with #oratoryprayerbook
Thanks to @acatholicinoxford for the photo.
#oxfordoratory
Worship
What does it actually mean to worship God? In the New Testament, the word we most often translate as ‘worship’ doesn’t mean to reverence another in some abstract sense. It always involves some kind of bodily action. When we think about the magi visiting the Holy Family, we sometimes convey this motion by describing them — after they fall to their knees — as ‘doing homage’. But it’s actually that same word here we might translate elsewhere as ‘worship’. It’s just that we recognise the need to describe the bodily sign of their submission and adoration of the new born King with something that sounds a bit more physical.
The word we usually translate as ‘worship’ ( proskuneo) comes literally from a root meaning ‘to make yourself like a dog before the other person’. It originally meant prostrating yourself on the floor to show your humble submission before another. By the time of the New Testament, people wouldn’t necessarily have had the root of this word in mind whenever they used it,* but the word still carries with it the idea of doing something with your body to express your worship.
The feast of Corpus Christi is all about this kind of bodily worship. It’s tied to the fact that we are not pure spirits, but that we are human beings, body and soul. To worship God is not just a spiritual act. The right worship of God does not consist in simply having the right kinds of thoughts towards him. But the worship of God involves the humble submission of our entire human being, body and soul, before the God who is greater than all of us.
And ever since the Incarnation, we do this not just before an abstract spirit. Because, from the moment of the Incarnation, God really does have a human body, that we can worship, that we fall down on our knees before, like the magi and the Canaanite woman, and so many others in the Gospel who kneel down and worship Christ. When we worship God, we kneel before God who is present in the flesh, under the appearances of bread and wine, in our churches all over the world.
Corpus Christi is a joyful celebration of Christ’s presence among us, and it gives us an opportunity to think about how we respond to that gift. All this talk of kneeling and worship might not sound so joyful, but one of the great paradoxes of Christianity is that we find our greatest freedom in the humble service of God. Our greatest joy really should be found in finding ways to express this loving worship. So at least once a year, it is no bad thing to think about how we express with our own bodies that worship of God’s body, and what ways we can find to worship him even more perfectly.
This Sunday, we will carry Christ’s Body through the streets of our city. We have a chance to demonstrate to the world our love, our joyful service, our worship of him, through our presence. The procession leaves our church at 2:30pm. Make sure you are there.
But we should also think about the more ordinary things, like making sure we show that worship whenever we are in his presence. We should show through our behaviour in church that we believe him to be there: by genuflecting before him in the tabernacle of the church, and by keeping the church quiet and prayerful.
We show our worship above all by kneeling down before him — like all those people in the Gospel — for the moment of Holy Communion. And we allow the priest to place the Host on our tongues, so that we don’t handle unnecessarily what is holy and precious, and no particles of Our Lord’s Body are ever dropped or lost through carelessness.
We continue that worship in our prayers of thanksgiving after Communion and once the Mass has ended. We certainly never leave church during Communion. And we might think of ways of extending the time we spend with Christ present in the Blessed Sacrament: by attending Mass during the week sometimes, or visiting him during the times each week when his Body is exposed solemnly on the altar for Adoration, or even just by visiting an empty church, where he is waiting for us to show him our worship.
Our Lord is hidden there, waiting for us to come and visit him, and make our request to him. See how good he is! He is there in the Sacrament of his love, sighing and interceding incessantly with his Father for sinners. To what outrages does he not expose himself, that he may remain in the midst of us! He is there to console us; and therefore we ought often to visit him. How pleasing to him is the short quarter of an hour that we steal from our occupations, from something of no use, to come and pray to him, to visit him, to console him for all the outrages he receives! When he sees pure souls coming eagerly to him, he smiles upon them. They come with that simplicity which pleases him so much, to ask his pardon for all sinners, for the outrages of so many ungrateful men. What happiness do we not feel in the presence of God, when we find ourselves alone at his feet before the holy tabernacles! ‘Come, my soul, redouble thy fervour; thou art alone adoring thy God. His eyes rest upon thee alone.’
— St John Mary Vianney
* One exception is that I do think Christ had this root meaning in mind when he spoke to the Canaanite woman in Matthew 15:21–28. He wasn’t randomly insulting her by comparing her to a dog, but drawing attention to the fact that she was making herself like a dog before him — i.e. worshipping him — because she recognised him to be God. In other words, he was acknowledging her worship as proof of her faith and humility.
These reflections are sent out each Wednesday to all those on our mailing list. Click here to sign up to our mailing list , and receive our Sunday E-newsletter and these reflections straight to your inbox.
Monday 5 June 2023
On Saturday, Fr Rupert led Men’s Oratory on a walking pilgrimage to Islip, birthplace of St Edward the Confessor. #oxfordoratory
Thursday 1 June 2023
Congratulations to Elizabeth who was received into the Church yesterday evening on the Feast of the Visitation. #oxfordoratory
Thursday 1 June 2023
Congratulations to Livi, baptised on the vigil of Pentecost.
“Therefore, Lord, we pray: graciously accept this oblation of our service, that of your whole family, which we make to you also for those to whom you have been pleased to give the new birth of water and the Holy Spirit, granting them forgiveness of all their sins; order our days in your peace, and command that we be delivered from eternal damnation and counted among the flock of those you have chosen. Through Christ our Lord. Amen.”
#oxfordoratory
Wednesday 31 May 2023
Courtesy
I recall how, as a child at school, we were sometimes made to learn poetry. At the time I hated it, and baulked at the idea of having to commit to memory The Ancient Mariner, and in fact, never did. But one poem which did touch me, was Belloc’s Courtesy. It began:
Of Courtesy, it is much lessThan Courage of Heart or Holiness,Yet in my Walks it seems to meThat the Grace of God is in Courtesy.
The poet goes on to tell us how, on one occasion he visited the ‘monks’ at Storrington in Sussex, and that ‘They took me straight into their Hall’where he ‘saw Three Pictures on a wall, And Courtesy was in them all.’
He then tells us the subject of those paintings:
The first the Annunciation;The second the Visitation;The third the Consolation,Of God that was Our Lady’s Son.
The first was of St. Gabriel;On Wings a-flame from Heaven he fell;And as he went upon one kneeHe shone with Heavenly Courtesy.
Our Lady out of Nazareth rode —It was Her month of heavy load;Yet was her face both great and kind,For Courtesy was in Her Mind.
The third it was our Little Lord,Whom all the Kings in arms adored;He was so small you could not seeHis large intent of Courtesy.
Today is the feast of the Visitation, when we celebrate how our Lady made the long and uncomfortable journey to see her older kinswoman, Elizabeth, and her husband Zachariah, who lived in the hill country of Judah. Courtesy seems to me to be a perfect description of what this moment is all about. Imagine the cordial welcome extended to Mary by the older woman, solicitous for her health and how both women were eager to share with one another the joy of the forthcoming births of their sons. Our Lady had herself gone to visit her older cousin, not simply because she wanted to ‘be there’ for her, but because she wanted to share her own good news, which was not hers alone but for her people and, ultimately for the entire world.
This is something Elizabeth seemed to know already! Her enthusiastic greeting is wonderful when she cries out ‘Oh that I should be visited by the Mother of my Lord’. Her unborn son joins in the greeting, kicking and letting his mother know that he too is part of this exciting thing that is happening. Elizabeth’s gracious words: ‘Blessed art thou among women and blessed is the fruit of thy womb’ have been enshrined in our prayer to the Virgin, incorporated with the Angelic Salutation: ‘Hail Mary, full of grace!’
And if today’s feast is about courtesy (so much more than stiff politeness or polished manners, but a warm and real concern for the wellbeing and interest of the other) then it is also about joy. Mary’s presence, together with that of her Divine Son, transformed the home of Elizabeth and Zachariah. ‘Elizabeth was filled with the Holy Spirit’ because of it. St Jose Maria puts it thus: ‘Mary brought joy to her cousin’s home, because she “brought” Christ’. Dame Julian liked to call Jesus ‘our courteous Lord,’ no doubt on account of his gracious dealings with us, flowing from his ‘large intent of Courtesy’!
Julian writes in her Showings:
And this is a supreme friendship of our courteous Lord, that he protects us so tenderly whilst we are in our sins; and furthermore he touches us most secretly, and shows us our sins by the sweet light of mercy and grace. But when we see ourselves so foul, then we believe that God may be angry with us because of our sins. Then we are moved by the Holy Spirit through contrition to prayer, and we desire with all our might an amendment of ourselves to appease God’s anger, until the time that we find rest of soul and ease of conscience. And then we hope that God has forgiven us our sin; and this is true. And then our courteous Lord shows himself to the soul, happily and with the gladdest countenance, welcoming it as a friend, as if it had been in pain and in prison, saying: My dear darling, I am glad that you have come to me in all your woe. I have always been with you, and now you see me loving, and we are made one in bliss.
So sins are forgiven by grace and mercy, and our soul is honourably received in joy, as it will be when it comes into heaven, as often as it comes by the operation of grace of the Holy Spirit and the power of Christ’s Passion.
Tuesday 30 May 2023
Even though we have just changed all the light bulbs, our church looks its best when we don’t need to use them.
#oxfordoratory
© 2023 Oxford Oratory. All rights reserved. The Oxford Oratory of St Philip Neri is a Registered Charity number 1018455
| https://www.oxfordoratory.org.uk/campaign/blog/post/9998-9998/blog/post/9916-look-up-to-heaven/ |
Publications - Global Disability Innovation Hub
The GDI Hub brings together academic excellence, innovative practice and co-creation; harnessing the power of technology for good.
Type
Conference Paper
Themes
Assistive & Accessible Technology
Culture and Participation
The Social Network: How People with Visual Impairment use Mobile Phones in Kibera, Kenya
Giulia Barbareschi,Catherine Holloway, Katherine Arnold, Grace Magomere, Wycliffe Ambeyi Wetende, Gabriel Ngare, Joyce Olenja
We present the findings of a case study of mobile technology use by People with Visual Impairment (VIPs) in Kibera, an informal settlement in Nairobi. We used contextual interviews, ethnographic observations and a co-design workshop to explore how VIPs use mobile phones in their daily lives, and how this use influences the social infrastructure of VIPs. Our findings suggest that mobile technology supports and shapes the creation of social infrastructure. However, this is only made possible through the existing support networks of the VIPs, which are mediated through four types of interaction: direct, supported, dependent and restricted.
CHI '20: Proceedings of the 2020 CHI Conference; 2020
Abstract
The Social Network: How People with Visual Impairment use Mobile Phones in Kibera, Kenya
Living in an informal settlement with a visual impairment can be very challenging resulting in social exclusion. Mobile phones have been shown to be hugely beneficial to people with sight loss in formal and high-income settings. However, little is known about whether these results hold true for people with visual impairment (VIPs) in informal settlements. We present the findings of a case study of mobile technology use by VIPs in Kibera, an informal settlement in Nairobi. We used contextual interviews, ethnographic observations and a co-design workshop to explore how VIPs use mobile phones in their daily lives, and how this use influences the social infrastructure of VIPs. Our findings suggest that mobile technology supports and shapes the creation of social infrastructure. However, this is only made possible through the existing support networks of the VIPs, which are mediated through four types of interaction: direct, supported, dependent and restricted.
The Social Network: How People with Visual Impairment use Mobile Phones in Kibera, Kenya
Giulia Barbareschi, Catherine Holloway, Katherine Arnold, Grace Magomere, Wycliffe Ambeyi Wetende, Gabriel Ngare, and Joyce Olenja. 2020. The Social Network: How People with Visual Impairment use Mobile Phones in Kibera, Kenya. In Proceedings of the 2020 CHI Conference on Human Factors in Computing Systems (CHI '20). Association for Computing Machinery, New York, NY, USA, 1–15.https://doi.org/10.1145/331383...
Type
Editorial
Themes
Culture and Participation
COVID-19 as social disability: the opportunity of social empathy for empowerment
Ikenna D Ebueny, Emma M Smith,Catherine Holloway, Rune Jensen, Lucía D'Arino, Malcolm MacLachlan
Social empathy is ‘the ability to more deeply understand people by perceiving or experiencing their life situations and as a result gain insight into structural inequalities and disparities’. Social empathy comprises three elements: individual empathy, contextual understanding and social responsibility. COVID-19 has created a population-wide experience of exclusion that is only usually experienced by subgroups of the general population. Notably, persons with disability, in their everyday lives, commonly experience many of the phenomena that have only recently been experienced by members of the general population. COVID-19 has conferred new experiential knowledgeon all of us. We have a rare opportunity to understand and better the lives of persons with disabilities for whom some aspects of the COVID- 19 experience are enduring. This allows us greater understanding of the importance of implementing in full a social and human rights model of disability, as outlined in the UNCRPD.
BMJ Global Health; 2020
Abstract
COVID-19 as social disability: the opportunity of social empathy for empowerment
COVID-19 has conferred new experiential knowledge on society and a rare opportunity to better understand the social model of disability and to improve the lives of persons with disabilities.
The COVID-19 experience may offer contextual knowledge of the prepandemic lives of persons with disabilities and foster greater social awareness, responsibility and opportunities for change towards a more inclusive society.
Information, family and social relationships, health protection and healthcare, education, transport and employment should be accessible for all groups of the population. The means must be developed and deployed to ensure equity – the deployment of resources so that people with different types of needs have the same opportunities for living good lives in inclusive communities.
We have learnt from COVID-19 that inclusive healthcare and universal access should be the new normal, that its provision as a social good is both unifying and empowering for society as a whole.
COVID-19 as social disability: the opportunity of social empathy for empowerment
Ebuenyi ID, Smith EM, Holloway C , et alCOVID-19 as social disability: the opportunity of social empathy for empowerment BMJ Global Health2020;5:e003039.
COVID-19 as social disability: the opportunity of social empathy for empowerment
Type
Editorial
Themes
Assistive & Accessible Technology
Research Group
Social Justice
Developing inclusive and resilient systems: COVID-19 and assistive technology
Emma M. Smith, Malcolm MacLachlan, Ikenna D. Ebuenyi,Catherine Holloway&Victoria Austin
While the inadequacies of our existing assistive technology systems, policies, and services have been highlighted by the acute and rapidly changing nature of the COVID-19 pandemic, these failures are also present and important during non-crisis times. Each of these actions, taken together, will not only address needs for more robust and resilient systems for future crises, but also the day-to-day needs of all assistive technology users. We have a responsibility as a global community, and within our respective countries, to address these inadequacies now to ensure an inclusive future.
Disability & Society; 2020
Abstract
Developing inclusive and resilient systems: COVID-19 and assistive technology
Assistive technology is a critical component of maintaining health, wellbeing, and the realization of rights for persons with disabilities. Assistive technologies, and their associated services, are also paramount to ensuring individuals with functional limitations have access to important health and social service information, particularly during a pandemic where they may be at higher risk than the general population. Social isolation and physical distancing have further marginalized many within this population. We have an opportunity to learn from the COVID-19response to develop more inclusive and resilient systems that will serve people with disabilities more effectively in the future. In this Current Issues piece, we present a starting point for discussion, based on our experiences working to promote access to assistive technologies through inclusive and sustainable systems and policies.
Developing inclusive and resilient systems: COVID-19 and assistive technology
Emma M. Smith, Malcolm MacLachlan, Ikenna D. Ebuenyi, Catherine Holloway & Victoria Austin (2021) Developing inclusive and resilient systems: COVID-19 and assistive technology, Disability & Society, 36:1, 151-154, DOI:10.1080/09687599.2020.1829558
Developing inclusive and resilient systems: COVID-19 and assistive technology
Type
Conference Paper
Disability design and innovation in computing research in low resource settings
Dafne Zuleima Morgado-Ramirez,Giulia Barbareschi, Maggie Kate Donovan-Hall, Mohammad Sobuh, Nida' Elayyan, Brenda T Nakandi, Robert Tamale Ssekitoleko, joyce Olenja, Grace Nyachomba Magomere, Sibylle Daymond, Jake Honeywill, Ian Harris, Nancy Mbugua, Laurence Kenney,Catherine Holloway
80% of people with disabilities worldwide live in low resourced settings, rural areas, informal settlements and in multidimensional poverty. ICT4D leverages technological innovations to deliver programs for international development. But very few do so with a focus on and involving people with disabilities in low resource settings. Also, most studies largely focus on publishing the results of the research with a focus on the positive stories and not the learnings and recommendations regarding research processes.
ASSETS '20: Proceedings of the 22nd International ACM SIGACCESS Conference on Computers and Accessibility; 2020
Abstract
Disability design and innovation in computing research in low resource settings
80% of people with disabilities worldwide live in low resourced settings, rural areas, informal settlements and in multidimensional poverty. ICT4D leverages technological innovations to deliver programs for international development. But very few do so with a focus on and involving people with disabilities in low resource settings. Also, most studies largely focus on publishing the results of the research with a focus on the positive stories and not the learnings and recommendations regarding research processes. In short, researchers rarely examine what was challenging in the process of collaboration. We present reflections from the field across four studies. Our contributions are: (1) an overview of past work in computing with a focus on disability in low resource settings and (2) learnings and recommendations from four collaborative projects in Uganda, Jordan and Kenya over the last two years, that are relevant for future HCI studies in low resource settings with communities with disabilities. We do this through a lens of Disability Interaction and ICT4D.
Dafne Zuleima Morgado-Ramirez, Giulia Barbareschi, Maggie Kate Donovan-Hall, Mohammad Sobuh, Nida' Elayyan, Brenda T Nakandi, Robert Tamale Ssekitoleko, joyce Olenja, Grace Nyachomba Magomere, Sibylle Daymond, Jake Honeywill, Ian Harris, Nancy Mbugua, Laurence Kenney, and Catherine Holloway. 2020. Disability design and innovation in computing research in low resource settings. In Proceedings of the 22nd International ACM SIGACCESS Conference on Computers and Accessibility (ASSETS '20). Association for Computing Machinery, New York, NY, USA, Article 11, 1–7.https://doi.org/10.1145/337362...
Type
Editorial
Research Group
Social Justice
Assistive Technology (AT), for What?
Vicki Austin, Catherine Holloway
This year (2022) has seen the publication of the World’s first Global Report on Assistive Technology (GReAT) [1]. This completes almost a decade of work to ensure assistive technology (AT) access is a core development issue. The lack of access to assistive products (APs), such as wheelchairs, hearing aids, and eyeglasses, as well as less well-referenced products such as incontinence pads, mobile phone applications, or walking sticks, affects as many as 2.5 billion people globally. Furthermore, the provision of APs would reap a 1:9 return on investment [2]. This could result in a family in need netting (or living without) over GBP 100,000 in their lifetime [2] or more, if we count dynamic overspills in the economy such as employment of assistive technology services and manufacturing of devices [3].
Societies; 2021
Abstract
Assistive Technology (AT), for What?
Amartya Sen’s seminal Tanner lecture: Equality of What?began a contestation on social justice and human wellbeing that saw a new human development paradigm emerge—the capability approach (CA)—which has been influential ever since. Following interviews with leading global assistive technology (AT) stakeholders, and users, this paper takes inspiration from Sen’s core question and posits, AT for what?arguing that AT should be understood as a mechanism to achieve the things that AT users’ value. Significantly, our research found no commonly agreed operational global framework for (disability) justice within which leading AT stakeholders were operating. Instead, actors were loosely aligned through funding priorities and the CRPD. We suggest that this raises the possibility for (welcome and needed) incoming actors to diverge from efficiently designed collective action, due to perverse incentives enabled by unanchored interventions. The Global Report on Assistive Technology (GReAT) helps, greatly! However, we find there are still vital gaps in coordination; as technology advances, and AT proliferates, no longer can the device-plus-service approach suffice. Rather, those of us interested in human flourishing might explore locating AT access within an operational global framework for disability justice, which recognizes AT as a mechanism to achieve broader aims, linked to people’s capabilities to choose what they can do and be.
Assistive Technology (AT), for What?
Austin, V.; Holloway, C. Assistive Technology (AT), for What? Societies2022, 12, 169.https://doi.org/10.3390/soc120...
Assistive Technology (AT), for What?
Type
Workshop
Themes
Assistive & Accessible Technology
Research Group
Disability Interactions
Could AI Democratise Education? Socio-Technical Imaginaries of an EdTech Revolution
Sahan Bulathwela, María Pérez-Ortiz,Catherine Holloway, John Shawe-Taylor
This paper starts by synthesising how AI might change how we learn and teach, focusing specifically on the case of personalised learning companions, and then move to discuss some socio-technical features that will be crucial for avoiding the perils of these AI systems worldwide (and perhaps ensuring their success). This paper also discusses the potential of using AI together with free, participatory and democratic resources, such as Wikipedia, Open Educational Resources and open-source tools. We also emphasise the need for collectively designing human-centered, transparent, interactive and collaborative AI-based algorithms that empower and give complete agency to stakeholders, as well as support new emerging pedagogies.
Workshop on Machine Learning for the Developing World (ML4D) at the Conference on Neural Information Processing Systems 2021; 2021
Abstract
Could AI Democratise Education? Socio-Technical Imaginaries of an EdTech Revolution
Artificial Intelligence (AI) in Education has been said to have the potential for building more personalised curricula, as well as democratising education worldwide and creating a Renaissance of new ways of teaching and learning. Millions of students are already starting to benefit from the use of these technologies, but millions more around the world are not. If this trend continues, the first delivery of AI in Education could be greater educational inequality, along with a global misallocation of educational resources motivated by the current technological determinism narrative. In this paper, we focus on speculating and posing questions around the future of AI in Education, with the aim of starting the pressing conversation that would set the right foundations for the new generation of education that is permeated by technology. This paper starts by synthesising how AI might change how we learn and teach, focusing specifically on the case of personalised learning companions, and then move to discuss some socio-technical features that will be crucial for avoiding the perils of these AI systems worldwide (and perhaps ensuring their success). This paper also discusses the potential of using AI together with free, participatory and democratic resources, such as Wikipedia, Open Educational Resources and open-source tools. We also emphasise the need for collectively designing human-centered, transparent, interactive and collaborative AI-based algorithms that empower and give complete agency to stakeholders, as well as support new emerging pedagogies. Finally, we ask what would it take for this educational revolution to provide egalitarian and empowering access to education, beyond any political, cultural, language, geographical and learning ability barriers.
Could AI Democratise Education? Socio-Technical Imaginaries of an EdTech Revolution
Type
Workshop
Themes
Assistive & Accessible Technology
Towards Proactive Information Retrieval in Noisy Text with Wikipedia Concepts
Tabish Ahmed, Sahan Bulathwela
The informational needs of people are highly contextual and can depend on many different factors such as their current knowledge state, interests and goals [1, 2, 3]. However, an effective information retrieval companion should minimise the human effort required in i) expressing a human information need and ii) navigating a lengthy result set. Using topical representations of the user history (e.g. [4]) can immensely help formulating zero shot queries and refining short user queries that enable proactive information retrieval (IR). While the world has digital textual information in abundance, it can often be noisy (e.g. extracted through Automatic Speech Recognition (ASR), PDF text extraction etc.), leading to state-of-the-art neural models being highly sensitive to the noise producing sub-optimal results [5]. This demands denoising steps to refine both query and document representation. In this paper, we argue that Wikipedia, an openly available encyclopedia, can be a humanly intuitive knowledge base [6] that has the potential to provide the world view many noisy information Retrieval systems need.
Published at the First Workshop on Proactive and Agent-Supported Information Retrieval at CIKM 2022; 2022
Abstract
Towards Proactive Information Retrieval in Noisy Text with Wikipedia Concepts
Extracting useful information from the user history to clearly understand informational needs is a crucial feature of a proactive information retrieval system. Regarding understanding information and relevance, Wikipedia can provide the background knowledge that an intelligent system needs. This work explores how exploiting the context of a query using Wikipedia concepts can improve proactive information retrieval on noisy text. We formulate two models that use entity linking to associate Wikipedia topics with the relevance model. Our experiments around a podcast segment retrieval task demonstrate that there is a clear signal of relevance in Wikipedia concepts while a ranking model can improve precision by incorporating them. We also find Wikifying the background context of a query can help disambiguate the meaning of the query, further helping proactive information retrieval.
Type
Article
Themes
Assistive & Accessible Technology
These tools help visually impaired scientists read data and journals
Alla Katsnelson
This article was featured in Nature and discusses tools that help visually impaired scientists read data and Journals. Innovation Manager, Daniel Hajas, was interviewed as part of this piece and highlights the need for an ecosystem approach, and access to data / visualisations for blind members of the research and science community.
Nature; 2023
Type
Editorial
Themes
Assistive & Accessible Technology
Research Group
Disability Interactions
The Digital and Assistive Technologies for Ageing initiative: learning from the GATE initiative
Chapal Khasnabis,Catherine Holloway, Malcolm MacLachlan
We are now in an era of assistive care and assistive living—whereby many people, of all ages, in good health, and those who are more frail, or with cognitive or functional impairments, are using a broad range of technologies to assist and enhance their daily living. Assistive living 1is becoming an important part of population health and rehabilitation, which can help to maximise an individual's abilities, regardless of age or functional capacity. This encouraging shift in ethos has been strengthened by the response to the COVID-19 pandemic, in which a plethora of digital and remote technologies have been used.
The Lancet; 2020
Type
Editorial
Themes
Assistive & Accessible Technology
Culture and Participation
Research Group
Social Justice
Critical Junctures in Assistive Technology and Disability Inclusion
Dr Maria Kett,Catherine Holloway,Vicki Austin,Dr Maria Kett
It is clear from the events of the last 18 months that while technology has a huge potential for transforming the way we live and work, the entire ecosystem—from manufacturing to the supply chain—is vulnerable to the vagaries of that ecosystem, as well as having the potential to exacerbate new and existing inequalities [1]. Nowhere has this been more apparent than in the lives of people with disabilities, who make up around 15% of the world’s population and already face barriers to accessing education, employment, healthcare and other services [2]. Some of these barriers are a result of unequal access and opportunities. However, there is a growing movement to better understand how assistive technology systems and services can be designed to enable more robust and equitable access for all. As part of this growing movement, the Paralympic Games in Tokyo this autumn saw the launch of a new global campaign to transform the lives of the world’s 1.2 bn persons with disabilities: the ‘WeThe15’ campaign reached more than 4.5 billion people through its marketing and stands ready to be the biggest of its kind in history. Next year, the World Health Organization (WHO) and the United Nations Children’s Fund (UNICEF), AT scale and GDI Hub will publish the first World Report on Access to Assistive Technology, which will include research from the £20 million, UK Aid funded, GDI Hub-led, programme, AT2030. Ahead of that, in this Special Issue, we focus on how some events and situations—as diverse as the coronavirus pandemic and the Paralympics—can act as ‘critical junctures’ that can enable a rethink of the status quo to facilitate and promote change.
Sustainability; 2021
Kett, M.; Holloway, C.; Austin, V. Critical Junctures in Assistive Technology and Disability Inclusion. Sustainability2021, 13, 12744.https://doi.org/10.3390/su1322...
Type
Editorial
Themes
Assistive & Accessible Technology
Research Group
Disability Interactions
Introduction to the companion papers to the global report on assistive technology
Johan Borg, Wei Zhang, Emma M. Smith,Cathy Holloway
GReAT, but do we care?
If accessible, assistive technology would be life changing for a billion people across the world today – and two billion people in 2050 (WHO,2018). It would make the difference between independence and dependence, inclusion and exclusion, life and death. It holds the potential to improve and transform health, education, livelihood and social participation; fundamental human rights everyone is entitled to. And if we are lucky to grow old, the chances are that we all would use assistive technology by then. But do we care?
Assistive Technology, The Official Journal of RESNA; 2021
Introduction to the companion papers to the global report on assistive technology
Johan Borg, Wei Zhang, Emma M. Smith & Cathy Holloway (2021) Introduction to the companion papers to the global report on assistive technology, Assistive Technology, 33:sup1, 1-2, DOI:10.1080/10400435.2021.2003658
Type
Conference Paper
Themes
Assistive & Accessible Technology
Value beyond function: analyzing the perception of wheelchair innovations in Kenya
Barbareschi, G; Daymond, S; Honeywill, J; Singh, A; Noble, D; Mbugua, N; Harris, I;Austin, V;Holloway, C
The World Health Organization (WHO) defines Assistive Technology (AT) as “an umbrella term covering the systems and services related to the delivery of assistive products and services” [6]. This definition highlights how AT encompasses not only the physical and digital products used by millions of persons with disabilities (PWDs) worldwide, but also the systems and services that accompany the provision of these devices [78].
ASSETS '20: The 22nd International ACM SIGACCESS Conference on Computers and Accessibility.; 2020
Abstract
Value beyond function: analyzing the perception of wheelchair innovations in Kenya
Innovations in the field of assistive technology are usually evaluated based on practical considerations related to their ability to perform certain functions. However, social and emotional aspects play a huge role in how people with disabilities interact with assistive products and services. Over a five months period, we tested an innovative wheelchair service provision model that leverages 3D printing and Computer Aided Design to provide bespoke wheelchairs in Kenya. The study involved eight expert wheelchair users and five healthcare professionals who routinely provide wheelchair services in their community. Results from the study show that both users and providers attributed great value to both the novel service delivery model and the wheelchairs produced as part of the study. The reasons for their appreciation went far beyond the practical considerations and were rooted in the fact that the service delivery model and the wheelchairs promoted core values of agency, empowerment and self-expression.
Value beyond function: analyzing the perception of wheelchair innovations in Kenya
Type
Conference Paper
Themes
Assistive & Accessible Technology
Culture and Participation
Inclusion and Independence: The impact of Mobile Technology on the Lives of Persons with Disabilities in Kenya and Bangladesh
Nusrat Jahan,Giulia Barbareschi, Clara Aranda Jan, Charles Musungu Mutuku, Naemur Rahman,Victoria Austin,Catherine Holloway
Worldwide it is estimated that there are over a billion people who live with some form of disability[1]. Approximately 80% of people with disabilities live in low-and-middle income countries (LMICs). The combination of an inaccessible environment compounded by socio-economic factors such as poverty and stigma, makes it more likely for people with disabilities to be marginalised and excluded from society[1]. Assistive Technologies (ATs) are known to bridge the accessibility gaps and allow for greater social inclusion. However, there is a lack of adequate access to ATs in LMICs, combined with often poorly designed services, which only magnifies these challenges, thus limiting the opportunities for persons with disabilities to live an independent life[2]. Despite the importance of AT, access to AT globally is inadequate with only 10 percent of those in need having access to the ATs that they need[2].
2020 IEEE Global Humanitarian Technology Conference
Abstract
Inclusion and Independence: The impact of Mobile Technology on the Lives of Persons with Disabilities in Kenya and Bangladesh
Globally, mobile technology plays a significant role connecting and supporting people with disabilities. However, there has been limited research focused on understanding the impact of mobile technology in the lives of persons with disabilities in low or middle- income countries. This paper presents the findings of a participatory photovoice study looking at the role that mobile phones play in the daily lives of 16 persons with disabilities in Kenya and Bangladesh. Participants used a combination of pictures and voice recordings to capture their own stories and illustrate the impact that mobile phone use has on their lives. Through thematic analysis, we categorized the benefits of mobile phones captured by participants as 1) Improved social connection; 2) Increased independence and 3) Access to opportunities. While mobile phones are ubiquitously used for communication, for persons with disabilities they become essential assistive technologies that bridge barriers to opportunities which are not accessible otherwise. Our paper adds evidence to the need for mobile phones for persons with disabilities to enable communication and connectivity in support of development.
Inclusion and Independence: The impact of Mobile Technology on the Lives of Persons with Disabilities in Kenya and Bangladesh
N. Jahan et al., "Inclusion and Independence: The impact of Mobile Technology on the Lives of Persons with Disabilities in Kenya and Bangladesh," 2020 IEEE Global Humanitarian Technology Conference (GHTC), Seattle, WA, USA, 2020, pp. 1-8, doi: 10.1109/GHTC46280.2020.9342934.
Inclusion and Independence: The impact of Mobile Technology on the Lives of Persons with Disabilities in Kenya and Bangladesh
Type
Conference Paper
Themes
Assistive & Accessible Technology
Research Group
Local Productions
A Preliminary Study to Understand How Mainstream Accessibility and Digital Assistive Technologies Reaches People in Lower- and Middle-Income Countries
Tigmanshu Bhatnagar, George Torrens, Ben Oldfrey, Priya MorjariaFelipe Ramos Barajas, Katherine PerryandCatherine Holloway
Access to information on digital platforms not only facilitates education, employment, entertainment, social interaction but also facilitates critical governmental services, ecommerce, healthcare services and entrepreneurship [1]. Article 9 of United Nations Convention on the Rights of Persons with Disabilities (UNCRPD) enforces its signatories to commit to provide full accessibility to every citizen of the nation [2]. This has helped to spearhead accessibility directives such as the European Accessibility Act [3] that aims to improve the functioning of markets for accessible products and services. Such directives contribute to ensure that mainstream digital technologies (smartphones, computers etc.) are accessible for everyone and without being socially remarkable, they are able to assist in daily living. Additionally, there is evidence that improving access in mainstream technologies improves product experience and usability for everyone [4]. However, mainstream access has not been fully realized, leading to inferior opportunities for people with disabilities, a disparity which is more prominent in lower and middle-income countries [5].
RESNA Annual Conference; 2021
Type
Toolkit
Innovate Now Toolkit
As an entrepreneur, learning how to solve problems by creating and experimenting with different strategies is a core pillar of the entrepreneurial mindset you need to succeed. However, there’s rarely a single correct way to solve problems as an entrepreneur, so you need to learn how to create and compare different solutions.
The open entrepreneurship toolkit is a set of learning materials that can help you and your team do just that. Covering the domains of user, product, market and business development, the set of cards have been designed to be used by two or more group members to actively experiment with different solutions.
Type
Workshop
Themes
Assistive & Accessible Technology
Culture and Participation
Rethinking the Senses: A Workshop on Multisensory Embodied Experiences and Disability Interactions
Maryam Bandukda, Aneesha Singh,Catherine Holloway,Nadia Berthouze, Emeline Brulé, Ana Tajadura-Jiménez, Oussama Metatla, Ana Javornik, and Anja Thieme
The emerging possibilities of multisensory interactions provide an exciting space for disability and open up opportunities to explore new experiences for perceiving one's own body, it's interactions with the environment and also to explore the environment itself. In addition, dynamic aspects of living with disability, life transitions, including ageing, psychological distress, long-term conditions such as chronic pain and new conditions such as long-COVID further affect people's abilities. Interactions with this diversity of embodiments can be enriched, empowered and augmented through using multisensory and cross-sensory modalities to create more inclusive technologies and experiences. To explore this, in this workshop we will explore three related sub-domains: immersive multi-sensory experiences, embodied experiences, and disability interactions and design.
CHI EA '21: Extended Abstracts of the 2021 CHI Conference on Human Factors in Computing Systems
Abstract
Rethinking the Senses: A Workshop on Multisensory Embodied Experiences and Disability Interactions
The emerging possibilities of multisensory interactions provide an exciting space for disability and open up opportunities to explore new experiences for perceiving one's own body, it's interactions with the environment and also to explore the environment itself. In addition, dynamic aspects of living with disability, life transitions, including ageing, psychological distress, long-term conditions such as chronic pain and new conditions such as long-COVID further affect people's abilities. Interactions with this diversity of embodiments can be enriched, empowered and augmented through using multisensory and cross-sensory modalities to create more inclusive technologies and experiences. To explore this, in this workshop we will explore three related sub-domains: immersive multi-sensory experiences, embodied experiences, and disability interactions and design. The aim is to better understand how we can re-think the senses in technology design for disability interactions and the dynamic self, constructed through continuously changing sensing capabilities either because of changing ability or because of the empowering technology. This workshop will: (i) bring together HCI researchers from different areas, (ii) discuss tools, frameworks and methods, and (iii) form a multidisciplinary community to build synergies for further collaboration.
Rethinking the Senses: A Workshop on Multisensory Embodied Experiences and Disability Interactions
Maryam Bandukda, Aneesha Singh, Catherine Holloway, Nadia Berthouze, Emeline Brulé, Ana Tajadura-Jiménez, Oussama Metatla, Ana Javornik, and Anja Thieme. 2021. Rethinking the Senses: A Workshop on Multisensory Embodied Experiences and Disability Interactions. Extended Abstracts of the 2021 CHI Conference on Human Factors in Computing Systems. Association for Computing Machinery, New York, NY, USA, Article 118, 1–5. DOI:https://doi.org/10.1145/341176...
Rethinking the Senses: A Workshop on Multisensory Embodied Experiences and Disability Interactions
Type
Conference Paper
Themes
Assistive & Accessible Technology
Opportunities for Supporting Self-efficacy through Orientation and Mobility Training Technologies for Blind and Partially Sighted People
Maryam Bandukda,Catherine Holloway, Aneesha Singh,Giulia Barbareschi, Nadia Berthouze
We conducted semi-structured interviews with 20 BPS people and 8 Mobility and Orientation Trainers (MOT). The interviews were thematically analysed and organised into four overarching themes discussing factors influencing the self-efficacy belief of BPS people: Tools and Strategies for O&M training, Technology Use in O&M Training, Changing Personal and Social Circumstances, and Social Influences. We further highlight opportunities for combinations of multimodal technologies to increase access to and effectiveness of O&M training.
ASSETS '21: Proceedings of the 23rd International ACM SIGACCESS Conference on Computers and Accessibility
Abstract
Opportunities for Supporting Self-efficacy through Orientation and Mobility Training Technologies for Blind and Partially Sighted People
Orientation and mobility (O&M) training provides essential skills and techniques for safe and independent mobility for blind and partially sighted (BPS) people. The demand for O&M training is increasing as the number of people living with vision impairment increases. Despite the growing portfolio of HCI research on assistive technologies (AT), few studies have examined the experiences of BPS people during O&M training, including the use of technology to aid O&M training. To address this gap, we conducted semi-structured interviews with 20 BPS people and 8 Mobility and Orientation Trainers (MOT). The interviews were thematically analysed and organised into four overarching themes discussing factors influencing the self-efficacy belief of BPS people: Tools and Strategies for O&M training, Technology Use in O&M Training, Changing Personal and Social Circumstances, and Social Influences. We further highlight opportunities for combinations of multimodal technologies to increase access to and effectiveness of O&M training.
Opportunities for Supporting Self-efficacy through Orientation and Mobility Training Technologies for Blind and Partially Sighted People
Type
Conference Paper
Themes
Assistive & Accessible Technology
What difference does tech make? Conceptualizations of Disability and Assistive Technology among Kenyan Youth: Conceptualizations of Disability and AT
Giulia Barbareschi, Norah Shitawa Kopi,Ben Oldfrey,Catherine Holloway
In this paper, we examine how young Kenyans without disabilities view people with disabilities and AT users. Findings show that while the portrayal of disability is often shaped by negative emotion, participants felt that many of the barriers affecting people with disabilities were created by society. Perceptions of AT differed –devices were not only seen as a mark of disability but also as a sign of access to resources. Therefore, what we see is an emergent picture where social barriers can be reinforced by poverty, and where poverty reinforces social barriers faced by people with disabilities. We conclude that access to appropriate technology alongside societal interventions tackling incorrect beliefs about disability can help to overcome the stigma faced by people with disabilities.
ASSETS '21: Proceedings of the 23rd International ACM SIGACCESS Conference on Computers and Accessibility
Abstract
What difference does tech make? Conceptualizations of Disability and Assistive Technology among Kenyan Youth: Conceptualizations of Disability and AT
Most research which investigates stigma towards with people with disabilities and the use of Assistive Technology (AT) are based in the Global North and focus on the experiences of people with disabilities and the consequences that stigma has on choices surrounding AT. However, stigma is a societal construct rooted in the attitude and beliefs that people without disabilities hold on disability and AT. Furthermore, the portrayal of people with disabilities and AT is dependent on the social context. In this paper, we examine how young Kenyans without disabilities view people with disabilities and AT users. Findings show that while the portrayal of disability is often shaped by negative emotion, participants felt that many of the barriers affecting people with disabilities were created by society. Perceptions of AT differed –devices were not only seen as a mark of disability but also as a sign of access to resources. Therefore, what we see is an emergent picture where social barriers can be reinforced by poverty, and where poverty reinforces social barriers faced by people with disabilities. We conclude that access to appropriate technology alongside societal interventions tackling incorrect beliefs about disability can help to overcome the stigma faced by people with disabilities.
What difference does tech make? Conceptualizations of Disability and Assistive Technology among Kenyan Youth: Conceptualizations of Disability and AT
Giulia Barbareschi, Norah Shitawa Kopi, Ben Oldfrey, and Catherine Holloway. 2021. What difference does tech make? Conceptualizations of Disability and Assistive Technology among Kenyan Youth: Conceptualizations of Disability and AT. In The 23rd International ACM SIGACCESS Conference on Computers and Accessibility( ASSETS '21). Association for Computing Machinery, New York, NY, USA, Article 18, 1–13. DOI:https://doi.org/10.1145/3441852.3471226
What difference does tech make? Conceptualizations of Disability and Assistive Technology among Kenyan Youth: Conceptualizations of Disability and AT
Type
Editorial
Themes
Assistive & Accessible Technology
A right to the frivolous? Renegotiating a wellbeing agenda for AT research
Giulia Barbareschi& Tom Shakespeare
Assistive products (APs) are broadly defined as “ any product (including devices, equipment, instruments, and software), either specially designed and produced or generally available, whose primary purpose is to maintain or improve an individual’s functioning and independence and thereby promote their wellbeing” (Khasnabis et al.,2015). Although the concept of wellbeing is extremely slippery and researchers have yet to agree on a single definition for it, as individuals we instinctively develop mental models about what does, and does not, promote our happiness and wellbeing. Considerations about values, wellbeing and happiness are extremely personal and are shaped by a variety of factors ranging from our age and socio-cultural background to our life experiences (Schwartz & Bardi,2001).
RESNA
Abstract
A right to the frivolous? Renegotiating a wellbeing agenda for AT research
Assistive products (APs) are broadly defined as “ any product (including devices, equipment, instruments, and software), either specially designed and produced or generally available, whose primary purpose is to maintain or improve an individual’s functioning and independence and thereby promote their wellbeing” (Khasnabis et al.,2015). Although the concept of wellbeing is extremely slippery and researchers have yet to agree on a single definition for it, as individuals we instinctively develop mental models about what does, and does not, promote our happiness and wellbeing. Considerations about values, wellbeing and happiness are extremely personal and are shaped by a variety of factors ranging from our age and socio-cultural background to our life experiences (Schwartz & Bardi,2001).
However, when it comes to assistive technology (AT) research, our focus seems to be primarily geared toward values and activities in the domains of education, employment, transport or health, often framed according to an outcome driven perspective that is heavily influenced by what is seen as useful (often what is measurable), vs what is frivolous (less tangible social or emotional aspects).
This disparity parallels the priorities of the disability rights movement and disability studies research that have helped to shape the research agenda around disability and AT. Often influenced by labor movement politics, or feminism, there appears to have been more concern with public and practical aspects of social life as opposed to the more private and sensitive ones (Shakespeare,2014). The focus on the public utilitarian function of AT becomes even more evident when we consider AT research carried out in the Global South. In this context the success of an intervention is usually assessed using measures of outcome and impact which can be somehow linked to economic improvement (Alkire,2016).
In this editorial, we are not suggesting that enabling people with disabilities to gain a good education, obtain a fulfilling job or be able to vote are not important goals for the APs we develop and research. But are those the only worthwhile goals? Should we not also enquire whether existing and future APs could help people with disabilities to develop meaningful friendships, enjoy fulfilling sex lives with their partners of choice, cook sociable dinners, or engage in their favorite hobbies? Although sporadic publications focus on the role of APs in the context of personal relationships, sexuality, or fun and play for people with disabilities do exist, these are rare, and often framed around utilitarian goals. For example, research around AT and play is largely focused on children and often examined in connection to learning outcomes. Similarly, sex and sexuality are often explored solely in connection to dysfunction, abuse or sexual health (Shakespeare & Richardson,2018).
These unbalanced narratives show how the AT research agenda is dictated by a set of universal priorities that are largely focused on global measurable goals that do not necessarily match the everyday values of people with disabilities. We invite researchers and practitioners to consider ways to find a better balance between public and private aspects of life, and between utilitarian and emotional values. Both approaches have a significant impact on the lives of people with disabilities.
Ultimately, as AT researchers we need to actively engage with people with disabilities to uncover their priorities, understand what different people with disabilities most value in life, and identify how current and future APs might help to make a positive impact on wellbeing. Aspects of life such as friendship, socialization, sexuality, love and play might indeed be more frivolous than practical ones such as education, health, employment and civil rights, but they are inherent to our shared humanity and fundamental to our happiness.
A right to the frivolous? Renegotiating a wellbeing agenda for AT research
Giulia Barbareschi & Tom Shakespeare (2021) A right to the frivolous? Renegotiating a wellbeing agenda for AT research, Assistive Technology, 33:5, 237, DOI:10.1080/10400435.2021.1984112
Type
Workshop
Themes
Assistive & Accessible Technology
Research Group
Disability Interactions
Disability Design and Innovation in Low Resource Settings: Addressing Inequality Through HCI.
Giulia Barbareschi,Dafne Zuleima Morgado-Ramirez,Catherine Holloway, Swami Manohar Swaminathan, Aditya Vashistha, and Edward Cutrell.
Approximately 15% of the world's population has a disability and 80% live in low resource-settings, often in situations of severe social isolation. Technology is often inaccessible or inappropriately designed, hence unable to fully respond to the needs of people with disabilities living in low resource settings. Also lack of awareness of technology contributes to limited access. This workshop will be a call to arms for researchers in HCI to engage with people with disabilities in low resourced settings to understand their needs and design technology that is both accessible and culturally appropriate.
Extended Abstracts of the 2021 CHI Conference on Human Factors in Computing Systems.
Abstract
Disability Design and Innovation in Low Resource Settings: Addressing Inequality Through HCI.
Approximately 15% of the world's population has a disability and 80% live in low resource-settings, often in situations of severe social isolation. Technology is often inaccessible or inappropriately designed, hence unable to fully respond to the needs of people with disabilities living in low resource settings. Also lack of awareness of technology contributes to limited access. This workshop will be a call to arms for researchers in HCI to engage with people with disabilities in low resourced settings to understand their needs and design technology that is both accessible and culturally appropriate. We will achieve this through sharing of research experiences, and exploration of challenges encountered when planning HCI4D studies featuring participants with disabilities. Thanks to the contributions of all attendees, we will build a roadmap to support researchers aiming to leverage post-colonial and participatory approaches for the development of accessible and empowering technology with truly global ambitions.
Disability Design and Innovation in Low Resource Settings: Addressing Inequality Through HCI.
Giulia Barbareschi, Dafne Zuleima Morgado-Ramirez, Catherine Holloway, Swami Manohar Swaminathan, Aditya Vashistha, and Edward Cutrell. 2021. Disability Design and Innovation in Low Resource Settings: Addressing Inequality Through HCI. Extended Abstracts of the 2021 CHI Conference on Human Factors in Computing Systems. Association for Computing Machinery, New York, NY, USA, Article 124, 1–5. DOI:https://doi.org/10.1145/3411763.3441340
Type
Conference Paper
Themes
Assistive & Accessible Technology
Inclusive Educational Technology
Transforming a Monolithic Sheet of Nitinol into a Passive Reconfigurable Tactile Pixel Array Display at Braille Resolution
Tigmanshu Bhatnagar, Nicolai Marquardt, Mark Miodownik,Catherine Holloway
Shape changing materials create a unique opportunity to design reconfigurable tactile display actuators. In this paper, we present a method that transforms a single thin monolithic sheet of Nitinol into a passive reconfigurable tactile pixel array at Braille resolution. We have designed a 27x27 tactile pixel array in which each pixel can be selectively actuated with an external source of heat. The pixels rise 0.4mm vertically with a peak blocked force of 0.28kg and have an average blocked force of 0.23kg at room temperature. After cooling, the pixels can be mechanically reconfigured back to their flat state for repeatable actuation. We demonstrate this actuator’s interactive capabilities through a novel erasable tactile drawing interface.
IEEE World Haptics Conference; 2021
Abstract
Transforming a Monolithic Sheet of Nitinol into a Passive Reconfigurable Tactile Pixel Array Display at Braille Resolution
Shape changing materials create a unique opportunity to design reconfigurable tactile display actuators. In this paper, we present a method that transforms a single thin monolithic sheet of Nitinol into a passive reconfigurable tactile pixel array at Braille resolution. We have designed a 27x27 tactile pixel array in which each pixel can be selectively actuated with an external source of heat. The pixels rise 0.4mm vertically with a peak blocked force of 0.28kg and have an average blocked force of 0.23kg at room temperature. After cooling, the pixels can be mechanically reconfigured back to their flat state for repeatable actuation. We demonstrate this actuator’s interactive capabilities through a novel erasable tactile drawing interface.
Transforming a Monolithic Sheet of Nitinol into a Passive Reconfigurable Tactile Pixel Array Display at Braille Resolution
T. Bhatnagar, N. Marquardt, M. Miodownik and C. Holloway, "Transforming a Monolithic Sheet of Nitinol into a Passive Reconfigurable Tactile Pixel Array Display at Braille Resolution," 2021 IEEE World Haptics Conference (WHC), 2021, pp. 409-414, doi: 10.1109/WHC49131.2021.9517239.
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InterSystems to Release Caché 2010 - Database Trends and Applications
InterSystems Corporation will next week roll out a new version of its Caché high-performance object database. The new release targets the growing demand by CIOs for economical high availability by introducing database mirroring, while also now addressing Java developers' need for high-volume high-performance processing combined with persistent storage for event processing systems. Robert Nagle, InterSystems vice president for software development, recently chatted with 5 Minute Briefing about the release and the new features it offers. Commenting on the growing interest in NoSQL databases, Nagle observes that many of the beneficial characteristics people see in NoSQL are in fact true of Caché - a flexible data model and zero DBA cost. 'But for us, what is unique is that it is not NoSQL, it is that it needs to be SQL - without the overhead of relational technology - because I think SQL is extremely important for almost every class of application that is deployed.'
InterSystems to Release Caché 2010
Industry Leader Q&A with Robert Nagle, InterSystems Vice President for Software DevelopmentInterSystems Corporation will next week roll out a new version of its Caché high-performance object database. The new release targets the growing demand by CIOs for economical high availability by introducing database mirroring, while also now addressing Java developers' need for high-volume high-performance processing combined with persistent storage for event processing systems. Robert Nagle, InterSystems vice president for software development, recently chatted with 5 Minute Briefing about the release and the new features it offers. Commenting on the growing interest in NoSQL databases, Nagle observes that many of the beneficial characteristics people see in NoSQL are in fact true of Caché - a flexible data model and zero DBA cost. "But for us, what is unique is that it is not NoSQL, it is that it needs to be SQL - without the overhead of relational technology - because I think SQL is extremely important for almost every class of application that is deployed."5 Minute Briefing: What differentiates Caché from other databases?Nagle: Caché is a system that we have been building for many decades now. Its unique characteristics are that it is extremely resource-stingy, very sort of parsimonious in what it does, and as a consequence, extraordinarily scalable. Complementing that, it has a very rich model for allowing developers to see their data. It is really designed for complex, almost unstructured data - although unstructured data has a very specific meaning. We have an engine that allows the modeling of that with great facility and gives you the ability to see that data as objects, as tables or in its raw form, and that gives a very rich development environment to application developers.5 Minute Briefing: Where is it used?Nagle: We have applications in almost every vertical sector. It is fair to say that Caché is the most widely used database for clinical applications around the world. But we also have deployments in financial services, in telecommunications, in government applications, in publishing, and so on down the list.5 Minute Briefing: Would you say the enhancements for Caché 2010 fall into two main areas?Nagle: Yes. One is really on the deployment side, and another is a new development avenue that is available.5 Minute Briefing: On the deployment side?Nagle: It goes back to our heritage of finding ways for people using our technologies to use less in the way of resources while offering more. Database mirroring uses redundant servers and redundant storage which can be purchased much less expensively but can deliver the same level of availability that people have today when they have used shared storage configurations and shared clusters. We support shared clusters and lots of our customers deploy them - and they work really well. But what we have done is given a new choice to people, to give them the option of delivering the same promises of application availability while reducing the cost.5 Minute Briefing: The new database mirroring can be done to a remote location?Nagle: Yes. The only thing that is required for mirroring is a TCP connection between the mirror members.We also feel that besides reducing cost, we have simplified the environment. And, philosophically, a simpler environment is one that is likely to have greater reliability. That, too, is part of our long-standing ethos - that the fewer moving parts you have, the more scalable your environment is, and the more reliable your environment is.From time immemorial, our applications have been deployed in real mission-critical applications, namely life and death ones involving clinical applications, so high availability and reliability has always been part of what we have offered. And, complexity is one of your enemies there. Simplifying things reduces risk.5 Minute Briefing: This would be used for disaster recovery scenarios as well as planned downtime -- for upgrades, for example?Nagle: It would be used for both planned and unplanned outages. We have got automatic takeover. If the primary server fails, the backup will take over immediately. If 2 days later the new primary fails, we can fail back to the original one and that all works fine. That is sort of an automatic failover option.We also offer configurations with mirroring for disaster recovery. And disaster recovery usually involves some kind of human decision process that says this is a disaster - there is some level of interruption because a portion of the city has gone blank, because it has lost power. And rather than waiting for that to come back online, we are going to redirect everyone to a different data center. Our asynchronous mirror option provides a disaster recovery model as well.5 Minute Briefing: And what is the second major new feature in Caché 2010?Nagle: It is more on the development side. Again, over the last 15 years, we have looked at ways of making the Caché environment be extraordinarily scalable, really nimble and at the same time offering a really rich development model for developers. Well, that is all presuming that you are willing to work on the Caché server; it hasn't had native Java support. There is a whole class of application developers for whom this level of exciting development framework as well as a rich deployment environment hasn't been available. With "eXTreme for Java," we are making that framework available to Java developers by giving them direct poke-through access into the core of the Caché server. They still work in Java, they have access to the rich, direct underlying data model and all the scalability that that implies, and the light use of resources that that implies, and they also have the richness that that offers, with object access and relational access to the same data.5 Minute Briefing: Who is this targeted at?Nagle: We are targeting that, in particular, at certain types of use cases where in the past people have not been able to use a real database. For example, a very high-volume data capture situation where there is a massive amount of data streaming in that can't be stored in a relational database fast enough for the demands of the applications. What people have tended to do is either build their own custom in-memory solution or they have bought some very specialized unique database technology. But, ultimately, their persistent storage, their long-term storage, is a relational database that gets updated after the fact. We can give Java application developers solving those kinds of problems full persistent database storage and at the same time let them achieve the rates that they haven't been able to achieve thus far.5 Minute Briefing: InterSystems feels this is a breakthrough for those developers?Nagle: Yes, we did something like this about 3 or 4 years back for C++ developers, and that has led to some really innovative applications especially in the area of financial services, where it is very easy for you to imagine scenarios where they have streams of ticker data coming in at immense rates. And they need that data inserted into a database really fast, and then you have got complex queries running against that data to make immediate market decisions about updating portfolios, or buying and selling stocks, or increasing derivatives, or whatever it may be. In the past, people were using custom databases or home-grown databases for that- which worked very well up to a limit - but often led to reliability issues because they didn't have a full database model behind what they did. We saw a lot of exciting uptake with the C++ offering that we introduced - and now we are extending the same richness for Java developers.5 Minute Briefing: Has the new Caché release been in beta for a while?Nagle: Yes, this has been in our field test since March of this year. For both of these new capabilities, we have had very strong positive reactions. For database mirroring, this new configuration choice has caused some of our largest enterprise customers and our largest ISVs to rethink some of their deployment models. Generally speaking, to a customer, they are excited about the opportunities that this offers for them to pass on costs to their end users.5 Minute Briefing: And the enhancements for Java developers?Nagle: The Java offering is in many respects new. While many of our existing customers do Java development, we have been more opening up new prospects with this, and we have had some exciting encounters in Europe and in the U.S. with people who are relatively new to Caché based on their ability to now exploit it through Java. So I think on both fronts, we are pretty enthusiastic.It's key for us that we spend a lot of time in innovation at the database level, which a lot of people believe is a solved problem. There is a large class of applications today for which the orthodoxy of databases is not the right answer and Caché continues to be one of the unique offerings that gives developers a new choice. They still have all of the richness for reporting purposes and ad hoc queries that SQL offers, but they have got a much more flexible and powerful development environment, and so I think that that level of innovation is important.5 Minute Briefing: What is InterSystems' perspective on the emerging trend toward NoSQL databases?Nagle: If you look at some of the current brouhaha about NoSQL databases, many of the characteristics that people see as beneficial for them are in fact true of Caché-a flexible data model, zero DBA cost. But for us, what is unique is that it is not NoSQL, it is that it needs to be SQL - without the overhead of relational technology - because I think SQL is extremely important for almost every class of application that is deployed. What we try to offer is a lightweight, flexible, extremely scalable, easy to manage, rich development environment database framework that still allows you to see your data through SQL - and not only to see it through SQL, but to see it through SQL at performance rates that meet or exceed what the relational databases can do.Visit the InterSystems website for more information about theCaché high performance object database.
| https://www.dbta.com/Editorial/News-Flashes/InterSystems-to-Release-Cach%C3%A9--2010-69994.aspx |
Zapach v. Elkins, Morris, Stroud & Co., Civ. No. 71-543. - Federal Cases - Case Law - VLEX 885018337
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Federal Cases
Zapach v. Elkins, Morris, Stroud & Co., Civ. No. 71-543.
<table><tbody><tr><td> Court</td><td> United States District Courts. 3th Circuit. United States District Court of Middle District of Pennsylvania</td></tr><tr><td> Writing for the Court</td><td> NEALON</td></tr><tr><td> Citation</td><td> 375 F. Supp. 669</td></tr><tr><td> Docket Number</td><td> Civ. No. 71-543.</td></tr><tr><td> Decision Date</td><td> 14 December 1973</td></tr><tr><td> Parties</td><td> Joseph ZAPACH and Anna Zapach
v.
ELKINS, MORRIS, STROUD & CO.</td></tr></tbody></table>
375 F. Supp.669
Joseph ZAPACH and Anna Zapach
v.
ELKINS, MORRIS, STROUD & CO.
Civ. No. 71-543.
United States District Court, M. D. Pennsylvania.
December 14, 1973.
Philip F. Hudock, Hazleton, Pa., for plaintiffs.
Kenneth R. Bayless, Laputka, Bayless, Ecker & Cohn, Hazleton, Pa., Ballard, Spahr, Andrews & Ingersol, Philadelphia, Pa., for defendant.
MEMORANDUM AND ORDER
NEALON, District Judge.
This matter is before the Court on defendant's motion for summary judgment and plaintiffs' cross-motion for summary judgment and dismissal of defendant's counterclaim.
Plaintiffs, Joseph and Anna Zapach, 1were brokerage customers of J. H. Brooks & Co. during all relevant times. The defendant, Elkins, Morris, Stroud & Co., subsequently acquired both the assets and liabilities of the Brooks firm. Plaintiffs allege that during 1968 and through October of 1969 they bought and sold securities on margin through the Brooks firm and that Brooks failed to
375 F. Supp. 670
abide by the applicable margin requirements as a result of which plaintiffs claim losses amounting to $31,318.34
The Securities Exchange Act of 1934 provides for the maintenance of margin accounts in accordance with rules and regulations to be promulgated by the Board of Governors of the Federal Reserve System. 2
Those rules provide that the customer must deposit sufficient cash or collateral into his account within five business days after a purchase of stock so as to satisfy the current margin percentages. 3The duty to police the account is placed on the broker, who is empowered to liquidate a customer's account to the extent necessary to meet the margin requirements. 4If the broker fails to obtain the required cash or collateral, and fails to sell the stock after the permissible five-day period, he renders himself liable for any losses when the purchased stock is eventually sold. Those rules form the basis of the complaint that the defendant did not liquidate plaintiffs' account upon plaintiffs' failure to deposit sufficient funds in their account so as to meet the applicable margin requirements for the purchase of stock. Since the stock allegedly was not sold until sometime after the five-day period and until it had sharply declined in value, plaintiffs claim a loss of $31,318.34, according to their method of accounting. Defendant, on the other band, asserts that the liquidation of plaintiffs' account resulted in a balance owed by plaintiffs of $7,287.07 on the original contracts of purchase. This amount is part of the damages sought in defendant's counterclaim.
375 F. Supp. 671
This entire controversy was apparently resolved on October 13, 1969, by an exchange of general releases, whereby defendant cancelled the asserted balance of $7,287.07 and paid an additional $2,700.00 to the plaintiffs. If the releases are valid, the case is at an end; if not, the plaintiffs may proceed.
To test the validity of the releases, both parties rely principally on Pearlstein v. Scudder and German,429 F.2d 1136(2d Cir.1970), cert. denied, 401 U.S. 1013, 91 S.Ct. 1250, 28 L.Ed.2d 550 (1971). In Pearlstein,plaintiffs had purchased bonds on credit and were obligated under Federal Reserve System Regulations 5to satisfy the balance within seven business days after date of purchase. When payment was not made and before the bonds were sold, defendant broker instituted suit to collect the balance. The suit was settled under a stipulation by which the plaintiffs were given additional time to pay for the bonds. Payment was not made, and, after the bonds were sold at a loss, plaintiffs sued, alleging margin violations. The Court held that the settlement "involved the promise by defendant of a continuation of credit which was illegal under the Act (Securities Exchange Act of 1934)." Pearlstein, supra,at 1142. The Court added that "Section 29(a) of the Securities Exchange Act holds void anystipulation obligating a party to waive compliance with the Act." 6(emphasis supplied) Pearlstein, supra,at 1143.
Initially, the Pearlsteininterpretation of Section 29(a) was construed as an in terroremprovision apparently voiding anyfinal settlement short of litigation. 7Cohen v. Tenney Corp.,318 F.Supp. 280(S.D.N.Y.1970); In Re Cohen's Will, 51 F.R.D. 167 (S.D.N.Y.1970). However, on motion for reargument in Cohen v. Tenney Corp., supra, the court reconsidered and stated:
"The import of
Pearlstein,
in my view, is not that all settlements of matured claims, short of litigation, are void; but rather that their terms are not necessarily above judicial scrutiny, as the district court in that case had erroneously ruled. (citing
...
4 practice notes
Goodman v. Epstein, No. 77-1209 United States United States Courts of Appeals. United States Court of Appeals (7th Circuit) September 25, 1978 ...490 F.2d 810, 816 (5th Cir.), Cert. denied, 419 U.S. 835, 95 S.Ct. 62, 42 L.Ed.2d 62 (1974); Zapach v. Elkins, Morris, Stroud & Co., 375 F.Supp. 669(M.D.Pa.1973); Childs v. RIC Group, Inc., 331 F.Supp. 1078 (N.D.Ga.1970), Aff'd, 447 F.2d 1407 (5th Cir. 1971) (per 44 The Court, in its now-f......
Korn v. Franchard Corporation, No. 67 Civ. 3445 (WCC). United States United States Courts of Appeals. United States Court of Appeals (5th Circuit) January 28, 1975 ...partners in no way excused compliance with any provision of federal law.4 See Zapach v. Elkins, Morris, 388 F. Supp. 1330 Stroud & Co., 375 F.Supp. 669(M.D. Pa.). Furthermore, the Pearlstein Court seemed to recognize that after an active controversy has arisen the remedial right of access ......
Gelineau v. New York University Hospital, Civ. A. No. 1755-73. United States United States District Courts. 3th Circuit. United States District Courts. 3th Circuit. District of New Jersey May 1, 1974 ...due process and fundamental fairness, exercise "in personam" jurisdiction over New York University Hospital predicated on the manner 375 F. Supp. 669in which services were performed by it in New York, and cannot require New York University Hospital to appear to defend or default Accordingl......
Hamilton v. Harrington, No. 86-1717 United States United States Courts of Appeals. United States Court of Appeals (7th Circuit) December 30, 1986 ...1326 (S.D.N.Y.1975); Mittendorf v. J.R. Williston & Beane, Inc., 372 F.Supp. 821 (S.D.N.Y.1975); Zapach v. Elkins, Morris, Stroud & Co., 375 F.Supp. 669(M.D.Pa.1973). Hamilton, Jr. argues that there were future, unripened claims in this case. Therefore, the release, according to the plaint......
4 cases
Goodman v. Epstein, No. 77-1209 United States United States Courts of Appeals. United States Court of Appeals (7th Circuit) September 25, 1978 ...490 F.2d 810, 816 (5th Cir.), Cert. denied, 419 U.S. 835, 95 S.Ct. 62, 42 L.Ed.2d 62 (1974); Zapach v. Elkins, Morris, Stroud & Co., 375 F.Supp. 669(M.D.Pa.1973); Childs v. RIC Group, Inc., 331 F.Supp. 1078 (N.D.Ga.1970), Aff'd, 447 F.2d 1407 (5th Cir. 1971) (per 44 The Court, in its now-f......
Korn v. Franchard Corporation, No. 67 Civ. 3445 (WCC). United States United States Courts of Appeals. United States Court of Appeals (5th Circuit) January 28, 1975 ...partners in no way excused compliance with any provision of federal law.4 See Zapach v. Elkins, Morris, 388 F. Supp. 1330 Stroud & Co., 375 F.Supp. 669(M.D. Pa.). Furthermore, the Pearlstein Court seemed to recognize that after an active controversy has arisen the remedial right of access ......
Gelineau v. New York University Hospital, Civ. A. No. 1755-73. United States United States District Courts. 3th Circuit. United States District Courts. 3th Circuit. District of New Jersey May 1, 1974 ...due process and fundamental fairness, exercise "in personam" jurisdiction over New York University Hospital predicated on the manner 375 F. Supp. 669in which services were performed by it in New York, and cannot require New York University Hospital to appear to defend or default Accordingl......
Hamilton v. Harrington, No. 86-1717 United States United States Courts of Appeals. United States Court of Appeals (7th Circuit) December 30, 1986 ...1326 (S.D.N.Y.1975); Mittendorf v. J.R. Williston & Beane, Inc., 372 F.Supp. 821 (S.D.N.Y.1975); Zapach v. Elkins, Morris, Stroud & Co., 375 F.Supp. 669(M.D.Pa.1973). Hamilton, Jr. argues that there were future, unripened claims in this case. Therefore, the release, according to the plaint......
| https://case-law.vlex.com/vid/zapach-v-elkins-morris-885018337 |
Facts about "Casablanca" : Classic Movie Hub (CMH)
Browse Fun Facts and Trivia about at Classic Movie Hub (CMH).
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Casablanca
"As Time Goes By" was written by lifelong bachelorHerman Hupfeldand debuted in 1931's Broadway show "Everybody's Welcome", sung byFrances Williams, It had been a personal favorite of playwright and high school teacherMurray Burnettwho, seven years later, visited Vienna just after the Nazis had entered. Later, after visiting a café in south France where a black pianist had entertained a mixed crowd of Nazis, French and refugees, Burnett was inspired to write the melodrama "Everybody Comes to Rick's", which was optioned for production byMartin GabelandCarly Wharton, and later, Warners. After the film's release, "As Time Goes By" stayed on radio's "Hit Parade" for 21 weeks. However, because of the coincidental musicians' union recording ban, the 1931Rudy Valleeversion became the smash hit. (It contains the rarely-sung introductory verse, not heard in the film.)Max Steiner, in a 1943 interview, admitted that the song "must have had something to attract so much attention".
"Here's looking at you, kid" was improvised by
Humphrey Bogart
in the Parisian scenes and worked so well that it was used later on again in the film. He originally used the same line in
Midnight
. It is also rumored that during breaks,
Ingrid Bergman
would play poker with other cast members. Since she was still learning English, Bogart would occasionally watch the game, and he added "Here's looking at you" to her poker repertoire.
"Rick's Café Américain" was modeled after Hotel El Minzah in Tangiers.
Humphrey Bogarthad to wear platform shoes to play alongsideIngrid Bergman.
Humphrey Bogart
,
Ingrid Bergman
and
Paul Henreid
later reprised their roles for a radio performance of on the CBS radio program "The Screen Guild Players", a war benefit show on April 26, 1943.
Humphrey Bogart
's wife
Mayo Methot
continually accused him of having an affair with
Ingrid Bergman
, often confronting him in his dressing room before a shot. Bogart would come onto the set in a rage. In fact, despite the undeniable on-screen chemistry between Bogart and Bergman, they hardly spoke, and the only time they bonded was when the two had lunch with
Geraldine Fitzgerald
. According to Fitzgerald, "the whole subject at lunch was how they could get out of that movie. They thought the dialogue was ridiculous and the situations were unbelievable... I knew Bogart very well, and I think he wanted to join forces with Bergman, to make sure they both said the same things." For whatever reasons, Bogart and Bergman rarely spoke after that.
S.Z. Sakall, who plays the maitre d' at Rick's Cafe, actually has more screen time thanPeter LorreorSydney Greenstreet.
Madeleine Lebeau
, who plays Yvonne, and
Marcel Dalio
, who plays croupier Emil, were husband and wife at the time of filming. They had not long before escaped the Nazis by fleeing their native France.
Dooley Wilson
(Sam) was a professional drummer who faked playing the piano. As the music was recorded at the same time as the film, the piano playing was actually a recording of a performance by
Elliot Carpenter
who was playing behind a curtain but who was positioned such that Dooley could watch, and copy, his hand movements.
Dooley Wilsonwas borrowed from Paramount at $500 a week.
Dooley Wilsonwas, in fact, the only member of the cast to have ever actually visited the city of Casablanca.
Joy Page
, who played the young Bulgarian wife, was the stepdaughter of studio head
Jack L. Warner
. She,
Humphrey Bogart
and
Dooley Wilson
were the only American-born people in the credited cast. This film was her debut.
Hal B. Wallisdidn't wantHumphrey Bogartwearing a hat too often in the film, as he thought it made Bogart look like a gangster.
Hal B. Wallis's first choice for director wasWilliam Wyler.
Sydney Greenstreet
wanted to wear something more ethnic to show that his character had assimilated into the Moroccan lifestyle. This idea was nixed by producer
Hal B. Wallis
who insisted that he wear his now-iconic white suit.
Ingrid BergmanandPaul Henreidmake their first appearance 24 minutes into the film.
Ingrid Bergman
considered her left side as her better side, and to the extent possible that was the side photographed throughout the film, so she is almost always on the right side of the screen looking towards the left regardless of who is in the shot with her. However, there are several shots where she is to the left and
Humphrey Bogart
is on the right, including the flashbacks to the street scene in Paris (0:41:50) and the scene at the window (0:43:40). There are also several scenes where Bergman is centered between
Paul Henreid
and Bogart, suggesting the triangle nature of their relationship; in these shots Henreid is usually to the left and Bogart is usually on the right, including the scene where she and Henreid enter the café at just before the famous "Battle of the Anthems" (1:07:40); the scene where Captain Renault arrests Victor Laszlo (1:34:00); and at the end of the final airport scene (1:39:00).
Ingrid Bergman's contract was owned by producerDavid O. Selznick, and producerHal B. Wallissent the film's writers,Philip G. EpsteinandJulius J. Epstein, to persuade Selznick to loan her to Warner Bros. for the picture. After 20 minutes of describing the plot to Selznick, Julius gave up and said, "Oh, what the hell! It's a lot of shit likeAlgiers!" Selznick nodded and agreed to the loan.
Ingrid Bergman
's line "Victor Laszlo is my husband, and was, even when I knew you in Paris" was almost cut from the film because during that time it was deemed inappropriate for a film to depict or suggest a woman romancing with another man if she were already married. However, it was pointed out that later in the film she explains that she had thought Laszlo was dead at the time, and the censors allowed the line to stay in.
Howard Hawks
had said in interviews that he was supposed to direct
Casablanca
and
Michael Curtiz
was supposed to direct
Sergeant York
. The directors had lunch together, where Hawks said he didn't know how to make this "musical comedy", while Curtiz didn't know anything about "those hill people." They switched projects. Hawks struggled on how to direct the scenes that involved singing, namely the "La Marseillaise" scene. It is ironic to note that most of his other films involved at least one singing scene.
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Speech token detection and discrimination in individual infants using functional near-infrared spectroscopy-ICH GCP
Mao D, Wunderlich J, Savkovic B, Jeffreys E, Nicholls N, Lee OW, Eager M, McKay CM. Speech token detection and discrimination in individual infants using functional near-infrared spectroscopy. Sci Rep. 2021 Dec 14;11(1):24006. doi: 10.1038/s41598-021-03595-z.。 ICH GCP。
Darren Mao, Julia Wunderlich, Borislav Savkovic, Emily Jeffreys, Namita Nicholls, Onn Wah Lee, Michael Eager, Colette M McKay, Darren Mao, Julia Wunderlich, Borislav Savkovic, Emily Jeffreys, Namita Nicholls, Onn Wah Lee, Michael Eager, Colette M McKay
Abstract
Speech detection and discrimination ability are important measures of hearing ability that may inform crucial audiological intervention decisions for individuals with a hearing impairment. However, behavioral assessment of speech discrimination can be difficult and inaccurate in infants, prompting the need for an objective measure of speech detection and discrimination ability. In this study, the authors used functional near-infrared spectroscopy (fNIRS) as the objective measure. Twenty-three infants, 2 to 10 months of age participated, all of whom had passed newborn hearing screening or diagnostic audiology testing. They were presented with speech tokens at a comfortable listening level in a natural sleep state using a habituation/dishabituation paradigm. The authors hypothesized that fNIRS responses to speech token detection as well as speech token contrast discrimination could be measured in individual infants. The authors found significant fNIRS responses to speech detection in 87% of tested infants (false positive rate 0%), as well as to speech discrimination in 35% of tested infants (false positive rate 9%). The results show initial promise for the use of fNIRS as an objective clinical tool for measuring infant speech detection and discrimination ability; the authors highlight the further optimizations of test procedures and analysis techniques that would be required to improve accuracy and reliability to levels needed for clinical decision-making.
Conflict of interest statement
The authors declare no competing interests.
© 2021. The Author(s).
Figures
Figure 1
Illustration of experimental set-up on the infant. Left: an image of the cap on a participant’s head. Right: The 8 × 8 source-detector montage that was placed over the temporal and prefrontal regions of the infant participants, resulting in four regions of interest. Sources are colored red, detectors are blue, and channels are indicated by purple lines.
Figure 2
Sensitivity profile and sensor channel locations for the left temporal and prefrontal regions. The sensitivity of each probe to detecting brain hemodynamics is represented on a logarithmic color scale ranging from − 2 to 0 (arbitrary units; higher number indicates higher sensitivity). Source and detector positions are indicated by the red and blue circles and corresponding labels respectively, and yellow lines show channels. This figure was generated with AtlasViewer.
Figure 3
Representation of the sound presentation protocol used in this study. ( A ) Details of the test run sequence and timing for each infant in the study. Each two-color segment represents a test run of a specific speech contrast pair. Note that the final 6 infants received only one contrast pair, and the test run was modified to replace the “Post-Nov” condition with 1 min of silence. ( B ) Representation of the stimulus protocol for a single experimental test run. One run comprised four sections labeled as “Hab 1”, “Hab 2”, “Novel” and “Post-Nov”, each containing 5 stimulus blocks. The habituation speech sound was presented in the blocks labeled “Hab 1”, “Hab 2” and “Post-Nov”, while the novel speech sound was presented in the blocks labeled “Novel”.
Figure 4
An example of TDDR and wavelet denoiser’s effect on the data. ( A ) The raw data processed with only optic density and modified beer-lambert law conversion, demonstrating spike-like artefacts from movements. ( B ) The data processed with only optical density, modified beer-lambert law and a bandpass filter (0.01 to 0.25 Hz), with the spikes still present and smoothed out from the filtering. ( C ) Data cleaned first by TDDR and wavelet denoising before standard processing as in ( A ), with visible reduction in artefacts.
Figure 5
Figure 6
Group HbO responses at each ROI and to the Hab 1, Hab 2 and Novel stimulus conditions. Each ROI’s responses are in a different panel, with the ROI indicated by highlight on the head montage illustration. Each trace represents the response averaged across participants.
Figure 7
Difference between “Novel” and “Hab 2” conditions for each speech token contrast pair. ( A ) Shows the group average responses for each speech token (one color each); the “Hab 2”and “Novel" responses are represented by the broken and solid traces respectively. ( B ) Shows the calculated response size difference as a bar graph; error bars are one standard error of the mean across participants. Labels on x-axis indicates the number of participants who were delivered that particular speech token pair stimuli. There is no significant difference between discrimination response sizes.
Figure 8
Individual infant detection and discrimination analysis. ( A,B ) Show examples from one participant SD011 of detection responses averaged across all channels and conditions for true ( A ) and control ( B ) stimulus blocks (shaded areas are 1 SEM). ( C,D ) Show the true and control discrimination responses respectively. ( E ) Shows the ROC curve, calculated across all 23 participants, for detection and discrimination response discovery respectively.
Figure 9
Comparison of responses to two sound presentation strategies. ( A ) Shows the “alternating” protocol, where two speech token pairs are presented in alternating runs. ( B ) Shows the “repeating” protocol, where the same speech token pair was repeated in five sequential runs. Shaded error bars show one standard deviation across participants. ( C ) Shows the calculated response sizes for both protocols as bar plots, with error bars showing one standard error of the mean; test statistics were calculated with these response sizes.
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Source:PubMed
| https://ichgcp.net/zh/clinical-trials-registry/publications/254904-speech-token-detection-and-discrimination-in-individual-infants-using-functional-near-infrared |
JCM | Special Issue : Emerging Technologies for Medical Imaging - Diagnostics, Monitoring and Therapy of Cancers
Journal of Clinical Medicine, an international, peer-reviewed Open Access journal.
Special Issue "Emerging Technologies for Medical Imaging - Diagnostics, Monitoring and Therapy of Cancers"
A special issue of Journal of Clinical Medicine(ISSN 2077-0383). This special issue belongs to the section "Nuclear Medicine & Radiology".
Deadline for manuscript submissions: closed (15 November 2020) | Viewed by 47170
Special Issue Editors
Prof. Dr. Mohsen Beheshti
E-Mail
Website
Guest Editor
Professor & Head, Teaching & Research Division of Translational Nuclear Medicine, Deputy Director, Department of Nuclear Medicine, University Hospital, RWTH University Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany
Interests:
PET Imaging; Nuclear Medicine; Computed Tomography; PET/CT; Molecular Imaging; Medical Imaging Physics; Cancer Imaging
E-Mail
Website
Guest Editor
1. Director, Department of Nuclear Medicine, University Hospital, RWTH University Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany
2. Department of Radiology and Nuclear Medicine, Maastricht University Medical Center (MUMC+), P. Debeylaan 25, 6229 HX Maastricht, P.O. Box 5800, 6202 AZ Maastricht, The Netherlands
Interests:
radiation detection; neuroimaging; medical image analysis; medical imaging
Special Issue Information
Dear Colleagues,
In the area of emerging approaches in personalized medicine, the diagnostic accuracy of tests, either imaging, lab values or genetic measures is one of the main cornerstones for its success. In this era, a theranostic approach using targeted radionuclide therapy has unique promise for personalized treatment of cancer, as both the targeting vehicle and the radionuclide can be tailored to the individual patient. In addition, the related information of medical imaging is used in initial decision making as well as in the monitoring of running therapies. Coming with the exponential development of information technologies and the extraordinary capacity of current software developments, with an important aspect being the ability to process huge amounts data in a very short time frame, imaging technologies as well as post processing approaches of imaging data have made an important progression in the past 10 years. In this Special Issue we would like to focus on new hardware and software developments that provide promising new aspects for improving patient care. Last but not least, the very important aspect of the use of artificial intelligence in image data acquisition, evaluation and postprocessing will be highlighted. The main focus in this Special Issue will be on all different aspects of molecular imaging and theranostic approaches evolving from this.
Prof. Dr. Mohsen BeheshtiProf. Dr. Felix M. Mottaghy Guest Editors
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Keywords
Molecular imaging
Hybrid imaging
Positron emission tomography
MRI
CT
Theranostics
Published Papers (16 papers)
Special Issue: Emerging Technologies for Medical Imaging Diagnostics, Monitoring and Therapy of Cancers
by Mohsen Beheshti and Felix M. Mottaghy
J. Clin. Med. 2021 , 10 (6), 1327; https://doi.org/10.3390/jcm10061327 - 23 Mar 2021
Abstract
Molecular imaging and therapy play an increasingly important role in the field of “precision medicine” as an emergent prospect for management of the cancerous disease [...] Full article
(This article belongs to the Special Issue Emerging Technologies for Medical Imaging - Diagnostics, Monitoring and Therapy of Cancers )
Research
MRI Texture Analysis for the Prediction of Stereotactic Radiosurgery Outcomes in Brain Metastases from Lung Cancer
by Jung Hyun Park , Byung Se Choi , Jung Ho Han , Chae-Yong Kim , Jungheum Cho , Yun Jung Bae , Leonard Sunwoo and Jae Hyoung Kim
J. Clin. Med. 2021 , 10 (2), 237; https://doi.org/10.3390/jcm10020237 - 11 Jan 2021
Abstract
This study aims to evaluate the utility of texture analysis in predicting the outcome of stereotactic radiosurgery (SRS) for brain metastases from lung cancer. From 83 patients with lung cancer who underwent SRS for brain metastasis, a total of 118 metastatic lesions were [...] Read more.
This study aims to evaluate the utility of texture analysis in predicting the outcome of stereotactic radiosurgery (SRS) for brain metastases from lung cancer. From 83 patients with lung cancer who underwent SRS for brain metastasis, a total of 118 metastatic lesions were included. Two neuroradiologists independently performed magnetic resonance imaging (MRI)-based texture analysis using the Imaging Biomarker Explorer software. Inter-reader reliability as well as univariable and multivariable analyses were performed for texture features and clinical parameters to determine independent predictors for local progression-free survival (PFS) and overall survival (OS). Furthermore, Harrell’s concordance index (C-index) was used to assess the performance of the independent texture features. The primary tumor histology of small cell lung cancer (SCLC) was the only clinical parameter significantly associated with local PFS in multivariable analysis. Run-length non-uniformity (RLN) and short-run emphasis were the independent texture features associated with local PFS. In the non-SCLC (NSCLC) subgroup analysis, RLN and local range mean were associated with local PFS. The C-index of independent texture features was 0.79 for the all-patients group and 0.73 for the NSCLC subgroup. In conclusion, texture analysis on pre-treatment MRI of lung cancer patients with brain metastases may have a role in predicting SRS response. Full article
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Application of Deep Learning in the Identification of Cerebral Hemodynamics Data Obtained from Functional Near-Infrared Spectroscopy: A Preliminary Study of Pre- and Post-Tooth Clenching Assessment
by Shinya Takagi , Shigemitsu Sakuma , Ichizo Morita , Eri Sugimoto , Yoshihiro Yamaguchi , Naoya Higuchi , Kyoko Inamoto , Yoshiko Ariji , Eiichiro Ariji and Hiroshi Murakami
J. Clin. Med. 2020 , 9 (11), 3475; https://doi.org/10.3390/jcm9113475 - 28 Oct 2020
Abstract
In fields using functional near-infrared spectroscopy (fNIRS), there is a need for an easy-to-understand method that allows visual presentation and rapid analysis of data and test results. This preliminary study examined whether deep learning (DL) could be applied to the analysis of fNIRS-derived [...] Read more.
In fields using functional near-infrared spectroscopy (fNIRS), there is a need for an easy-to-understand method that allows visual presentation and rapid analysis of data and test results. This preliminary study examined whether deep learning (DL) could be applied to the analysis of fNIRS-derived brain activity data. To create a visual presentation of the data, an imaging program was developed for the analysis of hemoglobin (Hb) data from the prefrontal cortex in healthy volunteers, obtained by fNIRS before and after tooth clenching. Three types of imaging data were prepared: oxygenated hemoglobin (oxy-Hb) data, deoxygenated hemoglobin (deoxy-Hb) data, and mixed data (using both oxy-Hb and deoxy-Hb data). To differentiate between rest and tooth clenching, a cross-validation test using the image data for DL and a convolutional neural network was performed. The network identification rate using Hb imaging data was relatively high (80‒90%). These results demonstrated that a method using DL for the assessment of fNIRS imaging data may provide a useful analysis system. Full article
(This article belongs to the Special Issue Emerging Technologies for Medical Imaging - Diagnostics, Monitoring and Therapy of Cancers )
18 F-FDG PET/MR versus MR Alone in Whole-Body Primary Staging and Restaging of Patients with Rectal Cancer: What Is the Benefit of PET?
by
Yan Li ,
Laura Isabel Mueller ,
Jan Peter Neuhaus ,
Stefanie Bertram ,
Benedikt Michael Schaarschmidt ,
Aydin Demircioglu ,
Johannes Maximilian Ludwig ,
Julian Kirchner ,
Christoph Rischpler ,
Ken Herrmann ,
Onofrio Antonio Catalano and
Lale Umutlu
J. Clin. Med. 2020 , 9 (10), 3163; https://doi.org/10.3390/jcm9103163 - 29 Sep 2020
Abstract
Background: To investigate and compare the diagnostic performance of 18 F-Fluorodeoxyglucose ( 18 F-FDG) PET/MR and MR alone in whole-body primary staging and restaging of patients with rectal cancer. Methods: A retrospective analysis was performed to evaluate diagnostic accuracies of combined reading of [...] Read more.
Background: To investigate and compare the diagnostic performance of 18 F-Fluorodeoxyglucose ( 18 F-FDG) PET/MR and MR alone in whole-body primary staging and restaging of patients with rectal cancer. Methods: A retrospective analysis was performed to evaluate diagnostic accuracies of combined reading of PET/MR and MR alone in T, N and M staging against the reference standard. Inter-observer agreement regarding TNM staging was calculated separately for PET/MR and MR alone. Results: A total of 39 studies of 34 patients could be evaluated. Diagnostic accuracies of PET/MR and MR alone were the same in locoregional T staging. For predicting N+ stage, the specificity of combined reading of PET and MR (0.917 and 0.833 for reader 1 and 2, respectively) was slightly higher than MR alone (0.833 and 0.75) without significantly increasing the overall accuracy (0.783 vs. 0.783 and 0.783 vs. 0.739). For detecting distant metastasis, the sensitivities of PET/MR and MR alone were shown equal (1.0 vs. 1.0 and 0.938 vs. 0.938), while the specificity of PET/MR was marginally lower (0.87 vs. 0.913 and 0.826 vs. 0.87). The inter-observer agreements were good to excellent in M (κ = 0.64 and 0.637 for PET/MR and MR alone, p < 0.001) and N staging (0.819 and 0.738, p < 0.001).Conclusion: PET did not yield a significant improvement in diagnostic accuracy of PET/MR in TNM staging of rectal cancer, since MR alone facilitated accurate classification of disease stage with good to excellent inter-observer agreement. Full article
(This article belongs to the Special Issue Emerging Technologies for Medical Imaging - Diagnostics, Monitoring and Therapy of Cancers )
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subject
Additional Value of 2-[ 18 F]FDG PET/CT Comparing to MRI in Treatment Approach of Anal Cancer Patients
by
Reyhaneh Manafi-Farid ,
Alexander Kupferthaler ,
Helwig Wundsam ,
Georg Gruber ,
Reza Vali ,
Clemens Venhoda ,
Christine Track ,
Ali Beheshti ,
Werner Langsteger ,
Hans Geinitz and
Mohsen Beheshti
J. Clin. Med. 2020 , 9 (9), 2715; https://doi.org/10.3390/jcm9092715 - 22 Aug 2020
Abstract
Accurate staging and treatment planning are imperative for precise management in Anal Cancer (ACa) patients. We aimed to evaluate the additive and prognostic value of pre-treatment 2-[ 18 F]fluoro-2-deoxy- d -glucose positron emission tomography/computed tomography (2-[ 18 F]FDG PET/CT) in the staging and [...] Read more.
Accurate staging and treatment planning are imperative for precise management in Anal Cancer (ACa) patients. We aimed to evaluate the additive and prognostic value of pre-treatment 2-[ 18 F]fluoro-2-deoxy- d -glucose positron emission tomography/computed tomography (2-[ 18 F]FDG PET/CT) in the staging and management of ACa compared to magnetic resonance imaging (MRI). This retrospective study was conducted on 54 patients. Pre-treatment 2-[ 18 F]FDG PET/CT studies and MRI reports were compared considering the primary tumor, pelvic lymph nodes, and metastatic lesions. The impact of 2-[ 18 F]FDG PET/CT in the management and its prognostic value, using maximum standardized uptake value (SUVmax), were assessed. Discordant findings were found in 46.3% of patients (5 in T; 1 in T and N; 18 in N; and 1 in M stage). 2-[ 18 F]FDG PET/CT resulted in up-staging in 9.26% and down-staging in 3.7% of patients. Perirectal lymph nodes were metabolically inactive in 12.9% of patients. Moreover, 2-[ 18 F]FDG PET/CT resulted in management change in 24.1% of patients. Finally, SUVmax provided no prognostic value. 2-[ 18 F]FDG PET/CT altered staging and management in a sizable number of patients in this study, and supports a need for a change in guidelines for it to be used as a routine complementary test in the initial management of ACa. Full article
(This article belongs to the Special Issue Emerging Technologies for Medical Imaging - Diagnostics, Monitoring and Therapy of Cancers )
Diagnostic Performance of [ 18 F]Fluorocholine and [ 68 Ga]Ga-PSMA PET/CT in Prostate Cancer: A Comparative Study
by Zeinab Paymani , Taryn Rohringer , Reza Vali , Wolfgang Loidl , Nafiseh Alemohammad , Hans Geinitz , Werner Langsteger and Mohsen Beheshti
J. Clin. Med. 2020 , 9 (7), 2308; https://doi.org/10.3390/jcm9072308 - 21 Jul 2020
Abstract
The current study endeavored to closely compare the detection rate of 68-Gallium labelled prostate-specific membrane antigen ([ 68 Ga]Ga-PSMA) versus [ 18 F]Fluorocholine in men with prostate cancer (PC), to investigate the benefits and pitfalls of each modality in the setting of various [...] Read more.
The current study endeavored to closely compare the detection rate of 68-Gallium labelled prostate-specific membrane antigen ([ 68 Ga]Ga-PSMA) versus [ 18 F]Fluorocholine in men with prostate cancer (PC), to investigate the benefits and pitfalls of each modality in the setting of various patient characteristics. We retrospectively analyzed 29 biopsy-proven PC patients in two categories, staging and restaging, who underwent both scans within a maximum of 30 days of each other. Variables including patient demographics, prostate specific antigen (PSA) level, Gleason score, clinical course, and following treatments were recorded. The number and location of suspicious lesions as well as uptake values were noted. A total of 148 suspicious lesions were detected, of which 70.9% (105/148) were concordantly visualized in both imaging modalities. [ 68 Ga]Ga-PSMA positron emission tomography/computed tomography (PET/CT) revealed a higher number of metastatic lesions per patients (91% vs 78%). The mean of maximum standardized uptake value (SUV max) in concordant lesions was significantly higher in [ 68 Ga]Ga-PSMA compared to [ 18 F]Fluorocholine PET/CT (14.6 ± 8.44 vs. 6.9 ± 3.4, p = 0.001). Discordant lesions were detected by both modalities, but more frequently by [ 68 Ga]Ga-PSMA PET/CT (20.3% in [ 68 Ga]Ga-PSMA versus 8.8% by [ 18 F]Fluorocholine PET/CT). In patients with PSA levels below 1.0 ng/mL and <2.0 ng/mL, [ 18 F]Fluorocholine PET/CT detection rate was half (57% and 55%, respectively) that of [ 68 Ga]Ga-PSMA PET/CT. Tumor, nodes and metastases (TNM) staging, and subsequently patient management, was only influenced in 4/29 patients (14%), particularly by [ 68 Ga]Ga-PSMA PET/CT with PSA values under 0.5 ng/mL. [ 68 Ga]Ga-PSMA PET/CT revealed superior diagnostic performance to [ 18 F]Fluorocholine PET/CT in staging and restaging of PC patients, especially in cases with low PSA levels. However, in a few hormone resistant high-risk PC patients, [ 18 F]Fluorocholine PET/CT may improve overall diagnostic accuracy. Full article
(This article belongs to the Special Issue Emerging Technologies for Medical Imaging - Diagnostics, Monitoring and Therapy of Cancers )
[ 99 mTc]Sestamibi SPECT Can Predict Proliferation Index, Angiogenesis, and Vascular Invasion in Parathyroid Patients: A Retrospective Study
by Nicoletta Urbano , Manuel Scimeca , Carmela Di Russo , Alessandro Mauriello , Elena Bonanno and Orazio Schillaci
J. Clin. Med. 2020 , 9 (7), 2213; https://doi.org/10.3390/jcm9072213 - 13 Jul 2020
Abstract
The aim of this study was to evaluate the possible association among sestamibi uptake and the main histopathological characteristics of parathyroid lesions related to aggressiveness such as the proliferation index (Ki67 expression and mitosis), angiogenesis (number of vessels), and vascular invasion in hyperparathyroidism [...] Read more.
The aim of this study was to evaluate the possible association among sestamibi uptake and the main histopathological characteristics of parathyroid lesions related to aggressiveness such as the proliferation index (Ki67 expression and mitosis), angiogenesis (number of vessels), and vascular invasion in hyperparathyroidism patients. To this end, 26 patients affected by primary hyperparathyroidism subjected to both scintigraphy with [ 99 mTc]Sestamibi and surgery/bioptic procedure were retrospectively enrolled. Hyperfunctioning of the parathyroid was detected in 19 patients. Our data showed a significant positive association among the sestamibi uptake and the proliferation index histologically evaluated both in terms of the number of Ki67 positive cells and mitosis. According to these data, lesions with a higher valuer of L/N (lesion to nonlesion ratio) frequently showed several vessels in tumor areas and histological evidence of vascular invasion. It is noteworthy that among patients with negative scintigraphy, 2 patients showed a neoplastic lesion after surgery (histological analysis). However, it is important to highlight that these lesions displayed very low proliferation indexes, which was evaluated in terms of number of both mitosis and Ki67-positive cells, some/rare vessels in the main lesion, and no evidence of vascular invasion. In conclusion, data obtained on patients with positive or negative scintigraphy support the hypothesis that sestamibi can be a tracer that is capable of predicting some biological characteristics of parathyroid tumors such as angiogenesis, proliferation indexes, and the invasion of surrounding tissues or vessels. Full article
(This article belongs to the Special Issue Emerging Technologies for Medical Imaging - Diagnostics, Monitoring and Therapy of Cancers )
Non-Invasive Assessment of Breast Cancer Molecular Subtypes with Multiparametric Magnetic Resonance Imaging Radiomics
by Doris Leithner , Marius E. Mayerhoefer , Danny F. Martinez , Maxine S. Jochelson , Elizabeth A. Morris , Sunitha B. Thakur and Katja Pinker
J. Clin. Med. 2020 , 9 (6), 1853; https://doi.org/10.3390/jcm9061853 - 14 Jun 2020
Abstract
We evaluated the performance of radiomics and artificial intelligence (AI) from multiparametric magnetic resonance imaging (MRI) for the assessment of breast cancer molecular subtypes. Ninety-one breast cancer patients who underwent 3T dynamic contrast-enhanced (DCE) MRI and diffusion-weighted imaging (DWI) with apparent diffusion coefficient [...] Read more.
We evaluated the performance of radiomics and artificial intelligence (AI) from multiparametric magnetic resonance imaging (MRI) for the assessment of breast cancer molecular subtypes. Ninety-one breast cancer patients who underwent 3T dynamic contrast-enhanced (DCE) MRI and diffusion-weighted imaging (DWI) with apparent diffusion coefficient (ADC) mapping were included retrospectively. Radiomic features were extracted from manually drawn regions of interest (n = 704 features per lesion) on initial DCE-MRI and ADC maps. The ten best features for subtype separation were selected using probability of error and average correlation coefficients. For pairwise comparisons with >20 patients in each group, a multi-layer perceptron feed-forward artificial neural network (MLP-ANN) was used (70% of cases for training, 30%, for validation, five times each). For all other separations, linear discriminant analysis (LDA) and leave-one-out cross-validation were applied. Histopathology served as the reference standard. MLP-ANN yielded an overall median area under the receiver-operating-characteristic curve (AUC) of 0.86 (0.77–0.92) for the separation of triple negative (TN) from other cancers. The separation of luminal A and TN cancers yielded an overall median AUC of 0.8 (0.75–0.83). Radiomics and AI from multiparametric MRI may aid in the non-invasive differentiation of TN and luminal A breast cancers from other subtypes. Full article
(This article belongs to the Special Issue Emerging Technologies for Medical Imaging - Diagnostics, Monitoring and Therapy of Cancers )
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Prognostic Implications of Combined Imaging and Histologic Criteria in Squamous Cell Carcinoma with Mandibular Invasion
by Chena Lee , Yoon Joo Choi , Kug Jin Jeon , Dong Wook Kim , Woong Nam , Hyung Jun Kim , In-Ho Cha and Sang Sun Han
J. Clin. Med. 2020 , 9 (5), 1335; https://doi.org/10.3390/jcm9051335 - 03 May 2020
Abstract
Prognosis prediction of squamous cell carcinoma (SCC) with mandibular invasion is controversial, and a more sophisticated staging system to aid prognosis could be developed with imaging characteristics of bone invasion. Imaging-feature analysis provides practical, stratified results for survival prognosis in oral SCC (OSCC) [...] Read more.
Prognosis prediction of squamous cell carcinoma (SCC) with mandibular invasion is controversial, and a more sophisticated staging system to aid prognosis could be developed with imaging characteristics of bone invasion. Imaging-feature analysis provides practical, stratified results for survival prognosis in oral SCC (OSCC) of the mandible, and imaging advances enable more detailed tumor visualization. We retrospectively evaluated significant bone-invasion features associated with poor outcomes in mandibular OSCC to assess the predictive value of staging criteria that combined imaging features and histologic grade (combined imaging–histology (IH) grade) in 65 patients (39 men, 26 women) with mandibular SCC diagnosed from 2006 to 2016. Clinicopathologic features, including T-stage and histologic grade, and prognosis were retrieved. Tumors were classified into three types by extent of mandibular invasion on pretreatment imaging studies. Moreover, we assessed the involvement of the mandibular canal. We examined the correlation of factors associated with locoregional recurrence and overall mortality. The Harrell Concordance Index (C-index) determined prognostic performance of predictors. Nineteen (29%) patients showed locoregional recurrence and 13 (20%) died. For locoregional recurrence and mortality rates, imaging-detected mandibular canal (MC) involvement is a stronger prognostic factor for recurrence (C-index = 0.61 > 0.58) and survival (C-index = 0.58 > 0.63) than histopathologically confirmed perineural invasion, as was the IH grade, especially IH Grade 3, which was significantly associated with worse locoregional recurrence ( p < 0.02). Imaging-based staging showed higher prognostic performance than T-staging (C-index = 0.57 (recurrence), 0.60 (death)), when combined with histologic grading (C-index = 0.69 for both) or used alone (C-index = 0.63 (locoregional recurrence), 0.69 (death)). Overall survival was significantly stratified by Imaging type and IH grade. Therefore, analysis of imaging features provided more specific, practical results for survival prognosis in mandibular OSCC. Imaging advances can potentially provide detailed gross views of tumor masses to facilitate development of prognostic criteria for OSCC. Full article
(This article belongs to the Special Issue Emerging Technologies for Medical Imaging - Diagnostics, Monitoring and Therapy of Cancers )
Artificial Intelligence-Based Diagnosis of Cardiac and Related Diseases
by Muhammad Arsalan , Muhammad Owais , Tahir Mahmood , Jiho Choi and Kang Ryoung Park
J. Clin. Med. 2020 , 9 (3), 871; https://doi.org/10.3390/jcm9030871 - 23 Mar 2020
Abstract
Automatic chest anatomy segmentation plays a key role in computer-aided disease diagnosis, such as for cardiomegaly, pleural effusion, emphysema, and pneumothorax. Among these diseases, cardiomegaly is considered a perilous disease, involving a high risk of sudden cardiac death. It can be diagnosed early [...] Read more.
Automatic chest anatomy segmentation plays a key role in computer-aided disease diagnosis, such as for cardiomegaly, pleural effusion, emphysema, and pneumothorax. Among these diseases, cardiomegaly is considered a perilous disease, involving a high risk of sudden cardiac death. It can be diagnosed early by an expert medical practitioner using a chest X-Ray (CXR) analysis. The cardiothoracic ratio (CTR) and transverse cardiac diameter (TCD) are the clinical criteria used to estimate the heart size for diagnosing cardiomegaly. Manual estimation of CTR and other diseases is a time-consuming process and requires significant work by the medical expert. Cardiomegaly and related diseases can be automatically estimated by accurate anatomical semantic segmentation of CXRs using artificial intelligence. Automatic segmentation of the lungs and heart from the CXRs is considered an intensive task owing to inferior quality images and intensity variations using nonideal imaging conditions. Although there are a few deep learning-based techniques for chest anatomy segmentation, most of them only consider single class lung segmentation with deep complex architectures that require a lot of trainable parameters. To address these issues, this study presents two multiclass residual mesh-based CXR segmentation networks, X-RayNet-1 and X-RayNet-2, which are specifically designed to provide fine segmentation performance with a few trainable parameters compared to conventional deep learning schemes. The proposed methods utilize semantic segmentation to support the diagnostic procedure of related diseases. To evaluate X-RayNet-1 and X-RayNet-2, experiments were performed with a publicly available Japanese Society of Radiological Technology (JSRT) dataset for multiclass segmentation of the lungs, heart, and clavicle bones; two other publicly available datasets, Montgomery County (MC) and Shenzhen X-Ray sets (SC), were evaluated for lung segmentation. The experimental results showed that X-RayNet-1 achieved fine performance for all datasets and X-RayNet-2 achieved competitive performance with a 75% parameter reduction. Full article
(This article belongs to the Special Issue Emerging Technologies for Medical Imaging - Diagnostics, Monitoring and Therapy of Cancers )
Artificial Intelligence-Based Mitosis Detection in Breast Cancer Histopathology Images Using Faster R-CNN and Deep CNNs
by Tahir Mahmood , Muhammad Arsalan , Muhammad Owais , Min Beom Lee and Kang Ryoung Park
J. Clin. Med. 2020 , 9 (3), 749; https://doi.org/10.3390/jcm9030749 - 10 Mar 2020
Abstract
Breast cancer is the leading cause of mortality in women. Early diagnosis of breast cancer can reduce the mortality rate. In the diagnosis, the mitotic cell count is an important biomarker for predicting the aggressiveness, prognosis, and grade of breast cancer. In general, [...] Read more.
Breast cancer is the leading cause of mortality in women. Early diagnosis of breast cancer can reduce the mortality rate. In the diagnosis, the mitotic cell count is an important biomarker for predicting the aggressiveness, prognosis, and grade of breast cancer. In general, pathologists manually examine histopathology images under high-resolution microscopes for the detection of mitotic cells. However, because of the minute differences between the mitotic and normal cells, this process is tiresome, time-consuming, and subjective. To overcome these challenges, artificial-intelligence-based (AI-based) techniques have been developed which automatically detect mitotic cells in the histopathology images. Such AI techniques accelerate the diagnosis and can be used as a second-opinion system for a medical doctor. Previously, conventional image-processing techniques were used for the detection of mitotic cells, which have low accuracy and high computational cost. Therefore, a number of deep-learning techniques that demonstrate outstanding performance and low computational cost were recently developed; however, they still require improvement in terms of accuracy and reliability. Therefore, we present a multistage mitotic-cell-detection method based on Faster region convolutional neural network (Faster R-CNN) and deep CNNs. Two open datasets (international conference on pattern recognition (ICPR) 2012 and ICPR 2014 (MITOS-ATYPIA-14)) of breast cancer histopathology were used in our experiments. The experimental results showed that our method achieves the state-of-the-art results of 0.876 precision, 0.841 recall, and 0.858 F1-measure for the ICPR 2012 dataset, and 0.848 precision, 0.583 recall, and 0.691 F1-measure for the ICPR 2014 dataset, which were higher than those obtained using previous methods. Moreover, we tested the generalization capability of our technique by testing on the tumor proliferation assessment challenge 2016 (TUPAC16) dataset and found that our technique also performs well in a cross-dataset experiment which proved the generalization capability of our proposed technique. Full article
(This article belongs to the Special Issue Emerging Technologies for Medical Imaging - Diagnostics, Monitoring and Therapy of Cancers )
► ▼ Show Figures
Figure 1
Breast-Specific Gamma Imaging with [ 99 mTc]Tc-Sestamibi: An In Vivo Analysis for Early Identification of Breast Cancer Lesions Expressing Bone Biomarkers
by Nicoletta Urbano , Manuel Scimeca , Carmela Di Russo , Elena Bonanno and Orazio Schillaci
J. Clin. Med. 2020 , 9 (3), 747; https://doi.org/10.3390/jcm9030747 - 10 Mar 2020
Abstract
The main purpose of this pilot investigation was to evaluate the possible relationship among [ 99 mTc]Tc-Sestamibi uptake, the presence of breast osteoblast-like cells, and the expression of molecules involved in bone metabolism, such as estrogen receptor, bone morphogenetic proteins-2, and PTX3. To [...] Read more.
The main purpose of this pilot investigation was to evaluate the possible relationship among [ 99 mTc]Tc-Sestamibi uptake, the presence of breast osteoblast-like cells, and the expression of molecules involved in bone metabolism, such as estrogen receptor, bone morphogenetic proteins-2, and PTX3. To this end, forty consecutive breast cancer patients who underwent both breast-specific gamma imaging with [ 99m Tc]Tc-Sestamibi and breast bioptic procedure were retrospectively enrolled. From each diagnostic paraffin block collected in the study, histological diagnosis, immunohistochemical investigations, and energy dispersive X-ray microanalysis were performed. Our data highlight the possible use of breast-specific gamma imaging with [ 99 mTc]Tc-Sestamibi for the early detection of breast cancer lesions expressing bone biomarkers in the presence of breast osteoblast-like cells. Specifically, we show a linear association among sestamibi uptake, the presence of breast osteoblast-like cells, and the expression of estrogen receptor, bone morphogenetics proteins-2, and PTX3. Notably, we also observed an increase of [ 99 mTc]Tc-Sestamibi in breast cancer lesions with magnesium-substituted hydroxyapatite. In conclusion, in this pilot study we evaluated data from the nuclear medicine unit and anatomic pathology department on breast cancer osteotropism, identifying a new possible interpretation of Breast Specific Gamma Imaging with [ 99 mTc]Tc-Sestamibi analysis. Full article
(This article belongs to the Special Issue Emerging Technologies for Medical Imaging - Diagnostics, Monitoring and Therapy of Cancers )
Review
Advances in Molecular Imaging and Radionuclide Therapy of Neuroendocrine Tumors
by Anna Yordanova , Hans-Jürgen Biersack and Hojjat Ahmadzadehfar
J. Clin. Med. 2020 , 9 (11), 3679; https://doi.org/10.3390/jcm9113679 - 16 Nov 2020
Abstract
Neuroendocrine neoplasms make up a heterogeneous group of tumors with inter-patient and intra-patient variabilities. Molecular imaging can help to identify and characterize neuroendocrine tumors (NETs). Furthermore, imaging and treatment with novel theranostics agents offers a new, tailored approach to managing NETs. Recent advances [...] Read more.
Neuroendocrine neoplasms make up a heterogeneous group of tumors with inter-patient and intra-patient variabilities. Molecular imaging can help to identify and characterize neuroendocrine tumors (NETs). Furthermore, imaging and treatment with novel theranostics agents offers a new, tailored approach to managing NETs. Recent advances in the management of NETs aim to enhance the effectiveness of targeted treatment with either modifications of known substances or the development of new substances with better targeting features. There have been several attempts to increase the detectability of NET lesions via positron emission tomography (PET) imaging and improvements in pretreatment planning using dosimetry. Especially notable is PET imaging with the radionuclide Copper-64. Increasing interest is also being paid to theranostics of grade 3 and purely differentiated NETs, for example, via targeting of the C-X-C motif chemokine receptor 4 (CXCR4). The aim of this review is to summarize the most relevant recent studies, which present promising new agents in molecular imaging and therapy for NETs, novel combination therapies and new applications of existing molecular imaging modalities in nuclear medicine. Full article
(This article belongs to the Special Issue Emerging Technologies for Medical Imaging - Diagnostics, Monitoring and Therapy of Cancers )
Impact of PET/CT for Assessing Response to Immunotherapy—A Clinical Perspective
by David Lang , Gerald Wahl , Nikolaus Poier , Sebastian Graf , David Kiesl , Bernd Lamprecht and Michael Gabriel
J. Clin. Med. 2020 , 9 (11), 3483; https://doi.org/10.3390/jcm9113483 - 28 Oct 2020
Abstract
Cancer immunotherapy using immune-checkpoint inhibitors (ICI) has revolutionized the therapeutic landscape of various malignancies like non-small-cell lung cancer or melanoma. Pre-therapy response prediction and assessment during ICI treatment is challenging due to the lack of reliable biomarkers and the possibility of atypical radiological [...] Read more.
Cancer immunotherapy using immune-checkpoint inhibitors (ICI) has revolutionized the therapeutic landscape of various malignancies like non-small-cell lung cancer or melanoma. Pre-therapy response prediction and assessment during ICI treatment is challenging due to the lack of reliable biomarkers and the possibility of atypical radiological response patterns. Positron emission tomography/computed tomography (PET/CT) enables the visualization and quantification of metabolic lesion activity additional to conventional CT imaging. Various biomarkers derived from PET/CT have been reported as predictors for response to ICI and may aid to overcome the challenges clinicians currently face in the management of ICI-treated patients. In this narrative review, experts in nuclear medicine, thoracic oncology, dermatooncology, hemato- and internal oncology, urological and head/neck tumors performed literature reviews in their respective field and a joint discussion on the use of PET/CT in the context of ICI treatment. The aims were to give a clinical overview on present standards and evidence, to identify current challenges and fields of research and to enable an outlook to future developments and their possible implications. Multiple promising studies concerning ICI response assessment or prediction using biomarkers derived from PET/CT alone or as composite biomarkers have been identified for various malignancies and disease stages. Of interest, additional major incentives in the field may evolve from novel tracers specifically targeting immune-checkpoint molecules which could allow not only response assessment and prognosis, but also visualization of histological tumor cell properties like programmed death-ligand (PD-L1) expression in vivo. Despite the broad range of existing literature on PET/CT-derived biomarkers in ICI therapy, implications for daily clinical practice remain elusive. High-quality prospective data are urgently warranted to determine whether patients benefit from the application of PET/CT in terms of prognosis. At the moment, the lack of such evidence as well as the absence of standardized imaging methods and biomarkers still precludes PET/CT imaging to be included in the relevant clinical practice guidelines. Full article
(This article belongs to the Special Issue Emerging Technologies for Medical Imaging - Diagnostics, Monitoring and Therapy of Cancers )
Figure 1
get_app
subject
Targeted Palliative Radionuclide Therapy for Metastatic Bone Pain
by
Reyhaneh Manafi-Farid ,
Fardad Masoumi ,
Ghasemali Divband ,
Bahare Saidi ,
Bahar Ataeinia ,
Fabian Hertel ,
Gregor Schweighofer-Zwink ,
Agnieszka Morgenroth and
Mohsen Beheshti
J. Clin. Med. 2020 , 9 (8), 2622; https://doi.org/10.3390/jcm9082622 - 12 Aug 2020
Abstract
Bone metastasis develops in multiple malignancies with a wide range of incidence. The presence of multiple bone metastases, leading to a multitude of complications and poorer prognosis. The corresponding refractory bone pain is still a challenging issue managed through multidisciplinary approaches to enhance [...] Read more.
Bone metastasis develops in multiple malignancies with a wide range of incidence. The presence of multiple bone metastases, leading to a multitude of complications and poorer prognosis. The corresponding refractory bone pain is still a challenging issue managed through multidisciplinary approaches to enhance the quality of life. Radiopharmaceuticals are mainly used in the latest courses of the disease. Bone-pain palliation with easy-to-administer radionuclides offers advantages, including simultaneous treatment of multiple metastatic foci, the repeatability and also the combination with other therapies. Several β¯- and α-emitters as well as pharmaceuticals, from the very first [ 89 Sr]strontium-dichloride to recently introduced [ 223 Ra]radium-dichloride, are investigated to identify an optimum agent. In addition, the combination of bone-seeking radiopharmaceuticals with chemotherapy or radiotherapy has been employed to enhance the outcome. Radiopharmaceuticals demonstrate an acceptable response rate in pain relief. Nevertheless, survival benefits have been documented in only a limited number of studies. In this review, we provide an overview of bone-seeking radiopharmaceuticals used for bone-pain palliation, their effectiveness and toxicity, as well as the results of the combination with other therapies. Bone-pain palliation with radiopharmaceuticals has been employed for eight decades. However, there are still new aspects yet to be established. Full article
(This article belongs to the Special Issue Emerging Technologies for Medical Imaging - Diagnostics, Monitoring and Therapy of Cancers )
► ▼ Show Figures
Figure 1
Advancements in PARP1 Targeted Nuclear Imaging and Theranostic Probes
by Ramya Ambur Sankaranarayanan , Susanne Kossatz , Wolfgang Weber , Mohsen Beheshti , Agnieszka Morgenroth and Felix M. Mottaghy
J. Clin. Med. 2020 , 9 (7), 2130; https://doi.org/10.3390/jcm9072130 - 06 Jul 2020
Abstract
The central paradigm of novel therapeutic approaches in cancer therapy is identifying and targeting molecular biomarkers. One such target is the nuclear DNA repair enzyme Poly-(ADP ribose) polymerase 1 (PARP1). Sensitivity to PARP inhibition in certain cancers such as gBRCA mut breast and [...] Read more.
The central paradigm of novel therapeutic approaches in cancer therapy is identifying and targeting molecular biomarkers. One such target is the nuclear DNA repair enzyme Poly-(ADP ribose) polymerase 1 (PARP1). Sensitivity to PARP inhibition in certain cancers such as gBRCA mut breast and ovarian cancers has led to its exploitation as a target. The overexpression of PARP1 in several types of cancer further evoked interest in its use as an imaging target. While PARP1-targeted inhibitors have fast developed and approved in this past decade, determination of PARP1 expression might help to predict the response to PARP inhibitor treatment. This has the potential of improving prognosis and moving towards tailored therapy options and/or dosages. This review summarizes the recent pre-clinical advancements in imaging and theranostic PARP1 targeted tracers. To assess PARP1 levels, several imaging probes with fluorescent or beta/gamma emitting radionuclides have been proposed and three have advanced to ongoing clinical evaluation. Apart from its diagnostic value in detection of primary tumors as well as metastases, this shall also help in delivering therapeutic radionuclides to PARP1 overexpressing tumors. Henceforth nuclear medicine has now advanced towards conjugating theranostic radionuclides to PARP1 inhibitors. This paves the way for a future of PARP1-targeted theranostics and personalized therapy. Full article
(This article belongs to the Special Issue Emerging Technologies for Medical Imaging - Diagnostics, Monitoring and Therapy of Cancers )
Displaying articles 1-16
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(PDF) Neutrophil extracellular traps primed intercellular communication in cancer progression as a promising therapeutic target
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Neutrophil extracellular traps primed intercellular communication in cancer progression as a promising therapeutic target
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March 2023
Biomarker Research11(1)
DOI: 10.1186/s40364-023-00463-y
License
CC BY 4.0
Authors:
<here is a image f2f62089ad6ff61c-d19572ff1996375a>
Bingqing Shang
Bingqing Shang
<here is a image f2f62089ad6ff61c-d19572ff1996375a>
Honglei Cui
Honglei Cui
<here is a image da1c6962ccac11c6-e423d3c2a5e090bd>
Ruiyang Xie
Cancer Institute and Hospital, Chinese Academy of Medical Sciences
<here is a image f2f62089ad6ff61c-d19572ff1996375a>
Jie Wu
Jie Wu
Abstract and Figures
In addition to the anti-infection response, neutrophils are linked to tumor progression through the secretion of inflammation components and neutrophil extracellular traps (NETs) formation. NET is a web-like structure constituted by a chromatin scaffold coated with specific nuclear and cytoplasmic proteins, such as histone and granule peptides. Increasing evidence has demonstrated that NETs are favorable factors to promote tumor growth, invasion, migration, and immunosuppression. However, the cell–cell interaction between NETs and other cells (tumor cells and immune cells) is complicated and poorly studied. This work is the first review to focus on the intercellular communication mediated by NETs in cancer. We summarized the complex cell–cell interaction between NETs and other cells in the tumor microenvironment. We also address the significance of NETs as both prognostic/predictive biomarkers and molecular targets for cancer therapy. Moreover, we presented a comprehensive landscape of cancer immunity, improving the therapeutic efficacy for advanced cancer in the future.
<here is a image 697b902e08c67585-0d70eb363fb2cca5>
Intercellular communication between NETs and tumor cells or immune cells. a NET-DNA served as a chemotactic factor, which was sensor by cell-surface receptor CCDC25 on the metastatic tumor cell, and subsequently activated the downstream ILK–β-Parvin signaling to accelerate the metastasis. b NETs functioning as a substrate for the integrins expressed on the tumor cell, could enhance the cell adhesion ability and sequester the CTC. c NET-remodeled laminin-111 contributed to tumor proliferation by activating the integrin a3β1 signaling of the dormant cancer cell. d NET clearance refers to the process by which macrophage phagocytoses the NET. NET clearance is often impaired in cases of abnormal immunity. Specific molecules could enhance the ability of NET clearance through the cAMP/PKA/AMPK axis. e The impact of NETs on the immunomodulatory function may be due in part to the phenomenon of NETs-shielding tumor cells, reducing the direct contact between effector cytotoxic lymphocytes and tumor cells. f NET-primed naïve CD4⁺ T cell was more inclined to the differential of Treg cell through increasing the mitochondrial OCR and OXPHOS. Genes essential for Treg differentiation and activity were up-regulated. Meanwhile, Teff programming genes were significantly down-regulated. g Activated platelets bind to the receptor P-selective (P-sel) glycoprotein ligand-1 (PSGL-1) on the surface of the neutrophil via P-selective protein and promote the production of NETs. And NETs such as the DNA backbone and adherent thrombosis-related enzymes can activate platelets in turn …
Figures - available from: Biomarker Research
Neutrophil extracellular traps primed
intercellular communication incancer
progression asapromising therapeutic target
Bingqing Shang 1†, Honglei Cui 1†, Ruiyang Xie 1 , Jie Wu 1, Hongzhe Shi 1, Xingang Bi 1, Lin Feng 2*and
Jianzhong Shou 1*
Abstract
In addition to the anti-infection response, neutrophils are linked to tumor progression through the secretion of
inflammation components and neutrophil extracellular traps (NETs) formation. NET is a web-like structure constituted
by a chromatin scaffold coated with specific nuclear and cytoplasmic proteins, such as histone and granule peptides.
Increasing evidence has demonstrated that NETs are favorable factors to promote tumor growth, invasion, migra-
tion, and immunosuppression. However, the cell–cell interaction between NETs and other cells (tumor cells and
immune cells) is complicated and poorly studied. This work is the first review to focus on the intercellular communi-
cation mediated by NETs in cancer. We summarized the complex cell–cell interaction between NETs and other cells
in the tumor microenvironment. We also address the significance of NETs as both prognostic/predictive biomarkers
and molecular targets for cancer therapy. Moreover, we presented a comprehensive landscape of cancer immunity,
improving the therapeutic efficacy for advanced cancer in the future.
KeywordsCancer, Neutrophil extracellular traps, Intercellular communication, Immune landscape, Biomarker,
Therapeutic target
Introduction
Neutrophils are the most abundant type of leukocytes
in human peripheral blood serving as the front line in
innate immunity [ 1]. Besides infections, ongoing efforts
have expanded the roles of neutrophils in a wide range
of human diseases, such as thrombosis, auto-immune
diseases, pulmonary diseases, and cancer progression
[ 2 ]. e contribution of tumor-associated neutrophils
(TANs) in cancer remains elusive, as a result of the com -
plex microenvironment of cancer [ 3]. Research using ani-
mal models has shown that TANs can be polarized into
an anti-tumor (N1) or pro-tumor (N2) subtype, which is
driven by the state of TGF-β [ 4].
In 2004, Brinkmann etal .discovered that neutrophil
suicide could release web-like structures decorated with
depolymerized chromatin and antimicrobial molecules,
named as NETs. ey elicited NETs using PMA and IL-8
invitro and demonstrated that NETs could resist viru -
lence factors and kill bacteria [ 5]. Apart from PMA and
IL-8, additional stimuli were found to be responsible for
the release of NETs, including protozoa, bacteria, fungi,
† Bingqing Shang and Honglei Cui contributed equally to this work.
*Correspondence:
Lin Feng
[email protected]
Jianzhong Shou
[email protected]
1 Department of Urology, National Cancer Center/National Clinical
Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical
Sciences and Peking Union Medical College, Panjiayuan Nanli 17#
Chaoyang District, Beijing 100021, PR, China
2 Department of Etiology and Carcinogenesis, State Key Laboratory
of Molecular Oncology, National Cancer Center/National Clinical Research
Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences
and Peking Union Medical College, Beijing, PR, China
Page 2 of 15
Shang etal. Biomarker Research (2023) 11:24
IFN-α/IFN-γ/C5a, GM-CSF/C5a, lipopolysaccharide
(LPS), antibody-antigen complexes, activated platelets,
and calcium ionophores [ 6]. Within NETs, there are
several proteins coated in the decondensed DNA, such
as histones, neutrophil elastase (NE), myeloperoxidase
(MPO) and cathepsin G [ 7– 9].
Like the role of TANs, increasing evidence has recently
revealed the role of NETs as a fundamental part in cancer
progression [ 10– 12]. e prior reviews mainly focused
on the crucial role of NETs in contributing to the devel -
opment and progression of cancer. Consistent with the
previous studies, our research validated the role of NET
as an unfavorable prognosis biomarker in most types of
cancer, by developing a panel of genes signature as NET-
score [ 13]. Nevertheless, this review first summarizes
the intercellular communication between NETs, tumor
cells, and immune cells in carcinogenesis. We aimed to
figure out the cellular interplay and molecular pathway
mechanism that regulate the innate immune and adap -
tive immune response in malignancies. e potential of
NETs as diagnostic and prognostic markers and novel
treatment targets is also discussed in this review.
The interplay betweenthetumor cell andNETs
e role of NETs in pro- and anti-tumorigenic func-
tions remains unclear in different cancers. Very few
articles now illustrated the in-vitro antitumor effect of
NETs. An experiment invitro showed that NETs could
impede growth and induce apoptosis in colorectal can -
cer cells [ 14]. Consistently, Schedel F etal .found NETs
inhibiting the migration and necrosis of melanoma cells
invitro [ 15]. However, NETs in the tumor microenviron -
ment (TME) mostly exert promotion in the growth and
progression of cancer, in the onset and spread of tumor
metastasis, and in the poor response of anti-tumor
therapy [ 12 , 16– 23]. e bond between cancer-cells
and NETs was revealed in the Ewing sarcoma at first, in
which the NETs were correlated with poor prognosis
for patients [ 12]. Compared to control mice, the neutro -
phils in the tumor-bearing mice represented an increased
ability to spontaneously form NETs [ 24 , 25], which was
associated with endothelial-to-mesenchymal transition
(EMT) driving and cancer metastasis [ 25– 27]. e can -
cer cell-derived factors supporting the NETosis include
mainly IL-8, G-CSF, GROα/β, and CXCR1/2 chemokine
receptor agonists [ 17 , 28]. NETs also strengthen the met -
astatic potential of cancer cells by other mechanisms,
including accumulation in the pre-metastatic niche or
the circulation for entrapping the circulating tumor cells
(CTCs) [ 17, 29].
Szczerba BM etal .manipulated single-cell RNA
sequencing (scRNA-seq) and investigated the ligand/
receptor pairs of the CTC–neutrophil cluster. ey
hypothesized that the expression of VCAM1 is a molecu -
lar feature possibly defining the CTC-neutrophil clus-
ter formation in breast cancer [ 30]. Understanding the
ligand/receptor pairing may explore new targets in can -
cer therapy.
Recently, several pieces of research demonstrated the
molecular mechanism of the intracellular network of
tumor cells and NETs. e most studied example of the
ligand/receptor interaction was the TLR family in the
tumor cell and NET-associated factors. e TLR fam -
ily is characterized as the essential part of the innate
immune and could recognize pathogen-associated
molecular patterns (PAMPs) [ 31]. TLR receptors are
ubiquitously expressed both in tumor and immune cells
[ 32 , 33 ], and exert a dual role in cancer [ 34 – 37]. To
date, several TLR agonists have shown inspiring results
for their survival benefits combined with immune vac -
cination, immune checkpoint inhibitors, and chemo -
therapy in clinical trials, especially for glioma [ 38 , 39 ].
Nonetheless, TLR agonist-associated infection and
the help of TLR overexpression in the carcinogenesis
or tumor progression should be emphasized [ 33 , 36 ,
40 ]. Higher levels of intratumor NETs and preopera -
tive serum MPO-DNA as a marker of NETs were cor -
related with shorter survival in metastatic colorectal
cancer. Mechanistically, NE as NETs-derived stimu -
latory factor directly activated the TLR4 pathway on
tumor cells and subsequently upregulated Peroxisomes
proliferator-activated receptor gamma coactivator
1-alpha (PGC1-α), driving mitochondrial homeostasis
and favoring the tumor growth [ 41]. In bladder can -
cer, Shinde-Jadhav S etal .found the level of NETs was
increased after radiation therapy (RT), which contrib -
uted to tumor radiotherapy resistance. ey further
demonstrated that the activated formation of NETs was
associated with HMGB1 via a TLR4-dependent manner,
and inhibiting NETs or HMGB1 could improve radia -
tion response [ 23]. For diffuse large B-cell lymphoma
(DLBCL) patients, Nie M etal. investigated the mech -
anism of interleukin-8 (IL-8), secreted by lymphoma
cells, binding to C-X-C Motif Chemokine Receptor 2
(CXCR2) on the cell-surface of neutrophil and induc -
ing NET formation. Furthermore, an increased level of
NETs activated TLR9 on the lymphoma cells, contrib -
uting to NFkB, STAT3, and p38 downstream pathways
activation. e novel cross-talk as IL8-CXCR2-TLR9
axis augmented the tumor progression in DLBCL [ 21 ].
Tohme etal .proposed that HMGB1 released from
NETs assisted in the TLR9 activation. TLR9 promoted
colorectal cancer cell proliferation, migration, or inva -
sion by activating the MAP kinase pathways [ 42]. e
neutrophils derived from metastatic hepatocellular
carcinoma (HCC) harbored an up-regulated capacity
of producing NETs, compared with those in healthy
adults. It was further investigated that NETs enhanced
the invasion capacity of trapped tumor cells through
the activation of the TLR4/9 receptor and the phospho -
rylation of P65 and cyclooxygenase-2 (COX2) overex -
pression. e direct inhibition of the TLR4/9-COX2
pathway wrecked the NET-driven metastatic potential
[ 43 ]. Apart from the TLR ligand-associated pathway,
CCDC25 is a transmembrane protein on the breast
cancer cells, which could interact with the NET-DNA
complex directly. As a result, it enhanced tumor cell
motility and tumor metastasis by activating the down -
stream pathway including integrin-linked kinase (ILK)
and β-Parvin. CCDC25-knockout cells abrogated the
NET-mediated potential metastasis [ 11]. Cell-to-cell
adhesion in cancer is complex and involved in each step
of tumor progression. It enables tumor cells to loosen
from the primary tumor mass and enhances cell attach -
ment to the metastatic site [ 44 , 45]. In the cell adhesion
process, the integrin ligands (a combination of α and β
subunits) determine the central role governing cancer
cell migration [ 44]. In a panel of tumor cell lines, Monti
M etal .revealed that NETs could adhere to tumor cells
with high levels of integrin α5β1, αvβ3, and αvβ5 [ 46 ].
Tumor-derived integrin β1 promoted the co-locali -
zation of NETs and tumor cells invivo and invitro.
Najmeh S etal .proposed the hypothesis that NETs
captured CTC through the mediator integrin β1 [ 29 ].
Mechanism research demonstrated that NETs-related
proteases, matrix metalloproteinase 9 (MMP9) and NE,
resulted in the cleavage of laminin. e NET-remod -
eled laminin-111 subsequently activated the integrin
a3β1 receptor on the tumor cell. e integrin a3β1 up-
regulated the focal adhesion Kinase (FAK), extracellu -
lar signal-regulated kinase (ERK), and yes-associated
Protein (YAP) and promoted the dormant tumor cell
awaken [ 10].
In conclusion, there is growing evidence from ligand/
receptor pair analysis that NETs primarily promote the
proliferation, adhesion, and metastatic capacity of tumor
cells (shown in Table 1). Meanwhile, the molecular
mechanism of its anti-tumorigenic effects requires fur -
ther exploration. NETs directly or the NETs-associated
factors interact with the receptors on the tumor cells and
thus alter the tumor cell function. Nevertheless, there
are few studies on the mechanism of interplay between
tumor cells and NETs, especially for their ligand-receptor
pairs. Furthermore, targeting the ligand-receptor pairing
or specific kinases rather than neutrophils or tumor cells
could be a potential strategy for anti-tumor treatment.
Potential interactions betweenthemacrophage andNETs
Macrophages polarize to activated pro-inflammatory
M1 and anti-inflammatory M2 phenotypes depend -
ing on the microenvironment stimuli [ 47 , 48]. M1
macrophages exert pro-inflammatory effects through
secreted cytokines, such as interleukin-1β (IL-1β), inter -
leukin-6 (IL-6), and tumor necrosis factor (TNF). In con-
trast to M1 phenotype macrophages, M2 macrophages
are predominantly correlated with resolving inflamma -
tion and promoting tissue repair [ 49]. Tumor-associated
macrophages (TAMs) are typically altered into M2 and
mediate immune dysfunction in the TME [ 50]. Similar to
neutrophils, macrophages also release web-like structures
as extracellular traps (ETs) [ 51]. Macrophage extracellu -
lar traps (METs) exert tumor-promoting roles by assist-
ing tumor growth, progression, and metastasis [ 51– 53 ].
For pancreatic neuroendocrine tumors (pNETs), NETs
and METs were deemed as the independent prognosis
indicators for recurrence-free survival (RFS). However,
Table 1 The interplay between the tumor cell and NETs
Stimulator or Ligand of NETsReceptors in the tumor cellRegulated functionType of CancerReference
IL-8, G-CSF, GROα/β-tumor premetastatic niche formationovarian cancer[ 17]
CXCR1/CXCR2 Agonists-immune-mediated cytotoxicitysolid malignancies[ 28]
NETLR4mitochondrial biogenesis and tumor
growth Colorectal cancer[ 41]
HMGB1TLR4radioresistancebladder cancer[ 23]
NETs TLR9tumor proliferation, migration, and
invasion Colorectal cancer[ 42]
NETs TLR9tumor proliferation and metastasisDiffuse large B-cell lymphoma[ 21]
NETs TLR4/9tumor metastasisHepatic cell carcinoma[ 43]
NET-DNA complexCCDC25tumor cell motility and tumor metastasisBreast cancer[ 11]
NETs integrin α5β1, αvβ3, and αvβ5tumor cell adhesionPan-cancer[ 46]
NETs integrin β1tumor cell adhesionLung cell carcinoma[ 29]
NETs-cleaved laminin-111integrin a3β1awaken dormant tumor cellBreast cancer[ 10]
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Page 6 of 15
Shang etal. Biomarker Research (2023) 11:24
Increasing evidence has illustrated the role of plate-
let in NETs formation. Clark etal .first described plate-
let involved in DNA extracellular trap formation in a
mouse model of sepsis. ey found that platelets, acti -
vated by LPS through TLR4, could bind neutrophils
and lead to their activation and NETs formation [ 95 ].
One potent mechanism of platelets-induced NETs for -
mation seems to be the combination of P-selectin to
its receptor P-selectin glycoprotein ligand-1 (PSGL-
1) on their surface [ 96]. Animal studies demonstrated
that platelets from mice with overexpressed P-selectin
were more prone to generate NETs when co-incubated
with neutrophils, while platelets from P-selectin knock-
out mice failed to induce NETs [ 97]. Moreover, using
anti ‐P ‐ selectin and PSGL ‐1 antibodies to abrogate the
interaction between neutrophils and platelets could
remarkably decrease NETs formation in the plasma of
glioma patients [ 98]. e pro-inflammatory molecule
platelet-derived high mobility group box1 (HMGB1),
secreted from activated platelets has also been shown to
facilitate NET formation [ 99]. According to this study,
platelets from colorectal cancer patients stimulated neu -
trophils to release NETs, which could be abolished by the
absence of HMGB1 [ 92]. Meanwhile, platelets acted as
carriers of tumor-derived exosomes, which in turn con -
tributed to the generation of NETs [ 90].
It was shown that platelets promote neutrophils to
generate NET and its components,which in turn acti -
vate platelets as wel l[ 100]. NETs could function in pro-
coagulant response by providing a scaffold for platelets,
red blood cells, extracellular vesicles, and pro-coagulant
molecules [ 101– 103]. NETs could convert platelets to a
procoagulant phenotype and stimulate the activation and
aggregation of platelets by upregulating phosphatidylser -
ine and P-selectin expression on its membrane [ 98 , 104].
Brian A. Boone etal .found that DNA and its receptor for
advanced glycation end products (RAGE) were necessary
for NETs-relevant platelet aggregation and RAGE KO
tumor-bearing mice exhibited decreased platelet aggre -
gation [ 93]. Another study showed that DNase I treat-
ment could attenuate platelet aggregation, while some
platelets still adhered to the glass slides. Histones that are
the most abundant proteins in NETs or NE are sufficient
to induce platelet aggregation [ 104]. Co-culture plate -
lets with histones H3 and H4 promote its aggregation,
whereas histones 1H, H2A, and H2B had no such effect
[ 102 ]. More specifically, histone-enhanced platelet aggre -
gation by recruiting fibrinogen and histone-dependent
platelet activation seems to be mediated by the signaling
pathway of TLR2 and TLR4 receptors, via the transcrip -
tion factor NF-κB [ 105].
Holistically, activated platelets simultaneously inter -
play with neutrophils, promoting NETs formation. NETs
provide a scaffold for platelets and induce activation and
aggregation of platelet via their complex components,
thus generating a positive feedback cycle to each other.
NETs asavaluable marker incancer fromtheclinical
perspective
Several techniques for the detection of NETs showed
promising clinical applications for diagnosis, therapeu -
tic response, and prognosis. ELISA technique was the
most commonly acknowledged to detect the circulating
NETs-associated complexes, allowing the quantitative
assessment of NETs. In certain studies, the circulating
level of NET-derived DNA was measured as MPO-DNA,
NE-DNA, or circulating DNA [ 11 , 106– 108]. Apart from
NET-related DNA complex, the circulating H3Cit level
was also identified as the number of NETs [ 109 , 110].
Meanwhile, circulating MPO-DNA, NE-DNA, and H3Cit
were more specific for NETs quantification than circulat -
ing DNA alone [ 107]. Based on the evidence of a cohort
of 283 gastric adenocarcinoma (GAC) patients, it seemed
that both the serum and plasma of blood samples could
all be employed for NETs detection [ 108]. e immuno -
histochemical (IHC) technique was also used to measure
NET formation in the primary tumor lesion or metastatic
site of the tumor tissue sample [ 79 , 111]. e NET for -
mation was identified as the neutrophils positive for the
H3Cit signal [ 112 , 113]. In some cases, the NETs level,
measured as other NETs-specific proteins like MPO, NE,
and so on, has been applied as a surrogated marker of
NETs[ 10 ,13 ,103 ].
e increment of circulating DNA in plasma, con -
sidered a specific marker of NETs in this research, was
founded in cancer-related stroke patients [ 114]. Never -
theless, this data should be cautiously interpreted due
to the circulating DNA also involving in the apoptotic,
necrotic, and so on [ 115]. NET-derived proteins like
MPO or NE could bind to DNA in the circulating system.
For both esophagogastric and lung adenocarcinoma, the
level of circulating MPO-DNA was elevated compared
to healthy people [ 106]. According to the analysis of pan -
creatic adenocarcinoma patients, the level of circulating
MPO-DNA before treatment was correlated positively
with the clinical stage [ 19]. e expression of serum
MPO-DNA was validated as a predictor of liver metas -
tasis for early-stage breast cancer patients [ 11]. Tohme S
etal . revealed that metastatic colorectal cancer patients
with elevated levels of serum MPO-DNA after liver
resection surgery were more likely to have a reduction in
disease-free survival (DFS) [ 42]. Yazdani HO etal .also
investigated that the pre-operatively serum MPO-DNA
complexes levels increased in proportion to the clini -
cal outcome, observing the added NETs level in patients
with shorter DFS and overall survival [ 41]. In addition,
the serum MPO-DNA complex level was confirmed to
monitor the HER2 inhibitor-associated vasculitis activity
| https://www.researchgate.net/publication/368925160_Neutrophil_extracellular_traps_primed_intercellular_communication_in_cancer_progression_as_a_promising_therapeutic_target |
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*'''1600s-1850''' {{FSC|295370|item|disp=Barbour Collection: Connecticut Vital Records Prior to 1850}}(*) at FamilySearch Catalog - index and images; ''some towns maybe missing''
*'''1600s-1850''' {{FSC|295370|item|disp=Barbour Collection: Connecticut Vital Records Prior to 1850}}(*) at FamilySearch Catalog - index and images; ''some towns maybe missing''
*'''1600s-1850''' [https://www.worldcat.org/title/barbour-collection-of-connecticut-town-vital-records/oclc/746977528&referer=brief_results The Barbour Collection of Connecticut Town Vital Records] ''This collection of bound typescripts is available at the listed libraries;'' ''some towns may be missing''
*'''1600s-1850''' [https://www.worldcat.org/title/barbour-collection-of-connecticut-town-vital-records/oclc/746977528&referer=brief_results The Barbour Collection of Connecticut Town Vital Records] ''This collection of bound typescripts is available at the listed libraries;'' ''some towns may be missing''
−
*'''1600s-1870''' [https://www.ancestry.com/search/collections/1034/ Connecticut, U.S., Town Birth Records, pre-1870 (Barbour Collection)] at Ancestry - index & images ,
($); ''some towns maybe missing'' +
*'''1600s-1870''' [https://www.ancestry.com/search/collections/1034/ Connecticut, U.S., Town Birth Records, pre-1870 (Barbour Collection)] at Ancestry - index & images ($); ''some towns maybe missing''
*'''1639-1941''' {{RecordSearch|2448938|Connecticut, Births and Baptisms, 1639-1941}} at FamilySearch — index
*'''1639-1941''' {{RecordSearch|2448938|Connecticut, Births and Baptisms, 1639-1941}} at FamilySearch — index
− *'''1640-1955''' {{RecordSearch|2658554|Connecticut, Charles R. Hale Collection, Vital Records, 1640-1955}} at FamilySearch — index +
*'''1784-1944''' {{FSC|302493|title-id|disp=Records of Births, Marriages, and Deaths, 1784-1944}}(*); East Lyme Registrar of Vital Statistics at FamilySearch Library Catalog — images
*'''1784-1944''' {{FSC|302493|title-id|disp=Records of Births, Marriages, and Deaths, 1784-1944}}(*); East Lyme Registrar of Vital Statistics at FamilySearch Library Catalog — images
====Marriages====
====Marriages====
−
*'''1600s-1700s''' [https://www.ancestry.com/search/collections/3824/ U.S., New England Marriages Prior to 1700] at Ancestry - index & images ,
($) +
*'''1600s-1700s''' [https://www.ancestry.com/search/collections/3824/ U.S., New England Marriages Prior to 1700] at Ancestry - index & images ($)
*'''1600s-1850''' {{FSC|295370|item|disp=Barbour Collection: Connecticut Vital Records Prior to 1850}}(*) at FamilySearch Catalog - index and images; ''some towns maybe missing''
*'''1600s-1850''' {{FSC|295370|item|disp=Barbour Collection: Connecticut Vital Records Prior to 1850}}(*) at FamilySearch Catalog - index and images; ''some towns maybe missing''
*'''1600s-1850''' [https://www.worldcat.org/title/barbour-collection-of-connecticut-town-vital-records/oclc/746977528&referer=brief_results The Barbour Collection of Connecticut Town Vital Records] ''This collection of bound typescripts is available at the listed libraries;'' ''some towns may be missing''
*'''1600s-1850''' [https://www.worldcat.org/title/barbour-collection-of-connecticut-town-vital-records/oclc/746977528&referer=brief_results The Barbour Collection of Connecticut Town Vital Records] ''This collection of bound typescripts is available at the listed libraries;'' ''some towns may be missing''
−
*'''1600s-1870''' [https://www.ancestry.com/search/collections/1062/ Connecticut, U.S., Town Marriage Records, pre-1870 (Barbour Collection)] at Ancestry - index & images ,
($); ''some towns maybe missing'' +
*'''1600s-1870''' [https://www.ancestry.com/search/collections/1062/ Connecticut, U.S., Town Marriage Records, pre-1870 (Barbour Collection)] at Ancestry - index & images ($); ''some towns maybe missing''
− *'''1640-1955''' {{RecordSearch|2658554|Connecticut, Charles R. Hale Collection, Vital Records, 1640-1955}} at FamilySearch — index +
*'''1784-1944''' {{FSC|302493|title-id|disp=Records of Births, Marriages, and Deaths, 1784-1944}}(*); East Lyme Registrar of Vital Statistics at FamilySearch Library Catalog — images
*'''1784-1944''' {{FSC|302493|title-id|disp=Records of Births, Marriages, and Deaths, 1784-1944}}(*); East Lyme Registrar of Vital Statistics at FamilySearch Library Catalog — images
−
*'''1790-1833''' [https://www.americanancestors.org/search/databasesearch/1704/connecticut-marriages-and-deaths-1790-1833 Connecticut: Marriages and Deaths, 1790-1833] at American Ancestors — index & images ,
($) +
*'''1790-1833''' [https://www.americanancestors.org/search/databasesearch/1704/connecticut-marriages-and-deaths-1790-1833 Connecticut: Marriages and Deaths, 1790-1833] at American Ancestors — index & images ($)
−
*'''1897-1968 ''' [https://www.ancestry.com/search/collections/70865/ Web: Connecticut, U.S., Marriage Records, 1897-1968] at Ancestry - index ,
($); ''Also at: [https://www.ctatatelibrarydata.org/marriage-records/ Connecticut State Library]'' +
*'''1897-1968 ''' [https://www.ancestry.com/search/collections/70865/ Web: Connecticut, U.S., Marriage Records, 1897-1968] at Ancestry - index ($); ''Also at: [https://www.ctatatelibrarydata.org/marriage-records/ Connecticut State Library]''
−
*'''1959-2012 ''' [https://www.ancestry.com/search/collections/7158/ Connecticut, U.S., Marriage Index, 1959-2012] at Ancestry - index ,
($) +
*'''1959-2012 ''' [https://www.ancestry.com/search/collections/7158/ Connecticut, U.S., Marriage Index, 1959-2012] at Ancestry - index ($)
====Deaths====
====Deaths====
*'''1600s-1850''' {{FSC|295370|item|disp=Barbour Collection: Connecticut Vital Records Prior to 1850}}(*) at FamilySearch Catalog - index and images; ''some towns maybe missing''
*'''1600s-1850''' {{FSC|295370|item|disp=Barbour Collection: Connecticut Vital Records Prior to 1850}}(*) at FamilySearch Catalog - index and images; ''some towns maybe missing''
*'''1600s-1850''' [https://www.worldcat.org/title/barbour-collection-of-connecticut-town-vital-records/oclc/746977528&referer=brief_results The Barbour Collection of Connecticut Town Vital Records] ''This collection of bound typescripts is available at the listed libraries;'' ''some towns may be missing''
*'''1600s-1850''' [https://www.worldcat.org/title/barbour-collection-of-connecticut-town-vital-records/oclc/746977528&referer=brief_results The Barbour Collection of Connecticut Town Vital Records] ''This collection of bound typescripts is available at the listed libraries;'' ''some towns may be missing''
−
*'''1600s-1870''' [https://www.ancestry.com/search/collections/1063/ Connecticut, U.S., Town Death Records, pre-1870 (Barbour Collection)] at Ancestry - index & images ,
($); ''some towns maybe missing'' +
*'''1600s-1870''' [https://www.ancestry.com/search/collections/1063/ Connecticut, U.S., Town Death Records, pre-1870 (Barbour Collection)] at Ancestry - index & images ($); ''some towns maybe missing''
*'''1640-1955''' {{RecordSearch|2448941|Connecticut, Deaths, 1640-1955}} — index
*'''1640-1955''' {{RecordSearch|2448941|Connecticut, Deaths, 1640-1955}} — index
− *'''1640-1955''' {{RecordSearch|2658554|Connecticut, Charles R. Hale Collection, Vital Records, 1640-1955}} at FamilySearch — index +
−
*'''1650-1934 ''' [https://www.ancestry.com/search/collections/2557/ Connecticut, U.S., Deaths and Burials Index, 1650-1934] at Ancestry - index ,
($) +
*'''1650-1934 ''' [https://www.ancestry.com/search/collections/2557/ Connecticut, U.S., Deaths and Burials Index, 1650-1934] at Ancestry - index ($)
*'''1784-1944''' {{FSC|302493|title-id|disp=Records of Births, Marriages, and Deaths, 1784-1944}}(*); East Lyme Registrar of Vital Statistics at FamilySearch Library Catalog — images
*'''1784-1944''' {{FSC|302493|title-id|disp=Records of Births, Marriages, and Deaths, 1784-1944}}(*); East Lyme Registrar of Vital Statistics at FamilySearch Library Catalog — images
−
*'''1790-1833''' [https://www.americanancestors.org/search/databasesearch/1704/connecticut-marriages-and-deaths-1790-1833 Connecticut: Marriages and Deaths, 1790-1833] at American Ancestors — index & images ,
($) +
*'''1790-1833''' [https://www.americanancestors.org/search/databasesearch/1704/connecticut-marriages-and-deaths-1790-1833 Connecticut: Marriages and Deaths, 1790-1833] at American Ancestors — index & images ($)
−
*'''1897-1968 ''' [https://www.ancestry.com/search/collections/70866/ Web: Connecticut, U.S., Death Records, 1897-1968] at Ancestry - index ,
($); ''Also at: [https://www.ctatatelibrarydata.org/death-records/ Connecticut State Library]'' +
*'''1897-1968 ''' [https://www.ancestry.com/search/collections/70866/ Web: Connecticut, U.S., Death Records, 1897-1968] at Ancestry - index ($); ''Also at: [https://www.ctatatelibrarydata.org/death-records/ Connecticut State Library]''
−
*'''1949-2012 ''' [https://www.ancestry.com/search/collections/4124/ Connecticut Death Index, 1949-2012] at Ancestry - index ,
($) +
*'''1949-2012 ''' [https://www.ancestry.com/search/collections/4124/ Connecticut Death Index, 1949-2012] at Ancestry - index ($)
====Divorce====
====Divorce====
−
*'''1968-1997 ''' [https://www.ancestry.com/search/collections/1706/ Connecticut, U.S., Divorce Index, 1968-1997] at Ancestry - index ,
($) +
*'''1968-1997 ''' [https://www.ancestry.com/search/collections/1706/ Connecticut, U.S., Divorce Index, 1968-1997] at Ancestry - index ($)
===Town Reports===
===Town Reports===
Line 68: Line 68:
===Cemeteries===
===Cemeteries===
+ *'''1640-1955''' {{RecordSearch|2658554|Connecticut, Charles R. Hale Collection, Vital Records, 1640-1955}} at FamilySearch — [[Connecticut, Charles R. Hale Collection, Vital Records - FamilySearch Historical Records|How to Use this Collection]]; index to burial records and obituaries
*[https://www.findagrave.com/cemetery/search?cemetery-name=&cemetery-loc=East+Lyme%2C+New+London+County%2C+Connecticut%2C+United+States+of+America&only-with-cemeteries=cemOnly&locationId=city_405449 East Lyme Cemeteries List] at FindAGrave
*[https://www.findagrave.com/cemetery/search?cemetery-name=&cemetery-loc=East+Lyme%2C+New+London+County%2C+Connecticut%2C+United+States+of+America&only-with-cemeteries=cemOnly&locationId=city_405449 East Lyme Cemeteries List] at FindAGrave
*{{FSC|769112|subject-id|disp= East Lyme Cemeteries}} at FamilySearch Catalog
*{{FSC|769112|subject-id|disp= East Lyme Cemeteries}} at FamilySearch Catalog
Line 80: Line 81:
To see the churches in East Lyme, visit. [https://www.familysearch.org/research/places/?reqParents=3779569&reqParentsLabel=East%20Lyme%2C%20New%20London%2C%20Connecticut%2C%20United%20States&reqParentsType=378&reqTypeGroups=3&reqTypeLabel=Churches%20and%20Church%20Parishes FamilySearch Places]<br><br>
To see the churches in East Lyme, visit. [https://www.familysearch.org/research/places/?reqParents=3779569&reqParentsLabel=East%20Lyme%2C%20New%20London%2C%20Connecticut%2C%20United%20States&reqParentsType=378&reqTypeGroups=3&reqTypeLabel=Churches%20and%20Church%20Parishes FamilySearch Places]<br><br>
Many Connecticut churches have deposited their records at the [[Connecticut State Library|Connecticut State Library]]. The following are church records available online for the town of East Lyme:<br><br>
Many Connecticut churches have deposited their records at the [[Connecticut State Library|Connecticut State Library]]. The following are church records available online for the town of East Lyme:<br><br>
−
*'''1630-1920''' [https://www.ancestry.com/search/collections/3032/ Connecticut, U.S., Church Record Abstracts, 1630-1920] at Ancestry - index & images ,
($) +
*'''1630-1920''' [https://www.ancestry.com/search/collections/3032/ Connecticut, U.S., Church Record Abstracts, 1630-1920] at Ancestry - index & images ($)
*'''1660-1955''' {{RecordSearch|2658799|Connecticut, Church Records, 1660-1955}} at FamilySearch; index — [[Connecticut Church Records - FamilySearch Historical Records|How to Use this Collection]]
*'''1660-1955''' {{RecordSearch|2658799|Connecticut, Church Records, 1660-1955}} at FamilySearch; index — [[Connecticut Church Records - FamilySearch Historical Records|How to Use this Collection]]
*[[Connecticut Church Records|Connecticut Church Records]]
*[[Connecticut Church Records|Connecticut Church Records]]
Line 86: Line 87:
===City Directories===
===City Directories===
−
*'''1898-1902''' [https://www.ancestry.com/search/collections/8777/ STATE, U.S., City Directories, East Lyme] at Ancestry - index & images ,
($), ''some years may be missing'' +
*'''1898-1902''' [https://www.ancestry.com/search/collections/8777/ STATE, U.S., City Directories, East Lyme] at Ancestry - index & images ($), ''some years may be missing''
−
*'''Various Dates''' [https://www.myheritage.com/research/collection-10705/us-city-directories U.S. City Directories, 1860-1960] at MyHeritage - index & images ,
($) ''some towns and years may be missing'' +
*'''Various Dates''' [https://www.myheritage.com/research/collection-10705/us-city-directories U.S. City Directories, 1860-1960] at MyHeritage - index & images ($) ''some towns and years may be missing''
===Compiled Genealogies===
===Compiled Genealogies===
===Court Records===
===Court Records===
*'''1636-1945''' {{FSC|3744705|item|disp=Records of the Judicial Department (Part A): Court Records in the Connecticut State Library, 1636-1945}}(*) Connecticut State Library at FamilySearch Catalog - images only
*'''1636-1945''' {{FSC|3744705|item|disp=Records of the Judicial Department (Part A): Court Records in the Connecticut State Library, 1636-1945}}(*) Connecticut State Library at FamilySearch Catalog - images only
−
*[https://www.jud.ct.gov/ State of Connecticut Judicial Branch-Media-How to Obtain Court Records] at jud.ct.gov ,
($) +
*[https://www.jud.ct.gov/ State of Connecticut Judicial Branch-Media-How to Obtain Court Records] at jud.ct.gov ($)
*[[Connecticut Court Records|Connecticut Court Records]] at FamilySearch Research Wiki
*[[Connecticut Court Records|Connecticut Court Records]] at FamilySearch Research Wiki
Line 134: Line 135:
*[[Connecticut_Military_Records#Online_Resources|Connecticut Military Records - World War II, 1941-1945]]
*[[Connecticut_Military_Records#Online_Resources|Connecticut Military Records - World War II, 1941-1945]]
*[[World War II United States Military Records, 1941 to 1945|United States Military Records - World War II, 1941-1945]]
*[[World War II United States Military Records, 1941 to 1945|United States Military Records - World War II, 1941-1945]]
+
+ ===Naturalization and Citizenship===
+ *''For more databases, see [[Connecticut Naturalization and Citizenship|Connecticut Naturalization and Citizenship]] and [[United States Naturalization and Citizenship Online Genealogy Records|U.S. Naturalization Online Genealogy Records]]''
+ *'''1791-1906''' [https://www.myheritage.com/research/collection-10694/us-naturalization-records-new-england-1791-1906 US Naturalization Records, New England, 1791-1906] at MyHeritage - index & images ($)
+ *'''1793-1975''' {{RecordSearch|3238391|Connecticut Naturalization Records, 1795-1942}} New London Court of Common Pleas, City Court, and Superior Court at FamilySearch — [[Connecticut Naturalization Records - FamilySearch Historical Records|How to Use this Collection]]; [[Connecticut Naturalization Records, Coverage Table - FamilySearch Historical Records|List of Records Included in Collection]]; index and images
+ *'''1893-1906''' [http://search.ancestry.com/search/db.aspx?dbid=61195 Connecticut, Federal Naturalization Records, 1790-1996] Connecticut Circuit Court at Ancestry; index & images ($)
+ *'''1893-1911''' {{RecordSearch|3238391|Connecticut Naturalization Records, 1795-1942}} U.S. Circuit Court at FamilySearch — [[Connecticut Naturalization Records - FamilySearch Historical Records|How to Use this Collection]]; index and images
+ *'''1910-1975''' [http://search.ancestry.com/search/db.aspx?dbid=61195 Connecticut, Federal Naturalization Records, 1790-1996] New London County Superior Court at Ancestry; index & images ($)
===Newspapers===
===Newspapers===
Line 142: Line 151:
===Obituaries===
===Obituaries===
−
*'''1629-1934''' [https://www.ancestry.com/search/collections/2900/ Connecticut, U.S., Hale Collection of Cemetery Inscriptions and Newspaper Notices, 1629-1934] at Ancestry - index & images ,
($) +
*'''1629-1934''' [https://www.ancestry.com/search/collections/2900/ Connecticut, U.S., Hale Collection of Cemetery Inscriptions and Newspaper Notices, 1629-1934] at Ancestry - index & images ($)
*'''1977-2014''' {{FSC|2452633|item|disp=Connecticut Obituaries, 1977-2014}}(*) NewsBank (Naples, Florida) at FamilySearch Catalog - images only
*'''1977-2014''' {{FSC|2452633|item|disp=Connecticut Obituaries, 1977-2014}}(*) NewsBank (Naples, Florida) at FamilySearch Catalog - images only
*[[Connecticut Obituaries|Connecticut Obituaries]] at FamilySearch Research Wiki
*[[Connecticut Obituaries|Connecticut Obituaries]] at FamilySearch Research Wiki
Line 174: Line 183:
In the 1600s, probate records were kept by the Connecticut and New Haven Colonies. In 1666, the two colonies joined and formed four new probate districts and counties: Hartford, New London, New Haven, and Fairfield. More probate districts were formed by 1719.<ref>AmericanAncestors, "Database News: Enhanced Connecticut: Early Probate Records, 1635-1750" New England Historic Genealogic Society, at https://dbnews.americanancestors.org/2019/05/10/database-news-enhanced-connecticut-early-probate-records-1635-1750/ (accessed 11 August 2022); Manwaring, Charles William, 1829-1905 "A digest of the early Connecticut probate records, vol. 1 Introduction" FamilySearch Library, FamilySearch International, at https://www.familysearch.org/library/books/records/item/121817-redirection (accessed 11 August 2022).</ref><br>
In the 1600s, probate records were kept by the Connecticut and New Haven Colonies. In 1666, the two colonies joined and formed four new probate districts and counties: Hartford, New London, New Haven, and Fairfield. More probate districts were formed by 1719.<ref>AmericanAncestors, "Database News: Enhanced Connecticut: Early Probate Records, 1635-1750" New England Historic Genealogic Society, at https://dbnews.americanancestors.org/2019/05/10/database-news-enhanced-connecticut-early-probate-records-1635-1750/ (accessed 11 August 2022); Manwaring, Charles William, 1829-1905 "A digest of the early Connecticut probate records, vol. 1 Introduction" FamilySearch Library, FamilySearch International, at https://www.familysearch.org/library/books/records/item/121817-redirection (accessed 11 August 2022).</ref><br>
−
*'''1609-1999''' [https://www.ancestry.com/search/collections/9049/ Connecticut, U.S., Wills and Probate Records, 1609-1999] at Ancestry - index & images ,
($) +
*'''1609-1999''' [https://www.ancestry.com/search/collections/9049/ Connecticut, U.S., Wills and Probate Records, 1609-1999] at Ancestry - index & images ($)
−
*'''1635-1750''' [https://www.americanancestors.org/search/databasesearch/82/connecticut-early-probate-records-1635-1750 Connecticut: Early Probate Records, 1635-1750] at American Ancestors — index & images ,
($) +
*'''1635-1750''' [https://www.americanancestors.org/search/databasesearch/82/connecticut-early-probate-records-1635-1750 Connecticut: Early Probate Records, 1635-1750] at American Ancestors — index & images ($)
*'''1787-1880''' {{FSC|141959|item|disp=Probate Files Collection, Early to 1880}}(*) at FamilySearch Catalog - images only
*'''1787-1880''' {{FSC|141959|item|disp=Probate Files Collection, Early to 1880}}(*) at FamilySearch Catalog - images only
*'''1843-1924''' {{FSC|384256|title-id|disp=Probate records, 1843-1924}}(*) at FamilySearch Catalog — images
*'''1843-1924''' {{FSC|384256|title-id|disp=Probate records, 1843-1924}}(*) at FamilySearch Catalog — images
Line 181: Line 190:
*'''1881-1915''' {{FSC|606675|item|disp=Probate Estate Files, 1881-1915}}(*) at FamilySearch Catalog - images only
*'''1881-1915''' {{FSC|606675|item|disp=Probate Estate Files, 1881-1915}}(*) at FamilySearch Catalog - images only
*[[Connecticut Probate Records|Connecticut Probate Records]]
*[[Connecticut Probate Records|Connecticut Probate Records]]
+
+ ===School Records===
===Tax Records===
===Tax Records===
*'''1862-1866''' {{FSC|577864|item|disp=Internal Revenue Assessment Lists for Connecticut, 1862-1866}}(*) United States. Commissioner of Internal Revenue, United States. National Archives and Records Administration (Repository), at FamilySearch Catalog - images only
*'''1862-1866''' {{FSC|577864|item|disp=Internal Revenue Assessment Lists for Connecticut, 1862-1866}}(*) United States. Commissioner of Internal Revenue, United States. National Archives and Records Administration (Repository), at FamilySearch Catalog - images only
+ *'''1865-1874''' [http://search.ancestry.com/search/db.aspx?dbid=62397 Connecticut, U.S., Excise Tax Lists, 1865-1874] at Ancestry — index & images ($)
*'''1915-1926''' {{FSC|598656|item|disp=Estate Record Card Index, 1915-1926}}(*) Connecticut. Inheritance Tax Division at FamilySearch Catalog - images only
*'''1915-1926''' {{FSC|598656|item|disp=Estate Record Card Index, 1915-1926}}(*) Connecticut. Inheritance Tax Division at FamilySearch Catalog - images only
*[[Connecticut Taxation|Connecticut Taxation]] at FamilySearch Research Wiki
*[[Connecticut Taxation|Connecticut Taxation]] at FamilySearch Research Wiki
Latest revision as of 14:36, 11 May 2023
United States New England Connecticut New London East Lyme
Modern town borders of East Lyme in New London County, Connecticut.
Contents 1 Town Information 1.1 Description 1.2 Parent Towns 1.3 Populated Places 1.4 Adjacent Towns 2 Town Records 2.1 Vital Records 2.1.1 Births 2.1.2 Marriages 2.1.3 Deaths 2.1.4 Divorce 2.2 Town Reports 3 Resources 3.1 Biographies 3.2 Cemeteries 3.3 Census 3.4 Church Records 3.5 City Directories 3.6 Compiled Genealogies 3.7 Court Records 3.8 Land Records 3.9 Local Histories 3.10 Maps 3.11 Military 3.11.1 Revolutionary War, 1775-1783 3.11.2 Civil War, 1861-1865 3.11.3 World War I, 1917-1918 3.11.4 World War II, 1941-1945 3.12 Naturalization and Citizenship 3.13 Newspapers 3.14 Obituaries 3.15 Other Town Records 3.16 Probate Records 3.17 School Records 3.18 Tax Records 4 Research Facilities 4.1 Archives 4.2 Libraries 4.3 Museums 4.4 FamilySearch Centers & Affiliate Libraries 4.5 Societies 5 References
Town Information
Description
East Lyme, Connecticut
at Wikipedia
Parent Towns
1839 - Created from Lyme, Waterford
Populated Places
Includes Neighborhoods, Villages, Unincorporated Communities,
Districts, and Census-Designated Places:
Adjacent Towns
Town Records
In New England most original vital records of birth, marriage, and death can be found at the town clerk's office
East Lyme Town Clerk
108 Pennsylvania Ave
Niantic, CT 06357
Phone: 860-739-6931, ext 1135
E-mail: [email protected]
East Lyme Town Clerk
Vital Records
Births
1600s-1850 Barbour Collection: Connecticut Vital Records Prior to 1850 (*) at FamilySearch Catalog - index and images;
some towns maybe missing
1600s-1850 The Barbour Collection of Connecticut Town Vital Records
This collection of bound typescripts is available at the listed libraries;
some towns may be missing
1600s-1870 Connecticut, U.S., Town Birth Records, pre-1870 (Barbour Collection)
at Ancestry - index & images ($) ; some towns maybe missing
1639-1941 Connecticut, Births and Baptisms, 1639-1941 at FamilySearch — index
1784-1944 Records of Births, Marriages, and Deaths, 1784-1944 (*) ; East Lyme Registrar of Vital Statistics at FamilySearch Library Catalog — images
Marriages
1600s-1700s U.S., New England Marriages Prior to 1700 at Ancestry - index & images
($)
1600s-1850 Barbour Collection: Connecticut Vital Records Prior to 1850 (*) at FamilySearch Catalog - index and images;
some towns maybe missing
1600s-1850 The Barbour Collection of Connecticut Town Vital Records
This collection of bound typescripts is available at the listed libraries;
some towns may be missing
1600s-1870 Connecticut, U.S., Town Marriage Records, pre-1870 (Barbour Collection) at Ancestry - index & images ($) ;
some towns maybe missing
1784-1944 Records of Births, Marriages, and Deaths, 1784-1944 (*) ; East Lyme Registrar of Vital Statistics at FamilySearch Library Catalog — images
1790-1833 Connecticut: Marriages and Deaths, 1790-1833
at American Ancestors — index & images ($)
1897-1968 Web: Connecticut, U.S., Marriage Records, 1897-1968 at Ancestry - index ($) ;
Also at: Connecticut State Library
1959-2012 Connecticut, U.S., Marriage Index, 1959-2012 at Ancestry - index ($)
Deaths
1600s-1850 Barbour Collection: Connecticut Vital Records Prior to 1850 (*) at FamilySearch Catalog - index and images;
some towns maybe missing
1600s-1850 The Barbour Collection of Connecticut Town Vital Records
This collection of bound typescripts is available at the listed libraries;
some towns may be missing
1600s-1870 Connecticut, U.S., Town Death Records, pre-1870 (Barbour Collection)
at Ancestry - index & images ($) ; some towns maybe missing
1640-1955 Connecticut, Deaths, 1640-1955 — index
1650-1934 Connecticut, U.S., Deaths and Burials Index, 1650-1934 at Ancestry - index
($)
1784-1944 Records of Births, Marriages, and Deaths, 1784-1944 (*) ; East Lyme Registrar of Vital Statistics at FamilySearch Library Catalog — images
1790-1833 Connecticut: Marriages and Deaths, 1790-1833
at American Ancestors — index & images ($)
1897-1968 Web: Connecticut, U.S., Death Records, 1897-1968 at Ancestry - index ($) ;
Also at: Connecticut State Library
1949-2012 Connecticut Death Index, 1949-2012 at Ancestry - index ($)
Divorce
1968-1997 Connecticut, U.S., Divorce Index, 1968-1997 at Ancestry - index ($)
Town Reports
Resources
For more County and State resources see:
Biographies
A Catalogue of the Names of the Early Puritan Settlers of the Colony of Connecticut: With the Time of Their Arrival in the Country and Colony, Their Standing in Society, Place of Residence, Condition of Life, Where From, Business, etc., as Far as is Found on Record.
By Royal Ralph Hinman. Hartford, Connecticut: Case, Tiffany Co., 1852. Salt Lake City, Utah: Digitized by FamilySearch International, 2017. Online at: FamilySearch Digital Library .
Connecticut Historical Collections: Containing a General Collection of Interesting Facts, Traditions, Biographical Sketches, Anecdotes, etc., Relating to the History and Antiquities of Every Town in Connecticut, With Geographical Descriptions, Illustrated by 190 Engravings.
By John Warner Barber. 2nd ed. New Haven, Connecticut: Durrie & Peck and J.W. Barber, 1837. Online at: FamilySearch Digital Library .
Encyclopedia of Connecticut Biography, Genealogical-Memorial: Representative Citizens.
By Samuel Hart. Boston, Massachusetts: American Historical Society, 1917-1923. Online at: FamilySearch Digital Library, Vol. 1-8, 11, 13 .
Ye Names & Ages of All Ye Old Folks in Every Hamlet, City and Town in Ye State of Connecticut, Now Living: With Ye Sketches of Twenty Living Centenarians
Compiled by Frederick H. Nash. New Haven, Connecticut: Price, Lee & Co., 1884. San Francisco, California: Internet Archive, 2012. Online at:
FamilySearch Digital Library .
Who's Who in Connecticut By Ward E. Duffy. Tucson, Arizona: W.C. Cox & Co., 1975.
Online at: FamilySearch Digital Library .
Connecticut Biography at FamilySearch
Research Wiki
Cemeteries
1640-1955 Connecticut, Charles R. Hale Collection, Vital Records, 1640-1955
at FamilySearch — How to Use this Collection ; index to burial records and obituaries
East Lyme Cemeteries List at FindAGrave
East Lyme Cemeteries at FamilySearch
Catalog
New London County Cemeteries at FamilySearch Catalog
New London County at FamilySearch Places
Census
Connecticut Census at FamilySearch Research Wiki
Church Records
At its founding, Congregationalism was the dominant religion in Connecticut and was even the state religion until 1818. Other common Christian denominations include the Methodist, Episcopal, Roman Catholic, and Baptist churches.
To see the churches in East Lyme, visit.
FamilySearch Places
Many Connecticut churches have deposited their records at the Connecticut State Library
. The following are church records available online for the town of East Lyme:
1630-1920 Connecticut, U.S., Church Record Abstracts, 1630-1920
at Ancestry - index & images ($)
1660-1955 Connecticut, Church Records, 1660-1955 at FamilySearch ; index — How to Use this Collection
Connecticut Church Records
City Directories
1898-1902 STATE, U.S., City Directories, East Lyme at Ancestry - index & images ($) , some years may be missing
Various Dates U.S. City Directories, 1860-1960 at MyHeritage - index & images ($)
some towns and years may be missing
Compiled Genealogies
Court Records
1636-1945 Records of the Judicial Department (Part A): Court Records in the Connecticut State Library, 1636-1945 (*)
Connecticut State Library at FamilySearch
Catalog - images only
State of Connecticut Judicial Branch-Media-How to Obtain Court Records at jud.ct.gov
($)
Connecticut Court Records at FamilySearch
Research Wiki
Land Records
1640-1846 Colonial Land Records of Connecticut, 1640-1846: Including Patents, Deeds and Surveys of Land (*) at FamilySearch Catalog - images
Connecticut Land and Property
Local Histories
Maps
This selection incudes town, county, state, and historical maps
Boundary Map of East Lyme at HomeTownLocator
East Lyme, Connecticut Town Guides at CT State Library
East Lyme at FamilySearch Places
East Lyme at Google Maps
East Lyme at Mapcarta
McConnell's Historical Maps of the United States at Library of Congress
Old Maps of Connecticut at Old-Maps.com
Connecticut Maps State Page
Military
Some Records are Searchable by Town
Revolutionary War, 1775-1783
For more Revolutionary War Military Records see:
Connecticut Military Records - Revolutionary War, 1775-1783
United States Military Records - Revolutionary War, 1775-1783
Civil War, 1861-1865
For more Civil War Military Records see:
Connecticut Military Records - Civil War, 1861-1865
United States Military Records - Civil War, 1861-1865
World War I, 1917-1918
For more World War I Military Records see:
Connecticut Military Records - World War I, 1917-1918
United States Military Records - World War I, 1917-1918
World War II, 1941-1945
For more World War II Military Records see:
Connecticut Military Records - World War II, 1941-1945
United States Military Records - World War II, 1941-1945
Naturalization and Citizenship
For more databases, see Connecticut Naturalization and Citizenship and U.S. Naturalization Online Genealogy Records
1791-1906 US Naturalization Records, New England, 1791-1906
at MyHeritage - index & images ($)
1793-1975 Connecticut Naturalization Records, 1795-1942
New London Court of Common Pleas, City Court, and Superior Court
at FamilySearch — How to Use this Collection ;
List of Records Included in Collection ; index and images
1893-1906 Connecticut, Federal Naturalization Records, 1790-1996
Connecticut Circuit Court at Ancestry; index & images ($)
1893-1911 Connecticut Naturalization Records, 1795-1942 U.S. Circuit Court at FamilySearch — How to Use this Collection ; index and images
1910-1975 Connecticut, Federal Naturalization Records, 1790-1996
New London County Superior Court at Ancestry; index & images ($)
Newspapers
1700s Connecticut Newspapers in the Eighteenth Century (*) by Jarvis Means Morse, 1899 at FamilySearch Catalog - images only
List of Newspapers in Connecticut at Wikipedia
The Press of Connecticut - Newspapers at portal.ct.gov
Connecticut Newspapers at FamilySearch
Research Wiki
Obituaries
1629-1934 Connecticut, U.S., Hale Collection of Cemetery Inscriptions and Newspaper Notices, 1629-1934
at Ancestry - index & images ($)
1977-2014 Connecticut Obituaries, 1977-2014 (*) NewsBank (Naples, Florida) at FamilySearch Catalog - images only
Connecticut Obituaries at FamilySearch
Research Wiki
United States Obituaries at FamilySearch
Research Wiki
Other Town Records
Burials
Appointments
Earmarks
Estrays (stray animals)
Freemens' oaths (men eligible to vote)
Land records
Mortgages
Name changes
Care of the poor
School records
Surveys
Tax lists
Town meeting minutes
Voter registrations
Warning outs (of town)
Probate Records
In the 1600s, probate records were kept by the Connecticut and New Haven Colonies. In 1666, the two colonies joined and formed four new probate districts and counties: Hartford, New London, New Haven, and Fairfield. More probate districts were formed by 1719. [1]
1609-1999 Connecticut, U.S., Wills and Probate Records, 1609-1999
at Ancestry - index & images ($)
1635-1750 Connecticut: Early Probate Records, 1635-1750
at American Ancestors — index & images ($)
1787-1880 Probate Files Collection, Early to 1880 (*) at FamilySearch Catalog - images only
1843-1924 Probate records, 1843-1924 (*)
at FamilySearch Catalog — images
1859-1931 Probate Records, 1859-1931 (*)
at FamilySearch Catalog — images
1881-1915 Probate Estate Files, 1881-1915 (*) at FamilySearch Catalog - images only
Connecticut Probate Records
School Records
Tax Records
1862-1866 Internal Revenue Assessment Lists for Connecticut, 1862-1866 (*) United States. Commissioner of Internal Revenue, United States. National Archives and Records Administration (Repository), at FamilySearch
Catalog - images only
1865-1874 Connecticut, U.S., Excise Tax Lists, 1865-1874
at Ancestry — index & images ($)
1915-1926 Estate Record Card Index, 1915-1926 (*) Connecticut. Inheritance Tax Division at FamilySearch Catalog - images only
Connecticut Taxation at FamilySearch
Research Wiki
Research Facilities
Archives
Libraries
East Lyme Public Library
39 Society Road
Niantic, CT 06357
Phone: 860-739-6926
E-mail: [email protected]
Facebook
Website
Museums
FamilySearch Centers & Affiliate Libraries
FamilySearch Center and Affiliate Library Locator map
- search for local FamilySearch Centers or Affiliate Libraries
FamilySearch Centers provide one-on-one assistance, free access to center-only databases, and to premium genealogical websites.
FamilySearch Affiliate Libraries have access to most center-only databases, but may not always have full services normally provided by a FamilySearch center.
Local Centers and Affiliate Libraries
Groton Connecticut FamilySearch Center
Madison Connecticut FamilySearch Center
Acton Public Library - an affiliate library
Groton Public Library - an affiliate library
Otis Library of Norwich, Connecticut - an affiliate library
Waterford Public Library - Connecticut - an affiliate library
Societies
East Lyme Historical Society
228 West Main Street
P. O. Box 112
East Lyme, CT 06333
Phone: 860-739-6070
E-mail: [email protected]
Facebook
Website
References
↑ AmericanAncestors, "Database News: Enhanced Connecticut: Early Probate Records, 1635-1750" New England Historic Genealogic Society, at
https://dbnews.americanancestors.org/2019/05/10/database-news-enhanced-connecticut-early-probate-records-1635-1750/
(accessed 11 August 2022); Manwaring, Charles William, 1829-1905 "A digest of the early Connecticut probate records, vol. 1 Introduction" FamilySearch Library, FamilySearch International, at
https://www.familysearch.org/library/books/records/item/121817-redirection
(accessed 11 August 2022).
[ hide ] [ hide ] v • d • e Towns in New London County in Connecticut, United States Genealogy articles
Bozrah | Colchester | East Lyme |
Franklin | Griswold | Groton | Lebanon |
Ledyard | Lisbon | Lyme | Montville | New London | North Stonington | Norwich |
Old Lyme | Preston | Salem | Sprague |
Stonington | Voluntown | Waterford
Retrieved from " https://www.familysearch.org/en/wiki/index.php?title=East_Lyme,_New_London_County,_Connecticut_Genealogy&oldid=5322977
" | https://www.familysearch.org/en/wiki/index.php?diff=cur&oldid=5236981 |
(PDF) Impact of ADHD as a Risk and a Treatment Factor in Intimate Partner Violence
PDF | Intimate partner violence (IPV) has a very high prevalence (25%) in society and has serious consequences for its victims. As former studies showed... | Find, read and cite all the research you need on ResearchGate
Impact of ADHD as a Risk and a Treatment Factor in Intimate Partner Violence
September 2022
European Psychiatry 65(S1):S19-S19
DOI: 10.1192/j.eurpsy.2022.74
Abstract
Intimate partner violence (IPV) has a very high prevalence (25%) in society and has serious consequences for its victims. As former studies showed minimal effectiveness of therapeutic interventions addressing IPV, the Dutch guideline for Familial/Domestic Violence (NVVP, 2008) recommends to focus more on systemic factors and on individual risk factors of IPV. ADHD is one of these individual risk factors. This presentation focuses on the association between ADHD and IPV, presenting data and clinical examples. ADHD was missed in 56% of a sample of forensic outpatients. Reasons for this issue of underdiagnosis of ADHD in case of aggression and IPV are discussed. Also, data of the ITAP (impact of treatment of ADHD on IPV) study are presented, showing that ADHD in offenders of IPV with ADHD scored higher on minor physical aggression, minor and severe psychological aggression and clinician-rated IPV than offenders without ADHD. Further, after a one year treatment of ADHD and IPV, decrease in IPV was mainly associated with decrease in ADHD symptoms. The importance of screening and treatment of ADHD symptoms in all IPV offenders is discussed to make treatment of IPV more effective.
Disclosure
No significant relationships.
that several of the identified variants influence gene-expression
levels or participate in chromatin interactions in brain areas impli-
cated in affective disorders. In the next step these findings should be
investigated in patient samples, and in other models of affective
disorders and related phenotypes.
Disclosure: No significant relationships.
Keywords: affective disorders; Genetics; GWAS; affective
temperaments
Adult Patients With ADHD at the Interface of General
and Forensic Psychiatry
S0020
ADHD in Prisoners.
Y. Ginsberg
Karolinska Institutet, Department Of Clinical Neuroscience, Centre
For Psychiatry Research, Stockholm, Sweden
doi: 10.1192/j.eurpsy.2022.73
The risk rate of criminality is increased in ADHD, especially in
children who, in addition to ADHD, express externalizing behavior
of oppositional defiant disorder (ODD), later followed by conduct
disorder (CD), substance misuse and antisocial personality dis-
order (ASPD). Studies report ADHD to be about ten times more
common in prison populations than in the general adult popula-
tion. Prisoners with ADHD have compared to prisoners without
ADHD, an earlier onset of offending, higher rates of coexistent
psychiatric disorders, and are more often incarcerated due to
violent- and drug-related offences. Within prison settings, inmates
with ADHD are more often reported for intra-institutional aggres-
sion and they are often experienced as more difficult to manage and
costly to rehabilitate. Further, they relapse comparably more often
and faster into criminality after being conditionally released. Des-
pite high prevalence rates of ADHD within prisons and serious
consequences related to untreated ADHD, few controlled trials
have evaluated methylphenidate treatment in prisoners with
ADHD and coexistent disorders. Evidence and clinical experience
of pharmacological and psychosocial interventions of prison popu-
lations with ADHD will be presented briefly.
Disclosure: No significant relationships.
Keywords: adhd; Prison; Treatment; Prevalence
S0021
Impact of ADHD as a Risk and a Treatment Factor in
Intimate Partner Violence.
N. Buitelaar
De Forensische Zorgspecialisten, De Waag, Utrecht, Netherlands
doi: 10.1192/j.eurpsy.2022.74
Intimate partner violence (IPV) has a very high prevalence (25%) in
society and has serious consequences for its victims. As former
studies showed minimal effectiveness of therapeutic interventions
addressing IPV, the Dutch guideline for Familial/Domestic Vio-
lence (NVVP, 2008) recommends to focus more on systemic factors
and on individual risk factors of IPV. ADHD is one of these
individual risk factors. This presentation focuses on the association
between ADHD and IPV, presenting data and clinical examples.
ADHD was missed in 56% of a sample of forensic outpatients.
Reasons for this issue of underdiagnosis of ADHD in case of
aggression and IPV are discussed. Also, data of the ITAP (impact
of treatment of ADHD on IPV) study are presented, showing that
ADHD in offenders of IPV with ADHD scored higher on minor
physical aggression, minor and severe psychological aggression and
clinician-rated IPV than offenders without ADHD. Further, after a
one year treatment of ADHD and IPV, decrease in IPV was mainly
associated with decrease in ADHD symptoms. The importance of
screening and treatment of ADHD symptoms in all IPV offenders is
discussed to make treatment of IPV more effective.
Disclosure: No significant relationships.
Keywords: Intimate Partner Violence; adhd; Treatment;
Underdiagnosis
Novel Options to Treat Cognitive Dysfunction in
Schizophrenia?
S0022
Psychotherapy of Biases in Cognition in Schizophrenia:
the SlowMo Randomised Controlled Trial for Paranoia,
Outcomes and Mechanisms
P. Garety
1
* , T. Ward
1
, R. Emsley
2
, K. Greenwood
3
and A. Hardy
1
1
King ’ s College London, Psychology, London, United Kingdom;
2
King ’ s College London, Biostatistics, London, United Kingdom and
3
University of Sussex, Psychology, Brighton, United Kingdom
*Corresponding author.
doi: 10.1192/j.eurpsy.2022.75
Reasoning biases, specifically jumping to conclusions and belief
inflexibility, may play a causal role in persistent paranoia. SlowMo,
a new digitally supported blended cognitive-behavioural therapy,
targets these biases. Adopting the terms ‘ fast ’ and ‘ slow thinking ’ as
a heuristic to support therapy, SlowMo encourages people to notice
a tendency to fast thinking, and to slow down for a moment to
reduce paranoia. SlowMo therapy is the first digital blended therapy
for paranoia, employing face to face therapy sessions with inter-
active digital content, and using mobile technology to promote
generalisation to daily life. We report a randomised controlled trial
with N = 362 participants with distressing and persistent
(3 þ months) paranoia, comparing 8 sessions of SlowMo plus Treat-
ment as Usual (TAU) with TAU alone. We examined SlowMo ’ s
effectiveness in reducing paranoia and improving reasoning biases;
its mechanisms of action; usability; and acceptability (Garety et al.,
2021). Outcomes: SlowMo was beneficial for paranoia: 10 /11
paranoia measures at 12 weeks and 8/11 at 24 weeks demonstrated
significant effects, and sustained moderate effects were observed on
all observer-rated measures of persecutory delusions. Improve-
ments in self-esteem, worry, wellbeing and quality of life were also
reported. Mediation: Consistent with the theory-driven design and
treatment rationale, improvements in slower thinking were found
to mediate change in paranoia at 12- and 24-week follow-ups.
However contrary to hypothesis, reduced fast thinking did not
mediate change in paranoia, whereas worry did. These findings
highlight the potential therapeutic mechanisms of action of
SlowMo which which are discussed further. Garety P, Ward T,
European Psychiatry S19
https://doi.org/10.1192/j.eurpsy.2022.74 Published online by Cambridge University Press
Theresa Mignone
| https://www.researchgate.net/publication/363228847_Impact_of_ADHD_as_a_Risk_and_a_Treatment_Factor_in_Intimate_Partner_Violence |
Final report for FNE16-842 - SARE Grant Management System
Decreasing small ruminant exposure to parasites by reducing slug and snail populations through a sheep/duck grazing system
Final report for FNE16-842
FNE16-842 (project overview)
Project Type: Farmer
Funds awarded in 2016: $10,963.00
Projected End Date: 03/31/2019
Grant Recipient: Wellspring Forest Farm
Region: Northeast
State: New York
Project Leader:
Steve and Elizabeth Gabriel
Email
Wellspring Forest Farm LLC
Project Information
Summary:
This project aimed to explore the potential benefits of multi-species grazing of sheep with ducks in order to address the parasite Parelaphostrongylus tenuis(P. tenuis, a.k.a brain worm/deer worm). This parasite's normal host is deer and then slugs/snails pick up infective vectors from deer manure and become intermediary hosts before affecting sheep or goats that eat the snails/slugs or slime on the litter. Since sheep and goats are not normal hosts, infection often leads to paralysis and death of the affected sheep or goat. In the past, we’ve demonstrated that ducks can reduce slug populations that are a pest to shiitake mushroom production (Project FNE12-745).
In order to monitor slug populations in 2017, we distributed traps made from soda bottles in 10 locations in each paddock, roughly 50 feet apart. We filled the trap with about 1 – 2″ of fresh beer. We monitored traps twice each week in 2017 ad 2018, counting slugs captured and also emptying and refilling with fresh beer, an important practice to ensure the traps would continue to attract slugs. A basic count of the total slugs was taken per paddock and recorded. We tracked these figures from June 19 through October 13 a total of about 17 weeks of study. We also looked at variables including precipitation and grass height. We were able to acheive some notable affect of grazing ducks on slug populations.
In summary, we can suggest a few important points and lessons learned that we think other farmers can benefit from:
Slug population dynamics are highly variable, and cannot be predicted using the month of the year, precipitation, or height of grass in a paddock. They rise and fall throughout the season dramatically.
In springtime and early summer, slug populations may be significantly higher than during the rest of the growing season, which potentially increases grazing ruminant exposure. Avoid the wettest grazing sites in early spring. Consider this as a place to target with ducks if it’s easy to do without extra effort.
Monitoring for slug population dynamics is difficult, and not a feasible task for most farms to undertake in a way that will provide clear directives for action.
Ducks DO reduce slug populations – but likely not for long periods of time.
A holistic approach to reducing parasite impacts on grazing animals suggests that ducks could play a role in slug control, but are not a reliable method to replace breeding for resistance, including high tannin forages in an animals diet, and other methods.
We have concluded that while some short-term impact/benefit can occur on slug populations from duck grazing activity, it may not be enough to justify the labor and time to monitor populations, coordinate moving them into the right place at the right time, all with special effort just to realize a benefit on reducing parasites.
In other words, if you are in a situation where you have ducks and are rotating them, you might receive some secondary benefits of running them through pasture, but its not worth going out of your way. This conclusion is not due to the fact that ducks aren’t inherently effective at reducing slug populations. It’s more about the challenges of varying dynamics, timing, and labor that make the prospect challenging.
Project Objectives:
Our goals for the project were to:
Objective 1: Determine if grazing 50 ducks reduces gastropod populations in half acre paddocks
Objective 2: Reduce brain worm parasite risk to grazing ruminants, thereby reducing the need for Ivomec, dexamethasone, and Safeguard
Objective 3: Determine ideal timing of leader-follower rotation that results in low gastropod population, minimal duck poop presence on pasture, and diverse and abundant forage
Introduction:
Wellspring Forest Farm is a 50-acre agroforestry inspired farm and homestead. The farm is co-owned and operated by Elizabeth and Steve Gabriel and we’ve been growing crops since 2011. We develop our operations systematically, analyzing resources and challenges of the site, our economic capacity, time, personal interest and market demands. We value that agroforestry offers opportunities for restoring the ecological health of the land while providing income for the farm.
Our main crop is mushrooms, which we sell to restaurants and through a CSA. We maintain a flock of 50 ducks that provide slug control to the shiitakes and nutrients to our gardens. We originally brought ducks onto the farm as a meat enterprise but determined that eggs would fit better with our goals long term. We sell eggs to local retail stores and restaurants. Since 2012, we have planted trees to eventually provide wind protection, fodder, shade and wood for our grazing sheep.
Sheep complemented the operation because our pasture is in need of regeneration and sheep are much more sustainable than mowing between the rows of tree crops. We expect to have around 28 sheep in 2016 and have a goal of managing about 20 ewes and 30 lambs each year from 2018 onward. Adding ducks to the sheep rotation, we hope further improve soil health, reduce sheep exposure to parasites and increase farm production.
This proposal focuses on Parelaphostrongylus tenuis(P. tenuis, a.k.a brain worm/deer worm). This parasite is on the rise and is especially problematic because there is no effective treatment plan with a strong likelihood of full recovery.
P. tenuis larvae are excreted in deer feces, common grazers of pasture. Larvae infect gastropods, which are consumed by ruminants. Just one larva in a sheep’s spinal cord can cause illness. The life cycle of land snails or slugs is mostly sexual reproducion followed by egg laying. The eggs take about one month to develop to an adult and the adults can live more than one year, hibernating in the witner. There is no method for monitoring P. tenuis – producers can only act once an animal shows clinical signs of infection. Anthelmintics and corticosteroids (Ivomec, dexamethasone, Safeguard) can treat the parasite, but have varying effectiveness and don’t meet organic standards. Despite treatment, some animals die or become permanently lame. Rarely is there full recovery. There is no way to predict the outcome.
This project built off our previous research (FNE12-745) where we determined best practices for utilizing ducks to control slugs in our log-grown shiitake enterprise. We are mostly interested in having ducks on the farm for this pest control benefit, but have also found a modest income from egg sales. Our success with ducks in the mushroom enterprise and anecdotally in our gardens and orchard systems has led us to see their benefit to many systems. Moving them into the sheep rotation may be beneficial, but there is likely an issue with getting the proper timing down to have efficacy. Our main question; is it worth rotating the ducks in sheep paddocks to reduce the slug population and thereby reducing our sheep flock's exposure to parasites?
The focus of this project sought to draw out the potential benefits of having animals on a landscape that, while not turning a huge profit, contribute to supporting the profitability of other more lucrative enterprises. In this case, our log-grown shiitake and pastured sheep enterprises are the most profitable systems on the farm, while ducks are a harder prospect from a profit standpoint. The cost of production for eggs, along with consumers expecting eggs to be cheap, means that there are very thin margins in egg production. Our goal has been to sell eggs in order to cover the cost of raising the ducks - from an inputs and labor standpoint. We could therefore benefit from the ecosystems services the ducks provide, produce our own eggs for consumption, and not have to pay for it.
To us, this is an important aspect of modern US farms. In recent times, the focus for farm production has been almost exclusively for market production, which means certain systems get left out of the business, whether they provide benefits or not. It wasn't so long ago that most family farms in the US balanced production for home, family, and community at a small scale with an additional selection of "cash crops" to provide money to the farm. We have found high value in mixing systems that produce goods at a smaller scale and fit well as a complement to those we focus more on a cash return. The ducks, our orchards, and vegetable production all fit into this "homestead" category, while we produce mushrooms, pastured lamb, maple syrup, and elderberry more for commercial markets.
Cooperators
Brett Chedzoy
[email protected]
Technical Advisor
Cornell Cooperative Extension Schuyler County (1862 Land Grant)
323 Owego St # 5 Montour Falls, NY 14865
(607) 742-3657 (office)
Research
Materials and methods:
Due to the historic D3 drought in our region during the 2016 grazing season, we opted to delay the start of monitoring slug populations to the 2017 and 2018 seasons. Our past experience meant we knew the work would produce less than valuable results, because slug populations are virtually non-existent during dry times. Additionally, the drought conditions meant that pasture did not grow after the sheep’s first rotation in May. We spent 2016 reorganizing our grazing system to accommodate drought and make use of hedgerows, which will help tremendously as we set out to collect data over the next two seasons.
We realized as we planned for the 2017 season that starting to rotate ducks into paddocks would not be useful without first establishing baseline data for each paddock, since it cannot be assumed that slug populations are the same for each location, nor do they stay consistent with the seasonal changes in weather patterns.
If we started integrating ducks right away, we might observe differences in control vs. treatment paddocks that we would attribute to duck activity, when the variability may in fact be due to other factors. The main factors we believe affect the presence of slugs in paddocks include 1) recent weather, especially precipitation, 2) length of the grass, 3) previous impacts on slug populations
Therefore, we decided that in 2017 we would collect slug population data and track our sheep grazing, as we might normally do. We could then look and see if there are any trends in slug populations, any differences among paddocks, and any correlation with weather events.
Figure 1.1: Map of Trap Sites
In order to monitor slug populations in 2017, we distributed traps made from soda bottles(see figure 1.1)in 10 locations in each paddock, roughly 50 feet apart. Each trap was sunk into the ground using a bulb digging tool and set so that the opening of the trap sits at ground level. We filled the trap with about 1 - 2" of fresh beer. The map(see figure 1.2)of these trap shows we aimed for a relatively even distribution of traps, though there is some variability in the shape of the paddock. We selected the paddocks in the wettest locations closest to the woods edge, as we assume these are more likely to have slugs (intermediate host) and also deer visiting the pasture, who are the origin host for the parasite in question.
Figure 1.2: Slug Trap
We monitored traps twice each week in 2017 ad 2018, counting slugs captured and also emptying and refilling with fresh beer, an important practice to ensure the traps would continue to attract slugs. A basic count of the total slugs was taken per paddock and recorded. We tracked these figures from June 19 through October 13 a total of about 17 weeks of study.
Big thanks to Jonathan, Shaun, Claire, Cat, Carly, and Chad, our on-farm helpers in 2017 and 2018, who were awesome and stayed positive even while counting slugs!
Research results and discussion:
As the graph below shows for the year 2017, results of the data collected indicate there will be some consistency to the pattern of slug presence among the collection of paddocks selected for this study. This is useful as we attempt to add ducks to 3 of the paddocks in 2018, to see if we can affect populations. If successful, those paddocks would hopefully deviate from the overall trends.
When comparing this graph to local precipitation data for the same timeframe, there is not a clear correlation between anything happening with precipitation and a "response" from slug populations:
We were ready to proceed to the treatment portion of the research in 2018, and will better track grazing in the paddocks, as well as grass height, as we are curious if this has any effect on slug presence. We will accomplish this by measuring the average height as we take slug counts. Our theory is that less grass = more drying out, which could have an effect.
2018 Results
For the second year, the goal was to track the changing dynamics of slug populations in the same paddocks, as well as attempt to implement the "treatments" - that is, a roughly week long residency of the ducks in 3 our of the 6 paddocks, to see if there was any impact they offered to reduce slug populations. While as previously mentioned we delayed the start of this projects in 2016 because of historic drought, 2018 was notably wet, after a normal/dry May and June. The months of July, August, and September each were 2 - 3 inches more rainfall than normal (almost double the amount) and for the year we are 10 - 15 inches over normal rainfall. This is important to mention from the outset, as the rain likely affected our data, since excessive rainfall was found to flood the traps on several occasions, which dilutes the beer and effectively suppresses the yeasts that attract the slugs.
That said, our overall slug counts were reasonably aligned with those of 2017, at least in terms of showing the high variability and change that naturally occurs in slug populations, as shown in the graph of counts for the 2018 season:
GRAPH: SLUG COUNT ALL PLOTS 2018 SEASON
There are two notable patterns when comparing both years that are useful. One is that in both seasons, the highest slug counts were in the spring, though we started counting in late June in 2017, and mid May in 2018. Regardless, in both seasons, the relatively high counts dropped below 100 per paddock by early July, and never returned to the spring and early summertime high points.
The other relevant pattern is that... there isn't really a consistent pattern. Rates are not consistent or constant, but rather ebb and flow. As noted in 2017, rainfall wasn't a reliable indicator of these dynamics, and in 2018 we looked at grass height, where we also found that the height of the grass didn't prove to be a helpful indicator of slug levels, either, as noted from a few sample paddock data sets. For some paddocks, we even intentionally let the grass grow very high (see paddock 3) to see if there was any effect - and there was no clear correlation.
GRAPHS: SLUG COUNT VS GRASS HEIGHT IN TREATMENT (WITH DUCKS) PADDOCKS (PLOTS) 1 AND 3.
While we had hoped to do two visits of the ducks to each of the three treatment paddocks (for six total treatments), because of the heavy rainfall and persistently wet soils, we were only able to do one set (three treatments). Our duck house, small tractor, slopes, and mucky soils led to many issues early in the season.
Before doing a treatment, we were also looking for a data set with a good high number of slugs in each paddock, because we figured if one or two paddocks had a low reading, it would be hard to see any dramatic effect the ducks might have. In retrospect, we missed our best window of opportunity in May, when counts were very high. We then had a lot of variability in June through mid July, and finally decided to just give it a try when we took our 7/24/18 readings and saw some reasonably high numbers of slug counts across the board (in light orange below):
Table: SLUG COUNTS ALL PADDOCKS IN 2018
The yellow blocks indicate samples that took place during the residency of the ducks in one of the treatment paddocks (1, 3, or 4). Each paddock was randomly selected from the entire sample group as the treatment areas. We attempted to sample as consistently as possible on a weekly basis, sometimes taking an additional sampling point during the season because of the rain affecting the viability of the slug traps. Perhaps the biggest takeaway from this project is how hard it is to track slug population dynamics, given all the variables at play.
During the treatment weeks, our ducks were brought in and kept in the space for approximately one week. If we zoom into this period of time and compare the results between the control paddocks and the treatment, one interesting pattern emerged:
Graph: SLUG COUNTS Untreated Paddocks: Plots 2, 5, 6 NO DUCKS
While the plots above show the characteristic rise and fall we see as a large pattern, the treatment paddocks had a noticeable flatlining of the counts during the residency period, though for widely differing durations. The flat line persisted in paddock 1 for seven days, versus ten days in paddock 3, and just four days in paddock 4. The arrows indicate how long the ducks were in each paddock:
Graph: SLUG COUNTS Treatment Paddocks: Plots 1, 3, 4 WITH DUCKS
Notable also is that in all cases, slug levels were already in decline for each treatment before the ducks arrived. But when we compare to the larger picture of all paddocks, we do see some indication of effect. With the first treatment (blue), all other paddocks rose, while paddock 1 stayed flat for a longer period. For the second treatment (gray), all other paddocks were on a sharp upward trend, while paddock 3 remained low. For the third treatment (yellow), all paddocks were on the decline, but started to rise again, whereas paddock 4 lagged a bit further behind:
Graph: SLUG COUNTS ALL PADDOCKS. PLOTS 1,3,4 DUCKS; PLOTS 2,5,6 NO DUCKS
Important to note is that while some effect was seen above from duck activity, it was not particularly long lasting. In all three cases, in just a few days after the ducks left the paddock, the slug numbers generally rejoined the overall pattern of population dynamics across all of the paddocks.
Since the pastures also clearly needed some rest and recovery time post-duck before sheep could graze, this approach doesn't seem to be particularity effective when taking in the larger context of our goal, which was to reduce exposure of our sheep to parasites. We found that a paddock needed 7 - 10 days of rest before the pasture was just grazeable, and thus by the time the sheep arrived there would be little benefit of any substantial reduction in slugs.
Given this result, and the amount of labor it took to monitor slug population dynamics, and the high variability within the 10 traps in each paddock, there is a larger question about the practicality of this on a farmer level.
Even if we could replicate this trial and get better results, could farmers easily decide if and when to put ducks into a rotation in a way that might offer clear benefits to their grazing animals? Since weather, precipitation, grass height, and overall slug population dynamics act independently of each other, there seems to be little benefit in attempting to utilize ducks in this way. Knowing there IS benefit to the presence of ducks, however, is useful. We just don't see a way to plan or control the affect in a way that is time effective.
Its notable that in two seasons, the population of slugs were significantly higher in the spring and early summer months. Also important is that for both seasons, the really high numbers were in paddocks 1, 2, and 3, which are situated lower in our landscape, border a creek, and often have wetter soils that take longer to dry out. Paddocks 4, 5, and 6 were higher in the landscape and dried out sooner. As an aside, we had two sheep contract P tenuis during the grant duration but we can in now way correlate those incidents to the presence or absence of ducks.
So, there may be benefit of putting ducks through the pasture in early Spring to reduce the overall slug populations, which could reduce their ability to reproduce. This is the general approach we concluded from our last grant, where we more effectively utilized ducks to control slugs in our woodland shiitake mushroom operation (https://projects.sare.org/sare_project/fne12-745/). The major difference is that its easy visually to see the effect of ducks clearing out slugs on our mushroom crop, but harder to measure the efficacy in pasture, since its literally harder to see the slugs, as well as monitor any effects on the "crop"- i.e. if the sheep are ingesting them (versus the slug damage visible with the mushrooms).
Research conclusions:
We have concluded that while some short term impact/benefit can occur on slug populations from duck grazing activity, it may not be enough to justify the labor and time to monitor populations, coordinate moving them into the right place at the right time, all with special effort just to realize a benefit on reducing parasites.In other words, if you are in a situation where you have ducks and are rotating them, you might receive some secondary benefits of running them through pasture, but its not worth going out of your way. This conclusion is not due to the fact that ducks aren't inherently effective at reducing slug populations. It's more about the challenges of varying dynamics, timing, and labor that make the prospect challenging.
This funding demonstrates the reality of trying to solve an on farm problem by managing a complex ecological dynamic. At the end of the day, this idea would just be one more way to reduce parasite impact on our grazing sheep, along with breeding and selection practices to favor resistance, and the inclusion of high-tannin forages in their diet to reduce the effects of parasite build up. We are proceeding in this multi-faceted approach, and will target duck activity in our wettest pastures, and especially in early spring time.
To revisit our original objectives one and two, we sought to assess if ducks could reduce slug populations meaningfully in a rotational grazing system. We found that, while we can potentially reduce a population in a given paddock, the effect is not one that lasts, and is therefore impractical as a meaningful activity to attempt.
As with any research project, more years and subsequent trials could further improve on the methods and attempt more treatments, which could offer better results. Its very time consuming to measure and refill traps on a more than weekly basis; and it was impossible to do every 2 - 3 days as would be ideal, given that the beer wears out.
Should we have found that ducks were effective, objective three was then to figure out a feasible leader-follower rotation for ducks and sheep. Since the duration of any effect is so short, this objective was not able to be met, since we'd need a longer recovery of the forages before getting the sheep on them, when slug populations would potentially be back to more "normal" levels.
In summary, we can suggest a few important points and lessons learned that we think other farmers can benefit from:
Slug population dynamics are highly variable, and cannot be predicted using the month of the year, precipitation, or height of grass in a paddock. They rise and fall throughout the season dramatically.
In springtime and early summer, slug populations may be significantly higher than during the rest of the growing season, which potentially increases grazing ruminant exposure. Avoid the wettest grazing sites in early spring. Consider this as a place to target with ducks if it's easy to do without extra effort.
Monitoring for slug population dynamics is difficult, and not a feasible task for most farms to undertake in a way that will provide clear directives for action.
Ducks DO reduce slug populations - but likely not for long periods of time.
A holistic approach to reducing parasite impacts on grazing animals suggests that ducks could play a role in slug control, but are not a reliable method to replace breeding for resistance, including high tannin forages in an animals diet, and other methods.
Participation Summary
1 Farmers participating in research
Education & Outreach Activities and Participation Summary
1 Curricula, factsheets or educational tools
2 Online trainings
4 Tours
4 Webinars / talks / presentations
3 Workshop field days
Participation Summary:
50 Farmers participated
20 Number of agricultural educator or service providers reached through education and outreach activities
Education/outreach description:
TOURS:
Permaculture Site Tours in August (2016, 2017, 2018) with average of 75 visitors per year.
CCE Tompkins Farm Days (July 2017) with 25 visitors.
For the Love of Duck!talk at NOFA-NY Conference, January 2017 with 30 participants.Ducks_NOFANY2017
Growing a Woodland Farm and HomesteadThree day Workshop (June 2017 and 2018) with 15 and 20 participants, respectively.
Silvopasture in PracticeThree Day Workshop, October 2018 with 22 participants.
Silvopasture in Practiceintensives at NOFA-VT and PASA Conferences, Winter 2018 (28 and 46 participants, respectively.)
Raising Duckstalk, 2018 PASA, with 40 participants
Silvopasture in Practicetalk Midwest Organic Farming Conference, Feb 2019 (209 participants)
Learning Outcomes
1 Farmers reported changes in knowledge, attitudes, skills and/or awareness as a result of their participation
Key areas in which farmers reported changes in knowledge, attitude, skills and/or awareness:
We will be offering an educational webinar in early 2019 and are completing and reformatting our guide book to be published before the project terms in March, will update this section during our final report.
Project Outcomes
1 Farmers changed or adopted a practice
1 Grant applied for that built upon this project
1 Grant received that built upon this project
$14,000.00 Dollar amount of grant received that built upon this project
1 New working collaboration
Project outcomes:
Outcomes include:
Better understanding of the complex dynamics of pest (slug) cycles in pasture
Appreciation for the role ducks can play in reducing impact, despite the challenges from a management standpoint
As a result of the project, we will be rotating our ducks through pasture, though as part of our regular movements, and not in relation to any sort of monitoring for slug numbers. We will target their impact in the wettest pastures in early spring and summer, when slug counts appear to be highest.
Assessment of Project Approach and Areas of Further Study:
We can attest after having done two grants attempting to quantify slug activity that the work is neither easy, nor enjoyable. Emptying traps and counting drowned slugs isn't enjoyable for anyone. Yet, we appreciate being able to look at the results of this consistent sampling.
As with any farming activity, weather presented an ongoing challenge. The first year we planned to sample was historically dry. The last year was historically wet. This is the reality, especially given climate change that is occurring. Yet it contradicts the desire for gathering data, in many respects.
It's also reality. We knew going into the project that ducks helped reduce slug impact, but we really wanted to see if we could come out of the project with a clear way to monitor and determine when to bring ducks in to reduce slug presence in our pasture. We were unable to acheive this, and so in some ways are back to square one; we know having ducks in pasture will offer some benefit, but we can't realistically monitor slug numbers and move ducks in any sort of ordered or measured way. It will be a bit of instinct, coupled with opportune timing. This is important as our attitude and perspective have changed. Moving forward, we will look for more ways to intentionally bring ducks into the pasture system.
| https://projects.sare.org/project-reports/fne16-842/ |
TC - Retrieval of snow freeboard of Antarctic sea ice using waveform fitting of CryoSat-2 returns
Retrieval of snow freeboard of Antarctic sea ice using waveform fitting of CryoSat-2 returns
Retrieval of snow freeboard of Antarctic sea ice using waveform fitting of CryoSat-2 returns Retrieval of snow freeboard of Antarctic sea ice using waveform fitting of CryoSat-2 returns Steven W. Fons and Nathan T. Kurtz
CORRESPONDING AUTHOR
[email protected]
Department of Atmospheric and Oceanic Sciences, University of Maryland, College Park, Maryland, USA
Earth System Science Interdisciplinary Center (ESSIC), University of Maryland, College Park, Maryland, USA
Cryospheric Sciences Laboratory, NASA Goddard Space Flight Center, Greenbelt, Maryland, USA
Cryospheric Sciences Laboratory, NASA Goddard Space Flight Center, Greenbelt, Maryland, USA
Abstract
In this paper we develop a CryoSat-2 algorithm to retrieve
the surface elevation of the air–snow interface over Antarctic sea ice. This algorithm
utilizes a two-layer physical model that accounts for scattering from a snow layer atop
sea ice as well as scattering from below the snow surface. The model produces waveforms
that are fit to CryoSat-2 level 1B data through a bounded trust region least-squares
fitting process. These fit waveforms are then used to track the air–snow interface and
retrieve the surface elevation at each point along the CryoSat-2 ground track, from which
the snow freeboard is computed. To validate this algorithm, we compare retrieved surface
elevation measurements and snow surface radar return power levels with those from
Operation IceBridge, which flew along a contemporaneous CryoSat-2 orbit in October 2011
and November 2012. Average elevation differences (standard deviations) along the flight
lines (IceBridge Airborne Topographic Mapper, ATM – CryoSat-2) are found to be 0.016 cm
(29.24 cm) in 2011 and 2.58 cm (26.65 cm) in 2012. The spatial distribution of monthly
average pan-Antarctic snow freeboard found using this method is similar to what was
observed from NASA's Ice, Cloud, and land Elevation Satellite (ICESat), where the
difference (standard deviation) between October 2011–2017 CryoSat-2 mean snow freeboard
and spring 2003–2007 mean freeboard from ICESat is 1.92 cm (9.23 cm). While our
results suggest that this physical model and waveform fitting method can be used to
retrieve snow freeboard from CryoSat-2, allowing for the potential to join laser and
radar altimetry data records in the Antarctic, larger ( ∼30cm) regional
differences from ICESat and along-track differences from ATM do exist, suggesting the
need for future improvements to the method. Snow–ice interface elevation retrieval is
also explored as a potential to obtain snow depth measurements. However, it is found that
this retrieval method often tracks a strong scattering layer within the snow layer
instead of the actual snow–ice interface, leading to an overestimation of ice freeboard
and an underestimation of snow depth in much of the Southern Ocean but with promising
results in areas such as the East Antarctic sector.
How to cite
How to cite.
Fons, S. W. and Kurtz, N. T.: Retrieval of snow freeboard of Antarctic sea ice using waveform fitting of CryoSat-2 returns, The Cryosphere, 13, 861–878, https://doi.org/10.5194/tc-13-861-2019, 2019.
Dates
1 Introduction
Antarctic sea ice plays a complex yet important role in the earth system processes of the
Southern Hemisphere. As the ice extent grows and shrinks over the course of a year, it
can influence atmospheric circulations and temperatures (Cavalieri and Parkinson, 1981;
Comiso et al., 2017), modify vertical and horizontal salinity profiles in the Southern
Ocean (Aagaard and Carmack, 1989; Haumann et al., 2016), and even affect the biota of the
south polar latitudes (Garrison, 1991; Legendre et al., 1992; Meiners et al., 2017).
Perhaps most notably, the high albedo of snow-covered Antarctic sea ice means it reflects
roughly 80 % of the incoming solar radiation back to space (Allison et al., 1993;
Massom et al., 2001; Brandt et al., 2005; Zatko and Warren, 2015), helping to regulate
the temperature of the south polar region and moderate the earth's energy budget. Unlike
the Arctic Ocean, the Southern Ocean is unbounded by continents, resulting in
geographically unlimited sea ice growth and vast areal extent. The average maximum extent
of Antarctic sea ice is about 18.5 million km 2, occurring in September each year
(Parkinson and Cavalieri, 2012). Despite a loss of sea ice extent in the Arctic since the
late 1970s (Cavalieri and Parkinson, 2012), passive satellite remote sensing records of
Antarctic sea ice have shown a slight increase in areal extent over the same period at a
rate of about 17 100 km 2yr −1(Parkinson and Cavalieri, 2012). Over the past
few years, passive satellite observations have shown considerable variability in
Antarctic sea ice extent. A record maximum extent of 19.58 million km 2was reached
on 30 September 2013 (Reid et al., 2015), only to be topped in September 2014 when the
extent reached 20.11 million km 2(Comiso et al., 2017). Less than 3 years later,
in March 2017, sea ice cover in the Antarctic dropped to just 2 million km 2, a
record low in the satellite era (Turner and Comiso, 2017). This minimum followed an
unparalleled retreat of Antarctic sea ice cover in 2016 (Turner et al., 2017).
In addition to ice extent, sea ice thickness is important for gauging the state of sea
ice in the polar regions. Beginning in the mid-to-late 20th century, ship-based in situ
measurements provided the only thickness data available in the Southern Ocean (Worby et
al., 2008). More recently, satellite altimetry instruments and techniques have proven
valuable in collecting sea ice thickness information. In order to calculate thickness
from altimetry, the freeboard must first be computed. Freeboard is defined as either the
height of the air–snow interface above the sea surface, termed the “snow freeboard” or
“total freeboard”, or as the height of the snow–ice interface above the sea surface,
known as the “ice freeboard”. Both types of freeboard can be used to compute thickness.
Typically, altimeter-based sea ice thickness is derived by assuming a hydrostatic balance
and combining the freeboard measurements with a measure of the snow depth atop sea ice as
well as approximations for the densities of the snow, sea ice, and sea water. In the
Antarctic, snow freeboard is used most often in this calculation (Li et al., 2018), which
is usually obtained using measurements from a laser altimeter.
Zwally et al. (2008) made the first estimates of satellite laser altimeter-based
Antarctic sea ice thickness by utilizing data from NASA's Ice, Cloud, and land Elevation
Satellite (ICESat) taken over the Weddell Sea. They computed the snow freeboard and
combined it with snow depth data taken from the Advanced Microwave Scanning Radiometer
for the Earth Observing System (AMSR-E). After Zwally et al. (2008), several studies
retrieved pan-Antarctic sea ice thickness from ICESat, each using slightly different
methods. Kurtz and Markus (2012) combined ICESat freeboards with in situ density
measurements and made the “zero ice freeboard” assumption that the snow depth was equal
to the snow freeboard, and thus no independent snow depth measurements were required.
Kern et al. (2016) compared multiple methods of computing thickness using ICESat
freeboard data by calculating snow depths from both AMSR-E and a static but seasonally
varying snow-depth-to-thickness ratio. A new one-layer method was developed by Li et
al. (2018) to compute thickness using ICESat data that built on the static ratio used by
Kern et al. (2016) and incorporated a dynamic snow depth-to-thickness ratio for every
data point. As these studies show, a large limitation to calculating Antarctic sea ice
thickness from laser altimetry, regardless of the method used, is the uncertainty in the
snow depth distribution on sea ice.
In addition to using laser altimetry to calculate sea ice thickness in the Antarctic,
radar altimetry has also been used in recent years. Most radar altimeters operate in the
Ku band at around 13.6 GHz, a frequency that has been shown to produce a dominant
backscatter from the snow–ice interface (Beaven et al., 1995). The retrieved freeboard
from radar altimetry, therefore, is generally assumed to be the ice freeboard especially
when the snow is relatively dry and thin. Ku-band retrievals of ice freeboard have been
employed in the Arctic (Laxon et al., 2003, 2013; Giles et al., 2008), where thinner and
drier snow conditions tend to exist (Webster et al., 2018). In the Antarctic, radar
freeboard calculations (and subsequent thickness calculations) are complicated
substantially by the depth and variable vertical structure of the snow on top of the sea
ice (Willatt et al., 2010; Price et al., 2015; Kwok, 2014). Due to the wealth of
available moisture from the surrounding ocean, Antarctic sea ice experiences more
frequent precipitation – and therefore greater snow depths – than that of the Arctic
(Massom et al., 2001; Maksym et al., 2012). The deep snow can be heavy enough to depress
the sea ice surface down near or even below the sea surface, leading to flooding and
wicking of the seawater within the snowpack (Massom et al., 2001; Willatt et al., 2010)
that can act to obscure returns from radar altimeters. Additionally, dense, warm, and/or
moist snow can cause the dominant scattering surface to be located within the snowpack at
a level that is higher than the snow–ice interface (Giles et al., 2008; Willatt et al.,
2010, 2011).
Freeboard retrievals that neglect range corrections for radar propagation through a snow
layer are referred to as “radar freeboards”. Radar freeboard was calculated in the
Antarctic by Schwegmann et al. (2016), who used data from CryoSat-2 and Envisat to
retrieve freeboard with the eventual aim to create a joined Envisat–CryoSat-2 sea ice
thickness record. To counteract the effects of the snow layer on electromagnetic wave
propagation, Paul et al. (2018) included a snow layer range correction to
radar freeboards computed using CryoSat-2 and Envisat to retrieve ice freeboard over both
Arctic and Antarctic sea ice. While the method put forth by Paul et al. (2018)
demonstrates usefulness in reconciling thickness between Envisat and CryoSat-2, there
still exist uncertainties in the sea ice thickness retrievals brought on by the validity
of the snow depth climatology used in the corrections.
When using Ku-band altimetry for retrievals of freeboard and thickness, the largest
source of uncertainty comes from the snow on sea ice. Uncertainty in the depth, salinity,
and vertical structure can impact ranging and freeboard calculation (Armitage and Ridout,
2015; Ricker et al., 2015; Nandanet al., 2017). In order to counteract this uncertainty
and improve the knowledge of the scattering effects of a snow layer on sea ice, our work
aims to utilize Ku-band altimetry from CryoSat-2 to retrieve the elevation of the
air–snow interface and subsequently the snow freeboard. While it is true that Ku-band
radar pulses generally penetrate the snow surface on sea ice and have a dominant
scattering layer beneath, what is often not included in freeboard retrieval algorithms,
especially those depending on an empirical waveform evaluation, is the fact that there
are physical and dielectric differences between air and snow (Hallikainen and
Winebrenner, 1992; Stiles and Ulaby, 1980) that results in scattering – albeit
comparatively weaker – from the air–snow interface (discussed in Sect. 3). Though this
scattering is not typically the dominant return from radar pulses, it has been shown that
it can be detected from airborne as well as ground-based sensors (Kurtz et al., 2013;
Willatt et al., 2010). Satellite radar returns of the air–snow interface elevation would
be important in the Antarctic where snow–ice interface returns are complex and
uncertain, and provide the possibility for snow depth estimations from radar altimetry.
Knowledge of the snow depth in the Antarctic would enable more accurate sea ice thickness
calculations, given that recent studies of Antarctic sea ice thickness rely on passive
microwave snow depth data (Kern et al., 2016), assumptions of snow depth being equal to
snow freeboard (Kurtz and Markus, 2012), parameterizations of snow depth from both snow
freeboard (Li et al., 2018) and multiyear ice fraction (Hendricks et al., 2018), or even
treatment of the snow and ice layers as a single layer with a modified density (Kern
et al., 2016).
Typically, CryoSat-2 pulses are limited by the receive bandwidth (320 MHz, corresponding
to a vertical resolution of 0.234 m) and therefore not able to resolve the air–snow
interface explicitly (Kwok, 2014). We show that through the use of a two-layer physical
model that accounts for the scattering effects of a snow layer on top of sea ice, we are
able to retrack the air–snow interface from CryoSat-2 radar waveforms, compute the
surface elevation, and then calculate snow freeboard. Our two-layer model builds on the
single-layer method developed by Kurtz et al. (2014). This study begins by explaining the
datasets that are used (Sect. 2), discusses the physical rationale (Sect. 3) and method
(Sect. 4) of retrieving snow freeboard from CryoSat-2, and shows an initial validation of
the approach (Sect. 5). Then, the freeboard calculations, results, and comparisons are
discussed in Sect. 6. Finally, a discussion on the application to snow depth retrievals
and possibility for future work is provided in Sects. 7 and 8.
2 Datasets
Data for this study primarily come from ESA's CryoSat-2 satellite, launched in 2010. The
principle payload aboard CryoSat-2 is SIRAL, a synthetic aperture interferometric radar
altimeter, which has a frequency in the Ku band at 13.575 GHz and a receive bandwidth of
320 MHz (Wingham et al., 2006). SIRAL operates in one of three modes: “low resolution”
mode (LRM), “synthetic aperture” (SAR) mode, or “synthetic aperture interferometric”
(SARin) mode. In the Southern Hemisphere, LRM is used over the Antarctic continent and
areas of open ocean and therefore is not considered in this study (Wingham et al., 2006).
SAR and SARin data, which are taken over the sea ice zone and the Antarctic coastal
regions, respectively, are both utilized in this work. Specifically, level 1B data from
both of these operating modes are used. SAR level 1B data consist of 256 samples per echo
while SARin data contain 512 samples per echo (Wingham et al., 2006). In order to
maintain consistency between the two modes both SAR and SARin data are here truncated to
128 samples per echo.
CryoSat-2 level 1B data utilize “multilooking” to provide an average echo waveform for
each point along the ground track. These multilooked echoes correspond to an approximate
footprint of 380 m along track and 1.5 km across track (Wingham et al., 2006). Within
the level 1B data, the one-way travel time from the center range gate to the satellite
center of mass is provided. This information is used to retrieve elevation above the
WGS84 ellipsoid. To do so, we first multiply the one-way travel time by the speed of
light in a vacuum. Then, geophysical and retracking corrections are applied following
Kurtz et al. (2014). Geophysical corrections are applied by using the CryoSat-2 data
products, which include the ionospheric delay, dry and wet tropospheric delay, oscillator
drift, dynamic atmosphere correction (which includes the inverse barometer effect), pole
tide, load tide, solid earth tide, ocean equilibrium tide, and long-period ocean tide.
The retracking corrections are obtained through the waveform fitting method, discussed in
Sect. 4. Adding the corrections to the raw range data provides the surface
elevation.
For this work, CryoSat-2 data from October 2011 to 2017 are utilized. October was chosen
so that a substantial sea ice extent is present in each year of data and also so there is
overlap with the spring ICESat campaigns, which ran roughly from October to
November 2003–2009. Seven years of data allows for a longer-term average to be computed
and facilitates better comparison with the ICESat spring seasonal average (Sect. 6.2).
Data from NASA's Operation IceBridge airborne campaign are used in multiple capacities
throughout this study. First, IceBridge 2–8 GHz snow radar (denoted “snow radar” in
figures; Leuschen, 2014) and 13–17 GHz Ku-band radar altimeter (Leuschen et al., 2014)
data are used to confirm the presence of scattering of the radar beam from the air–snow
interface (Sect. 3). These data are taken from flights over the Weddell Sea on
13 October 2011 and 7 November 2012, which correspond to planned underflights of a
contemporaneous CryoSat-2 orbit. This flight line is known as the “Sea Ice –
Endurance” mission and is shown in Fig. 1.Second, these coincident observations are
used in Sect. 5 for direct comparisons of elevations found between IceBridge and
CryoSat-2 in order to validate this CryoSat-2 algorithm. Specifically, ATM elevation data
(Studinger, 2014) are used and compared against that of CryoSat-2.
Figure 1Maps of the Operation IceBridge 13 October 2011(a)and 7 November 2012(b)Sea Ice Endurance campaign flight paths (in black)
along with the contemporaneous CryoSat-2 ground track (in green). Flight
paths are overlaid on hourly average sea ice surface temperatures from
MERRA-2 at the midpoint time of the IceBridge flight (MERRA-2 data from
GMAO, 2015).
Sea ice freeboard data taken from ICESat between 2003 and 2007 (Kurtz and Markus, 2012)
are used primarily as a comparative measure in this work. This product is gridded to
25 km and uses a distance-weighted Gaussian function to fill gaps in the gridded data.
Specifically, seasonal average freeboard values from the various ICESat campaigns are
compared with CryoSat-2 monthly average freeboard data obtained using this algorithm. The
austral spring ICESat freeboard dataset consists of measurements made from October and
November 2003–2007 (Fig. 2). These ICESat freeboard and thickness data are publicly
available online at https://neptune.gsfc.nasa.gov/csb/index.php?section=272(last
access: December 2018).
Lastly, sea ice concentration data are used to filter out grid boxes that are largely
uncovered with ice. We utilize the Comiso Bootstrap monthly average product, version 3,
that provides sea ice concentration on a 25 km polar stereographic grid, and remove grid
boxes with monthly average concentrations less than 50 %. This product is derived
using brightness temperatures from Nimbus-7 Scanning Multichannel Microwave Radiometer (SMMR) and the Defense Meteorological Satellite Program (DMSP) SSM/I-SSMIS passive microwave data (Comiso, 2017).
Figure 2ICESat austral spring mean freeboard, consisting of measurements
taken in October and November 2003–2007.
3 Observed Ku-band scattering of radar from Antarctic sea ice
While more recent studies have shown the effects that a snow layer can have on Ku-band
ranging and freeboard retrievals (Armitage and Ridout, 2015; Ricker et al., 2015; Nandan
et al., 2017), past works that utilize Ku-band altimetry for ice freeboard retrieval tend
to neglect scattering that occurs from the snow surface and volume, and assume that the
dominant return occurs from the snow–ice interface (Beaven et at., 1995; Laxon et al.,
2013; Kurtz et al., 2014). For most cases, especially in the Arctic where the snow cover
is relatively thin and dry, this assumption is generally valid (Willatt et al., 2011;
Armitage and Ridout, 2015). However, the physical differences between air and snow
indicate that scattering can occur from the air–snow interface as well (Hallikainen and
Winebrenner, 1992). This air–snow interface scattering is the fundamental basis for
measuring snow freeboard using radar altimetry. Kwok (2014) used Operation IceBridge data
to find that scattering from the air–snow interface does contribute to the return at
Ku-band frequencies. To further prove this fact, we use Operation IceBridge echogram data
from the Ku-band and snow radars (Fig. 3) that provide a vertical profile of the radar
backscatter along the flight path displayed in Fig. 1. These echograms come from the
November 2012 campaign.
Comparing the lower-frequency snow radar, which is known to
detect the air-snow interface (Kurtz and Farrell, 2011), with the higher-frequency Ku-band radaraltimeter, one
can see the difference in scattering between the snow-covered floe points and the leads
in both radar profiles.
Figure 3Example echograms from Operation IceBridge snow radar(a)and Ku-band
radar(b)taken from the November 2012 Sea Ice Endurance campaign. Black points
denote locations of maximum power and red points denote the first location where the
power rises 10 dB above the noise level, both found from the peak-picking algorithm
discussed in the text. The length of the transect covered in this echogram is 3.02 km. The
mean (standard deviation) noise level for the snow radar is found to be −29.1dB
(1.39 dB) while the signal level at the air–snow interface is found to be −16.8dB
(1.47 dB). For the Ku-band altimeter, the noise level is found to be −30.3dB
(1.32 dB) while the air–snow interface signal level is found to be −17.9db
(2.09 dB), showing the surface return is well above the noise for both instruments.
In this study, a simple “peak picking” algorithm is employed to mark the vertical
locations of both the maximum backscatter and the first point that rises 10 dB above the
noise level for each horizontal point along the flight line. While not explicitly
extracting layers from the IceBridge data, these points are used as initial guesses of
the air–snow and snow–ice interfaces for the model (Sect. 4). These initial guesses are
not exactly the expected backscatter coefficients from the two layers, but instead a
rough approximation from their peak powers. The peak-picked air–snow interface power is
compared to that of the maximum (assumed snow–ice interface) power, as displayed in
Fig. 4. This frequency distribution shows that for the 2012 IceBridge campaign over
Antarctic sea ice, the difference of the air–snow interface power from the maximum power
is smaller for the snow radar, with a mean of 12.94 dB, than for the Ku-band altimeter,
which has a mean difference of 14.00 dB. This result is expected, as it means that the
scattering power from the air–snow interface is closer in magnitude to that of the
snow–ice interface in snow radar returns. However, the curves have a similar
distribution and mean, indicating that the Ku-band radar return likely consists of
scattering from the air–snow interface as well. Overall, a comparison of the IceBridge
radars provides further evidence that scattering of Ku-band radar pulses can occur at the
air–snow interface. The following sections use this notion to retrieve snow freeboard
from CryoSat-2 returns.
Figure 4Frequency distributions of the difference in air–snow interface power from
snow–ice interface power taken from the November 2012 IceBridge Sea Ice Endurance
campaign. The blue curve represents the snow radar, while the black curve represents the
Ku-band radar. Note that the locations of the air–snow and snow–ice interfaces are
approximations found from the peak-picking algorithm (Fig. 3) and are not exactly the
expected backscatter coefficients from the two layers.
4 Surface elevation retrieval methodology
In this section, we introduce a new two-layer retrieval method that expands
on the single-layer method employed by Kurtz et al. (2014). Following that
work, this study retrieves surface elevation from CryoSat-2 data by first
using a physical model to simulate return waveforms from sea ice. Then, a
least-squares fitting routine is used to
fit the simulated waveform to the CryoSat-2 level 1B data. Sea ice
parameters, including the surface elevation, can then be computed from the
fit waveform. The following section describes this process. For a more
detailed derivation of the theoretical basis surrounding the physical model
and waveform fitting routine, see Kurtz et al. (2014).
4.1 Physical waveform model
When assuming a uniformly backscattering surface, Kurtz et al. (2014)
expressed the received radar echo, Ψ( τ ), as
Ψ ( τ ) = P t ( τ ) ⊗ I ( τ ) ⊗ p ( τ ) ,
where τis the echo delay time relative to the time of scattering from the mean
scattering surface and ⊗represents a convolution of the compressed transmit
pulse, P t ( τ ); the rough surface impulse response, I ( τ ); and the
surface height probability density function, p ( τ )(Brown, 1977; Kurtz et al.,
2014). The terms are defined as
P t ( τ ) = p 0 sin c 2 ( B w τ ) ,
where p 0is the peak power of the pulse and B wis the received
bandwidth;
p ( τ ) = 1 √ 2 π σ c exp ( - 1 2 ( τ σ c ) 2 ) ,
where cis the speed of light in vacuo and σ c = 2 c, the
standard deviation of the surface height in the time domain; and
I ( τ ) = λ 2 G 2 0 D 0 c σ 0 ( 0 ∘ ) 32 π h 3 η N b - 1 2 ∑ k = - N b - 1 2 H ( τ + η h ξ 2 k c ) exp [ - 2 ξ 2 k η 2 ( 1 γ 2 1 + 1 γ 2 2 ) + c η h γ 2 1 ( τ + η h ξ 2 k c ) ] c η ∫ h γ 2 1 d θ exp [ - 4 ξ k √ c h η 3 ( τ + η h ξ 2 k c ) cos θ ( 1 γ 2 1 + 1 γ 2 2 ) - 2 c cos ( 2 θ ) h η γ 2 2 ( τ + η h ξ 2 k c ) ] ( 1 + α h 2 ( ( h ξ k η ) + c h η ( τ + η h ξ 2 k c ) + 2 ( h ξ k η ) cos θ √ c h η ( τ + η h ξ 2 k c ) ) ) - 3 / 2 ( N b ∑ n = 0 ( 0.54 - 0.46 cos ( 2 π n N b - π ) ) cos ( 2 k 0 υ s ( n - N b 2 ) √ c τ η h + ξ 2 k cos θ - ξ k ) ) 2 ,
where the variables (average values, when applicable, following Kurtz et al., 2014)
for CryoSat-2 are as follows: λ(0.0221 m) is the
center wavelength, G 0(42 dB) is the one-way antenna gain, D 0(30.6 dB) is the one-way gain of the synthetic beam, c(299 792 485 m s −1)
is the speed of light in vacuo, σ 0(0 ∘) is
the nadir backscatter coefficient, h(725 km) is the satellite altitude, η(1.113) is a geometric factor, N b(64) is the number of
synthetic beams, τis the echo delay time, ξ kis the look
angle of the synthetic beam kfrom nadir, His a Heaviside step function, γ 1(6767.6) is the elliptical antenna pattern term 1, γ 2(664.06) is the elliptical antenna pattern term 2, αis the
angular backscattering efficiency, k 0(284.307 m −1) is the carrier
wave number, υ s(7435 m s −1) is the satellite velocity, σis the standard deviation of surface height, and B w(320 MHz)
is the received bandwidth.
Under the assumption that only surface scattering is present and occurs from the
snow–ice interface alone (i.e., nosurface scattering from the air–snow interface nor
volume scattering from within the snow or ice layers), Eq. (1) is able to accurately
model a received CryoSat-2 echo over the Arctic (Kurtz et al., 2014). However, due to
thicker snow depths on Antarctic sea ice as compared to the Arctic, scattering effects
from the snow layer cannot be neglected when retrieving surface elevation. Therefore,
Eq. (1) is here modified to become
Ψ ( τ ) = P t ( τ ) ⊗ I ( τ ) ⊗ p ( τ ) ⊗ ν ( τ ) ,
where ν ( τ )is the scattering cross section per unit volume as a function of echo
delay time (Kurtz et al., 2014). Following Arthern et al. (2001) and Kurtz et al. (2014), ν ( τ )is defined in terms of physical parameters including the surface backscatter
coefficients of snow and ice, σ 0 surf - snowand σ 0 surf - ice, respectively, and the integrated volume backscatter
of snow and ice, σ 0 vol - snowand σ 0 vol - ice,
respectively. Together, the total backscatter can be written as
σ 0 = σ 0 surf - snow + σ 0 vol - snow + σ 0 surf - ice + σ 0 vol - ice .
For snow on sea ice, ν ( τ )becomes
ν ( τ ) = { 0 , τ < - 2 h s c snow σ 0 surf - snow δ ( τ + 2 h s c snow ) + σ 0 vol - snow k e - snow exp [ - c snow k e - snow ( τ + 2 h s c snow ) ] , - 2 h s c snow ≤ τ < 0 σ 0 surf - ice k 2 t - snow exp [ - k e - snow h s 2 ] δ ( τ ) + σ 0 vol - ice k e - ice exp [ - k e - snow h s 2 - c ice k e - ice τ ] , τ ≥ 0 }
which accounts for signal attenuation in the snow and ice layers and loss of
power at the air–snow and snow–ice interfaces. Equation (7) comes from
Kurtz et al. (2014) and uses the form of τ =0at the snow–ice
interface. In Eq. (7),
σ 0 vol - snow = σ vol - snow k 2 t - snow k e - snow , σ 0 vol - ice = σ vol - ice k 2 t - snow k 2 t - ice k e - ice .
Static parameters in Eqs. (7)–(9) are given values to model a snow layer on sea ice. We
assign the two-way extinction coefficients of snow, k e-snow, and sea ice, k e-ice, to be 0.1 and 5 m −1, respectively, following Ulaby et
al. (1986). The speed of light through snow and ice are c snowand c ice, respectively, where c snow = c n snowand c ice = c n ice. Here, n snow =1.281and n ice =1.732, where n snowcorresponds to a snow layer with a
density of 320 kg m −3(Tiuri et al., 1984; Ulaby et al., 1986). A density of
320 kg m −3was chosen as an assumption to best represent pan-Antarctic snow on sea
ice following results from several in situ surveys (Massom et al., 2001; Willatt et al.,
2010; Lewis et al., 2011). Finally, k t-snowand k t-iceare the
transmission coefficients between the air–snow and snow–ice interfaces, respectively.
Both transmission coefficients are generally close to one (Onstott, 1992); we use values
of k t-snow =0.9849and k t-ice =0.9775as calculated from the
Fresnel reflection coefficient using the values of n snowand n ice. The snow depth, h s, is computed from the echo delay shift
of the air–snow and snow–ice interfaces, free parameters t snowand t,
respectively, which are discussed in Sect. 4.3. The remaining free parameters are given
as inputs to the model and are defined in the following section.
The main assumption in this approach is that scattering is expected to come from two
defined layers (i.e., the air–snow and snow–ice interfaces) and uniformly throughout
the volume. Antarctic sea ice can exhibit complex layer structures that could obscure
this simple two-layer method; however, no pan-Antarctic understanding of snow-covered sea
ice composition currently exists. Therefore, this two-layer assumption is used as an
approximation of the broad-scale sea ice cover.
4.2 Waveform fitting routine
To fit the modeled waveform to CryoSat-2 data, a bounded trust region Newton least-squares fitting routine (MATLAB function lsqcurvefit) is employed. This routine
fits the model to the data by iteratively adjusting model input parameters and
calculating the difference between the modeled and CryoSat-2 level 1B waveform data,
until a minimum solution – or the established maximum number of iterations – is
reached. Building off of Kurtz et al. (2014), this process can be shown with the
equations
P m = A f L ( τ , α , σ ) ⊗ p ( τ , σ ) ⊗ ν ( τ , t snow , σ 0 surf - snow , σ 0 surf - ice , σ 0 vol - snow , σ 0 vol - ice )
and
min 128 ∑ i = 1 [ P m ( τ i ) - P r ( τ i + t ) ] 2 ,
where Lis a lookup table of P t ( τ )⊗ I ( τ )as defined in Kurtz
et al. (2014), P mis the modeled waveform, P ris the observed
echo waveform, and τ iis the observed echo power at point ion the waveform.
These equations result in nine free parameters: the amplitude scale factor, A f; the echo delay shift factor at the air–snow and snow–ice interfaces t snowand t, respectively; the angular backscattering efficiency, α; the standard deviation of surface height, σ; and the terms that together make
up the total backscatter, σ 0 surf - snow, σ 0 surf - ice, σ 0 vol - snow, and σ 0 vol - ice. These parameters are adjusted with each iteration of the
fitting routine and are explained further in Sects. 4.3.1 and 4.3.2. An initial guess for
each of the free parameters – in addition to upper and lower bounds – is provided to
the fitting routine. Doing so ensures that the solution reached will closely resemble
that of the physical system. Approaches for determining the initial guesses for both lead
and floe characterized echoes are outlined in the following section.
This algorithm uses the squared norm of the residual (“resnorm”) as a metric for
goodness of fit. Modeled waveforms with a resnorm less than or equal to 0.3 are
considered to be good fits and have the output parameters used in the retracking
correction calculation and surface elevation retrieval. Waveforms with greater fitting
error are run again using a different initial guess for α. If the resnorm is
still high, the CryoSat-2 echo is not used in the retrieval process. Figure 5 shows a
spatial distribution of the mean October resnorm values for 2011–2017. The largest
residuals are consistently located around the ice edge and near to the continent, while
the smallest are collocated with areas of high lead-type fraction (Fig. 5), such as the
Ross Sea. Since the specular lead waveforms are easily fit with little residual,the
overall average distribution shown here is consistently under 0.3 (total mean of 0.13).
However, many floe-type points have values closer to the 0.3 threshold. Although we have
observed that a resnorm threshold of 0.3 results in reasonably representative modeled
waveforms, we understand that the use of a single metric can oversimplify the goodness of
fit and leaves room for errors in the shape of the modeled waveform. Future work will
look into incorporating a more comprehensive metric for goodness of fit.
Figure 5October 2011–2017 average maps of lead-type waveform
fraction(a), floe-type waveform fraction(b), valid
waveform fraction(c), and resnorm value(d).
4.3 Lead/floe classification
Prior to constructing a physical model and fitting it to the data, each
CryoSat-2 echo is first characterized as either a lead or a floe based on
parameters derived from the individual waveform. Specifically, the pulse
peakiness (PP) and stack standard deviation (SSD) parameters are used to
distinguish between the two surface types, following Laxon et al. (2013). PP
is defined as
PP = max ( P r ) 128 ∑ i = 1 1 P r ( i )
from Armitage and Davidson (2014). SSD comes from the CryoSat-2 level 1B
data product and is due to the variation in the backscatter as a function of
incidence angle (Wingham et al., 2006). Figure 5 shows average detection
rates for lead and floe points using this method, discussed in the following sections.
4.3.1 Leads
CryoSat-2 echoes are categorized as leads if the return waveform has a PP>0.18and a SSD<4(Laxon et al., 2013). Since by definition leads have no
snow cover, it is assumed that all scattering of the radar pulse originates from one
surface. In this case, that surface is either refrozen new ice or open water. It is also
assumed that no volume scattering occurs from leads. Therefore, the volume scattering
term in Eq. (10) goes to a delta function at τ =0, resulting in four free
parameters: the amplitude scale factor, A f; the echo delay shift factor, t;
the angular backscattering efficiency, α; and the standard deviation of surface
height, σ. The initial guess for A fis set equal to the waveform peak
power, with the bounds set to ±50% of the peak power. The echo delay shift, t, is given an initial guess equal to the point of maximum power, denoted with t i.
The σis first estimated to be 0.01 for lead points, with bounds taken to be 0 ≤ σ ≤ 0.05. The initial guess for α, denoted as α 0, is
calculated as the ratio of tail-to-peak power and uses a mean of 10 ns following the
location of peak power. The bounds of αare α 0 100 ≤ α 0 ≤ 100 α 0. Using the above initial guesses in the fitting routine
leads to a modeled waveform that well represents the CryoSat-2 data over leads (Kurtz et
al., 2014). The echo delay factor, t, provides the location of the surface as a
function of radar return time, which is used in the surface elevation retrieval of each
lead-classified echo. The largest fraction of lead-classified points occurs in the Ross
Sea, consistent with the location of the Ross Sea Polynya (Fig. 5). However, it is also a
region known for new-ice formation that could return specular lead-type waveforms, and
potentially lead to an overestimation of the sea-surface height (discussed in Sect. 6).
4.3.2 Floes
Radar echoes with a PP<0.09and a SSD>4are classified as sea
ice floes (Laxon et al., 2013). Due to the presence of a snow layer on top of the sea
ice, all nine free parameters (introduced in Sect. 4.2) are employed. These include the
four mentioned in the previous section, as well as t snow– the echo delay
shift factor of the air–snow interface – σ 0 surf - snow, σ 0 vol - snow, σ 0 surf - ice, and σ 0 vol - ice. The initial guess and bounds for A fare
taken to be the same as used for lead points, while the remaining eight differ from
leads. For t snow, the initial guess ( t i−snow) comes from the
ICESat datasets of the seasonal average total freeboard. We use the “zero ice
freeboard” assumption (Kurtz et al., 2012) that the snow–ice interface is depressed to
the sea surface, meaning the ICESat freeboard would be approximately equal to the snow
depth. Though this assumption is generally thought to be valid in the Antarctic, it may
not hold true in all regions of the Antarctic (Adolphs, 1998; Weissling and Ackley, 2011;
Xie et al., 2011; Kwok and Maksym, 2014). Therefore, this fitting routine attempts to
adapt and move away from the zero ice freeboard assumption, with the results being
explored in later sections. The ICESat freeboard height at the location of each CryoSat-2
radar pulse is taken and converted in terms of radar return time, which provides a
suitable initial guess of the air–snow interface. Bounds of t i−snoware
taken to be ±5ns. The initial guess for t( t i) is taken to be the
first point where the waveform power reaches 70 % of the power of the first peak,
following Laxon et al. (2013). This is a commonly used threshold retracking method to
detect the snow–ice interface from CryoSat-2. Bounds are taken to be ±6ns. The σis first estimated to be 0.15 for floe points, with bounds set to 0 ≤ σ ≤ 1. The initial guess for αis similar to that in the lead
characterization, with the exception that the mean power of points between 90 and 120 ns
is used in the ratio of tail-to-peak power. Bounds for α 0are set as α 0 100 ≤ α 0 ≤ 100 α 0.
The remaining surface backscatter coefficients and integrated volume backscatter of snow
and ice are initially estimated using values taken from Operation IceBridge Ku-band radar
echograms from the Weddell Sea flights. Estimation of the surface backscatter comes from
an average of all valid peaks chosen from the echogram peak-picker method for the
air–snow and snow–ice interfaces of both flights. The snow and ice volume backscatter
values are parameterized using average layer backscatter values between the two
interfaces and 10 range bins beyond the snow–ice interface, respectively. The initial
guesses (bounds) are set to be as follows: σ 0 surf - snow = - 15dB
( ±5dB), σ 0 vol - snow = - 11dB ( ±5dB), σ 0 surf - ice = - 1dB ( ±10dB), and σ 0 vol - ice = - 8dB ( ±10dB).The largest fraction of floe-type points are found in the
Weddell Sea and along the ice edge, where older and rougher ice is generally found
(Fig. 5). These distributions compare qualitatively to that found in Paul et al. (2018),
with the exception that this method finds a larger region of lead-type dominant waveforms
in the Ross Sea than Paul et al. (2018).
The modeled waveform (examples shown in Fig. 6) is sensitive to the initial guess
provided, and therefore care was taken to ensure the initial guesses come from physically
realistic values. A change in the initial guesses results in different final fits, and
subsequently a different freeboard distribution. Figure 6 shows a waveform sensitivity
study looking at a variety of modeled waveforms that differ only in the initial guess for
the standard deviation of surface height ( σ, Fig. 6a, b, c) and the total backscatter coefficient
( σ 0, Fig. 6d, e, f). The range of σwas taken to be between 0.01 (very smooth
surface) to 0.4 (rough surface), while σ 0was varied between three different
parameterizations: values from Kurtz et al. (2014), values taken from the IceBridge snow
radar data, and from the Ku-band data (above). The resulting freeboard distributions
found using an initial guess of σ =0.35and σ 0taken from Kurtz et
al. (2014) are shown as a difference from the values chosen in this study ( σ =0.15, σ 0taken from Ku-band radar data) in Fig. 6c and f. In this case, the
effect of altering the backscatter parameterization had a larger effect on freeboard than
altering σ. It is evident that physically inconsistent initial guesses can result
in altered freeboard distributions, with the magnitude of the impact potentially being
large (broad-scale difference of ∼25cm in Fig. 6c). While this uncertainty surely
adds to that of the overall results, the use of physically consistent first guesses acts
to reduce the uncertainty as much as possible. Thus, a future area of study will be to
determine better empirical first guess choices for the static free parameters currently
used in the model.
Figure 6A sensitivity study of two initial guess parameters: the standard deviation of
surface height, σ, and the total backscatter, σ 0.(a)Modeled
waveform (before fitting) varying the initial guess value of σbetween 0.01 (very
smooth surface) and 0.4 (rough surface).(b)Waveforms fit to CryoSat-2 data
varying the initial guess value of σbetween 0.01 and 0.4.(c)October 2016 average freeboard difference: σ =0.35as the initial
guess – σ =0.15as the initial guess. Panel(d)as in(a)using
three different backscatter parameterizations taken from the OIB Ku-band radar profile,
snow radar profile, and Kurtz et al. (2014). Panel(e)as in(b)with the
three different backscatter parameterizations. Panel(f)as in(c)showing
Kurtz et al. (2014) backscatter as the initial guess – Ku-Band backscatter as the
initial guess. Inlaid plots are zoomed in on the waveform peaks. The methodology for
freeboard calculations is explained in Sect. 6.1.
5 Initial validation
To evaluate the performance of this algorithm, the returned surface
elevation is compared to independent measurements of surface elevation from
Operation IceBridge. Specifically, ATM data taken from the IceBridge
underflight of the CryoSat-2 orbit (Fig. 1) are compared with retracked
CryoSat-2 elevation data derived using this algorithm. Thecomparison is
done between surface elevation measurements before any freeboard
calculations are made, ensuring that differences observed are a factor of
the retrieval alone. In order to facilitate a direct comparison, ATM level 2
Icessn elevation data are averaged to the same ground footprint size as a
CryoSat-2 echo. Additionally, equivalent geophysical corrections are
computed and applied (following Yi et al., 2018) to both the CryoSat-2 and
ATM datasets, ensuring that both measurements are in the same frame of
reference. These geophysical corrections include effects from tides, which
are computed using the TPXO8-Atlas model (Egbert and Erofeeva, 2002); the
mean sea-surface height, which are computed using the Technical University
of Denmark DTU15MSS dataset (Anderson et al., 2016); and the dynamic
atmosphere, which are computed using correction data from the Mog2G model
(Carrère and Lyard, 2003).
Surface temperatures from MERRA-2 (GMAO, 2015) at the midpoint time of both IceBridge
flights are found in Fig. 1. The 2011 flight had a large (about 20 ∘C)
north–south temperature gradient that could result in different snow and ice properties
along the flight line, and thus could explain differences observed along the line. In
2012, there was almost no temperature gradient along the flight line. Additionally,
surface temperatures remained below freezing for the 2 weeks prior to both flights, with
light snowfall of around 5 mm day −1occurring 3 (4) days prior to the flight in
2011 (2012) but stopping 2 (3) days before the flight. The time difference between the
IceBridge flight and CryoSat-2 overpass was between 0 and 3.1 h in 2011 and between 0
and 2.2 h in 2012.
Figure 7a and b show ATM and CryoSat-2 surface elevation profiles from both the 2011 and
2012 IceBridge underflights. In these cases, the initial guess for the air–snow
interface location in the CryoSat-2 fitting routine comes from the ICESat seasonal
average dataset. Overall, the CryoSat-2 retracked elevation profiles capture the general
trends found in the ATM profiles. The mean difference in elevation of CryoSat-2 from ATM
for the entire flight line is 0.016 cm in 2011 and 2.58 cm in 2012. A frequency
distribution of this difference is shown in Fig. 7c and d. Both years display a
Gaussian-like distribution centered near zero (i.e., no difference) with standard
deviations of 0.29 m in 2011 and 0.27 m in 2012. It is likely that some of the
differences are due to initial temporal and spatial discrepancies between the IceBridge
and CryoSat-2 data collections. Correlations coefficients are 0.44 in 2011 and 0.40 in
2012, which, although in the low-to-mid range, is likely brought on by the inherent noise
in the data at the shot-to-shot level and non-overlapping footprints of the two sensors
(Yi et al., 2018). Although mean resnorm values from the CryoSat-2 flight lines are
0.1124 in 2011 and 0.0990 in 2012, signifying good fits, it is still possible that errors
in air–snow interface elevation couldhave arisen from errors in fits that were below
the single-metric resnorm threshold but not representative of the actual CryoSat-2
waveform. This resnorm threshold is likely the cause of the “jumps” seen in the
CryoSat-2 data, as testing a higher resnorm threshold led to more jumps, while testing
a lower resnorm threshold led to fewer jumps, but worse agreement to ATM. There also
appears to be a slight underestimation of ATM by CryoSat-2 in both profiles, which could
be brought on by the original footprint sizes, as the smaller ATM footprint is more
sensitive to small-scale peaks/ridges than CryoSat-2.
Figure 7Surface (air–snow interface) elevation profiles of Operation IceBridge ATM
(blue) and CryoSat-2 (orange) from the October 2011(a)and November 2012(b)campaigns. Frequency distributions of the elevation difference (ATM –
CryoSat-2) along the 2011(c)and 2012(d)profiles are also shown. The
mode of the differences is 0.025 m in 2011 and −0.24m in 2012. The 2011 profile
contains measurements from (lat, long) -63.99, -45.11 to -75.04, -49.33
while the 2012 profile contains measurements from -66.14, -43.31 to -74.25, -46.46.
Overall, this initial validation shows the potential of our CryoSat-2
algorithm to retrieve reasonable surface elevation measurements over
Antarctic sea ice. This promising result warrants further exploration into
freeboard retrieval using this method, discussed in the next section.
6 Snow freeboard retrieval
6.1 Freeboard calculation
The retrieved elevation of the air–snow interface from this method is used to calculate
the snow freeboard of Antarctic sea ice. First, CryoSat-2 data are processed
1 month at a time
and the outlying data points are filtered out to reduce the inherent noise of
the data. The filtering is done by removing any point that has an output parameter more
than 3 standard deviations away from the mean of the respective parameter. These
output parameters include quantities such as the surface elevation, retracking
correction, PP, SSD, and τ. Additionally, points with a τvalue less than −100ns were found to produce anomalous surface elevations and therefore are filtered
out. Then, surface elevation data consisting only of echo points characterized as leads
are gridded to a 25 km polar stereographic grid and averaged over the month. Grid boxes
with fewer than five points and/or monthly concentrations less than 50 % are ignored.
This grid is effectively the mean sea-surface elevation. Snow freeboard is calculated by
taking each surface elevation point along the CryoSat-2 orbit and subtracting the
corresponding mean sea-surface elevation value. Any snow freeboard points less than −0.1m and greater than 2.1m are filtered out. Between the initial filtering and
this freeboard filtering, 41.68 % of the total waveforms are filtered out, leaving
58.32 % as valid waveforms. This process is done from the entire month of data, and
the remaining freeboard values are gridded to 25 km to produce a map of the monthly mean
snow freeboard. To study multiyear means for a given month, each monthly snow freeboard
grid is averaged over a range of years. In this case, grid boxes with data from fewer
than two years are ignored. Both the monthly and multiyear mean snow freeboard grids are
smoothed by taking the average of all grid boxes within two grid boxes in all directions,
which reduces the spatial resolution to 125 km. Smoothing is applied to reduce noise in
the CryoSat-2 data and also to fill gaps in the data.
Figure 8 shows maps of October monthly averaged snow freeboard values from 2011–2017 as
well as the mean of all 7 years. The freeboard distribution corresponds well to what
is expected in the Antarctic: the largest values occur in the Weddell and Amundsen seas
– where ice production and heavy snow falls are typically prevalent – as well as along
the coast of East Antarctica – where snowfall accumulation is also typically large. The
smallest values tend to be found off the coast of East Antarctica between 0 and
90 ∘E. Additionally, the region of low freeboard shown in the Ross Sea each year
is consistent with the presence of young ice from the Ross Sea Polynya, but could be
biased lower due to the large region of lead-type waveforms classified in the area,
leading to a higher sea-surface height and lower freeboard. While the overall pattern
remains similar in each map, there is clear interannual variability. For example, the
Amundsen Sea region along the Antarctic coastline exhibits a widespread area of very
large (over 50 cm) freeboard in 2011, while the same coastal region between 100 and
150 ∘W shows values between 20 and 35 cm in 2016. Thicker snow freeboard can be
found adjacent to the ice extent edge in each of the years, with the average map clearly
showing greater freeboard values along the ice edge in the western Pacific Ocean (about
90 to 180 ∘E). This thick freeboard at the ice edge is consistent with the older
and thicker ice that has been previously found in the Antarctic frontal ice zone (Nghiem
et al., 2016), but could also be due to surface waves penetrating the ice cover,
resulting in an altered floe size distribution (Fox and Haskell, 2001) and also a high
freeboard bias. Additionally, the high freeboard found here could be a product of the
lower CryoSat-2 data density further from the pole as well as the variety of different
ice types found in the frontal ice zone.
Figure 8October monthly average snow freeboard from 2011 to 2017, as well as the mean of
all years, found using this retrieval method.
A time series of mean October snow freeboard from 2011 to 2017 found using this method is
shown in Fig. 9, with total sea ice area plotted for reference (Fetterer et al., 2017).
Apart from slight increases in freeboard from 2012 to 2013 and 2016 to 2017, there is an
overall decrease found between 2011 and 2017 of 0.5 cm yr −1. The smallest measured
freeboard occurred in 2016 (25.8 cm), which is collocated with a minimum in sea ice area
that occurred in the same year. The total average snow freeboard in October from 2011 to
2017 is found to be 27.6 cm with a standard deviation of 13.0 cm. Interestingly, the
sea ice area and snow freeboard time series appear highly correlated between 2011 and
2017 ( r =0.77) alluding to a potential relationship between freeboard/thickness and area
in the Antarctic. This relationship, however, is beyond the scope of this paper and will
be explored in future work.
Figure 9October monthly average Antarctic snow freeboard
(black) and total sea ice area
(blue) for reference. Sea ice area data are gathered from the NSIDC
(Fetterer et al., 2017) and can be found at https://nsidc.org/data/G02135/versions/3.
6.2 Pan-Antarctic freeboard comparisons
To assess the performance of this algorithm on a pan-Antarctic scale, monthly averaged
freeboard values from CryoSat-2 are compared with seasonal average freeboard from ICESat.
Figure 10 shows a difference map between CryoSat-2 and ICESat total freeboard, where
positive (negative) values indicate regions where CryoSat-2 measures greater (lesser)
freeboard as compared to ICESat. The most notable difference occurs in the Weddell Sea
off of the Antarctic Peninsula, where CryoSat-2 records a freeboard value much lower
(around 30 cm) than ICESat. A similar region can be found in the Amundsen Sea, where
CryoSat-2 measurements are again less than ICESat. CryoSat-2 measures a larger freeboard
along most of the sea ice edge, as well as along the Antarctic coast from about
20 ∘W to 60 ∘E. Apart from these areas of noticeable differences
between the two datasets, the remainder of the sea ice zone is fairly comparable among
both. The total mean difference is only 2.9 cmwith a standard deviation of just under
10 cm and a mode difference of 0.8 cm (Fig. 10).
Figure 10Snow freeboard differences showing(a)CryoSat-2 October 2011–2017
average minus ICESat spring 2003–2007 average and(b)ICESat spring 2006
average minus ICESat spring 2003–2007 average. The year 2006 is included as an example
year to highlight the interannual variability in the freeboard distribution.
Though this compatibility is encouraging, it is important to note that
comparison is indirect in nature. The CryoSat-2 dataset covers October
2011–2017, 7 years of data, while this ICESat dataset covers
October–November 2003–2007, 5 years of data. These non-overlapping time
periods have different lengths, and the ICESat dataset contains data from
October and November in some of the campaigns. Therefore, this comparison
shows that our algorithm can produce results similar to the average values
found with ICESat, but requires temporally coincident data – such as those
forthcoming from ICESat-2 – to best assess the accuracy of the retrieval
approach.
Qualitatively, the snow freeboard distribution found in Fig. 8 is comparable
to that shown in Schwegmann et al. (2016) and Paul et al. (2018). In all
studies, the largest freeboard is found along the coast in the Amundsen Sea,
East Antarctica, and in the Weddell Sea, while the smallest freeboard is
found in the Ross Sea and off East Antarctica between 0 and
90 ∘E. Similar to what was found in the comparison with ICESat,
both Schwegmann et al. (2016) and Paul et al. (2018) find a higher freeboard
immediately off the Antarctic Peninsula near the Larson Ice Shelf than is
found with this method, which could signal a regional difficulty to retrieve
snow freeboard using this algorithm or a complication with the thicker
and/or rougher ice that tends to be found in this region. However, these
comparisons are still rather indirect, given that the prior works retrieve
radar freeboard (Schwegmann et al., 2016) and ice freeboard (Paul et al.,
2018) while this method retrieves snow freeboard. Once again, coincident
measurements of snow freeboard from ICESat-2 will be invaluable as a
comparative tool.
7 Application to snow depth retrievals
Given that this algorithm outputs the location of both the air–snow and snow–ice
interfaces as a function of radar return time, it seems logical that snow depth could be
extracted from these data. It is likely, however, that the complexities of Antarctic sea ice inhibit
this method in tracking the correct snow–ice interface, resulting in a
lower-than-expected snow depth distribution (judging from passive microwave measurements; Markus and Cavalieri,
1998; and in situ surveys; Massom et al., 2001). Figure 11 shows
a map of the average October 2011–2017 snow depth on sea ice, calculated by subtracting
the snow–ice interface elevation from the air–snow interface elevation. It can be seen
that for a majority of the Antarctic, a snow depth of around 0.1 m is present. This
algorithm appears to be tracking the dominant sub-surface return as a layer within the
snowpack as opposed to the ice interface itself, as has been seen in previous studies
(e.g., Giles et al., 2008; Willatt et al., 2010). A potential explanation is that the
complex snow stratigraphy found during in situ surveys of the Antarctic sea ice pack
(Massom et al., 2001; Willatt et al., 2010; Lewis et al., 2011) and attenuation due to
seawater flooding and wicking could be prevalent throughout the Antarctic, and that
layers of ice and/or brine could be responsible for an interface return that is higher
than the actual snow–ice interface.
A similar result is found when comparing retrieved CryoSat-2 snow depths in
the Weddell Sea to that from Operation IceBridge. Using the peak-picking
algorithm on IceBridge data from the 13 October 2011 flight line, we
calculate an approximate mean snow depth of 0.26 m. This value is close to
the snow depth that was calculated by Kwok and Maksym (2014, Table 2 S2–S4)
for the same flight line (approximately 0.29 m). From CryoSat-2, the mean
snow depth along the flight line is found to be 0.15 m, which is lower than
the measured values potentially due to the much larger footprint size and
more limited bandwidth from the satellite data.
Despite the widespread small snow depth values, the region off the coast of East
Antarctica in Fig. 11 (between 90 and 60 ∘E) exhibits values closer to what is
expected. Here, there is a greater snow depth of around 0.3 m. This region is known to
have positive ice freeboard values (Worby et al., 1998; Maksym and Markus, 2008; Markus
et al., 2011) meaning that flooding and saltwater intrusion would play less of a role
than in other areas. The near-realistic snow depth measurements here provide evidence
that our algorithm could be effective in retrieving snow depth under certain snow
conditions, seasons, or locations, but speaks to the inherent complexity and uncertainty
associated with Antarctic sea ice. Furthermore, the fact that these snow depth
measurements are not higher over other areas of known positive ice freeboard, such as the
western Weddell Sea, could signal regional issues with the algorithm to retrieve the
snow–ice interface. More work is needed in evaluating the tracking of thesnow–ice
interface using this method to use it together with the air–snow interface for snow
depth on sea ice estimation.
8 Conclusions and future work
In this work, a method for retrieving snow freeboard from CryoSat-2 data is developed. It
is based on the fundamental idea that scattering of Ku-band radar pulses can originate
from the air–snow interface of snow on sea ice. We incorporate this scattering into a
physical waveform model and use a least-squares fitting routine to fit the model to
CryoSat-2 level 1B waveforms. The returned fit waveform and associated parameters
includes, among others, the location of the air–snow interface as a function of radar
return time. We are able to use that location to retrack the snow surface elevation, and
from this, calculate snow freeboard. Through a comparison of this method with independent
measurements, we are able to evaluate the performance of our retrieval. Specifically,
surface elevation measurements from Operation IceBridge ATM, taken in October 2011 and
November 2012 along a coincident flight line, help to provide an initial confirmation
that the retrieval results were comparable to other data sources. Mean (standard
deviation) elevation differences between ATM and CryoSat-2 were found to be just
0.016 cm (29.24 cm) in 2011 and 2.6 cm (26.65 cm) in 2012. Seasonal averaged
freeboard data from ICESat allowed for the comparison of the pan-Antarctic freeboard.
Though the CryoSat-2 and ICESat freeboard data come from non-overlapping time periods of
different lengths and months, there was still general agreement with the freeboard
distribution. The mean (standard deviation) difference between CryoSat-2 and ICESat
freeboard is 2.94 cm (9.23 cm). The fact that the largest differences between CryoSat-2
and ICESat occur in regions of known thick snow depths could signal a difficulty of the
algorithm over the thickest snow, suggesting an area for future improvements to the
model. In general, this retrieval algorithm shows promise that snow freeboard can be
measured from CryoSat-2 alone.
Though the retrieved air–snow interface elevation and snow freeboard closely resemble
that from independent measurements, the retrieved snow–ice interface elevation appears
to be larger than expected. Calculated snow depth, therefore, is lower than typically
expected throughout most of the Antarctic sea ice cover as compared to in situ and
passive microwave data. Due to strong attenuation of radar returns from brine layers
within the snow pack (Nandan et al., 2017), it may not be possible to retrieve the actual
snow–ice interface from a Ku-band altimeter in some regions of the Antarctic. However,
the region near the Antarctic coast in the western Pacific Ocean (Fig. 11) displays snow
depths that are much closer to expected, signaling the possibility of snow depth
retrieval under certain ice types and conditions. More work is needed to understand why
this region shows near-realistic snow depths while other regions with similar ice
characteristics (e.g., positive ice freeboard in the western Weddell Sea) do not.
Figure 11October 2011–2017 average difference between the retrieved air–snow and
snow–ice interfaces as an exploration into the potential retrieval of snow depth.
Overall, this study has expanded the functionality of CryoSat-2 as a tool for observing
the snow freeboard of Antarctic sea ice, adding to the existing studies retrieving radar
freeboard (Schwegmann et al., 2016) and ice freeboard(Paul et al., 2018). In September
2018, CryoSat-2 was joined in space by ICESat-2, NASA's second-generation satellite laser
altimeter system (Markus et al., 2017). These coincident altimeters will provide the
ability to observe the polar regions like never before. For this work specifically,
ICESat-2 data will be used as both a comparative measure – for direct monthly
comparisons of snow freeboard – as well as an initial guess for the waveform fitting
model. These new measurements of air–snow interface elevation and snow freeboard from
ICESat-2 will help to further validate this retrieval algorithm.
Future work will look into combing these CryoSat-2 snow freeboard measurements with those
from laser altimetry to produce an ICESat–CryoSat-2–ICESat-2 time series of snow
freeboard in the Antarctic. This reconciled laser–radar altimetric record of snow
freeboard would span more than 15 years from 2003 throughout the lifetime of ICESat-2,
providing a long and robust dataset that could be used in other studies of sea ice.
Together with ESA's Climate Change Initiative dataset combing CryoSat-2 and Envisat
(Schwegmann et al., 2016; Paul et al., 2018), these long-term datasets could lead to
improved retrievals of sea ice thickness and an enhanced understanding of sea ice in the
Antarctic.
Data availability
CryoSat-2 SAR and SARIn data are publicly available from
ESA ( https://science-pds.cryosat.esa.int; last access: February 2019).
Operation IceBridge data from all instruments are publicly available
from the National Snow and Ice Data Center (NSIDC). For this study, we used the
following.
(i) ATM:https://doi.org/10.5067/CPRXXK3F39RV(Studinger, 2014),
(ii) Snow radar:https://doi.org/10.5067/FAZTWP500V70(Leuschen, 2014),
(iii) Ku-band radar:https://doi.org/10.5067/D7DX7J7J5JN9(Leuschen et al., 2014).
Sea ice concentration data can also be downloaded from NSIDC
(https://doi.org/10.5067/7Q8HCCWS4I0R; Comiso, 2017).
ICESat freeboard data are publicly available from NASA and
can be downloaded from https://neptune.gsfc.nasa.gov/csb/index.php?section=272(Kurtz and Markus, 2012; last access: December 2018).
Links to other auxiliary data sets are provided in the text.
Author contributions
NTK developed the framework model and fitting code. SWF adapted the code
and carried out the analysis. SWF prepared the manuscript with
contributions from NTK.
Competing interests
The authors declare that they have no conflict of interest.
Acknowledgements
The authors would like to thank the European Space Agency for providing data
from CryoSat-2, as well as the reviewers and editor for their constructive feedback.
This work is funded by NASA's Airborne Science and Cryospheric Sciences
programs.Edited by: Ted MaksymReviewed by: Stefan Hendricks and one anonymous referee
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Surfactant-assisted Hydrothermal Synthesis of Ceria-Zirconia Nanostructured Materials for Catalytic Applications | Request PDF
Request PDF | On Jan 1, 2013, Cimi Daniel published Surfactant-assisted Hydrothermal Synthesis of Ceria-Zirconia Nanostructured Materials for Catalytic Applications | Find, read and cite all the research you need on ResearchGate
Article
Surfactant-assisted Hydrothermal Synthesis of Ceria-Zirconia Nanostructured Materials for Catalytic Applications
January 2013
IOSR Journal of Applied Chemistry5(1):23-29
DOI: 10.9790/5736-0512329
Authors:
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe>
Cimi A Daniel
... However, the specific surface area of oxides prepared by these methods in most cases does not exceed 100 m 2 /g [30,39]. To obtain systems with a high specific surface area and developed porous structure, template-based synthesis methods are widely used [40]
[41]
[42], yet this method is associated with the material hightemperature treatment to destroy the template and eliminate the residual organic components formed upon decomposition of the template. ...
Template-free one-step synthesis of micro-mesoporous CeO2–ZrO2 mixed oxides with a high surface area for selective hydrogenation
Article
Feb 2020
CERAM INT
<here is a image 7550d963d0f16f31-f6e591bfe1351cec> Kseniia Vikanova
<here is a image 5a09e586044bdd88-01c03e0a3e1d02c4> Elena A. Redina
<here is a image 8df8ff13efce81aa-35349d7c6cbb73ac> G. I. Kapustin
Leonid M. Kustov
Ceria-zirconia oxide materials with a specific surface area ranging from 160 to 240 m²/g and different meso- and micropores ratio were obtained by a simple deposition-precipitation method with urea (DPU), which allows preparation of ceria-zirconia oxides directly in one-step while avoiding the formation of oxo-hydroxo species and further thermal treatment to obtain oxide phases. Moreover, a microwave-assisted DPU method allowed the decrease of the synthesis time from 24 to 3.5 h. The prepared samples were studied by TG-DTA, BET, N2 adsorption, XRD, SEM, and TEM methods. Pt-containing catalysts based on synthesized oxides have shown a high catalytic activity in selective hydrogenation of benzaldehyde, citral, and cinnamaldehyde at room temperature and atmospheric pressure.
Pengaruh Suhu Sintesis Katalis Partikel Ceria Zirconia terhadap Efektivitas Proses Delignifikasi
Article
Full-text available
Apr 2020
<here is a image 2c00c170edfefa2a-0ba20b86b1b52b51> Okky Putri Prastuti
Fandi Angga Prasetya
<here is a image 1f953c339c462eac-1586d982dc09d45b> Ufafa Anggarini
Hesty Rahayu
Biomass is organic material produced through photosynthetic processes. The presence of lignin on the cell wall will inhibit cellulose to be converted into products. Delignification will open the lignocellulose structure to make cellulose more accessible. The delignification process can be done by adding the Ceria-Zirconia catalyst to the biomass sample. The aim of this research is to determine the effect of synthesis temperature on Ceria Zirconia synthesis and to investigate the ability of Ceria Zirconia as a biomass delignification catalyst. Ceria- Zirconia Catalyst can be produced through the batch hydrothermal method. The precursors used were chemical solutions in the form of Ce(NO3)3.6H2O and ZrO(NO3)2.2H2O 0.06 M with a ratio of 1: 1, the synthesis temperature variables used were of 180oC, 200oC dan 220oC. Ceria Zirconia Catalysts will then be analyzed for their abilities through a 10 and 20 minute delignification process. The results showed that the increasing synthesis temperature will increase the ability of Ceria-Zirconia catalyst in the delignification process.
A high-performance ceramic fuel cell with samarium doped ceria–carbonate composite electrolyte at low temperatures
Article
May 2006
ELECTROCHEM COMMUN
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Jianbing Huang
Lizhai Yang
<here is a image 7a6e34667ad2eced-f47525e32b1fe8bf> Ruifeng Gao
<here is a image aa15a8c6157e9013-e0d098b26692e55a> Cheng Wang
An anode-supported ceramic fuel cell with samarium doped ceria (SDC)–carbonate (Li2CO3–Na2CO3) composite electrolyte was fabricated by a hot-press technique and tested at 450–600°C. NiO and lithiated NiO were used as the anode and cathode, respectively, with an effective electrode area of 3.14cm2. An open-circuit voltage (OCV) of 1.04V and a current density of 0.70A/cm2 at 0.6V was achieved with dry hydrogen as fuel and air as oxidant at 500°C. The stability of the cell has been examined for more than 110h at different temperatures. The results demonstrated that the cell operated stably at 500–600°C with excellent performances, e.g., a steady output of about 0.49W/cm2 at 550°C for at least 35h, but it became unstable at 450–475°C due to the malfunction of composite electrolyte and deactivation of electrodes. The high performances together with potential low costs (both raw materials and fabrication process) make the SDC–carbonate composites a promising electrolyte material for cost-effective ceramic fuel cells that operate at 500-600°C.
Redox Behavior of Surface-Modified CeO2−ZrO2 Catalysts by Chemical Filing Process
Article
Feb 2000
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Tetsuya Ozaki
Toshiyuki Masui
Ken-ichi Machida
Hirotaro Mori
Surface modification of CeO2−ZrO2 solid solutions took place using formation and transport of volatile vapor complexes such as AlCl3−CeCl3 and AlCl3−ZrCl4, which was denoted as “chemical filing.” XPS analysis showed surface Ce enrichment, and transmission electron microscopy and Raman spectra revealed that a defective phase was formed on the surface of the samples by the chemical filing. The reduction temperature of the samples after the chemical filing was about 50 K lower than that of the fresh sample and further decreased by a reduction/reoxidation cycle. The redox property of the chemically filed sample was maintained even after the redox cycles at high temperatures, indicating its excellent durability compared to the solid solution prepared by a conventional procedure.
Catalytic activity of CeO2–ZrO2 mixed oxide catalysts prepared via sol–gel technique: CO oxidation
Article
Jul 2001
CATAL TODAY
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Matina Thammachart
<here is a image f5d060e53dccb38b-b08480e3efda6c39> Vissanu Meeyoo
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Thirasak Rirksomboon
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Somchai Osuwan
CeO2–ZrO2 mixed oxide catalysts were prepared via a sol–gel technique and tested for carbon monoxide (CO) oxidation. Highly uniform nano-size solid solution particles of ceria–zirconia were attained under the conditions of this study (ca 100°C). The stabilization of the surface areas of the catalysts can be achieved by the addition of zirconium. The CO oxidation activity of the mixed oxides was found to be dependent on Ce/Zr ratio, which relates to the degree of reducibility. The catalytic activity for CO oxidation decreases with a decrease in Ce/Zr ratio. This might be due to the difference in phase compositions of the mixed oxides. It can be postulated that the cubic phase, fluorite structure, which is mainly found in Ce1−xZrxO2 (where x<0.5) could be reduced easily than the tetragonal phase found in Ce1−xZrxO2 (where x>0.5). Among the mixed oxide catalysts, Ce0.75Zr0.25O2 was reported to exhibit the highest activity for CO oxidation.
Preparation and characterization of high surface area niobia, ceria–niobia and ceria–zirconia
Article
Apr 2000
CATAL TODAY
Roberta Brayner
<here is a image e51ef752bcba9fda-fcb8f94cdbab1c9d> Dragos Ciuparu
Gilberto Marques da. Cruz
François Bozon-Verduraz
Niobia, zirconia, ceria–niobia and ceria–zirconia oxide nanoparticles are prepared by soft chemical routes and show valuable textural properties. The pore volume and specific surface area keep significant values even after calcination at 873 K. According to DRX and STEM-EDX measurements, solid solutions are obtained in the case of ceria–zirconia, whereas separate phases are identified in ceria–niobia; in the latter case, however, UV–Vis diffuse reflectance spectroscopy shows also the formation of defects (color centers) arising from a partial dissolution at the interface of the oxide phases.
Characterization of ceria-coated alumina carrier
Article
Aug 2002
APPL CATAL A-GEN
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Sonia Damyanova
<here is a image 467162432301df42-f8d9fcb30c44c309> Gabriella Andrea de Castro Perez
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> M. Schmal
<here is a image 8859a3f2d28ae2a3-97e22c9cf2b21775> J.M.C. Bueno
CeO2–Al2O3 mixed oxides with different CeO2 loading (in the range of 0.5–12 wt.%) were prepared by wetness impregnation of alumina with aqueous solution of di-ammonium hexanitrate cerate (NH4)2[Ce(NO3)6]. The samples after calcination at 773 and 1073 K were characterized by different techniques, using X-ray diffraction (XRD), UV–VIS diffuse reflectance spectroscopy (DRS), X-ray photoelectron spectroscopy (XPS) and temperature-programmed reduction (TPR). It is shown that different types of cerium oxide species are formed on the surface depending on the amount of CeO2 and temperature of calcination of the samples. XRD showed the formation of nanocrystallites of ceria on alumina surface when the amount of CeO2 is higher than 6 wt.%; at lower concentrations ceria was found to be amorphous. The ceria loading lower than 6 wt.% stabilizes the textural properties of alumina. At loading of 1 wt.% of CeO2 XPS spectra reveals the presence of a strong interaction between ceria and alumina leading to a formation of superficial CeAlO3-like phase. TPR results show that well dispersed CeO2 particles present on the surface of alumina form CeAlO3 at temperature of reduction in the range of 873–993 K, while for the reduction of CeO2 crystallites, a higher temperature of reduction of 1190 K is needed.
Mesoporous and nanostructured CeO2 as supports of nano-sized gold catalysts for low-temperature water-gas shift reaction
Article
Feb 2008
CATAL TODAY
<here is a image c36e36004d90d4ad-d00c90048e77060e> Zhong-Yong Yuan
<here is a image 87bad6918c5d05b0-bd3f07c059c91917> V. Idakiev
Aurélien Vantomme
<here is a image ef8e134005598229-0ab7fdd396d3163e> Bao-Lian Su
Mesoporous particles and 1D nanorods of cerium oxides have been prepared by modifying the hydrothermal route of a surfactant-assisted controllable synthesis. Mesoporous cerias were obtained in a sealed glass vessel under continuous stirring, while ceria nanorods were obtained in a Teflon-lined autoclave without stirring. The mesoporous cerias did not show long-range mesoscopic organization, exhibiting a broad mesopore size distribution in the region 8–15 nm. A BET surface area of 100 m2/g with a total pore volume of 0.33 cm3/g is obtained for as-synthesized mesoporous ceria. The ceria nanorods exhibit a cubic crystalline structure after calcination, having the lengths in the range of 150–300 nm and diameters in the range of 10–25 nm. The growth direction of ceria nanorods is along [1 1 0]. A surface area of above 50 m2/g is obtained in the calcined nanorods. These synthesized ceria materials were used as supports of nano-sized gold catalysts, prepared by deposition–precipitation method. Their catalytic activity was evaluated by the low-temperature water-gas shift reaction. The gold/mesoporous ceria catalytic system exhibited higher catalytic activity than gold/ceria nanorods. It is revealed that the mesoporous and nanostructured cerias are of much interest as potential supports for gold-based catalysts that are effective for low-temperature water-gas shift reaction.
Characterization of model automotive exhaust catalysts: Pd on ceria and ceria–zirconia supports
Article
Apr 1999
CATAL TODAY
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Hugn-wen Jen
George W. Graham
W. Chun
Olivier Touret
Pure cerias, silica-doped ceria, ceria–zirconia solid solutions, and ceria–zirconia solid solutions with partial incorporation of praseodymium in the structure were prepared by Rhodia as high-surface-area powders and used as supports in model Pd automotive three-way catalysts prepared at Ford. The catalysts were aged for 12 h at 1050°C, both in air and under redox conditions simulating automotive exhaust gases. Both the fresh and aged catalysts were characterized by a combination of techniques including oxygen storage capacity (OSC) measurements. After aging, catalysts prepared on the solid solution materials provided much greater OSC than those based on pure ceria or silica-doped ceria. Addition of 5 wt% praseodymia as a substitute for ceria improved the thermal stability of the ceria–zirconia, however, without increasing the OSC of the model catalysts. The ceria–zirconia based catalysts revealed a new temperature-programmed reduction peak, between 100°C and 200°C, after 1050°C aging, which is attributed to Pd-assisted bulk reduction of ceria. Significant differences in OSC were noted between catalysts prepared on a series of 70 wt% ceria–30 wt% zirconia supports prepared by different processes, despite virtually identical characteristics of the aged materials as judged by the other techniques. These observations indicate that different processing methods lead to different physical and chemical characteristics of aged catalysts, not readily discerned by conventional characterization techniques, but nonetheless affecting the performance.
Fabrication and characteristics of planar-type methane reformer using ceria-based oxygen permeable membrane
Article
Sep 2008
SOLID STATE IONICS
<here is a image 50e9d891872315a6-d5cac9d564e56ac7> Hitoshi Takamura
Masayuki Ogawa
Koichi Suehiro
Masuo Okada
This paper describes the fabrication of a planar-type methane reformer based on a composite-type oxygen permeable membrane and its reforming properties. The membrane reformer module comprising of (Ce0.85Sm0.15)O2–15 vol.%MnFe2O4 and a ferric stainless steel separator with a same thermal expansion coefficient was successfully developed. For the reformer module, high CH4 conversion, CO and H2 selectivity of 96%, 84%, and 89% were achieved, respectively. Based on an electrical conductivity isotherm, joule heat caused by oxygen permeation in the module was estimated to be approximately 8.4 W. In addition, the effect of ZrO2-doping on the mechanical properties and oxygen permeability of the composite material was investigated. The highest Zr-content sample, (Ce0.85Sm0.15)0.2Zr0.8O2–15 vol.% MnFe2O4, showed a tetragonal structure. As a result of the crystal structural change, superior mechanical properties of Young's modulus of 337 GPa and fracture toughness of 2.8 MPa m1/2 were obtained.
Adsorptive properties of magnetite surfaces as studied by temperature-programmed desorption: Studies of O2, NO, CO2, and CO adsorption Structural properties and catalytic oxidation of benzene to phenol over CuO-impregnated mesoporous silica
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Terrence J. Udovic, J.A. Dumesic.( 1984). Adsorptive properties of magnetite surfaces as studied by temperature-programmed
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Mesoporous and nanostructured CeO2 as supports of nano-sized gold catalysts for low-temperature water-gas shift reaction
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Aurelien Idakiev
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| https://www.researchgate.net/publication/271107289_Surfactant-assisted_Hydrothermal_Synthesis_of_Ceria-Zirconia_Nanostructured_Materials_for_Catalytic_Applications |
Houstonia caerulea (Bluets) - a photographic essay | North American Rock Garden Society
This message is a photographic essay on one of my favorite plants, Houstonia caerulea(Hedyotiscaerulea), common name Bluets, a member of the Rubiaceae.
While H. caeruleais not generally thought of as an alpine plant, it does grow up into the mountains, and depending on whether one considers H. caerulea var. faxonorumvalid or not, the genus does get up into alpine zones in the White Mts of New Hampshire. There are choice mountain species in Western USA as well. At any rate, H. caeruleais such a tiny bun-forming plant and blooming for such a long period, that it certainly warrants a place in the rock garden.
Ubiquitous in Eastern USA and here in Massachusetts (Northeastern USA), it is extremely variable, always charming, yet perhaps because it is so common, the plant is largely underappreciated. Nor has the great range of variability been explored, documented, and enacted upon. Typically seen growing on sunny to partially shaded highway embankments in areas with poor soil that support only sparse grass and mosses, it is a familiar sight in its most insignificant manifestation, a mere wisp of a plant making filmy sprays of tiny white or faintly bluish flowers.
But I have seen specimens that dazzle the eye and spark the imagination, a rock gardener's dream to be sure. Typically such spectacular plants, as I have spotted them, are growing in moist locations in neighborhood lawns amongst lush, deep green spring grass, where trespasser's shall not venture, but the eye strains for glimpses of 6" round domed mounds of pristine white, as if imitating Aretian Androsace, at least from afar, but merely growing in someone's lawn! The prospect so close, yet unreachable. I imagine knocking on someone's door with what would surely seem a bizarre and suspect request to gain access to these magnificent domes of white, for a petite snippet, when they are mere "weeds" in someone's un-mown spring lawn.
Occasionally serendipity happens. On an unusually hot Sunday afternoon late April 2009, I ran a local 10k road race in Groton, Massachusetts. After the race, I walked back to a large business where runners were allowed to park. I crossed the multi-acrelawn in front of the business, approaching a partly sunny hollow at the edge of a grove of mature trees, and there before me was a fantastic colony of Houstoniacaerulea. These were in a somewhat drier site without the luxuriant hemispherical domes mentioned previously, but nonetheless an exciting colony of variable Bluets.
Let me share some photos exploring the diversity of this colony. Most were pure white, but some light blues were present too. In western Massachusetts, I have seen some very deep blue forms indeed, but none of such color were to be found here, however the range of flower size, impressive floriferousness ratio on some plants, and forms with tight foliage masses, more than compensated. What this colony revealed to me was, the superior forms with extraordinary flower count were not necessarily a factor of soil and moisture, but were indeed genetically separate individual plants where one could select superior forms. I hope to have some of these growing in my lawn soon!
Now I am not sure which species(s) we have in Minnesota. I've never looked close enough to see if stamens were attached to the corona or not, or exerted, but the overall growth pattern points to H. longifolia. I have observed them in northeastern and southern MN. One MN flora text from the 1960's only list longifolia as extant in northern MN, not mentioningcaeruleaat all. A Spring Flora of Wisconsinlists both species, withcaeruleain the sounthern part of that state. I'll have to look closer. A trek to SW MN is on my to do list this June. I may even catch the Coryphantha viviparain bloom.
At any rate, the hustonia in sw MN grow in neutral to alkaline, dry soil. In ne MN, they are in acid dry soil. Without anything to back up my decision except the general growth pattern, I am guessing both are longifolia.
Now I have to wade through my oceans of images to extract a few to prove Houstonia caeruleatolerates the desolate wastes of mid America: We finally succeeded with by planting it in a BOG with Pitcher plants and Dactylorhize majalis! I had great luck with Houstonia serpyllifoliawhen I lived in Boulder: it filled a big scree with its mats and their dazzling azure blooms: I really like that plant. It grew very well with various trumpet and star gentians. Our Western Houstonias are all being called Hedyotis it seems: they are not generally as cute, except for the adorable tiny Hedyotis rubrafrom the high Chihuahuan desert and steppe where it can be very common: I find it impossible to grow.
Re: Houstonia caerulea (Bluets) - a photographic essay
Kuchel wrote:
Hi Mark,
I tried very unsuccessfully to post something here yesterday, but it did not work. I wanted to show a Houstonia I had grown from seed and that is coming back again this spring. I will have to work on using attachments. Anyway Housonia is also growing wild here in Vermont.
MarianneFairlee, Vermont
Marianne, try the steps I mention in your other posting where you describe some difficulties uploading images, click this link to see my response:http://nargs.org/smf/index.php?topic=4.msg1151#msg1151
I'd very much like to see your Houstonia photo, so try the steps I describe, then report back with details about what the specific problems might be... let me know how far you get in the steps I describe. Also, are you using a Mac or a PC?
Re: Houstonia caerulea (Bluets) - a photographic essay
I have decided to try your Bluets once more if I find any for sale or seed. Does the Bluets come in bluer color? If I remember right those I have tried were bluer than shown in your pictures Mark, or does the pictures (or my screen) lie?
Re: Houstonia caerulea (Bluets) - a photographic essay
Hoy wrote:
I have decided to try your Bluets once more if I find any for sale or seed. Does the Bluets come in bluer color? If I remember right those I have tried were bluer than shown in your pictures Mark, or does the pictures (or my screen) lie?
Most often bluets are white lightly shaded with blue, although as you can see in the populations near me, there are pure whites, and some very pale blues too. There are forms with much deeper blue color, but I don't have any of those yet, but I do want to get a good blue one day. Check the link below for a good blue form.
Previously I posted the following link to a good blue-flowered form by SRGC member Helen Poirier, living in New Brunswick, Canada.http://www.srgc.org.uk/smf/index.php?action=dlattach;topic=4790.0;attach...
Re: Houstonia caerulea (Bluets) - a photographic essay
Yes! That is the color I remember of the plants I bought once. Thanks. I will try to get hold of different colors, maybe better chance for crossing and better viable seed.
Re: Houstonia caerulea (Bluets) - a photographic essay
Hi Mark -- Thanks for your help. I will learn how to post pics eventually. I am using a new Mac and I am having trouble changing from a PC. My Houstonia photo will probably arrive when everyone stops talking about them.
Marianne
Re: Houstonia caerulea (Bluets) - a photographic essay
Scanning through my digital photo library, I came upon two more photos of Houstoniacaeruleain a rock garden setting, taken in a friend's garden, one is white and the other is light blue.
Re: Houstonia caerulea (Bluets) - a photographic essay
The abnormally hot weather and string of sunny days pushed things along faster than usual, and suddenly the Houstoniacaeruleaplants are starting into their main flush of flowering.
It is interesting that the winter-green bun turns out to be bluest form, whereas the winter red-leaf bun turns out to be white ever so slightly tinged blue. The bluest one also has flowers 2-3 times larger than the others.
Re: Houstonia caerulea (Bluets) - a photographic essay
McDonough wrote:
The abnormally hot weather and string of sunny days pushed things along faster than usual, and suddenly the Houstoniacaeruleaplants are starting into their main flush of flowering.
It is interesting that the winter-green bun turns out to be bluest form, whereas the winter red-leaf bun turns out to be white ever so slightly tinged blue. The bluest one also has flowers 2-3 times larger than the others.
We have the usual dull weather, neither hot nor cold, neither sun nor rain! The forecast is more sun from today, but not high temperatures (about 10C at day and 4C at night).Don't you think the whitest forms lack pigments (carotenoids) in their leaves too? They have to compensate making anthocyanins instead.
Re: Houstonia caerulea (Bluets) - a photographic essay
This shot taken specifically to show the degree of slope these are planted on. I'm delighted, they have seeded around from last year's planting, and lots of babies coming up... they'll flower no matter how tiny a young plant they are.
Re: Houstonia caerulea (Bluets) - a photographic essay
Some more views as the plants are starting to "flower up a storm". More and more single baby seedlings appear, each putting up a single sweet floret. The eventually goal is to have bluets as an underplanting to my various Trillium species.
An interesting phenomenon I have observed first hand, is the deepening of flower color, some that were basically white with the slightest hint of blue, have become decidedly blue. Not sure if this is due to the weather, soil, or just a naturally occurring feature.
Re: Houstonia caerulea (Bluets) - a photographic essay
markI agree that H.caeruleadoes not get the credit it deserves. We always want what is hard to grow! 8)
I tried H.caerulealast year for the first time. Planted in the full shade of my moist north facing bed with sprinklers set to go off twice a day every other day. It did well in the spring and was still alive in the fall but no sign of it this spring. I will have to try Panayoti's method and grow it as a bog plant in dappled shade. I wonder if our humidity is too low?? I know that even with the water I put down, the ground was never what I would call wet for more than half a day. I thought full shade would work better since we are at 4000' and the UV rays are intense. So intense more than one occasion badly sun burned cacti cuttings from lower elevation sights.
Re: Houstonia caerulea (Bluets) - a photographic essay
I have tried bluets twice but they disappear after a year or two. And the humidity here is certainly not too low! On the contrary I think of trying this little gem on drier land and with more sun.
Re: Houstonia caerulea (Bluets) - a photographic essay
I was in Marcellus NY yesterday (yes that Marcellus of the shale) and observed entire neighborhoods with Houstonia carpets right in the lawns. I have started some from seed from the sewed ex and hope to establish them in my ever diminishing lawn.
Re: Houstonia caerulea (Bluets) - a photographic essay
Peachey wrote:
I was in Marcellus NY yesterday (yes that Marcellus of the shale) and observed entire neighborhoods with Houstonia carpets right in the lawns. I have started some from seed from the sewed ex and hope to establish them in my ever diminishing lawn.
Harold: glad to hear you have an ever diminishing lawn, I've got one of those too ;D Yes, the frustrating part of Houstonia, it always seems that the best looking ones grow in other people's lawns. That said, I'm convinced with my find of an extraordinary colony of H.caeruleahere locally, that there is definitely genetics involved; there are forms that clump up and flower prolifically, seed well, and appear to be strong growers, too often there are weak forms that bloom more sparsely and tend to be short-lived. So, one never knows where the seed comes from through Seedexes. I do hope to collect seed from my plants, to donate to NARGS, as I've never seen such excellent forms before. I shall also be revisiting the colony in a week and a half with my running shoes on and camera in hand, the day of the Groton 10K Road Race.
Trond: yes, for your climate I suggest trying Houstonia in more sun, and in a drier spot. The best ones are typically in full sun to high, open, partial dappled shade.
John: I don't know how to advise you to grow Houstoniacaeruleain your 6"-per-year of rain desert climate. Perhaps the reverse of what I recommend for Trond, do as you suggest and grow in shade or dappled shade. Not sure about the bog thing though, these tend to be dry growers, although they can luxuriate in moister soil while growing first thing in spring. Just as an experiment, try growing in partial shade in aclaysoil. As an aside, you might also have a better chance than those of us in wetter climates, to grow Houstoniarubra, a small bun-forming western dryland species.
Good luck everyone growing this plant... the first thing I do each day when going out to the garden, is run over to my fledgling Hosutonia colony and gaze for a while :D
Re: Houstonia caerulea (Bluets) - a photographic essay
MarkLuckily! I have a pot sown with H.rubra. I have my fingers crossed. They are cute little things! From the shot I saw the flowers are flat, pale pink, four bladed pinwheels. They have a stiff, waxy look.The leaves are narrow gray/green succulent fingers, typical dry climate adaptations.I have high hopes of growing it.
Re: Houstonia caerulea (Bluets) - a photographic essay
On then anniversary of my finding a terrific Houstoniacaeruleapatch, this past weekend I once again entered a 10k roadrace, followed by scouting around the grounds of a business that allowed runners to park and shuttle from. I found a couple different patches of Houstonia, but in one wooded hollow just in front of the building, there were drifts of Anemonequinquefoliain flower, and the diminutive Panax trifolius.
1. View of the deciduous wooded hollow and driveway passing around it. Here Houstonis grew best at the fringes where they received more light, and were fiound as only small individual non-clumping plants in the shadier spots.
2. Small and large patches of Anemonequinquefolia, very attractive but short-lived in bloom.
3. Only a little bit of variation with A.quinquefolia, there were dark-leaf forms, but with normal white flowers.
4. There were a few A.quinquefoliatinged pink on the back of the petals. Flowers that go over, turn beige.
5. A.quinquefolia, Panax trifolius, and Linnaeaborealis
6. View of woodland edge, with variable populations of Houstoniacaerulea.
7-9 Variable forms of Houstoniacaerulea
10. Lots of bluets, can you spot the one 5-petalled flower... it is just an aberration on normal 4-petalled plants.
Re: Houstonia caerulea (Bluets) - a photographic essay
You had to do a fast run to have time to look for flowers!Reminds me of once I was looking for plants in a wood here and came "exploding" out of a thicket just in front of a unsuspecting lady (had not seen her) walking on the path. I think she is still running...
The Houstonias are marvellous! And the A.quinquefoliatoo. They are a little different from A.nemorosa. Panax trifoliuslooks like a fine woodland plant (I am always hunting for plants that will grow in my woodland).
Re: Houstonia caerulea (Bluets) - a photographic essay
After a full month of flowering, the plants are getting bigger and more floriferous than I imagined they would, there appears to be no end of flowering in sight. They have certainly exceeded my expectations. And I'm glad too, that my attempt to pick snippets off a variety of forms has paid off, as under more optimal conditions without competition from grass, their special characteristics become amplified. The large-flowered blue one has petals that curve upwards, thus has a different look to the flowers.
Re: Houstonia caerulea (Bluets) - a photographic essay
You are tempting me!
Re: Houstonia caerulea (Bluets) - a photographic essay
I got this plant last year as Houstonia serpyllifoliavery nice blue growing an a small bog garden.
Re: Houstonia caerulea (Bluets) - a photographic essay
Very nice Harold, a good clear blue color, I like it, wish I had some as blue as that! Hopefully it'll seed around for you.
I'm starting to tuck little bits of H.caeruleaat the edges of woodland paths, in the tiniest of spots between rocks and logs, and they look so perky and natural. Here is one such scenario:
Re: Houstonia caerulea (Bluets) - a photographic essay
Very cute flowers!Can hardly wait for my seedlings to appear ;D
Re: Houstonia caerulea (Bluets) - a photographic essay
Funny how they thrive in barren compacted clay soil, but die out in garden soil, at least in my part of Massachusetts. Occasionally get a few in the lawn, too.
"Solarized" a patch of barren soil and they bloomed there next spring, suggesting that plants germinating in the early fall can flower the next spring.
Charles Swanson NE Massachusetts
Re: Houstonia caerulea (Bluets) - a photographic essay
Late in the season, Houstoniacaerulearetracts into a basal cushion of foliage. Older plants tend to die off, so I would call this species a short-lived perennial, fortunately seedlings are popping up here and there, which I welcome. In the first photo you can see some seedling plants off to the right of a parent plant, with some dried flower stem remnants. In the photo on the right is a mound that flowered prolifically all spring and well into the summer, showing a profusion of dried stem remnants, the mound looking strong and hunkered down for the winter.
Reviving an old post here.
Reviving an old post here. Yesterday I potted up a dense domed hummock of Houstonia careulea, plus a couple seedling clumps from it, into a clay pot, to enjoy the evergreen mounds over winter on my deck. The pot is from Grand Ridge Nursery (Phil Pearson, Steve Doonan) of Issaquah Washington, that I brought back with me when I returned to Massachusetts in 1986 after a 4 years living near Seattle Washington. These pots are special, beautiful high-fire pots designed to resist winter breakage, intended for alpine plants; 26 years years outside and planted and still intact. Using indigenous rock (all I need to do is dig a hole to unearth lots and lots of such rocks), the stone mulch, while appearing a different color, is the same crumbling rock that I break up with a hammer.
Not all Houstonia caerulea clump up so nice and dense, many grow as wispy little nothings, but those that do tend to grow densely are genetically stable, and make wonderful little cushions that look great all winter. In spring they will flower for more than 2 months, smothered with short-stemmed clouds of white tinged blue.
| https://www.nargs.org/comment/3242 |
Example usage for com.fasterxml.jackson.core JsonParser skipChildren
Example usage for com.fasterxml.jackson.core JsonParser skipChildren
List of usage examples for com.fasterxml.jackson.core JsonParser skipChildren
Introduction
In this page you can find the example usage for com.fasterxml.jackson.core JsonParser skipChildren.
Prototype
public abstract JsonParser skipChildren() throws IOException , JsonParseException;
Source Link
Document
Method that will skip all child tokens of an array or object token that the parser currently points to, iff stream points to JsonToken#START_OBJECT or JsonToken#START_ARRAY .
Usage
From source file:
com.adobe.communities.ugc.migration.importer.UGCImportHelper.java
protected static void importTranslation( final JsonParser jsonParser, final Resource post) throws IOException {
JsonToken token = jsonParser.getCurrentToken(); final Map < String , Object > properties = new HashMap < String , Object >(); if (token != JsonToken.START_OBJECT) { throw new IOException ( "expected a start object token, got " + token.asString());
} / * f r o m w w w . j a v a 2 s . c o m * / properties.put( "jcr:primaryType" , "social:asiResource" ); Resource translationFolder = null;
token = jsonParser.nextToken(); while (token == JsonToken.FIELD_NAME) {
token = jsonParser.nextToken(); //advance to the field value if (jsonParser.getCurrentName().equals((ContentTypeDefinitions.LABEL_TRANSLATIONS))) { if (null == translationFolder) { // begin by creating the translation folder resource translationFolder = post.getResourceResolver().create(post, "translation" , properties);
} //now check to see if any translations exist if (token == JsonToken.START_OBJECT) {
token = jsonParser.nextToken(); if (token == JsonToken.FIELD_NAME) { while (token == JsonToken.FIELD_NAME) { // each new field represents another translation final Map < String , Object > translationProperties = new HashMap < String , Object >();
translationProperties.put( "jcr:primaryType" , "social:asiResource" ); String languageLabel = jsonParser.getCurrentName();
token = jsonParser.nextToken(); if (token != JsonToken.START_OBJECT) { throw new IOException ( "expected a start object token for translation item, got " + token.asString());
}
token = jsonParser.nextToken(); while (token != JsonToken.END_OBJECT) {
jsonParser.nextToken(); //get next field value if (jsonParser.getCurrentName()
.equals(ContentTypeDefinitions.LABEL_TIMESTAMP_FIELDS)) {
jsonParser.nextToken(); // advance to first field name while (!jsonParser.getCurrentToken().equals(JsonToken.END_ARRAY)) { final String timestampLabel = jsonParser.getValueAsString(); if (translationProperties.containsKey(timestampLabel)) { final Calendar calendar = new GregorianCalendar ();
calendar.setTimeInMillis( Long .parseLong(( String ) translationProperties.get(timestampLabel)));
translationProperties.put(timestampLabel, calendar.getTime());
}
jsonParser.nextToken();
}
} else if (jsonParser.getCurrentName()
.equals(ContentTypeDefinitions.LABEL_SUBNODES)) {
jsonParser.skipChildren();
} else {
translationProperties.put(jsonParser.getCurrentName(), URLDecoder .decode(jsonParser.getValueAsString(), "UTF-8" ));
}
token = jsonParser.nextToken(); //get next field label } // add the language-specific translation under the translation folder resource Resource translation = post.getResourceResolver().create(post.getChild( "translation" ),
languageLabel, translationProperties); if (null == translation) { throw new IOException ( "translation not actually imported" );
}
}
jsonParser.nextToken(); //skip END_OBJECT token for translation } else if (token == JsonToken.END_OBJECT) { // no actual translation to import, so we're done here jsonParser.nextToken(); }
} else { throw new IOException ( "expected translations to be contained in an object, saw instead: " + token.asString());
}
} else if (jsonParser.getCurrentName().equals( "mtlanguage" )
|| jsonParser.getCurrentName().equals( "jcr:createdBy" )) {
properties.put(jsonParser.getCurrentName(), jsonParser.getValueAsString());
} else if (jsonParser.getCurrentName().equals( "jcr:created" )) { final Calendar calendar = new GregorianCalendar ();
calendar.setTimeInMillis(jsonParser.getLongValue());
properties.put( "jcr:created" , calendar.getTime());
}
token = jsonParser.nextToken();
} if (null == translationFolder && properties.containsKey( "mtlanguage" )) { // it's possible that no translations existed, so we need to make sure the translation resource (which // includes the original post's detected language) is created anyway post.getResourceResolver().create(post, "translation" , properties);
}
}
From source file:
com.adobe.communities.ugc.migration.importer.GenericUGCImporter.java
/**
* Handle each of the importable types of ugc content
* @param jsonParser - the parsing stream
* @param resource - the parent resource of whatever it is we're importing (must already exist)
* @throws ServletException / / w w w . j a v a 2 s . c o m * @throws IOException
*/ protected void importFile( final JsonParser jsonParser, final Resource resource, final ResourceResolver resolver) throws ServletException, IOException { final UGCImportHelper importHelper = new UGCImportHelper();
JsonToken token1 = jsonParser.getCurrentToken();
importHelper.setSocialUtils(socialUtils); if (token1.equals(JsonToken.START_OBJECT)) {
jsonParser.nextToken(); if (jsonParser.getCurrentName().equals(ContentTypeDefinitions.LABEL_CONTENT_TYPE)) {
jsonParser.nextToken(); final String contentType = jsonParser.getValueAsString(); if (contentType.equals(ContentTypeDefinitions.LABEL_QNA_FORUM)) {
importHelper.setQnaForumOperations(qnaForumOperations);
} else if (contentType.equals(ContentTypeDefinitions.LABEL_FORUM)) {
importHelper.setForumOperations(forumOperations);
} else if (contentType.equals(ContentTypeDefinitions.LABEL_CALENDAR)) {
importHelper.setCalendarOperations(calendarOperations);
} else if (contentType.equals(ContentTypeDefinitions.LABEL_JOURNAL)) {
importHelper.setJournalOperations(journalOperations);
} else if (contentType.equals(ContentTypeDefinitions.LABEL_FILELIBRARY)) {
importHelper.setFileLibraryOperations(fileLibraryOperations);
}
importHelper.setTallyService(tallyOperationsService); // (everything potentially needs tally) importHelper.setCommentOperations(commentOperations); // nearly anything can have comments on it jsonParser.nextToken(); // content if (jsonParser.getCurrentName().equals(ContentTypeDefinitions.LABEL_CONTENT)) {
jsonParser.nextToken();
token1 = jsonParser.getCurrentToken(); if (token1.equals(JsonToken.START_OBJECT) || token1.equals(JsonToken.START_ARRAY)) { if (!resolver.isLive()) { throw new ServletException( "Resolver is already closed" );
}
} else { throw new ServletException( "Start object token not found for content" );
} if (token1.equals(JsonToken.START_OBJECT)) { try { if (contentType.equals(ContentTypeDefinitions.LABEL_QNA_FORUM)) {
importHelper.importQnaContent(jsonParser, resource, resolver);
} else if (contentType.equals(ContentTypeDefinitions.LABEL_FORUM)) {
importHelper.importForumContent(jsonParser, resource, resolver);
} else if (contentType.equals(ContentTypeDefinitions.LABEL_COMMENTS)) {
importHelper.importCommentsContent(jsonParser, resource, resolver);
} else if (contentType.equals(ContentTypeDefinitions.LABEL_JOURNAL)) {
importHelper.importJournalContent(jsonParser, resource, resolver);
} else if (contentType.equals(ContentTypeDefinitions.LABEL_FILELIBRARY)) {
importHelper.importFileLibrary(jsonParser, resource, resolver);
} else {
LOG.info( "Unsupported content type: {}" , contentType); jsonParser.skipChildren(); }
jsonParser.nextToken();
} catch ( final IOException e) { throw new ServletException(e);
}
jsonParser.nextToken(); // skip over END_OBJECT } else { try { if (contentType.equals(ContentTypeDefinitions.LABEL_CALENDAR)) {
importHelper.importCalendarContent(jsonParser, resource, resolver);
} else if (contentType.equals(ContentTypeDefinitions.LABEL_TALLY)) {
importHelper.importTallyContent(jsonParser, resource, resolver);
} else {
LOG.info( "Unsupported content type: {}" , contentType);
jsonParser.skipChildren();
}
jsonParser.nextToken();
} catch ( final IOException e) { throw new ServletException(e);
}
jsonParser.nextToken(); // skip over END_ARRAY }
} else { throw new ServletException( "Content not found" );
}
} else { throw new ServletException( "No content type specified" );
}
} else { throw new ServletException( "Invalid Json format" );
}
}
From source file:
com.adobe.communities.ugc.migration.importer.ImportFileUploadServlet.java
/**
* Handle each of the importable types of ugc content
* @param jsonParser - the parsing stream
* @param resource - the parent resource of whatever it is we're importing (must already exist)
* @throws ServletException / * f r o m w w w . j a v a 2 s . c o m * / * @throws IOException
*/ private void importFile( final JsonParser jsonParser, final Resource resource, final ResourceResolver resolver) throws ServletException, IOException { final UGCImportHelper importHelper = new UGCImportHelper();
JsonToken token1 = jsonParser.getCurrentToken(); if (token1.equals(JsonToken.START_OBJECT)) {
jsonParser.nextToken(); if (jsonParser.getCurrentName().equals(ContentTypeDefinitions.LABEL_CONTENT_TYPE)) {
jsonParser.nextToken(); final String contentType = jsonParser.getValueAsString(); if (contentType.equals(ContentTypeDefinitions.LABEL_QNA_FORUM)) {
importHelper.setQnaForumOperations(qnaForumOperations);
} else if (contentType.equals(ContentTypeDefinitions.LABEL_FORUM)) {
importHelper.setForumOperations(forumOperations);
} else if (contentType.equals(ContentTypeDefinitions.LABEL_COMMENTS)) {
importHelper.setCommentOperations(commentOperations);
} else if (contentType.equals(ContentTypeDefinitions.LABEL_CALENDAR)) {
importHelper.setCalendarOperations(calendarOperations);
} else if (contentType.equals(ContentTypeDefinitions.LABEL_JOURNAL)) {
importHelper.setJournalOperations(journalOperations);
} else if (contentType.equals(ContentTypeDefinitions.LABEL_TALLY)) {
importHelper.setSocialUtils(socialUtils);
}
importHelper.setTallyService(tallyOperationsService); // (everything potentially needs tally) jsonParser.nextToken(); // content if (jsonParser.getCurrentName().equals(ContentTypeDefinitions.LABEL_CONTENT)) {
jsonParser.nextToken();
token1 = jsonParser.getCurrentToken(); if (token1.equals(JsonToken.START_OBJECT) || token1.equals(JsonToken.START_ARRAY)) { if (!resolver.isLive()) { throw new ServletException( "Resolver is already closed" );
}
} else { throw new ServletException( "Start object token not found for content" );
} if (token1.equals(JsonToken.START_OBJECT)) { try { if (contentType.equals(ContentTypeDefinitions.LABEL_QNA_FORUM)) {
importHelper.importQnaContent(jsonParser, resource, resolver);
} else if (contentType.equals(ContentTypeDefinitions.LABEL_FORUM)) {
importHelper.importForumContent(jsonParser, resource, resolver);
} else if (contentType.equals(ContentTypeDefinitions.LABEL_COMMENTS)) {
importHelper.importCommentsContent(jsonParser, resource, resolver);
} else if (contentType.equals(ContentTypeDefinitions.LABEL_JOURNAL)) {
importHelper.importJournalContent(jsonParser, resource, resolver);
} else {
LOG.info( "Unsupported content type: {}" , contentType); jsonParser.skipChildren(); }
jsonParser.nextToken();
} catch ( final IOException e) { throw new ServletException(e);
}
jsonParser.nextToken(); // skip over END_OBJECT } else { try { if (contentType.equals(ContentTypeDefinitions.LABEL_CALENDAR)) {
importHelper.importCalendarContent(jsonParser, resource);
} else if (contentType.equals(ContentTypeDefinitions.LABEL_TALLY)) {
importHelper.importTallyContent(jsonParser, resource);
} else {
LOG.info( "Unsupported content type: {}" , contentType);
jsonParser.skipChildren();
}
jsonParser.nextToken();
} catch ( final IOException e) { throw new ServletException(e);
}
jsonParser.nextToken(); // skip over END_ARRAY }
} else { throw new ServletException( "Content not found" );
}
} else { throw new ServletException( "No content type specified" );
}
} else { throw new ServletException( "Invalid Json format" );
}
}
From source file:
com.adobe.communities.ugc.migration.importer.UGCImportHelper.java
protected void extractTopic( final JsonParser jsonParser, final Resource resource, final ResourceResolver resolver, final CommentOperations operations) throws IOException , ServletException { if (jsonParser.getCurrentToken().equals(JsonToken.END_OBJECT)) { return ; // replies could just be an empty object (i.e. "ugc:replies":{} ) in which case, do nothing } / * f r o m w w w . j a v a 2 s . c o m * / final Map < String , Object > properties = new HashMap < String , Object >();
properties.put( "social:key" , jsonParser.getCurrentName()); Resource post = null;
jsonParser.nextToken(); if (jsonParser.getCurrentToken().equals(JsonToken.START_OBJECT)) {
jsonParser.nextToken(); String author = null; List < DataSource > attachments = new ArrayList < DataSource >(); while (!jsonParser.getCurrentToken().equals(JsonToken.END_OBJECT)) { final String label = jsonParser.getCurrentName();
JsonToken token = jsonParser.nextToken(); if (jsonParser.getCurrentToken().isScalarValue()) { // either a string, boolean, or long value if (token.isNumeric()) {
properties.put(label, jsonParser.getValueAsLong());
} else { final String value = jsonParser.getValueAsString(); if (value.equals( "true" ) || value.equals( "false" )) {
properties.put(label, jsonParser.getValueAsBoolean());
} else { final String decodedValue = URLDecoder .decode(value, "UTF-8" ); if (label.equals( "language" )) {
properties.put( "mtlanguage" , decodedValue);
} else {
properties.put(label, decodedValue); if (label.equals( "userIdentifier" )) {
author = decodedValue;
} else if (label.equals( "jcr:description" )) {
properties.put( "message" , decodedValue);
}
}
}
}
} else if (label.equals(ContentTypeDefinitions.LABEL_ATTACHMENTS)) {
attachments = getAttachments(jsonParser);
} else if (label.equals(ContentTypeDefinitions.LABEL_REPLIES)
|| label.equals(ContentTypeDefinitions.LABEL_TALLY)
|| label.equals(ContentTypeDefinitions.LABEL_TRANSLATION)
|| label.equals(ContentTypeDefinitions.LABEL_SUBNODES)) { // replies and sub-nodes ALWAYS come after all other properties and attachments have been listed, // so we can create the post now if we haven't already, and then dive in if (post == null) { try {
post = createPost(resource, author, properties, attachments,
resolver.adaptTo(Session. class ), operations);
resProvider = SocialResourceUtils.getSocialResource(post).getResourceProvider();
} catch ( Exception e) { throw new ServletException(e.getMessage(), e);
}
} if (label.equals(ContentTypeDefinitions.LABEL_REPLIES)) { if (token.equals(JsonToken.START_OBJECT)) {
jsonParser.nextToken(); while (!token.equals(JsonToken.END_OBJECT)) {
extractTopic(jsonParser, post, resolver, operations);
token = jsonParser.nextToken();
}
} else { throw new IOException ( "Expected an object for the subnodes" );
}
} else if (label.equals(ContentTypeDefinitions.LABEL_SUBNODES)) { if (token.equals(JsonToken.START_OBJECT)) {
token = jsonParser.nextToken(); try { while (!token.equals(JsonToken.END_OBJECT)) { final String subnodeType = jsonParser.getCurrentName();
token = jsonParser.nextToken(); if (token.equals(JsonToken.START_OBJECT)) { jsonParser.skipChildren(); token = jsonParser.nextToken();
}
}
} catch ( final IOException e) { throw new IOException ( "unable to skip child of sub-nodes" , e);
}
} else { final String field = jsonParser.getValueAsString(); throw new IOException ( "Expected an object for the subnodes. Instead: " + field);
}
} else if (label.equals(ContentTypeDefinitions.LABEL_TALLY)) {
UGCImportHelper.extractTally(post, jsonParser, resProvider, tallyOperationsService);
} else if (label.equals(ContentTypeDefinitions.LABEL_TRANSLATION)) {
importTranslation(jsonParser, post);
resProvider.commit(post.getResourceResolver());
}
} else if (jsonParser.getCurrentToken().equals(JsonToken.START_OBJECT)) {
properties.put(label, UGCImportHelper.extractSubmap(jsonParser));
} else if (jsonParser.getCurrentToken().equals(JsonToken.START_ARRAY)) {
jsonParser.nextToken(); // skip the START_ARRAY token if (label.equals(ContentTypeDefinitions.LABEL_TIMESTAMP_FIELDS)) { while (!jsonParser.getCurrentToken().equals(JsonToken.END_ARRAY)) { final String timestampLabel = jsonParser.getValueAsString(); if (properties.containsKey(timestampLabel)
&& properties.get(timestampLabel) instanceof Long ) { final Calendar calendar = new GregorianCalendar ();
calendar.setTimeInMillis(( Long ) properties.get(timestampLabel));
properties.put(timestampLabel, calendar.getTime());
}
jsonParser.nextToken();
}
} else { final List < String > subArray = new ArrayList < String >(); while (!jsonParser.getCurrentToken().equals(JsonToken.END_ARRAY)) {
subArray.add(jsonParser.getValueAsString());
jsonParser.nextToken();
} String [] strings = new String [subArray.size()]; for ( int i = 0; i < subArray.size(); i++) {
strings[i] = subArray.get(i);
}
properties.put(label, strings);
}
}
jsonParser.nextToken();
} if (post == null) { try {
post = createPost(resource, author, properties, attachments, resolver.adaptTo(Session. class ),
operations); if (null == resProvider) {
resProvider = SocialResourceUtils.getSocialResource(post).getResourceProvider();
} // resProvider.commit(resolver); } catch ( Exception e) { throw new ServletException(e.getMessage(), e);
}
}
} else { throw new IOException ( "Improperly formed JSON - expected an OBJECT_START token, but got " + jsonParser.getCurrentToken().toString());
}
}
From source file:
org.apache.hadoop.hbase.rest.TestTableScan.java
@Test public void testStreamingJSON() throws Exception { //Test with start row and end row. StringBuilder builder = new StringBuilder ();
builder.append( "/*" );
builder.append( "?" );
builder.append(Constants.SCAN_COLUMN + "=" + COLUMN_1);
builder.append( "&" );
builder.append(Constants.SCAN_START_ROW + "=aaa" );
builder.append( "&" );
builder.append(Constants.SCAN_END_ROW + "=aay" ); Response response = client.get( "/" + TABLE + builder.toString(), Constants.MIMETYPE_JSON);
assertEquals(200, response.getCode()); int count = 0;
ObjectMapper mapper = new JacksonJaxbJsonProvider().locateMapper(CellSetModel. class ,
MediaType.APPLICATION_JSON_TYPE);
JsonFactory jfactory = new JsonFactory(mapper); JsonParser jParser = jfactory.createJsonParser(response.getStream()); boolean found = false; while (jParser.nextToken() != JsonToken.END_OBJECT) { if (jParser.getCurrentToken() == JsonToken.START_OBJECT && found) {
RowModel row = jParser.readValueAs(RowModel. class );
assertNotNull(row.getKey()); for ( int i = 0; i < row.getCells().size(); i++) { if (count == 0) {
assertEquals( "aaa" , Bytes.toString(row.getKey()));
} / / w w w . j a v a 2 s . c o m if (count == 23) {
assertEquals( "aax" , Bytes.toString(row.getKey()));
}
count++;
} jParser.skipChildren(); } else {
found = jParser.getCurrentToken() == JsonToken.START_ARRAY;
}
}
assertEquals(24, count);
}
From source file:
org.jbpm.designer.bpmn2.impl.Bpmn2JsonUnmarshaller.java
public BaseElement unmarshallItem(JsonParser parser, String preProcessingData)
throws
JsonParseException,
IOException
{
String
resourceId = null;
/
*
f
r
o
m
w
w
w
.
j
a
v
a
2
s
.
c
o
m
*
/
Map
<
String
,
String
> properties = null;
String
stencil = null;
List
<BaseElement> childElements =
new
ArrayList
<BaseElement>();
List
<
String
> outgoing =
new
ArrayList
<
String
>();
while
(parser.nextToken() != JsonToken.END_OBJECT) {
String
fieldname = parser.getCurrentName();
parser.nextToken();
if
(
"resourceId"
.equals(fieldname)) {
resourceId = parser.getText();
}
else
if
(
"properties"
.equals(fieldname)) {
properties = unmarshallProperties(parser);
}
else
if
(
"stencil"
.equals(fieldname)) {
// "stencil":{"id":"Task"},
parser.nextToken();
parser.nextToken();
stencil = parser.getText();
parser.nextToken();
}
else
if
(
"childShapes"
.equals(fieldname)) {
while
(parser.nextToken() != JsonToken.END_ARRAY) {
// open the
// object
// the childShapes element is a json array. We opened the
// array.
childElements.add(unmarshallItem(parser, preProcessingData));
}
}
else
if
(
"bounds"
.equals(fieldname)) {
// bounds: {"lowerRight":{"x":484.0,"y":198.0},"upperLeft":{"x":454.0,"y":168.0}}
parser.nextToken();
parser.nextToken();
parser.nextToken();
parser.nextToken();
Integer
x2 = parser.getIntValue();
parser.nextToken();
parser.nextToken();
Integer
y2 = parser.getIntValue();
parser.nextToken();
parser.nextToken();
parser.nextToken();
parser.nextToken();
parser.nextToken();
Integer
x1 = parser.getIntValue();
parser.nextToken();
parser.nextToken();
Integer
y1 = parser.getIntValue();
parser.nextToken();
parser.nextToken();
// by default the org.eclipse.dd.dc bounds says
// its features are set if they are non-zero
// we need to change that so that nodes placed on the canvas borders
// where x or y can be zero still are treated as set features
// otherwise they will not end up as attributes in the produced xml
BoundsImpl b =
new
BoundsImpl() {
@
Override
public
boolean
eIsSet(
int
featureID) {
switch
(featureID) {
case
0:
if
(
this
.height >= 0.0F) {
return
true;
}
return
false;
case
1:
if
(
this
.width >= 0.0F) {
return
true;
}
return
false;
case
2:
if
(
this
.x >= 0.0F) {
return
true;
}
return
false;
case
3:
if
(
this
.y >= 0.0F) {
return
true;
}
return
false;
default
:
return
super
.eIsSet(featureID);
}
}
};
b.setX(x1);
b.setY(y1);
b.setWidth(x2 - x1);
b.setHeight(y2 - y1);
this
._bounds.put(resourceId, b);
}
else
if
(
"dockers"
.equals(fieldname)) {
// "dockers":[{"x":50,"y":40},{"x":353.5,"y":115},{"x":353.5,"y":152},{"x":50,"y":40}],
List
<
Point
> dockers =
new
ArrayList
<
Point
>();
JsonToken nextToken = parser.nextToken();
boolean
end = JsonToken.END_ARRAY.equals(nextToken);
while
(!end) {
nextToken = parser.nextToken();
nextToken = parser.nextToken();
Integer
x = parser.getIntValue();
parser.nextToken();
parser.nextToken();
Integer
y = parser.getIntValue();
Point
point = DcFactory.eINSTANCE.createPoint();
point.setX(x);
point.setY(y);
dockers.add(point);
parser.nextToken();
nextToken = parser.nextToken();
end = JsonToken.END_ARRAY.equals(nextToken);
}
this
._dockers.put(resourceId, dockers);
}
else
if
(
"outgoing"
.equals(fieldname)) {
while
(parser.nextToken() != JsonToken.END_ARRAY) {
// {resourceId: oryx_1AAA8C9A-39A5-42FC-8ED1-507A7F3728EA}
parser.nextToken();
parser.nextToken();
outgoing.add(parser.getText());
parser.nextToken();
}
// pass on the array
parser.skipChildren();
}
else
if
(
"target"
.equals(fieldname)) {
// we already collected that info with the outgoing field.
parser.skipChildren();
// "target": {
// "resourceId": "oryx_A75E7546-DF71-48EA-84D3-2A8FD4A47568"
// }
// add to the map:
// parser.nextToken(); // resourceId:
// parser.nextToken(); // the value we want to save
// targetId = parser.getText();
// parser.nextToken(); // }, closing the object
}
}
properties.put(
"resourceId"
, resourceId);
boolean
customElement = isCustomElement(properties.get(
"tasktype"
), preProcessingData);
BaseElement baseElt =
this
.createBaseElement(stencil, properties.get(
"tasktype"
), customElement);
// register the sequence flow targets.
if
(baseElt
instanceof
SequenceFlow) {
_sequenceFlowTargets.addAll(outgoing);
}
_outgoingFlows.put(baseElt, outgoing);
_objMap.put(baseElt, resourceId);
// keep the object around to do connections
_idMap.put(resourceId, baseElt);
// baseElt.setId(resourceId); commented out as bpmn2 seems to create
// duplicate ids right now.
applyProperties(baseElt, properties, preProcessingData);
if
(baseElt
instanceof
Definitions) {
Process
rootLevelProcess = null;
if
(childElements == null || childElements.size() < 1) {
if
(rootLevelProcess == null) {
rootLevelProcess = Bpmn2Factory.eINSTANCE.createProcess();
// set the properties and item definitions first
if
(properties.get(
"vardefs"
) != null && properties.get(
"vardefs"
).length() > 0) {
String
[] vardefs = properties.get(
"vardefs"
).split(
",\\s*"
);
for
(
String
vardef : vardefs) {
Property prop = Bpmn2Factory.eINSTANCE.createProperty();
ItemDefinition itemdef = Bpmn2Factory.eINSTANCE.createItemDefinition();
// check if we define a structure ref in the definition
if
(vardef.contains(
":"
)) {
String
[] vardefParts = vardef.split(
":\\s*"
);
prop.setId(vardefParts[0]);
itemdef.setId(
"_"
+ prop.getId() +
"Item"
);
boolean
haveKPI = false;
String
kpiValue =
""
;
if
(vardefParts.length == 3) {
itemdef.setStructureRef(vardefParts[1]);
if
(vardefParts[2].equals(
"true"
)) {
haveKPI = true;
kpiValue = vardefParts[2];
}
}
if
(vardefParts.length == 2) {
if
(vardefParts[1].equals(
"true"
) || vardefParts[1].equals(
"false"
)) {
if
(vardefParts[1].equals(
"true"
)) {
haveKPI = true;
kpiValue = vardefParts[1];
}
}
else
{
itemdef.setStructureRef(vardefParts[1]);
}
}
if
(haveKPI) {
Utils.setMetaDataExtensionValue(prop,
"customKPI"
, wrapInCDATABlock(kpiValue));
}
}
else
{
prop.setId(vardef);
itemdef.setId(
"_"
+ prop.getId() +
"Item"
);
}
prop.setItemSubjectRef(itemdef);
rootLevelProcess.getProperties().add(prop);
((Definitions) baseElt).getRootElements().add(itemdef);
}
}
if
(properties.get(
"adhocprocess"
) != null && properties.get(
"adhocprocess"
).equals(
"true"
)) {
ExtendedMetaData metadata = ExtendedMetaData.INSTANCE;
EAttributeImpl extensionAttribute = (EAttributeImpl) metadata
.demandFeature(
"http://www.jboss.org/drools"
,
"adHoc"
, false, false);
SimpleFeatureMapEntry extensionEntry =
new
SimpleFeatureMapEntry(extensionAttribute,
properties.get(
"adhocprocess"
));
rootLevelProcess.getAnyAttribute().add(extensionEntry);
}
if
(properties.get(
"customdescription"
) != null
&& properties.get(
"customdescription"
).length() > 0) {
Utils.setMetaDataExtensionValue(rootLevelProcess,
"customDescription"
,
wrapInCDATABlock(properties.get(
"customdescription"
)));
}
if
(properties.get(
"customcaseidprefix"
) != null
&& properties.get(
"customcaseidprefix"
).length() > 0) {
Utils.setMetaDataExtensionValue(rootLevelProcess,
"customCaseIdPrefix"
,
wrapInCDATABlock(properties.get(
"customcaseidprefix"
)));
}
if
(properties.get(
"customcaseroles"
) != null
&& properties.get(
"customcaseroles"
).length() > 0) {
Utils.setMetaDataExtensionValue(rootLevelProcess,
"customCaseRoles"
,
wrapInCDATABlock(properties.get(
"customcaseroles"
)));
}
// customsladuedate metadata
applySlaDueDateProperties(rootLevelProcess, properties);
rootLevelProcess.setId(properties.get(
"id"
));
applyProcessProperties(rootLevelProcess, properties);
((Definitions) baseElt).getRootElements().add(rootLevelProcess);
}
}
else
{
for
(BaseElement child : childElements) {
// tasks are only permitted under processes.
// a process should be created implicitly for tasks at the root
// level.
// process designer doesn't make a difference between tasks and
// global tasks.
// if a task has sequence edges it is considered a task,
// otherwise it is considered a global task.
// if (child instanceof Task && _outgoingFlows.get(child).isEmpty() && !_sequenceFlowTargets.contains(_objMap.get(child))) {
// // no edges on a task at the top level! We replace it with a
// // global task.
// GlobalTask task = null;
// if (child instanceof ScriptTask) {
// task = Bpmn2Factory.eINSTANCE.createGlobalScriptTask();
// ((GlobalScriptTask) task).setScript(((ScriptTask) child).getScript());
// ((GlobalScriptTask) task).setScriptLanguage(((ScriptTask) child).getScriptFormat());
// // TODO scriptLanguage missing on scriptTask
// } else if (child instanceof UserTask) {
// task = Bpmn2Factory.eINSTANCE.createGlobalUserTask();
// } else if (child instanceof ServiceTask) {
// // we don't have a global service task! Fallback on a
// // normal global task
// task = Bpmn2Factory.eINSTANCE.createGlobalTask();
// } else if (child instanceof BusinessRuleTask) {
// task = Bpmn2Factory.eINSTANCE.createGlobalBusinessRuleTask();
// } else if (child instanceof ManualTask) {
// task = Bpmn2Factory.eINSTANCE.createGlobalManualTask();
// } else {
// task = Bpmn2Factory.eINSTANCE.createGlobalTask();
// }
//
// task.setName(((Task) child).getName());
// task.setIoSpecification(((Task) child).getIoSpecification());
// task.getDocumentation().addAll(((Task) child).getDocumentation());
// ((Definitions) baseElt).getRootElements().add(task);
// continue;
// } else {
if
(child
instanceof
SequenceFlow) {
// for some reason sequence flows are placed as root elements.
// find if the target has a container, and if we can use it:
List
<
String
> ids = _outgoingFlows.get(child);
FlowElementsContainer container = null;
for
(
String
id : ids) {
// yes, we iterate, but we'll take the first in the list that will work.
Object
obj = _idMap.get(id);
if
(obj
instanceof
EObject
&& ((EObject) obj).eContainer()
instanceof
FlowElementsContainer) {
container = (FlowElementsContainer) ((EObject) obj).eContainer();
break
;
}
}
if
(container != null) {
container.getFlowElements().add((SequenceFlow) child);
continue
;
}
}
if
(child
instanceof
Task || child
instanceof
SequenceFlow || child
instanceof
Gateway
|| child
instanceof
Event
|| child
instanceof
Artifact || child
instanceof
DataObject
|| child
instanceof
SubProcess || child
instanceof
Lane || child
instanceof
CallActivity
|| child
instanceof
TextAnnotation) {
if
(rootLevelProcess == null) {
rootLevelProcess = Bpmn2Factory.eINSTANCE.createProcess();
// set the properties and item definitions first
if
(properties.get(
"vardefs"
) != null && properties.get(
"vardefs"
).length() > 0) {
String
[] vardefs = properties.get(
"vardefs"
).split(
",\\s*"
);
for
(
String
vardef : vardefs) {
Property prop = Bpmn2Factory.eINSTANCE.createProperty();
ItemDefinition itemdef = Bpmn2Factory.eINSTANCE.createItemDefinition();
// check if we define a structure ref in the definition
if
(vardef.contains(
":"
)) {
String
[] vardefParts = vardef.split(
":\\s*"
);
prop.setId(vardefParts[0]);
itemdef.setId(
"_"
+ prop.getId() +
"Item"
);
boolean
haveKPI = false;
String
kpiValue =
""
;
if
(vardefParts.length == 3) {
itemdef.setStructureRef(vardefParts[1]);
if
(vardefParts[2].equals(
"true"
)) {
haveKPI = true;
kpiValue = vardefParts[2];
}
}
if
(vardefParts.length == 2) {
if
(vardefParts[1].equals(
"true"
) || vardefParts[1].equals(
"false"
)) {
if
(vardefParts[1].equals(
"true"
)) {
haveKPI = true;
kpiValue = vardefParts[1];
}
}
else
{
itemdef.setStructureRef(vardefParts[1]);
}
}
if
(haveKPI) {
Utils.setMetaDataExtensionValue(prop,
"customKPI"
,
wrapInCDATABlock(kpiValue));
}
}
else
{
prop.setId(vardef);
itemdef.setId(
"_"
+ prop.getId() +
"Item"
);
}
prop.setItemSubjectRef(itemdef);
rootLevelProcess.getProperties().add(prop);
((Definitions) baseElt).getRootElements().add(itemdef);
}
}
if
(properties.get(
"adhocprocess"
) != null
&& properties.get(
"adhocprocess"
).equals(
"true"
)) {
ExtendedMetaData metadata = ExtendedMetaData.INSTANCE;
EAttributeImpl extensionAttribute = (EAttributeImpl) metadata
.demandFeature(
"http://www.jboss.org/drools"
,
"adHoc"
, false, false);
SimpleFeatureMapEntry extensionEntry =
new
SimpleFeatureMapEntry(extensionAttribute,
properties.get(
"adhocprocess"
));
rootLevelProcess.getAnyAttribute().add(extensionEntry);
}
if
(properties.get(
"customdescription"
) != null
&& properties.get(
"customdescription"
).length() > 0) {
Utils.setMetaDataExtensionValue(rootLevelProcess,
"customDescription"
,
wrapInCDATABlock(properties.get(
"customdescription"
)));
}
if
(properties.get(
"customcaseidprefix"
) != null
&& properties.get(
"customcaseidprefix"
).length() > 0) {
Utils.setMetaDataExtensionValue(rootLevelProcess,
"customCaseIdPrefix"
,
wrapInCDATABlock(properties.get(
"customcaseidprefix"
)));
}
if
(properties.get(
"customcaseroles"
) != null
&& properties.get(
"customcaseroles"
).length() > 0) {
Utils.setMetaDataExtensionValue(rootLevelProcess,
"customCaseRoles"
,
wrapInCDATABlock(properties.get(
"customcaseroles"
)));
}
// customsladuedate metadata
applySlaDueDateProperties(rootLevelProcess, properties);
rootLevelProcess.setId(properties.get(
"id"
));
applyProcessProperties(rootLevelProcess, properties);
((Definitions) baseElt).getRootElements().add(rootLevelProcess);
}
}
if
(child
instanceof
Task) {
rootLevelProcess.getFlowElements().add((Task) child);
}
else
if
(child
instanceof
CallActivity) {
rootLevelProcess.getFlowElements().add((CallActivity) child);
}
else
if
(child
instanceof
RootElement) {
((Definitions) baseElt).getRootElements().add((RootElement) child);
}
else
if
(child
instanceof
SequenceFlow) {
rootLevelProcess.getFlowElements().add((SequenceFlow) child);
}
else
if
(child
instanceof
Gateway) {
rootLevelProcess.getFlowElements().add((Gateway) child);
}
else
if
(child
instanceof
Event
) {
rootLevelProcess.getFlowElements().add((
Event
) child);
}
else
if
(child
instanceof
TextAnnotation) {
rootLevelProcess.getFlowElements().add((TextAnnotation) child);
}
else
if
(child
instanceof
Artifact) {
rootLevelProcess.getArtifacts().add((Artifact) child);
}
else
if
(child
instanceof
DataObject) {
// bubble up data objects
//rootLevelProcess.getFlowElements().add(0, (DataObject) child);
rootLevelProcess.getFlowElements().add((DataObject) child);
// ItemDefinition def = ((DataObject) child).getItemSubjectRef();
// if (def != null) {
// if (def.eResource() == null) {
// ((Definitions) rootLevelProcess.eContainer()).getRootElements().add(0, def);
// }
// Import imported = def.getImport();
// if (imported != null && imported.eResource() == null) {
// ((Definitions) rootLevelProcess.eContainer()).getImports().add(0, imported);
// }
// }
}
else
if
(child
instanceof
SubProcess) {
rootLevelProcess.getFlowElements().add((SubProcess) child);
}
else
if
(child
instanceof
Lane) {
// lanes handled later
}
else
{
_logger.error(
"Don't know what to do of "
+ child);
}
// }
}
}
}
else
if
(baseElt
instanceof
Process
) {
for
(BaseElement child : childElements) {
if
(child
instanceof
Lane) {
if
(((
Process
) baseElt).getLaneSets().isEmpty()) {
((
Process
) baseElt).getLaneSets().add(Bpmn2Factory.eINSTANCE.createLaneSet());
}
((
Process
) baseElt).getLaneSets().get(0).getLanes().add((Lane) child);
addLaneFlowNodes((
Process
) baseElt, (Lane) child);
}
else
if
(child
instanceof
Artifact) {
((
Process
) baseElt).getArtifacts().add((Artifact) child);
}
else
{
_logger.error(
"Don't know what to do of "
+ child);
}
}
}
else
if
(baseElt
instanceof
SubProcess) {
for
(BaseElement child : childElements) {
if
(child
instanceof
FlowElement) {
((SubProcess) baseElt).getFlowElements().add((FlowElement) child);
}
else
if
(child
instanceof
Artifact) {
((SubProcess) baseElt).getArtifacts().add((Artifact) child);
}
else
{
_logger.error(
"Subprocess - don't know what to do of "
+ child);
}
}
}
else
if
(baseElt
instanceof
Message) {
// we do not support base-element messages from the json. They are created dynamically for events that use them.
}
else
if
(baseElt
instanceof
Lane) {
for
(BaseElement child : childElements) {
if
(child
instanceof
FlowNode) {
((Lane) baseElt).getFlowNodeRefs().add((FlowNode) child);
}
// no support for child-lanes at this point
// else if (child instanceof Lane) {
// if (((Lane) baseElt).getChildLaneSet() == null) {
// ((Lane) baseElt).setChildLaneSet(Bpmn2Factory.eINSTANCE.createLaneSet());
// }
// ((Lane) baseElt).getChildLaneSet().getLanes().add((Lane) child);
// }
else
if
(child
instanceof
Artifact) {
_artifacts.add((Artifact) child);
}
else
{
_logger.error(
"Don't know what to do of "
+ childElements);
}
}
_lanes.add((Lane) baseElt);
}
else
{
if
(!childElements.isEmpty()) {
_logger.error(
"Don't know what to do of "
+ childElements +
" with "
+ baseElt);
}
}
return
baseElt;
}
From source file:
org.kie.workbench.common.stunner.bpmn.backend.legacy.Bpmn2JsonUnmarshaller.java
public BaseElement unmarshallItem(JsonParser parser, String preProcessingData) throws IOException {
String
resourceId = null;
/
/
w
w
w
.
j
a
v
a
2
s
.
c
o
m
Map
<
String
,
String
> properties = null;
String
stencil = null;
List
<BaseElement> childElements =
new
ArrayList
<BaseElement>();
List
<
String
> outgoing =
new
ArrayList
<
String
>();
while
(parser.nextToken() != JsonToken.END_OBJECT) {
String
fieldname = parser.getCurrentName();
parser.nextToken();
if
(
"resourceId"
.equals(fieldname)) {
resourceId = parser.getText();
}
else
if
(
"properties"
.equals(fieldname)) {
properties = unmarshallProperties(parser);
}
else
if
(
"stencil"
.equals(fieldname)) {
// "stencil":{"id":"Task"},
parser.nextToken();
parser.nextToken();
stencil = parser.getText();
parser.nextToken();
}
else
if
(
"childShapes"
.equals(fieldname)) {
while
(parser.nextToken() != JsonToken.END_ARRAY) {
// open the
// object
// the childShapes element is a json array. We opened the
// array.
childElements.add(unmarshallItem(parser, preProcessingData));
}
}
else
if
(
"bounds"
.equals(fieldname)) {
// bounds: {"lowerRight":{"x":484.0,"y":198.0},"upperLeft":{"x":454.0,"y":168.0}}
parser.nextToken();
parser.nextToken();
parser.nextToken();
parser.nextToken();
Integer
x2 = parser.getIntValue();
parser.nextToken();
parser.nextToken();
Integer
y2 = parser.getIntValue();
parser.nextToken();
parser.nextToken();
parser.nextToken();
parser.nextToken();
parser.nextToken();
Integer
x1 = parser.getIntValue();
parser.nextToken();
parser.nextToken();
Integer
y1 = parser.getIntValue();
parser.nextToken();
parser.nextToken();
Bounds
b = DcFactory.eINSTANCE.createBounds();
b.setX(x1);
b.setY(y1);
b.setWidth(x2 - x1);
b.setHeight(y2 - y1);
this
._bounds.put(resourceId, b);
}
else
if
(
"dockers"
.equals(fieldname)) {
// "dockers":[{"x":50,"y":40},{"x":353.5,"y":115},{"x":353.5,"y":152},{"x":50,"y":40}],
List
<
Point
> dockers =
new
ArrayList
<
Point
>();
JsonToken nextToken = parser.nextToken();
boolean
end = JsonToken.END_ARRAY.equals(nextToken);
while
(!end) {
nextToken = parser.nextToken();
nextToken = parser.nextToken();
Integer
x = parser.getIntValue();
parser.nextToken();
parser.nextToken();
Integer
y = parser.getIntValue();
Point
point = DcFactory.eINSTANCE.createPoint();
point.setX(x);
point.setY(y);
dockers.add(point);
parser.nextToken();
nextToken = parser.nextToken();
end = JsonToken.END_ARRAY.equals(nextToken);
}
this
._dockers.put(resourceId, dockers);
}
else
if
(
"outgoing"
.equals(fieldname)) {
while
(parser.nextToken() != JsonToken.END_ARRAY) {
// {resourceId: oryx_1AAA8C9A-39A5-42FC-8ED1-507A7F3728EA}
parser.nextToken();
parser.nextToken();
outgoing.add(parser.getText());
parser.nextToken();
}
// pass on the array
parser.skipChildren();
}
else
if
(
"target"
.equals(fieldname)) {
// we already collected that info with the outgoing field.
parser.skipChildren();
// "target": {
// "resourceId": "oryx_A75E7546-DF71-48EA-84D3-2A8FD4A47568"
// }
// add to the map:
// parser.nextToken(); // resourceId:
// parser.nextToken(); // the value we want to save
// targetId = parser.getText();
// parser.nextToken(); // }, closing the object
}
}
properties.put(
"resourceId"
, resourceId);
boolean
customElement = isCustomElement(properties.get(
"tasktype"
), preProcessingData);
BaseElement baseElt =
this
.createBaseElement(stencil, properties.get(
"tasktype"
), customElement);
// register the sequence flow targets.
if
(baseElt
instanceof
SequenceFlow) {
_sequenceFlowTargets.addAll(outgoing);
}
_outgoingFlows.put(baseElt, outgoing);
_objMap.put(baseElt, resourceId);
// keep the object around to do connections
_idMap.put(resourceId, baseElt);
// baseElt.setId(resourceId); commented out as bpmn2 seems to create
// duplicate ids right now.
applyProperties(baseElt, properties, preProcessingData);
if
(baseElt
instanceof
Definitions) {
Process
rootLevelProcess = null;
if
(childElements == null || childElements.size() < 1) {
if
(rootLevelProcess == null) {
rootLevelProcess = Bpmn2Factory.eINSTANCE.createProcess();
// set the properties and item definitions first
if
(properties.get(
"vardefs"
) != null && properties.get(
"vardefs"
).length() > 0) {
String
[] vardefs = properties.get(
"vardefs"
).split(
",\\s*"
);
for
(
String
vardef : vardefs) {
Property prop = Bpmn2Factory.eINSTANCE.createProperty();
ItemDefinition itemdef = Bpmn2Factory.eINSTANCE.createItemDefinition();
// check if we define a structure ref in the definition
if
(vardef.contains(
":"
)) {
String
[] vardefParts = vardef.split(
":\\s*"
);
prop.setId(vardefParts[0]);
itemdef.setId(
"_"
+ prop.getId() +
"Item"
);
boolean
haveKPI = false;
String
kpiValue =
""
;
if
(vardefParts.length == 3) {
itemdef.setStructureRef(vardefParts[1]);
if
(vardefParts[2].equals(
"true"
)) {
haveKPI = true;
kpiValue = vardefParts[2];
}
}
if
(vardefParts.length == 2) {
if
(vardefParts[1].equals(
"true"
) || vardefParts[1].equals(
"false"
)) {
if
(vardefParts[1].equals(
"true"
)) {
haveKPI = true;
kpiValue = vardefParts[1];
}
}
else
{
itemdef.setStructureRef(vardefParts[1]);
}
}
if
(haveKPI) {
Utils.setMetaDataExtensionValue(prop,
"customKPI"
, wrapInCDATABlock(kpiValue));
}
}
else
{
prop.setId(vardef);
itemdef.setId(
"_"
+ prop.getId() +
"Item"
);
}
prop.setItemSubjectRef(itemdef);
rootLevelProcess.getProperties().add(prop);
((Definitions) baseElt).getRootElements().add(itemdef);
}
}
if
(properties.get(
"adhocprocess"
) != null && properties.get(
"adhocprocess"
).equals(
"true"
)) {
ExtendedMetaData metadata = ExtendedMetaData.INSTANCE;
EAttributeImpl extensionAttribute = (EAttributeImpl) metadata
.demandFeature(
"http://www.jboss.org/drools"
,
"adHoc"
, false, false);
SimpleFeatureMapEntry extensionEntry =
new
SimpleFeatureMapEntry(extensionAttribute,
properties.get(
"adhocprocess"
));
rootLevelProcess.getAnyAttribute().add(extensionEntry);
}
if
(properties.get(
"customdescription"
) != null
&& properties.get(
"customdescription"
).length() > 0) {
Utils.setMetaDataExtensionValue(rootLevelProcess,
"customDescription"
,
wrapInCDATABlock(properties.get(
"customdescription"
)));
}
rootLevelProcess.setId(properties.get(
"id"
));
applyProcessProperties(rootLevelProcess, properties);
((Definitions) baseElt).getRootElements().add(rootLevelProcess);
}
}
else
{
for
(BaseElement child : childElements) {
// tasks are only permitted under processes.
// a process should be created implicitly for tasks at the root
// level.
// process designer doesn't make a difference between tasks and
// global tasks.
// if a task has sequence edges it is considered a task,
// otherwise it is considered a global task.
// if (child instanceof Task && _outgoingFlows.get(child).isEmpty() && !_sequenceFlowTargets.contains(_objMap.get(child))) {
// // no edges on a task at the top level! We replace it with a
// // global task.
// GlobalTask task = null;
// if (child instanceof ScriptTask) {
// task = Bpmn2Factory.eINSTANCE.createGlobalScriptTask();
// ((GlobalScriptTask) task).setScript(((ScriptTask) child).getScript());
// ((GlobalScriptTask) task).setScriptLanguage(((ScriptTask) child).getScriptFormat());
// // TODO scriptLanguage missing on scriptTask
// } else if (child instanceof UserTask) {
// task = Bpmn2Factory.eINSTANCE.createGlobalUserTask();
// } else if (child instanceof ServiceTask) {
// // we don't have a global service task! Fallback on a
// // normal global task
// task = Bpmn2Factory.eINSTANCE.createGlobalTask();
// } else if (child instanceof BusinessRuleTask) {
// task = Bpmn2Factory.eINSTANCE.createGlobalBusinessRuleTask();
// } else if (child instanceof ManualTask) {
// task = Bpmn2Factory.eINSTANCE.createGlobalManualTask();
// } else {
// task = Bpmn2Factory.eINSTANCE.createGlobalTask();
// }
//
// task.setName(((Task) child).getName());
// task.setIoSpecification(((Task) child).getIoSpecification());
// task.getDocumentation().addAll(((Task) child).getDocumentation());
// ((Definitions) baseElt).getRootElements().add(task);
// continue;
// } else {
if
(child
instanceof
SequenceFlow) {
// for some reason sequence flows are placed as root elements.
// find if the target has a container, and if we can use it:
List
<
String
> ids = _outgoingFlows.get(child);
FlowElementsContainer container = null;
for
(
String
id : ids) {
// yes, we iterate, but we'll take the first in the list that will work.
Object
obj = _idMap.get(id);
if
(obj
instanceof
EObject
&& ((EObject) obj).eContainer()
instanceof
FlowElementsContainer) {
container = (FlowElementsContainer) ((EObject) obj).eContainer();
break
;
}
}
if
(container != null) {
container.getFlowElements().add((SequenceFlow) child);
continue
;
}
}
if
(child
instanceof
instanceof
Lane || child
instanceof
CallActivity
|| child
instanceof
TextAnnotation) {
if
(rootLevelProcess == null) {
rootLevelProcess = Bpmn2Factory.eINSTANCE.createProcess();
(properties.get(
"vardefs"
) != null && properties.get(
"vardefs"
).length() > 0) {
String
[] vardefs = properties.get(
"vardefs"
).split(
",\\s*"
);
for
(
String
vardef : vardefs) {
Property prop = Bpmn2Factory.eINSTANCE.createProperty();
ItemDefinition itemdef = Bpmn2Factory.eINSTANCE.createItemDefinition();
// check if we define a structure ref in the definition
if
(vardef.contains(
":"
)) {
String
[] vardefParts = vardef.split(
);
prop.setId(vardefParts[0]);
itemdef.setId(
"_"
+ prop.getId() +
"Item"
);
boolean
haveKPI = false;
String
kpiValue =
""
;
if
(vardefParts.length == 3) {
itemdef.setStructureRef(vardefParts[1]);
if
(vardefParts[2].equals(
"true"
)) {
haveKPI = true;
kpiValue = vardefParts[2];
}
}
if
(vardefParts.length == 2) {
if
(vardefParts[1].equals(
"true"
"false"
)) {
if
(vardefParts[1].equals(
"true"
)) {
haveKPI = true;
kpiValue = vardefParts[1];
}
}
else
{
itemdef.setStructureRef(vardefParts[1]);
}
}
if
(haveKPI) {
Utils.setMetaDataExtensionValue(prop,
"customKPI"
,
wrapInCDATABlock(kpiValue));
}
}
else
{
prop.setId(vardef);
itemdef.setId(
"_"
+ prop.getId() +
"Item"
);
}
prop.setItemSubjectRef(itemdef);
rootLevelProcess.getProperties().add(prop);
((Definitions) baseElt).getRootElements().add(itemdef);
}
}
if
(properties.get(
"adhocprocess"
) != null
&& properties.get(
).equals(
"true"
)) {
ExtendedMetaData metadata = ExtendedMetaData.INSTANCE;
EAttributeImpl extensionAttribute = (EAttributeImpl) metadata
.demandFeature(
"http://www.jboss.org/drools"
,
"adHoc"
, false, false);
SimpleFeatureMapEntry extensionEntry =
new
SimpleFeatureMapEntry(extensionAttribute,
properties.get(
"adhocprocess"
));
rootLevelProcess.getAnyAttribute().add(extensionEntry);
}
if
(properties.get(
"customdescription"
) != null
&& properties.get(
"customdescription"
).length() > 0) {
Utils.setMetaDataExtensionValue(rootLevelProcess,
"customDescription"
,
wrapInCDATABlock(properties.get(
"customdescription"
)));
}
rootLevelProcess.setId(properties.get(
"id"
if
(child
instanceof
Task) {
rootLevelProcess.getFlowElements().add((Task) child);
}
else
if
(child
instanceof
CallActivity) {
rootLevelProcess.getFlowElements().add((CallActivity) child);
}
else
if
(child
instanceof
RootElement) {
((Definitions) baseElt).getRootElements().add((RootElement) child);
}
else
if
(child
instanceof
SequenceFlow) {
rootLevelProcess.getFlowElements().add((SequenceFlow) child);
}
else
if
Gateway) {
rootLevelProcess.getFlowElements().add((Gateway) child);
}
else
if
(child
instanceof
Event
) {
rootLevelProcess.getFlowElements().add((
Event
) child);
}
else
if
(child
instanceof
TextAnnotation) {
rootLevelProcess.getFlowElements().add((TextAnnotation) child);
}
else
if
(child
instanceof
Artifact) {
rootLevelProcess.getArtifacts().add((Artifact) child);
}
else
if
DataObject) {
// bubble up data objects
//rootLevelProcess.getFlowElements().add(0, (DataObject) child);
rootLevelProcess.getFlowElements().add((DataObject) child);
// ItemDefinition def = ((DataObject) child).getItemSubjectRef();
// if (def != null) {
// if (def.eResource() == null) {
// ((Definitions) rootLevelProcess.eContainer()).getRootElements().add(0, def);
// }
// Import imported = def.getImport();
// if (imported != null && imported.eResource() == null) {
// ((Definitions) rootLevelProcess.eContainer()).getImports().add(0, imported);
// }
// }
}
else
if
(child
instanceof
SubProcess) {
rootLevelProcess.getFlowElements().add((SubProcess) child);
}
else
if
(child
instanceof
Lane) {
// lanes handled later
}
else
{
_logger.error(
"Don't know what to do of "
+ child);
}
// }
}
}
}
else
if
(baseElt
instanceof
Process
) {
for
(BaseElement child : childElements) {
if
(child
instanceof
Lane) {
if
(((
Process
) baseElt).getLaneSets().isEmpty()) {
((
Process
) baseElt).getLaneSets().add(Bpmn2Factory.eINSTANCE.createLaneSet());
}
((
Process
) baseElt).getLaneSets().get(0).getLanes().add((Lane) child);
addLaneFlowNodes((
Process
) baseElt, (Lane) child);
}
else
if
(child
instanceof
Artifact) {
((
Process
) baseElt).getArtifacts().add((Artifact) child);
}
else
{
_logger.error(
"Don't know what to do of "
+ child);
}
}
}
else
if
(baseElt
instanceof
SubProcess) {
for
(BaseElement child : childElements) {
if
(child
instanceof
FlowElement) {
((SubProcess) baseElt).getFlowElements().add((FlowElement) child);
}
else
if
(child
instanceof
Artifact) {
((SubProcess) baseElt).getArtifacts().add((Artifact) child);
}
else
{
_logger.error(
"Subprocess - don't know what to do of "
+ child);
}
}
}
else
if
(baseElt
instanceof
Message) {
// we do not support base-element messages from the json. They are created dynamically for events that use them.
}
else
if
(baseElt
instanceof
Lane) {
for
(BaseElement child : childElements) {
if
(child
instanceof
FlowNode) {
((Lane) baseElt).getFlowNodeRefs().add((FlowNode) child);
}
// no support for child-lanes at this point
// else if (child instanceof Lane) {
// if (((Lane) baseElt).getChildLaneSet() == null) {
// ((Lane) baseElt).setChildLaneSet(Bpmn2Factory.eINSTANCE.createLaneSet());
// }
// ((Lane) baseElt).getChildLaneSet().getLanes().add((Lane) child);
// }
else
if
(child
instanceof
Artifact) {
_artifacts.add((Artifact) child);
}
else
{
_logger.error(
"Don't know what to do of "
+ childElements);
}
}
_lanes.add((Lane) baseElt);
}
else
{
if
(!childElements.isEmpty()) {
_logger.error(
"Don't know what to do of "
+ childElements +
" with "
+ baseElt);
}
}
return
baseElt;
}
| http://www.java2s.com/example/java-api/com/fasterxml/jackson/core/jsonparser/skipchildren-0-3.html |
Antibody Drug Conjugate Development in Gastrointestinal Cancers: Hopes and Hurdles from Clinical Trials - DocsLib
Wu et al. Cancer Drug Resist 2018;1:204-18 Cancer DOI: 10.20517/cdr.2018.16 Drug Resistance Review Open Access Antibody drug conjugate development in
Wu et al. Cancer Drug Resist 2018;1:204-18 Cancer DOI: 10.20517/cdr.2018.16 Drug Resistance
Antibody drug conjugate development in gastrointestinal cancers: hopes and hurdles from clinical trials
Xiaorong Wu, Thomas Kilpatrick, Ian Chau
Department of Medical oncology, Royal Marsden Hospital NHS foundation trust, Sutton SM2 5PT, UK.
Correspondence to: Dr. Ian Chau, Department of Medical Oncology, Royal Marsden Hospital NHS foundation trust, Downs Road, Sutton SM2 5PT, UK. E-mail:[email protected]
How to cite this article: Wu X, Kilpatrick T, Chau I. Antibody drug conjugate development in gastrointestinal cancers: hopes and hurdles from clinical trials. Cancer Drug Resist 2018;1:204-18. http://dx.doi.org/10.20517/cdr.2018.16
Received: 31 Aug 2018 First Decision: 8 Oct 2018 Revised: 13 Nov 2018 Accepted: 16 Nov 2018 Published: 19 Dec 2018
Science Editors: Elisa Giovannetti, Jose A. Rodriguez Copy Editor: Cui Yu Production Editor: Huan-Liang Wu
Abstract Gastrointestinal (GI) cancers represent the leading cause of cancer-related mortality worldwide. Antibody drug conjugates (ADCs) are a rapidly growing new class of anti-cancer agents which may improve GI cancer patient survival. ADCs combine tumour-antigen specific antibodies with cytotoxic drugs to deliver tumour cell specificchemotherapy. Currently, only two ADCs [brentuximab vedotinandtrastuzumabemtansine (T-DM1)] have been Food and Drug Administration approved for the treatment of lymphoma and metastatic breast cancer, respectively. Clinical research evaluating ADCs in GI cancers has shown limited success. In this review, we will retrace the relevant clinical trials investigating ADCs in GI cancers, especially ADCs targeting human epidermal growth receptor 2, mesothelin, guanylyl cyclase C, carcinogenic antigen-related cell adhesion molecule 5 (also known as CEACAM5) and other GI malignancy specific targets. We will review potential hurdles for their success and provide new perspective for future treatment.
Keywords: Antibody drug conjugates, human epidermal growth receptor 2, mesothelin, guanylyl cyclase C, carcinogenic antigen-related cell adhesion molecule 5 gastric cancer,colorectal cancer, pancreatic cancer, T-DM1, DS-8201a
INTRODUCTION Gastrointestinal (GI) cancers comprise a heterogeneous group of cancers that include gastric, oesophageal, pancreatic, hepatobiliary, colorectal and anal cancers. GI cancers are the most common tumour type encountered worldwide and represent the leading cause of cancer-related mortality[1]. The only potentially curative strategy for GI cancers is surgery; however the majority of GI cancers are unresectable at diagnosis. Systemic or palliative treatments such as chemotherapy, radiotherapy,monoclonal antibody(mAb) therapy or combination therapies have greatly improved survival rates in the last decade; however, the
© The Author(s) 2018. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
www.cdrjournal.com Wu et al. Cancer Drug Resist 2018;1:204-18 I http://dx.doi.org/10.20517/cdr.2018.16 Page 205 5 years survival of GI cancers remains poor. A new class of treatments under development is antibody drug conjugates (ADCs).
ADCs combine a tumour-antigen specific mAb with a cytotoxic drug (or “payload”) using a linker. ADCs exert their cytotoxic effects after the mAb directly binds to a tumour specific antigen and the ADC complex is internalized into the tumour cell. The complex is then degraded, which frees the cytotoxic drug to exert its cytotoxic effects on tumour cells. ADCs represent an attractive oncology treatment modality as they allow targeted delivery of cytotoxic agents directly to cancer cells, causing minimal toxicity to normal tissue[2-4]. Only two ADCs are currently approved by US Food and Drug Administration and the European Medicines Agency. Brentuximab vedotin, targeting cancer antigen CD30, was first approved in 2011 for the treatment of patients with relapsed or refractory CD30-expressing Hodgkin’s and anaplastic large cell lymphomas[5,6]. T-DM1 (also known as trastuzumab emtansine or ado-trastuzumab emtansine) was approved in 2013 for use in patients with human epidermal growth receptor 2 (HER2)-expressing metastatic breast cancers who have disease progression following standard chemotherapy or HER2 targeted therapy[7]. Since 2013, more than 60 ADCs have reached clinical trials under investigation for haematological and oncological indications.
There are no ADCs in use for GI malignancies and many clinical trials that assess ADCs in GI cancers remain in the early stages. Due to the acting mechanism of ADCs, ideal target antigens are highly expressed on tumour cells and minimally expressed on healthy cells. GI potential tumour antigens under evaluation as ADC targets currently include HER2, mesothelin, guanylyl cyclase C (GCC), carcinogenic antigen-related cell adhesion molecule 5 (CEACAM5) and other tumour antigens. This review will examine ADC trials in GI cancers [Table 1], and discuss the possible challenges for their success and new strategies in the future to facilitate improvement of GI cancer management.
HER2 TARGETED ADCS HER2 is a tyrosine protein kinase receptor which has been demonstrated to be expressed in certain GI malignancies, including gastro-oesophageal, gastric, pancreatic, gallbladder and colorectal cancers[8,9]. The HER2 mAb trastuzumab is the first biological therapy to have shown a median survival benefit of nearly 3 months in combination with chemotherapy for HER2 positive advanced gastric/gastro-oesophageal junction cancer compared to chemotherapy alone[10]. Thus, HER2 is a suitable target for ADCs in GI cancers.
T-DM1 Trastuzumab emtansine, or T-DM1, is made by conjugation of the microtubule polymerization inhibitor, emtansine, to trastuzumab via a noncleavable linker[11]. A phase I study of T-DM1 in breast cancer suggested that T-DM1 was well tolerated at maximum tolerated dose (MTD) of 2.4 mg/kg with potential antitumor activity[12]. However, despite significant efficacy and minimal toxicity in HER2 positive advanced breast cancer[13,14], T-DM1 was not superior to taxanes (docetaxel or paclitaxel) in patients with previously treated HER2 positive advanced gastric cancer[15]. The phase II/III GATSBY study enrolled patients with HER2- positive advanced gastric cancer who progressed during or after first-line therapy. Patients were randomly assigned to treatment groups of T-DM1 3.6 mg/kg every 3 weeks (n = 70) or 2.4 mg/kg weekly (n = 228) or a taxane (n = 117). The median overall survival (OS) was 7.9 months (95% CI 6.7-9.5) with T-DM1 2.4 mg/kg weekly and 8.6 months (95% CI 7.1-11.2) with taxane treatment (HR 1.15; 95% CI 0.87-1.51, one- sided P = 0.86). The results of the secondary efficacy endpoints, including progression-free survival (PFS), objective response rate (ORR) and duration of response were consistent with the primary endpoints. In the GATSBY trial, the T-DM1 2.4 mg/kg group showed slightly lower incidence of ≥ grade 3 adverse events (AE) compared to taxane group. The most common ≥ grade 3 AE in the T-DM1 group were anaemia (26%) and thrombocytopenia (11%) compared with neutropaenia (39%) and anaemia (26%) in the taxane group[15]. As a Page 206 Wu et al. Cancer Drug Resist 2018;1:204-18 I http://dx.doi.org/10.20517/cdr.2018.16
Table 1. Antibody drug conjugate trials in gastrointestinal cancers
Target ADC GI tumour types NCT number Trial title Phase Status antigen T-DM1 HER2 Gastric cancer NCT01641939 A study of trastuzumab emtansine versus Phase II/III Terminated taxane in participants with human epidermal HER2-positive advanced gastric cancer T-DM1 HER2 Gastric cancer NCT01702558 A combination study of kadcyla Phase II Completed (trastuzumab emtansine) and capecitabine in participants with human HER2-positive metastatic breast cancer (mBC) or HER2- positive locally advanced/metastatic gastric cancer (LA/mGC) T-DM1 HER2 Pancreas cancer NCT02999672 A study to determine best tumor response Phase II Completed cholangiocarcinoma with trastuzumab emtansine in human HER2 overexpressing solid tumors (KAMELEON) T-DM1 HER2 Metastatic colorectal NCT03418558 Study of trastuzumab-emtansine in patients Phase II Recruiting cancer with HER2-positive metastatic colorectal cancer progressing after trastuzumab and lapatinib (RESCUE) T-DM1 HER2 Metastatic colorectal NCT03225937 Evaluation of trastuzumab in combination Phase II Recruiting cancer with lapatinib orpertuzumabin combination with trastuzumab-emtansine to treat patients with HER2-positive metastatic colorectal cancer (HERACLES) DS-8201a HER2 gastric or NCT02564900 Phase 1, two-part, multicentre, non- Phase I Recruiting gastroesophageal randomized, open-label, multiple dose first- junction in-human study of DS-8201A, in Subjects adenocarcinoma with advanced solid malignant tumors DS-8201a HER2 Gastric or NCT03329690 A phase 2, multicentre, open-label study of Phase II Recruiting gastroesophageal DS-8201a in subjects with HER2-expressing junction advanced gastric or gastroesophageal adenocarcinoma junction adenocarcinoma DS-8201a HER2 Gastric cancer NCT03368196 Phase 1, multicentre, open label study of DS- Phase I Recruiting 8201a to assess safety and pharmacokinetics in subjects with HER2 positive advanced and/or refractory gastric, gastroesophageal junction adenocarcinoma, or breast cancer DS-8201a HER2 Colorectal cancer NCT03384940 A phase 2, multicentre, open-label study of Phase II Recruiting DS-8201a in subjects with HER2-expressing advanced colorectal cancer XMT-1522 HER2 Gastric cancer NCT02952729 A phase 1b, first-in-human, dose escalation Phase I Recruiting and expansion study of XMT-1522 in patients with advanced breast cancer and other advanced tumors expressing HER2 MEDI4276 HER2 Gastric cancer NCT02576548 A phase 1/2 multicentre, open-label, dose- Phase I Completed escalation, and dose-expansion study to evaluate the safety, pharmacokinetics, immunogenicity, and antitumor activity of MEDI4276 in subjects with select HER2- expressing advanced solid tumors SYD985 HER2 Gastric cancer NCT02277717 A two part first-in-human phase I study (with Phase I Active but not expanded cohorts) with the antibody-drug recruiting conjugate SYD985 to evaluate the safety, pharmacokinetics and efficacy in patients with locally advanced or metastatic solid tumors ARX788 HER2 Gastric cancer NCT03255070 A phase 1, multicentre, open-label, Phase I Recruiting multiple dose-escalation study of ARX788, intravenously administered as a single agent in subjects with advanced cancers with HER2 expression ARX788 HER2 Gastric cancer NCT02512237 A phase 1, multicentre, open-label, Phase I Recruiting multiple dose-escalation study of ARX788, intravenously administered as a single agent in subjects with advanced cancers with HER2 expression ADCT-502 HER2 Gastric cancer NCT03125200 A phase 1, open-label, dose-escalation Phase I Terminated study to evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of ADCT-502 in patients with advanced solid tumors with HER2 expression Wu et al. Cancer Drug Resist 2018;1:204-18 I http://dx.doi.org/10.20517/cdr.2018.16 Page 207
DMOT4039A Mesothelin Pancreatic cancer NCT01469793 A phase I, open label study of the safety and Phase I Completed pharmacokinetics of escalating doses of DMOT4039A in patients with unresectable pancreatic or platinum-resistant ovarian cancer Anetumab Mesothelin Solid tumour NCT01439152 An open label phase I dose escalation Phase I Active but not ravtansine study to evaluate the safety, tolerability, recruiting pharmacokinetics, pharmacodynamics, and maximum tolerated dose of the anti- mesothelin antibody drug conjugate BAY94- 9343 in subjects with advanced solid tumors Anetumab Mesothelin Unknown NCT02485119 An open label, phase I study to evaluate the Phase I Completed ravtansine safety, tolerability and pharmacokinetics of BAY94-9343 given by intravenous infusion every 3 weeks (Q3W) in Japanese subjects with advanced malignancies Anetumab Mesothelin Pancreatic cancer NCT03023722 An open-label, phase II study of intravenous Phase II Recruiting ravtansine anetumab ravtansine (BAY 94-9343), an anti-mesothelin antibody drug conjugate, in pretreated mesothelin-expressing advanced pancreatic cancer Anetumab Mesothelin Cholangiocarcinoma NCT03102320 Phase 1b multi-indication study of anetumab Phase Ib Recruiting ravtansine Pancreatic cancer ravtansine (BAY94-9343) in patients with mesothelin expressing advanced or recurrent malignancies BMS 986148 Mesothelin Unknown NCT02884726 A phase 1 study of the safety and tolerability Phase I Completed of BMS 986148 in subjects with advanced and/or metastatic solid tumors BMS 986148 Mesothelin Pancreatic and gastric NCT02341625 A phase I/IIa study of BMS-986148, a Phase I/II Active but not cancer mesothelin directed antibody drug conjugate, recruiting in subjects with select advanced solid tumors MLN0264 GCC Gastrointestinal NCT01577758 An open-label, dose escalation, phase 1, Phase I Completed malignancies first-in-human study of MLN0264 in adult patients with advanced gastrointestinal malignancies expressing GCC MLN0264 GCC Gastric cancer NCT02202759 A phase 2 trial of MLN0264 in previously Phase II Terminated treated patients with metastatic or recurrent adenocarcinoma of the stomach or gastroesophageal junction expressing GCC MLN0264 GCC Pancreatic cancer NCT02202785 A phase 2 trial of MLN0264 in previously Phase II Terminated treated patients with advanced or metastatic pancreatic adenocarcinoma expressing GCC MLN0264 GCC Gastrointestinal NCT02391038 A phase 1/2 trial of MLN0264 in previously Phase I Terminated malignancies treated asian patients with advanced gastrointestinal (GI) carcinoma (phase 1) or metastatic or recurrent gastric or gastroesophageal junction adenocarcinoma (phase 2) expressing GCC TAK-164 GCC Gastrointestinal NCT03449030 An open-label, dose escalation, phase 1, first- Phase I Recruiting malignancies in-human study of TAK-164, an antibody- drug conjugate, in patients with advanced gastrointestinal cancers expressing GCC SAR408701 CEACAM5 Gastrointestinal NCT02187848 First-in-human phase I trial of the anti- Phase I/II Recruiting malignancies CEACAM5 antibody-drug conjugate SAR408701 in patients with advanced solid tumours IMMU-130 CEACAM5 Metastatic colorectal NCT01605318 Phase I/II trial oflabetuzumabgovitecan Phase I/II Completed (Labetuzumab cancer (anti-CEACAM5/SN-38 antibody-drug govitecan) conjugate) in patients with refractory or relapsing metastatic colorectal cancer IMMU-130 CEACAM5 Metastatic colorectal IMMU-130, an Sn-38 antibody-drug 2 phase I Completed (labetuzumab cancer conjugate (ADC) targeting CEACAM5, trials govitecan) is therapeutically active in metastatic colorectal cancer (mCRC) Cantuzumab CanAg Gastrointestinal Phase I study of cantuzumabmertansinePhase I Completed mertansine malignancies administered as a single intravenous infusion once weekly in patients with advanced solid tumours Cantuzumab CanAg GastrointestinalCantuzumab mertansinein a three- Phase I Completed mertansine malignancies times a week schedule: a phase I and pharmacokinetic study Page 208 Wu et al. Cancer Drug Resist 2018;1:204-18 I http://dx.doi.org/10.20517/cdr.2018.16
Cantuzumab CanAg Gastrointestinal Cantuzumab mertansine, a maytansinoid Phase I Completed mertansine malignancies immunoconjugate directed to the CanAg antigen: a phase I , pharmacokinetic, and biologic correlative study PF-06263507 5T4 Gastrointestinal A study of PF-06263507 in patients with Phase I Terminated malignancies advanced solid tumors
HER2: growth factor receptor 2; GCC: guanylyl cyclase C consequence, T-DM1 performed poorly as a second-line option for HER2 positive advanced gastric cancer.
Several mechanisms may explain the absence of OS benefit in patients with advanced gastric cancer treated with T-DM1 compared to patients treated with taxanes. First, emtansine may have limited antitumor efficacy in gastric cancer; there is evidence showing that the microtubule polymerization inhibitor vinorelbine was less active in gastric cancer than in other cancers[16]. Additionally, patients in the GATSBY trial were selected based on archival HER2 status, which might be altered by previous anti-HER2 treatment. In addition, there is evidence of HER2 discordance between primary and metastatic tumours and between tumours before and after first line chemotherapy for metastatic disease (with or without trastuzumab)[17-21]. Meanwhile, high incidence of heterogeneous HER2 overexpression in gastric cancer might affect activity of T-DM1 because the non-cleavable linker does not allow for bystander activity[22,23]. Future clinical trials are warranted to clarify the role of T-DM1 either combining with chemotherapy or withimmunotherapyin advanced gastric cancer. The phase I/II TRAX-HER2 trial (NCT01702558) of capecitabine +/- T-DM1 has recently completed, which demonstrated that the combination of T-DM1 and capecitabine is tolerable in HER2-positive advanced breast and gastric cancer patients[24]. However, there was no statistically significant difference in ORR between patients with metastatic breast cancer who received T-DM1 + capecitabine vs. T-DM1 alone (44.4% vs. 36.3%; P = 0.336)[25]. Two phase II clinical trials (NCT03418558 and NCT03225937) are currently recruiting patients with metastatic colorectal cancer to evaluate the anti-tumour benefits of T-DM1 alone or in combination with programmed cell death receptor 1 (PD-1) inhibitorpembrolizumab.
DS-8201A DS-8201a is a new HER2-targeted ADC, which conjugates a humanized anti-HER2 antibody to a topoisomerase I inhibitor, deruxtecan, by a cleavable peptide-linker[26]. Unlike T-DM1, DS-8201a has a potent bystander killing effect due to its cleavable linker, which is beneficial in treating heterogeneous HER2 overexpressing tumours, such as gastric cancer. Also DS-8201a has a higher drug to antibody ratio (7 or 8) compared to that of T-DM1 (3 or 4). DS-8201a demonstrated promising antitumor activity in T-DM1 resistant HER2 expressing gastric cancer in pre-clinical trials because of these unique characteristics[27,28]. A phase I multi-centre, dose escalation study (NCT02564900) reported in 2016 that DS-8201a was well tolerated with satisfactory safety profiles. Only 14% of patients n( = 3/22) experienced more than grade 3 AE. The most common AE were GI and haematological toxicities. A dose of 6.4 mg/kg every three weeks was selected as the recommend phase II dose (RPIID). However there were no dose limiting toxicities identified in this study and the MTD was not established. An ORR of 35% and a disease control rate (DCR) of 90% were reported across several tumour types including breast and gastric cancer[29,30]. An updated report of this study (NCT02564900) in February 2018 further confirmed that ORR and DCR were 44% (16/36) and 78% (28/36) respectively in HER2 expressing gastric cancer patients. It also reported that 83% of subjects were experiencing tumour shrinkage[31]. In addition, DS-8201a showed efficacy in patients with HER2 expressing non-breast and non-gastric malignancies. ORR (including outcomes awaiting confirmation) and DCR were 33% and 91% respectively in 12 evaluable patients. Common side effects from DS-8201a were nausea, reduced appetite, vomiting and reduced platelet count[32]. The study of DS-8201a progressed to a phase II trial (NCT03329690) to evaluate superiority of DS-8201a vs. either irinotecan or paclitaxel monotherapy in gastric cancer. Another phase II trial (NCT03384940) has also commenced to investigate benefit of DS-8201a in advanced colorectal cancer. Wu et al. Cancer Drug Resist 2018;1:204-18 I http://dx.doi.org/10.20517/cdr.2018.16 Page 209 NEW GENERATION HER2 TARGETED ADCS XMT-1522 employs a novel human anti-HER2 antibody conjugated with an auristatin (microtubule polymerization inhibitor)-derivative payload, Auristatin F-Hydroxypropylamide, via a biodegradable hydrophilic polymer, which increased drug to antibody ratio of XMT-1522 to 10-15[33]. In pre-clinical trials, XMT-1522 exhibited anti-tumour efficacy in highly HER2-expressing gastric cancer models. Tumour regression was seen either with XMT-1522 alone or with the XMT-152/trastuzumab/pertuzumab triple combination[34]. A dose escalation phase I study (NCT02952729) in patients with HER2-expressing breast, lung and gastric cancers demonstrated that XMT-1522 was well-tolerated up to the 21.3 mg/m2 dose level with only grade 1 or 2 AE observed. The common AE were impaired liver function, fatigue, nausea, vomiting, reduced appetite and headache. MTD was not established in this study as no dose limiting toxicity was identified. As of February 1st 2018, there are 19 patients enrolled where DCR was 83% (5/6) for patients dosed at 16 or 21.3 mg/m2. Two stable disease (SD) outcomes were seen in gastric cancer patients and others in breast cancer patients. Dose escalation continues with more results expected[35].
MEDI-4276 is another ADC approach to HER2 expressing tumours. MEDI-4276 is a biparatopic ADC that targets two different epitopes on HER2, with site-specific conjugation to a tubulysin-based microtubule inhibitor. MEDI-4276 utilizes a cleavable linker that enables it to mediate bystander killing activity[36]. Pre- clinical trials indicated that MEDI-4276 has anti-tumour activity in vitro, including in T-DM1 resistant cells. A phase I/II dose escalation trial (NCT02576548) had recruited 43 patients with HER2-expressing breast or gastric cancers by November 2017. MTD at 0.9 mg/kg showed dose limiting toxicity of grade 3 elevated alanine aminotranferase (ALT)/aspartate aminotransferase (AST) or grade 3 diarrhea. Common AE were nausea, fatigue, vomiting and elevated ALT/AST. In this study, MEDI-4276 exhibited anti-tumour activity with 1 complete response, 1 partial response (PR) and 12 (28%) SD[37]. A further report is awaited.
SYD985 consists of trastuzumab conjugated to the DNA alkylating agent duocarmycin via a cleavable linker. Multiple pre-clinical trials strongly suggested that SYD985 had extended anti-tumour activity in HER2 low-expressing or HER2 negative breast, gastric, ovarian or uterine cancer cell lines, when compared directly to T-DM1. Unlike T-DM1, SYD985 is able to induce efficient bystander killing effect in vivo, which contributes to significantly improved anti-tumour activity of SYD985 when compared to T-DM1[38-41]. A phase I dose expansion cohort study (NCT02277717) showed promising efficacy of SYD985 in heavily pretreated breast cancer patients, including hormone-receptor positive and triple negative breast cancer. The MTD was 2.4 mg/kg with a manageable safety profile, mainly characterized by grade 1/2 AE of fatigue, dry eyes, conjunctivitis and increased lacrimation. Dose limiting toxicity included grade 3/4 AE including neutropaenia and conjunctivitis. The ORRs were 27% and 40% respectively in hormone-receptor positive and triple negative breast cancer patients; several patients continue on SYD985. Further dose expansion date is pending in gastric cancer patients[42].
ARX-788 is a site-specific ADC conjugating amberstatin (tubulin inhibitor) to a HER2 antibody at two specific sites via a non-cleavable linker. Pre-clinical studies reported that ARX-788 demonstrated increased anti-tumour activity in breast, ovarian, lung and gastric cancer xenograft models compared to T-DM1. Unlike T-DM1, the site-specific conjugated form of ARX-788 has increased stability of up to 3 weeks which improved its therapeutic window and anti-tumour activity[43]. There are currently two dose escalation phase I trials recruiting patients with HER2-expressing breast and gastric cancers (NCT03255070 and NCT02512237) with the intention to identify a safety profile of ARX-788 and potential anti-tumour efficacy.
ADCT-502 is made of an engineered version of trastuzumab, site-specifically conjugated to a highly cytotoxic pyrrolobenzodiazepine-based drug, tesirine, via a protease cleavable linker. It has a drug to antibody ratio of 1.7 and demonstrates bystander killing effect in vitro. There is superiority in anti-tumour effect of ADCT- 502 compared to T-DM1 in various tumour xenografts, including those with low HER2 expression levels[44]. Page 210 Wu et al. Cancer Drug Resist 2018;1:204-18 I http://dx.doi.org/10.20517/cdr.2018.16 ADCT-502 is currently in a phase I dose escalation trial (NCT03125200) involving patients with HER2 expressing advanced solid tumours, including gastroesophageal cancer.
These new generation HER2 targeted ADCs showed superior anti-tumour activity compared to T-DM1 in various pre-clinical trials, even in HER2 low-expressing or HER2 negative cancer models. Consequently these new generation of HER2 targeted ADCs provide a potential treatment option not only in patients who become resistant/refractory to T-DM1, but also in patients whose tumours express low-level or no HER2, and are not eligible for treatment with T-DM1.
MESOTHELIN TARGETED ADCS Mesothelin is a tumour differentiation antigen that is highly expressed in certain human malignancies which includes 86%-100% of pancreatic ductal adenocarcinomas[45], 97% of ovarian adenocarcinomas and 89%- 100% ofmesotheliomas. The limited expression of mesothelin in essential human tissue and high expression in certain cancers make mesothelin a good target for cancer therapy, such as in pancreatic cancer[46]. Several anti-mesothelin antibody based treatments are under clinical investigation, which include vaccines, T-cell therapy and ADC therapy[47].Amatuximabis the first monoclonal mesothelin targeted antibody. In a phase II clinical trial (NCT00570713), Amatuximab combined withgemcitabineshowed no clinical benefit in patients with pancreatic cancer when compared to placebo groups[48]. Further investigation of mesothelin targeted therapy, such as new generation anti-mesothelin antibodies and ADCs, are in progress.
DMOT4039A is the first generation of mesothelin targeted ADCs. DMOT4039A consists of humanized anti-mesothelin mAb conjugated to an antimitotic agent, monomethyl auristatin (MMAE) via a protease cleavable linker. DMOT4039A has a drug to antibody ratio of approximately 3.5:1. A pre-clinical trial showed tumour growth inhibition in pancreatic cancer xenografts treated with DMOT4039A[49]. A phase I study of DMOT4039A (NCT01469793) in patients with unresectable pancreatic cancer or platinum resistant ovarian cancer demonstrated that DMOT4039A has antitumor activity with an acceptable safety profile. In this study, the RPIID level was determined to be either 2.4 mg/kg three weekly or 1.0 mg/kg weekly. Dose limiting toxicities included grade 3 hyperglycaemia and hypophosphatemia. eight percent (2/26) of patients with pancreatic cancer on the three weekly regime achieved PR and 35% (9/26) of patients had SD as best response with a median duration of 5.7 months. The low response rate might be explained by inherent variability in assessing small cohorts or heterogeneous expression of mesothelin in pancreatic cancer[50]. Therefore, DMOT4039A warrants further clinical trials in combination with either chemotherapy or immunotherapy in patients with pancreatic cancer.
Anetumab ravtansine, also called BAY 94-9394 is another potent mesothelin targeted ADC. Anetumab ravtansine is composed of human anti-mesothelin antibodies conjugated to the microtubule polymerase inhibitor, DM4, through a disulphide bond. Pre-clinical trials showed that anetumab ravtansine exhibited antiproliferative activity with bystander effect in mesothelin positive cancer cell lines, which included pancreatic cancer and patient-derived pancreatic cancer xenograft models[51]. In a phase I trial (NCT01439152), MTD of anetumab ravtansine was established at 6.5 mg/kg given every three weeks. The AE included reversible keratitis, asymptomatic liver impairment and GI disorders[52]. A parallel trial (NCT02485119) enrolling Japanese patients showed similar results. Several phase I/II clinical trials are actively recruiting patients presenting with different malignancies. A phase Ib study (NCT03102320) is recruiting patients with mesothelin expressing advanced cholangiocarcinoma or advanced pancreatic adenocarcinoma. This study aims to test the MTD of anetumab ravtansine in combination with either cisplatin or gemcitabine for cholangiocarcinoma or adenocarcinoma of the pancreas[53]. A phase II, multicentre, non-randomized trial (NCT03023722) is evaluating the efficacy of anetumab ravtansine in patients with pre-treated mesothelin- expressing advanced pancreatic cancer[54]. Wu et al. Cancer Drug Resist 2018;1:204-18 I http://dx.doi.org/10.20517/cdr.2018.16 Page 211 BMS-986148 is another ADC that targets to mesothelin. Limited information is known regarding this ADC. BMS-986148 may be related to MDX-1204, which is a conjugation of an anti-mesothelin antibody to the alkylating agent, duocarmycin[55]. A phase I study (NCT02884726) in a single centre in Japan was completed and will provide reports about safety and tolerability of BMS-986148 in patients with advanced and/or metastatic solid tumours. A phase I/II clinical trial (NCT02341625) is currently active, but not recruiting. The goal is to determine the MTD and safety profile of BMS-986148 administered alone or in combination withnivolumabin patients withmesothelioma, non-small cell lung cancer, ovarian cancer, pancreatic cancer and gastric cancer.
GCC TARGETED ADCS GCC is a heat-stable enterotoxin receptor, which is only expressed on intestinal epithelial cells but not extra- GI cells. Previous studies showed that GCC is highly expressed in 60% to 70% of pancreatic, gastric and oesophageal cancers and 95% of primary/metastatic colorectal cancers[56,57]. As a consequence, GCC provides another feasible target for oncology treatment in GI malignancies.
TAK-264 (also called MLN0264) is an ADC that consists of a fully human anti-GCC mAb conjugated, via a protease-cleavable linker, to the microtubule-disrupting agent MMAE. Pre-clinical trials demonstrated that TAK-264 has selective antitumor activity in GCC-expressing colorectal and pancreatic cancer lines and xenografts[57,58]. A multicentre, dose escalation phase I study (NCT01577758) suggested that the MTD of TAK- 264 is 1.8 mg/kg every 3 weeks. At this dose level, TAK-264 has a manageable safety profile with common AE including nausea, reduced appetite, diarrhea and fatigue. In this study, forty-one patients were enrolled, including 35 (85%) with metastatic colorectal cancer. Overall, thirty-nine patients were response-evaluable; three patients experienced SD; 1 patient with gastric adenocarcinoma had a PR[59]. A parallel phase I study (NCT02391038) in Asian patients demonstrated a similar safety profile with TAK-264. However, in this study, none of the patients experienced a dose limiting toxicity and the MTD was not reached up to 1.8 mg/ kg three weekly. All 12 patients were response evaluable; three patients had SD[60]. Preliminary evidence that showed clinical benefit of TAK-264 in phase I trials warranted pursuit of a phase II (NCT02202785) clinical study. This study tested efficacy of TAK-264 in patients with previously treated advanced or metastatic pancreatic cancer. Forty-three patients were enrolled and treated with 1.8 mg/kg TAK-264 every three weeks. Ninety-one percent patients showed measurable response; the ORR was 3% including 1 patient having PR. Nine patients (23%) achieved SD based on investigator assessment. The study was terminated early due to limited benefit[61]. A phase I study that recruited patients with gastric/gastroesophageal junction cancers (NCT02202759) showed similar results. Among 38 patients enrolled, thirty-six patients were response evaluable; the ORR was 6% including 2 patients (6%) having achieved PR. Fifteen patients (42%) achieved SD. The study was terminated after stage I due to low patient response[62]. However, no clear mechanisms were identified to explain the low efficacy of TAK-264. One reason might be the large size of TAK-264, which reduced internalization and consequently results in low activity. GCC remains a favorable target for ADC development for patients with high GCC expression.
A novel GCC targeted ADC, TAK-164, has progressed to the early phases of clinical trials. TAK-164 is comprised of an anti-GCC mAb conjugated to the DNA alkylating agent, DGN549 (also known as IGN-P1). Pre-clinical trials demonstrated that TAK-164 had potential antitumor activity in colorectal or other GI xenografts[63]. Currently, a phase I trial (NCT03449030) is recruiting patients with GCC expressing advanced GI cancers.
CEACAM5 TARGETED ADCS CEACAMs are a large family of twelve glycosyl phosphatidyl inositol anchored glycoproteins involved in cell adhesion and cell signaling during complex biological processes such as cancer progression, inflammatio Page 212 Wu et al. Cancer Drug Resist 2018;1:204-18 I http://dx.doi.org/10.20517/cdr.2018.16 angiogenesis, and metastasis. CEACAM5 has been recognized as a tumour marker of colorectal cancers for the last 50 years and is highly expressed at the surface of tumour cells, including more than 80% of colorectal cancer cells. CEACAM5 has been recently exploited as a target for immunotherapy and vaccine-based therapeutics. In the animal models of colorectal and pancreatic cancers, antibodies against CEACAM5 have shown their potential effectiveness in cancer treatment[64]. Therefore, CEACAM5 is another potential target in ADCs development.
SAR408701 (SAR) is an ADC comprising an anti-CEACAM5 antibody, a cleavable N-succinimidyl 4-(2-pyridyldithio) pentanoate linker and the microtubule-targeting mitosis inhibitor, DM4. Pre-clinical studies have shown promising anti-tumour efficacy with SAR in colorectal cancer, lung and gastric xenografts[65]. A phase I study (NCT02187848) investigated the safety and pharmacokinetics of SAR in patients with GI tumours expressing CEACAM5. In this study, SAR showed an acceptable safety profile with the MTD established as 100 mg/m2. The most commons AE were fatigue, visual/eye changes and GI disturbances. Twelve colorectal cancer patients were tested as CEACAM5 positive, three of which sustained PR (lasting > 4 months)[66]. A dose expansion trial in CEACAM5-expressing solid tumours (including colorectal and gastric cancers) is ongoing with further results on the way (NCT02187848).
Labetuzumab govitecan (IMMU-130) is a CEACAM5 targeted ADC which conjugates the CEACAM5 antibody labetuzumab to the active metabolite of irinotecan, SN-38, through a proprietary linker. Labetuzumab govitecan showed improved efficacy and reduced toxicity compared to irinotecan in pre- clinical colorectal cancer xenografts[67-69]. Two phase I studies investigating the activity of labetuzumab govitecan in patients with metastatic colorectal cancer were reported in a conference abstract in 2014. In both trials, eligible patients had been pre-treated with standard chemotherapy (such as irinotecan) and had an elevated CEA (> 5 ng/dL). In the first study, labetuzumab govitecan was given every two weeks; the MTD was 16 mg/kg. One patient (out of 8) received 18 cycles of treatment and achieved PR with a 40.6% reduction in liver and lung lesions, lasting for 4.7 months. In the second study, MTD was the same when labetuzumab govitecan was given 4 mg/kg twice weekly. Three/six patients experienced PR with 40% tumour shrinkage. In these two phase I trials, labetuzumab govitecan was well tolerated with the most common AE including neutropaenia and diarrhea[70].
A phase I/II, multicentre dose-finding trial (NCT01605318) investigated the therapeutic index of labetuzumab govitecan in patients with relapsed or refractory metastatic colorectal cancer. Eighty-six patients were recruited with an elevated serum CEA (> 5 ng/mL) and had progressed after a median of five prior treatments (including irinotecan). Weekly doses (8 or 10 mg/kg) or twice weekly doses (4 or 6 mg/kg) with 1 week breaks were demonstrated to be tolerable. The most common AE were neutropaenia, leukopenia, anaemia and diarrhea. In this trial, thirty-eight percent patients (27/72) achieved a reduction in tumour size with one patient achieving a sustained PR lasting for 2.7 years. Fifty-eight percent (42/72) patients achieved SD with 33% (24/72) of these outcomes lasting more than 4 months. Median PFS for all 86 patients was 3.6 months (95% CI 2-4 months) and median OS was 6.9 months (95% CI 5.7-7.8). Compared to the PFS and median OS of regorafenib (1.9 and 6.4 months, respectively), which is currently recommended as third line treatment for relapsed or refractory metastatic colorectal cancer, labetuzumab govitecan provides another option in the third-line setting[71]. Labetuzumab govitecan also showed less toxicity than irinotecan, particularly with regard to diarrhea. Combination approaches of labetuzumab govitecan with other agents should be investigated; a pre-clinical study has demonstrated an enhanced anti-tumour effect in colorectal cancer cells of labetuzumab govitecan combined withbevacizumab[72].
OTHER ADCS IN GI CANCERS Cantuzumab mertansine is an ADC combining huC242, a highly selective mAb targeting CanAg, with DM1 via a disulphide linker. CanAg is a transmembrane glycoprotein that is highly expressed in pancreatic Wu et al. Cancer Drug Resist 2018;1:204-18 I http://dx.doi.org/10.20517/cdr.2018.16 Page 213 cancer, cholangiocarcinoma and colorectal cancer[73]. Cantuzumab mertansine was highly effective against CanAg positive tumours in pre-clinical studies that showed complete responses in CanAg positive gastric, colon, pancreatic and non-small cell lung cancer xenografts[74]. Three phase I studies have assessed cantuzumab mertansine in solid tumours, including GI cancer patients. AE included fatigue, deranged liver function tests and GI disturbances. Best response was SD, lasting 4-5 months on average[73,75,76]. Cantuzumab mertansine did not progress to phase II study for unknown reasons.
PF-06263507 is an ADC comprising humanized anti-5T4 antibodies (huA1), a non-cleavable linker and a monomethylauristatin F payload (a microtubule polymerization inhibitor)[77]. 5T4 is a surface antigen expressed in many tumour types including pancreatic, oesophageal, colorectal and gastric cancers. High levels of 5T4 expression have been associated with poorer clinical outcomes in colorectal, ovarian and gastric cancers[78-81]. In a phase 1 study, twenty-six patients with solid tumours (including GI cancers) were treated with PF-06263507 with the MTD determined to be 4.34 mg/kg. 5T4 expression was not assessed. No ORRs were observed; two patients achieved SD. The most common AE were fatigue, photophobia, dry eyes and GI disturbances[77]. Pre-clinical studies have since demonstrated how 5T4 positive cells can down-regulate expression of 5T4 in response to 5T4 targeting ADCs, leading to resistance over time[82-84]. Pre-clinical studies have also revealed enhanced anti-tumour activity of combination treatments involving PF-06263507[85,86].
CONCLUSION AND FUTURE PROSPECTS GI malignancies represent the most common cancers and are a leading cause of cancer-related death worldwide. ADCs are a rapidly growing cancer treatment that are expected to selectively deliver cytotoxic drugs to cancer cells for increased efficacy, while minimizing toxicity to normal healthy cells. In this review, we have outlined pre-clinical and clinical evidence of current popular ADCs trials in GI malignancies, including HER2, mesothelin, GCC and CEACAM5 targeted ADCs. However, none of these ADCs have advanced into clinical practice for treating GI cancers.
Future strategies to investigate the efficacy of ADCs should assess combinations with other oncology modalities including chemotherapy, radiotherapy, immune checkpoint inhibitors or targeted therapy. Most clinical trials of ADCs in GI malignancies to date have attempted to demonstrate superiority as monotherapy. However, their higher tolerability and safer toxicity profiles, when compared to cytotoxic chemotherapy, indicate that they may be suitable to combine with other agents. Although the TRAX- HER2 study did not show superiority of the T-DM1/capecitabine combination compared to T-DM1 alone in patients with metastatic breast or gastric cancer, many other chemotherapy/ADC combinations are under consideration to enhance anti-tumour effects of ADCs. Furthermore, ADCs with DNA damaging agents (especially microtubule inhibitors) as the payload have the potential to enhance and sustain anti-tumour effects when combined with immune checkpoint inhibitors such as anti-PD1 antibodies (Pembrolizumab, Nivolumab) or anti-programmed death ligand 1 antibodies (atezolizumab). There is accumulating pre- clinical evidence to suggest that DNA damaging agents can promote anti-tumour immune responses by increasing antigen presentation, activating dendritic cells and promoting immunogenic cells death[87]. Pre- clinical trials proved that T-DM1 renders HER2 positive breast cancer cells highly susceptible to PD-1 blockade[88]. An active phase I/II clinical trial (NCT02318901) is evaluating the potential of T-DM1 in combination with pembrolizumab in advanced breast, gastric, oesophageal and colorectal cancers. Finally, HER2 over expression was identified as a factor contributing to radio-resistance in breast cancers. Radiation may result in a more potent anti-tumour effect when combined with anti-HER2 therapy. Further exploration of concurrent administration of T-DM1 with radiotherapy is warranted in GI cancers[89]. The challenges of combining ADCs with other modalities includes choice of ADC with other cytotoxic agents, dose of compounds, toxicity of combination and scheduling/sequencing of combinations.
Another major trend in ADC research is to design new generations of ADCs with increased homogeneity, stability and potency through the large variety of ADC technologies developed over the past decade. The Page 214 Wu et al. Cancer Drug Resist 2018;1:204-18 I http://dx.doi.org/10.20517/cdr.2018.16 current third generation of ADCs has significantly benefited from the engineering of IgG molecules, which are well suited for drug conjugation and enhance the homogeneity and therapeutic index of ADCs. Moreover, the first biparatopic ADC, MEDI-4276, targets two non-overlapping epitopes on the same HER2 antigen and can thus potentially improve drug delivery to tumours while reducing drug exposure to normal tissue. A variety of new formats of mAbs are under investigation in pre-clinical stages, providing new opportunities to develop antibody-dual-drug conjugates or nanobodies/single chain fragment/peptide-drug conjugates in the future. In addition, diversification of linking strategies such as cleavable/non-cleavable linkers and charged/non-polar linkers have been utilized in linker design to balance the need for stability in the circulation and efficient cleavage upon delivery into tumour cells, therein enhancing or reducing bystander effects. Several linking strategies are also under investigation to increase solubility and drug- antibody ratio of ADCs[3].
Finally, patient selection strategies in the clinical study of ADCs can make the difference between success and disappointment. The level of antigen expression on cancer cells’ surface is a key parameter in predicting the likelihood of the amount of payload delivered to a cancer cell in a tumour. Thus, selecting patients whose target antigen density (on their cancer cells’ surface) is above a threshold level is important to optimising ADC activity. However, one of the challenges to meet this criterion is identifying the presence of target antigens in real time and by minimally invasive techniques. Several strategies to develop new diagnostic tests to assess the level of cell target antigens are under investigation. For example, 89Zr radiolabeled trastuzumab positron emission tomography scans are able to demonstrate, in real time, HER2 expression levels with the advantage of being relatively non-invasive[90]. Circulating DNA can also predict HER2 status, reducing the need for invasive biopsies. There is clearly much yet to explore in the future for biomarkers to predict whether patients will respond to ADC treatment.
In summary, incorporating ADCs into future GI malignancy treatment offers exciting opportunity for better outcomes for cancer patients. Future strategies will focus on optimal application of ADCs, especially in establishing the best combination modalities for treating different GI tumours, designing new generation of ADCs with high potency and stability as well as co-developing biomarker detection technologies for better patient selection.
DECLARATIONS Acknowledgement All authors would like to acknowledge National Health Service funding to the National Institute for Health Research Biomedical Research Centre at the Royal Marsden NHS Foundation Trust and The Institute of Cancer Research.
Authors’ contributions Wrote the manuscript: Wu X, Kilpatrick T Edited, reviewed and approved the manuscript: Chau I
Availability of data and materials Not applicable.
Financial support and sponsorship None.
Conflicts of interest Chau I is on the advisory board for Eli-Lilly, Bristol Myers Squibb, MSD, Bayer, Roche, Merck-Serono, Five Prime Therapeutics and Astra-Zeneca. He has received research support from Eli-Lilly, Janssen-Cilag, Sanofi Wu et al. Cancer Drug Resist 2018;1:204-18 I http://dx.doi.org/10.20517/cdr.2018.16 Page 215 Oncology, Merck-Serono and honorarium from Eli-Lilly.
Ethical approval and consent to participate Not applicable.
Consent for publication Not applicable.
Copyright © The Author(s) 2018.
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e certainly did not limit himself to these sources but sought insight from the non-Christian (e.g., Hellenistic, Jewish, and Arabic) philosophical (even theological) traditions as well. Thus, one can conclude that the scholastic method “<em>creates</em> and <em>distinguishes</em> Scholastic theology as a scientific or academic theology, and thus as a particular undertaking, from other sorts of theology” (Ulrich Leinsle, <em>Introduction to Scholastic Theology</em>, 8).</p>
<p>The language of “scholastic” or “scholasticism” derives from the Greek word σχολή, which can mean leisure, or “leisure devoted to the sciences.” Σχολαστικός is used for the first time by Aristotle (d. 322 BCE) in his <em>Politics</em> signifying an activity done for its own sake that is unfettered by the immediate requirements of living. Later philosophers continue to use this language to describe someone who lives for contemplation (θεωρία) and/or concerned with all elements of education and schooling. In the high Middle Ages, the term <em>scholasticus</em> is <em>not</em> used in reference to a particular kind of theology but becomes, in the modern era, a term that carries negative connotations and implies reference to Aristotle, barbaric Latin, hair-splitting, sophistry, useless logical disputations and pastoral barrenness. In time “scholastic theology” stands over against “positive theology,” in that scholastic theology engages in speculation whereas positive theology stands in reference to exegesis and canon law, for instance. Yet, already in the early sixteenth century that both Desiderius Erasmus of Rotterdam (d. 1536) and Martin Luther (d. 1546), for example, criticized scholasticism and its methodology.</p>
<p>Erasmus was a leading light of the European Renaissance and a frequent critic of the late medieval Church. Nonetheless, he remained in the Roman Church, choosing not to align with the Protestant Reformation. His best-known literary work is In <em>Praise of Folly</em>, a critique of abuses published in 1511. In the work Folly, personified as a woman, claims that what appears to be Folly outwardly, is actually wise inwardly. Folly rails against that which she judges to be foolish in the areas of politics and society. But Erasmus’ biting satire is also used to level criticisms against the Church, including theologians, monks, clergyman and scholastic theology. Regarding the latter,</p>
<blockquote class="wp-block-quote"><p>Then there are the theologians, a remarkably supercilious and touchy lot … for they abound in newly coined expressions and strange-sounding words … These subtle refinements of subtleties are made still more subtle by all the different lines of scholastic argument, so that you’d extricate yourself faster from a labyrinth than from the tortuous obscurities of realists, nominalists, Thomists, Albertists, Ockhamists, and Scotists … Such is the erudition and complexity they all display that I fancy the apostles themselves would need the help of another Holy Spirit if they were obliged to join issue on these topics with our new breed of theologian.</p></blockquote>
<p>Erasmus’ main issue with scholastic theologians is that they obscure the meaning of their theology and ignore the fact that theology’s goal is holiness.</p>
<p>One of Luther’s earliest works is the <em>Disputation against Scholastic Theology</em>, in which Luther says that scholastic theology holds to too high a view of human reason, thinks that free will is less corrupted by sin than it actually is and suggests that the Gospel is insufficient because of an overreliance on philosophy, especially Aristotle. For example, “If a syllogistic form of reasoning holds in divine matters, then the doctrine of the Trinity is demonstrable and not the object of faith” (§39). Luther sees that scholastic theology teaches that for one to be a theologian one has to become one with Aristotle. Luther adamantly opposes this understanding: “To state that a theologian who is not a logician is a monstrous heretic—this is a monstrous and heretical statement” (§45). Luther’s critique of scholasticism did not diminish over the years even if he followed positions of some of the scholastic theologians when he felt they were right.</p>
<p>Thus, one can see that scholastic theology is the result of a particular set of historical moments, it came about almost by accident but became so popular so quickly that it by and large displaced the kind of theological method that preceded it (i.e., monastic theology). This, of course, does not make it “bad” or inferior but as it grew it became a kind of thing that was hated by those who thought that theology should be done in a different key. Again, it lost its proper end for the <em>telos</em> of communion with God was largely missing in favor of endless discussion and the domestication of the inscrutable and deep things of God. The situation has not greatly improved in the intervening centuries. Hence the need for a revised monastic theological method. Apart from that, theology will continue to suffer.</p>
<p>The post <a rel="nofollow" href="https://scriptoriumdaily.com/the-rise-of-the-scholastic-theological-method/">The Rise of the Scholastic Theological Method</a> appeared first on <a rel="nofollow" href="https://scriptoriumdaily.com">The Scriptorium Daily</a>.</p>
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<title>The Christ-Life</title>
<link>https://scriptoriumdaily.com/the-christ-life/</link>
<dc:creator><![CDATA[Isaac Blois]]></dc:creator>
<pubDate>Mon, 10 Oct 2022 17:39:03 +0000</pubDate>
<category><![CDATA[Theology]]></category>
<guid isPermaLink="false">https://scriptoriumdaily.com/?p=34088</guid>
<description><![CDATA[<p>“Many years later, as he faced the firing squad, Colonel Aureliano Buendía was to remember that distant afternoon when his father took him to discover ice.” With these words, Gabriel García Márquez begins his famous novel One Hundred Years of Solitude. It takes more than <a class="excerpt-read-more" href="https://scriptoriumdaily.com/the-christ-life/" title="ReadThe Christ-Life"><i class="icon-read-more-arrow"></i></a></p>
<p>The post <a rel="nofollow" href="https://scriptoriumdaily.com/the-christ-life/">The Christ-Life</a> appeared first on <a rel="nofollow" href="https://scriptoriumdaily.com">The Scriptorium Daily</a>.</p>
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<p>“Many years later, as he faced the firing squad, Colonel Aureliano Buendía was to remember that distant afternoon when his father took him to discover ice.” With these words, Gabriel García Márquez begins his famous novel <em>One Hundred Years of Solitude</em>. It takes more than a hundred pages of telling the mythic saga of the Buendía family before we get to the actual scene when the Colonel faces that firing squad, but even at the beginning we see how facing death reframes life for this character, causing him to reflect on what truly matters from his past. Another famous novelist—Dostoevsky—employs this trope about a near-death experience, writing in his novel <em>The Idiot</em> of a character about to be executed on a scaffold, at which moment the man ponders what life might look like if he were to survive: “I would turn every minute into an age, nothing would be wasted, every minute would be accounted for.” In this case, facing death allows for a renewed experience of life, bringing everything into sharper focus and instilling it with greater meaning.</p>
<p>Paul too writes Philippians under the shadow of execution. He’s chained up, awaiting the verdict of his Roman trial where the chances are strong that, just like his Lord, he’ll receive the verdict of a capital punishment. And just as for these other men, facing death guides Paul to rethink life.</p>
<p>At this early point in Philippians, Paul is writing a report to his friends concerning the news about how things are faring with him in prison. But whereas most people would focus on all the ups and downs faced in the squalid prison setting, Paul instead shifts the focus away from his own experience and over to the prospects of the gospel about Christ. Much less concerned with how he himself is faring, he highlights the advance of the gospel, and even hones in on how his own body will hopefully serve as the physical space at which Christ will be exalted—most likely through Paul’s public testimony about Christ at the soon-coming trial. Notice how Christ’s magnification will occur through Paul’s “not being ashamed” but instead by his “boldness” (1:20). Paul feels supported and encouraged in this upcoming public task through the support of his friends—they are praying for him, and because of that God’s Spirit is strengthening him (v.19), and this is cause for great rejoicing.</p>
<p>In addition to the exaltation of Christ that will come from his spoken witness at the trial, the apostle also looks ahead to the aftermath of the trial, which seems to present two very different possible outcomes, marked by the clause “whether by life or by death” (1:20). That is, after speaking up for Christ at the Roman trial he is about to face, the verdict will go either one of two ways: he’ll survive (“whether by life”), or he’ll be killed (“whether by death”).</p>
<p>Interestingly, faced with such a drastic situation, Paul begins to reflect on the meaning and value of each of these two options. He seems almost to present a sort of soliloquy (like Hamlet’s “To be or not to be”) in which the apostle is “thinking out loud” in front of his Philippian audience, pondering and evaluating between the pros and cons of the two options presented to him: either that of living, or that of dying. But, just as Paul does with everything else in his life, these two options of living and dying are passed through the grid of Christ, since for Paul Jesus controls every aspect of reality. Indeed, the person of Jesus looms large across every page of this short 4-chapter letter, with either Jesus’s name or a pronoun referring to Jesus occurring in almost every sentence! Christ reigns supreme for Paul, and so when he’s analyzing the prospects of his own living or dying, it is always and only in relation to Christ that these two options acquire their meaning and their significance.</p>
<p>What I want to look at in what follows will thus track with this two-part structure, learning from Paul how Christ reframes life and death. Such reflections on “The Christ-Life” draw on Paul’s well-known maxim in Phil 1:21 (“Living is Christ and dying is gain.”). Our reflections will actually start, though, with the second of these re-framings, that regarding death, because it is in the way that Christ forces Paul to reimagine what death is that the truly radical nature of Paul’s vision of Christ rises to the surface.</p>
<h2>Christ Reshapes Death</h2>
<p>The first way that Christ has reshaped everything for Paul is that he has changed how the apostle imagines death. For many, both in Paul’s world and in our own, death is the ultimate enemy, the thing to be avoided at all costs, and that which hurts the most once it strikes. Why does death hurt so bad? Because it slams the door on so much of what we have come to regard as our own. It is the final bow before the curtain closes, and once off stage, the fear is that our story will be over. Humans, just as their lower counterparts in the beasts, have a strong, inborn instinct for survival, and we will fight with ferocity when we feel our life is being threatened.</p>
<p>There have been some who were able to fight back against this natural instinct to fear death, who were strong enough to welcome it as “gain.” We read in Torrey a play by the Greek play-write Sophocles about a girl named Antigone who chooses to rebel against what she feels to be a wrongful law denying burial to her brother. Out of fierce loyalty to her kin, she flouts the law and buries him anyway, accepting whatever consequence might come from it. When threatened with execution for her crime, she exclaims, “If I die before my time, I say it is a gain (κέρδος αὔτ ̓ ἐγὼ λέγω). Who lives in sorrows many as are mine (ὅστις γὰρ ἐν πολλοῖσιν ὡς ἐγὼ κακοῖς ζῇ) how shall they not be glad to gain death? (πῶς ὅδ ̓ οὐχὶ κατθανὼν κέρδος φέρει;). And so to me to meet this fate’s no grief.” Plagued by the sorrows of life, Antigone welcomes gladly the gain of death, especially since she will be dying in the right, having refused to cave to the pressures of injustice surrounding her. Others too have followed Antigone’s lead, imagining death as a welcome guest because it provides release from the troubles and sorrows of life. It is an escape, a way out, and so death means gain.</p>
<p>For Paul, though, this is not the case. For Paul, death is not a way out; instead, it is a way in. The apostle speaks here of his “desire” to depart life, and that desire is locked onto a specific goal: being “with Christ” (1:23). <span class="footnote_referrer"><a role="button" tabindex="0" onclick="footnote_moveToReference_34088_18('footnote_plugin_reference_34088_18_1');" onkeypress="footnote_moveToReference_34088_18('footnote_plugin_reference_34088_18_1');" ><sup id="footnote_plugin_tooltip_34088_18_1" class="footnote_plugin_tooltip_text">[1]</sup></a><span id="footnote_plugin_tooltip_text_34088_18_1" class="footnote_tooltip">Paul’s idea about post-mortem existence allowing for individuals to be “with” the divine has an important parallel in Plato’s philosophical presentation of post-mortem existence. In the … <span class="footnote_tooltip_continue" onclick="footnote_moveToReference_34088_18('footnote_plugin_reference_34088_18_1');">Continue reading</span></span></span><script type="text/javascript"> jQuery('#footnote_plugin_tooltip_34088_18_1').tooltip({ tip: '#footnote_plugin_tooltip_text_34088_18_1', tipClass: 'footnote_tooltip', effect: 'fade', predelay: 0, fadeInSpeed: 200, delay: 400, fadeOutSpeed: 200, position: 'top center', relative: true, offset: [-7, 0], });</script> Often times in Christian settings effort is taken to combat our desires, to curb our longings and to restrain our passions. What I love about Paul’s reframing of death here is that his scenario actually chides us for not desiring strongly enough. C. S. Lewis says it well: “It would seem that our Lord finds our desires not too strong, but too weak. We are half-hearted creatures, fooling about with drink and sex and ambition when infinite joy is offered us, like an ignorant child who wants to go on making mud pies in a slum because he cannot<br>imagine what is meant by the offer of a holiday at the sea.” Paul gives the strongest affirmation I can think of for fostering a deep longing and desire within us, one that’s directed at relationship. Paul’s is not a longing for stuff; it’s a longing for being “with” someone, the Lord whom he has come to know as the most beautiful one, to know whom represents the most “surpassing” knowledge available for us, for the sake of which it would be right to count all else “loss” (3:9), indeed, Christ is so valuable that it should cause us to sell everything so that we might purchase this pearl of great price.</p>
<p>Paul is not the only one to direct his desires toward death and the grave. We read of characters in stories who love someone so strongly that when that lover dies, they long to follow them down into the grave. This is powerfully presented in Victor Hugo’s <em>Notre Dame</em> novel at the end of which the hunchback Quasimodo is so grieved by the loss of his beloved Esmerelda that after her tragic death and then burial he actually digs up her grave to climb in and die alongside her. Heathcliff does something similarly morbid in Brontë’s <em>Wuthering Heights</em>. And even our own father Abraham in Genesis, when he thinks his favorite son Joseph has died, exclaims: “I shall go down to Sheol to my son” (Gen 37:35). But Paul’s longing for death is not like this—his love is not a clinging to the grave, but is actually a yearning for renewed life. Not the laying down with a corpse, but instead the rising up to join “with” his resurrected lord, to enjoy pleasures at his right hand forevermore.</p>
<p>Thus, when Paul says in his powerful yet compact language that “death is gain” (1:21b), what he is saying is that the gain of being with Christ amounts to the highest, most satisfying, happiest experience that we as humans can have. “Being with Christ” is truly “better by far” than every other experience a human might encounter. If it takes death to enter into this state of bliss and deep joy, then Paul will accept it gladly, because death is not an exit but an entrance, not a way out of life but rather a way into the truest life there is.</p>
<p>Being with Christ is Paul’s greatest longing. Here he tells us that he can only have it if he “departs” from life. At other points, Paul indicates his close and intimate connection with Christ even now during his lifetime. And there is joy and richness available for him and other believers even now through fostering a closeness with Christ. But our fleshly bodies do prove a hindrance that finally must be overcome by passing through that final death. There is a closeness and intimacy with Christ that awaits us yet, and for this we long with eager expectation and desire.</p>
<p>So for Paul in chains, facing the executioner’s notice, death is no threat but instead is a welcome comrade. J. K. Rowling, in the seventh book in her Harry Potter series, tells the story of the three Peverell brothers. All three of the brothers find different ways to try outsmarting death: one brother tries to beat death through the strength of a powerful wand; another brother tries through using a stone that can raise dead loved ones back to life; but the third brother tries a more roundabout and subtle method, employing an invisibility cloak to hide from Death. But after time, that third brother realizes that death is not quite the enemy that they all thought he was, and at the end of his life the brother takes off the cloak and, “[greeting] death as a friend, [he] went with him gladly.” We too as believers can greet death gladly, not because it’s desirable in itself but because it provides us access to that which is most desirable: being with Christ. Death is gain, because to be with Christ surpasses all other of life’s goods to such an extent that it turns them into loss.</p>
<h2>Christ Reshapes Life</h2>
<p>And so we’ve seen how facing death prompted Paul to rethink death—it brought him to a radically altered perspective about what death means. It means not loss, but instead great gain. And insofar as Paul is comparing, in soliloquy fashion, the two options of either living or dying, it would seem that it’s a slam dunk as to which of the two is the better option. On that basis, one would think that his choice (should he have a choice in the matter) has already been made: of course, he will opt for death, since that will bring him to his greatest desire, being with Christ.</p>
<p>We’re in for a surprise, though, here. After having radically reshaped what death means, now Paul’s also going to fundamentally reshape what it means to live, and this will impact then the comparative valuation that he’s making between the two options.</p>
<p>Recall that what gave to death such a radically different significance was its relation to Christ—it provided access to being with Christ which made all the difference. Well, now too the idea of living must also be placed in relation to Christ. Think about how that survival instinct I mentioned previously works: it prompts the individual to fight to maintain her own existence, so as not to let anything deprive her of life, holding onto it as her own possession. But what if your life was not your own? What if, rather than a thing to be possessed and held onto, life was primarily something to be given away for the sake of others?</p>
<p>When Paul imagines the prospect of Christ being magnified in his body at the upcoming trial by means of his life, the way he describes this is “living is Christ.” If Paul makes it through the trial, the life he then starts living will not be his own; it will be the Christ-life, a life so characterized by Christ that its very meaning and significance are anchored in who Christ is and what he stands for. It may be cheating a bit to look ahead in the letter, but Paul is about to give us in chapter 2 of Philippians a gripping portrait of who Christ is and what he’s about, and it’s a portrait that bleeds outward to form and shape all the other contours of the letter.</p>
<p>If living is Christ, then what is the Christ-life all about? Fundamentally, Christ lives his own life not for himself, but for the benefit of others. First and foremost, Jesus submits in obedience to his heavenly Father. Rather than holding tight to his own privileges and rights as the God-man, Jesus willingly takes up the role of a slave, undergoing a death that will benefit the very ones who are persecuting him. Every consideration of Christ is taken up with the “interests of others,” turning away from any “selfish ambition” that might “exploit” his legitimate prerogatives so as to improve his own lot at the expense of those around him. Far from it, Jesus instead undertakes a life of service, taking on the “form of a slave” (2:7), and in so doing he shows us what the true human life should have been from the get-go. It is this servant way of living that then acquires the Father’s official stamp of approval, since only the servant-human receives exaltation and resurrection, with the name of the slave-turned-Lord Jesus Christ emblazoned at the top of the universe, with every creature, in heaven, and earth, and under the earth, bowing in worship to the servant king.</p>
<p>And so life as it’s been redefined by Jesus is a servant way of being. The Christ-life is a servant life; a life lived not for self but for others. Paul appropriates this version of life—which is the true version of life—for himself in our passage in chapter one. Though death would have been “far better,” life becomes “far more necessary,” and this new category that the apostle introduces—that of things “necessary” or beneficial when referred to someone else—actually trumps the “more satisfactory” category. To make decisions solely on the basis of that which is most pleasing to oneself would be to fall into the trap of the sinful human, to go one’s own way at the expense of one’s brother (this is the way of Cain). Desires are good, especially the desire and longing for relationship with Christ; but God has called us to a life of service and love, and this calling must ultimately take precedence over the life of satisfaction and pleasure.</p>
<p>Paul recognizes that his beloved friends at Philippi are relying on him, they need his help and support back there on the ground in their city. His returning back to them after release from prison would serve to advance their joy in the faith, and he is confident that God will work things out for this return to happen, since that result would be so beneficial for the lives of these women and men, these saints in Christ, whom he cares so deeply about. His renewed ministry labors among them will bear much fruit, it will produce great exultation and celebration among the struggling church—just what they need to help them through the difficult times of persecution and tension that they’re currently facing. And so Paul is sure—this has got to be God’s plan for the outcome.</p>
<p>Though when it comes to Paul’s own deep longings and desire he would wish that he could actually be released from his duties of service so that he can finally be present personally and intimately with the Lord whom he’s given his all to serve, yet Paul affirms that there is yet more work to be done, and he willingly and even heroically prepares to step back into the hard work of serving others. Such a servant-existence is precisely the life to which he is about to call this community a few paragraphs later in the letter, and so he prepares the way for that exhortation by modeling in his own life that which he hopes they would take on in theirs. Though filled with labors, such a servant-life is fruitful and so it’s full of joy.</p>
<p>Overall, when confronted with death, Paul helps us reframe how we think about these two key options—really the only two options—of life and death. Ironically, both options mean Christ. To go on living is to embrace the Christ-life, a life of service for the sake of others, foregoing one’s own desires so as to regard others better than self. On the other hand, to die is to enter fully into relationship with Christ, to leap over that final barrier between us and our Lord and to directly and intimately be “with” Jesus. Lord, may it be soon, for us all!</p>
<div class="speaker-mute footnotes_reference_container"> <div class="footnote_container_prepare"><p><span role="button" tabindex="0" class="footnote_reference_container_label pointer" onclick="footnote_expand_collapse_reference_container_34088_18();">References</span><span role="button" tabindex="0" class="footnote_reference_container_collapse_button" style="display: none;" onclick="footnote_expand_collapse_reference_container_34088_18();">[<a id="footnote_reference_container_collapse_button_34088_18">+</a>]</span></p></div> <div id="footnote_references_container_34088_18" style=""><table class="footnotes_table footnote-reference-container"><caption class="accessibility">References</caption> <tbody>
<tr class="footnotes_plugin_reference_row"> <th scope="row" class="footnote_plugin_index_combi pointer" onclick="footnote_moveToAnchor_34088_18('footnote_plugin_tooltip_34088_18_1');"><a id="footnote_plugin_reference_34088_18_1" class="footnote_backlink"><span class="footnote_index_arrow">↑</span>1</a></th> <td class="footnote_plugin_text">Paul’s idea about post-mortem existence allowing for individuals to be “with” the divine has an important parallel in Plato’s philosophical presentation of post-mortem existence. In the <em>Phaedo</em>, Socrates defends the claim that his upcoming execution is not a “misfortune” by mentioning the swans, who “sing most beautifully” when “they realize that they must die,” for “they rejoice that they are about to depart (ἀπιέναι) to <em>join</em> the god (παρὰ τὸν θεὸν) whose servants they are” (85a).</td></tr>
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<title>The Superiority of a Monastic Theological Method</title>
<link>https://scriptoriumdaily.com/the-superiority-of-a-monastic-theological-method/</link>
<dc:creator><![CDATA[Greg Peters]]></dc:creator>
<pubDate>Mon, 03 Oct 2022 17:37:51 +0000</pubDate>
<category><![CDATA[Theology]]></category>
<guid isPermaLink="false">https://scriptoriumdaily.com/?p=34097</guid>
<description><![CDATA[<p>This is post 1 of 4 in a series on the monastic theological method. It looks forward to the publication of Greg Peters’ new book: Monastic Theology as Theological Method: The Superiority of the Monastery to the University. Join us in this article as Dr. <a class="excerpt-read-more" href="https://scriptoriumdaily.com/the-superiority-of-a-monastic-theological-method/" title="ReadThe Superiority of a Monastic Theological Method"><i class="icon-read-more-arrow"></i></a></p>
<p>The post <a rel="nofollow" href="https://scriptoriumdaily.com/the-superiority-of-a-monastic-theological-method/">The Superiority of a Monastic Theological Method</a> appeared first on <a rel="nofollow" href="https://scriptoriumdaily.com">The Scriptorium Daily</a>.</p>
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<h4><strong>This is post 1 of 4 in a series on the monastic theological method. It looks forward to the publication of Greg Peters’ new book: <em>Monastic Theology as Theological Method: The Superiority of the Monastery to the University</em>. Join us in this article as Dr. Peters distills the differences of approach between monastic and scholastic theology and sets the vision for the forthcoming book:</strong></h4>
<p></p>
<p>It recently came to me that I have been formally studying monasticism for just under thirty years.<br>I discovered Bernard of Clairvaux in a not-very-creatively-named Church History II class in Fall<br>1993 at Philadelphia College of Bible (now Cairn University). Dr. Chip Hard told us that<br>Bernard was a Cistercian monk. Being a Southern Baptist kid from central Virginia I thought to<br>myself, what’s a Cistercian? Actually, what’s a monk? And so began a study of monasticism that<br>has not abated.</p>
<p>It was early in my monastic studies that I found Jean Leclcerq’s <a href="https://www.fordhampress.com/9780823204076/the-love-of-learning-and-the-desire-god/"><em>The Love of Learning and the<br>Desire for God</em></a>. But it is only now that I have come to realize that Leclercq’s distinction between<br>“monastic theology” and “scholastic theology” is <em>not</em> just a way to categorize the historical<br>development of early and medieval theology but are actually two ways of doing theology. That is,<br>monastic theology and scholastic theology are distinct theological methods and I think I<br>understand how they are distinct and I think I can argue that a monastic theological method is<br>superior to a scholastic one. And if it is superior to a scholastic theological method, then it is<br>superior to many modern forms of theological methodology which are the children,<br>grandchildren, great grandchildren and perhaps even bastard children of this thing called<br>“Scholasticism,” which relies on a scholastic theological methodology.</p>
<p>Despite appearances, the discipline of theology is in trouble. It is true that there continues to be a<br>steady stream of theological publications and without doubt there are still doctoral programs with<br>theology students and seminaries brimming with divinity students. There are centers for pastor-<br>theologians, a nationwide “Theology on Tap” program, a network of Christian study centers<br>dedicated to lay theological training and conversation, and another network of theological<br>institutes offering advanced degrees and programs outside the traditional seminary structure.<br>Further, there remains publishing houses focused on theological books. And, of course, there are<br>still thousands of churches dedicated to preaching and catechesis, perhaps even theological<br>preachin
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A collection of writings from Marx and Engels, consisting of 50 volumes, known as the Marx-Engels Collected Works (MECW). The collection includes all of Marx's and Engels' major works, as well as previously unpublished or lesser-known texts (e.g. letters, newspaper articles, manuscripts and so on). However, the collection does not include all of Marx's and Engels' writings (such as Marx's and Engels' notes and reading excerpts); a more comprehensive collection/project (though not in English) is the Marx-Engels Gesamtausgabe (MEGA), which is still underway.
Marx and Engels collected works
Illustration of Marx and Engels
A collection of writings from Marx and Engels, consisting of 50 volumes, known as the Marx-Engels Collected Works (MECW). The collection includes all of Marx's and Engels' major works, as well as previously unpublished or lesser-known texts (e.g. letters, newspaper articles, manuscripts and so on). However, the collection does not include all of Marx's and Engels' writings (such as Marx's and Engels' notes and reading excerpts); a more comprehensive collection/project (though not in English) is the Marx-Engels Gesamtausgabe (MEGA), which is still underway.
Author
Karl Marx
Friedrich Engels
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Below is a breakdown of the content of each volume, and attached below is each volume in PDF format. The content-breakdown is incomplete and only tries to capture the more significant/noteworthy writings in each volume (which is of course subjective). In subsequent book chapters are volumes 1 and 2 with each component article in text format.
Readers should bear in mind that the PDFs were compiled by the Institute of Marxism-Leninism, and so contain commentary and introductions not by Marx and Engels, but by themselves with a specific political agenda, which differs significantly from that of Marx and Engels, who declared that the emancipation of the working class was the task of the working class itself.
I. Various philosophical, political, historical and economic works
Vol. 1 (1835-1843)
Early writings of Marx
The Difference Between the Democritean and Epicurean Philosophy of Nature - Marx
Vol. 2 (1838-1842)
Early writings of Engels
Vol. 3 (1843-1844)
Early writings of Marx and Engels
"On the Jewish Question" - Marx
A Contribution to the Critique of Hegel's Philosophy of Law (introduction published by Marx in the Deutsch-Französische Jahrbücher ; rest of manuscript published posthumously) - Marx
Economic and Philosophic Manuscripts of 1844 (manuscripts published posthumously) - Marx
Vol. 4 (1844-1845)
The Holy Family, or Critique of Critical Criticism - Marx & Engels
The Condition of the Working-Class in England - Engels
Vol. 5 (1845-1847)
The German Ideology (manuscript published posthumously) - Marx & Engels
"Theses on Feuerbach" (part of the manuscript for The German Ideology ; posthumously published by Engels) - Marx
Vol. 6 (1845-1848)
Manifesto of the Communist Party - Marx & Engels
The Poverty of Philosophy - Marx
Vol. 7 (1848)
Articles by Marx and Engels appearing in Marx's newspaper Neue Rheinische Zeitung: Organ der Demokratie ( NRhZ )
Vol. 8 (1848-1849)
Articles by Marx and Engels appearing in Marx's NRhZ
Vol. 9 (1849)
Articles by Marx and Engels appearing in Marx's NRhZ
Vol. 10 (1849-1851)
The Class Struggles in France, 1848-1850 - Marx
The Campaign for the German Imperial Constitution - Engels
The Peasant War in Germany - Engels
Vol. 11 (1851-1853)
Revolution and Counter-Revolution in Germany - Engels
The Eighteenth Brumaire of Louis Bonaparte - Marx
Vol. 12 (1853-1854)
Articles by Marx and Engels appearing in the New-York Daily Tribune ( NYDT )
Vol. 13 (1854-1855)
Articles by Marx and Engels appearing in the NYDT
Vol. 14 (1855-1856)
Articles by Marx and Engels appearing in the NYDT
Vol. 15 (1856-1858)
Articles by Marx and Engels appearing in the NYDT
Vol. 16 (1858-1860)
Articles by Marx and Engels appearing in the NYDT
Vol. 17 (1859-1860)
Herr Vogt - Marx
Articles by Marx and Engels appearing in the NYDT
Vol. 18 (1857-1862)
Articles written by Marx and Engels for The New American Cyclopaedia
Vol. 19 (1861-1864)
Articles by Marx and Engels appearing in the NYDT and Die Presse (including articles on the American Civil War)
Vol. 20 (1864-1868)
Writings by Marx and Engels concerning the First International
Value, Price and Profit - Marx
Vol. 21 (1867-1870)
Writings by Marx and Engels concerning the First International
Vol. 22 (1870-1871)
Writings by Marx and Engels concerning the First International
The Civil War in France - Marx
Vol. 23 (1871-1874)
Writings by Marx and Engels concerning the First International
The Bakuninists at Work - Engels
The Housing Question - Engels
"On Authority" - Engels
Vol. 24 (1874-1883)
Marx's letters to Mikhail Saltykov-Shchedrin (1877), editor of the Russian magazine Otechestvenniye Zapiski , and to Vera Zasulich (1881), both concerning the Russian commune/mir and the possibility of Russia avoiding capitalist development
Critique of the Gotha Program (based on Marx's manuscript Marginal Notes on the Programme of the German Workers' Party , along with a letter, both of which Marx sent to Wilhelm Bracke of the Social Democratic Workers' Party of Germany; posthumously published together by Engels with the preceding title) - Marx
Socialism: Utopian and Scientific - Engels
Vol. 25 (n.d.)
Herr Eugen Dühring's Revolution in Science - Engels
Dialectics of Nature (posthumously published manuscript) - Engels
Vol. 26 (1882-1889)
The Origin of the Family, Private Property and the State: In the Light of the Researches of Lewis H. Morgan - Engels
Ludwig Feuerbach and the End of Classical German Philosophy - Engels
Vol. 27 (1890-1895)
Late writings of Engels
II. Marx's Capital and associated writings
Vol. 28 (1857-1861)
Marx's economic manuscript of 1857-58 ( Grundrisse )
Vol. 29 (1857-1861)
Marx's economic manuscript of 1857-58 ( Grundrisse )
A Contribution to the Critique of Political Economy - Marx
Vol. 30 (1861-1863)
Marx's economic manuscript of 1861-63 ( Theories of Surplus Value / Capital Vol. IV )
Vol. 31 (1861-1863)
Marx's economic manuscript of 1861-63 ( Theories of Surplus Value / Capital Vol. IV )
Vol. 32 (1861-1863)
Marx's economic manuscript of 1861-63 ( Theories of Surplus Value / Capital Vol. IV )
Vol. 33 (1861-1863)
Marx's economic manuscript of 1861-63
Vol. 34 (1861-1864)
Marx's economic manuscript of 1861-63
Vol. 35 (n.d.)
Capital: A Critique of Political Economy. Volume I: The Production Process of Capital - Marx
Vol. 36 (n.d.)
Capital: A Critique of Political Economy. Volume II: The Circulation Process of Capital (manuscript posthumously edited and published by Engels) - Marx
Vol. 37 (n.d.)
Capital: A Critique of Political Economy. Volume III: The Process of Capitalist Production as a Whole (manuscript posthumously edited and published by Engels) - Marx
III. Correspondence/Letters
Vol. 38 (1844-1851)
Vol. 39 (1852-1855)
Vol. 40 (1856-1859)
Vol. 41 (1860-1864)
Vol. 42 (1864-1868)
Vol. 43 (1868-1870)
Vol. 44 (1870-1873)
Vol. 45 (1874-1879)
Vol. 46 (1880-1883)
Vol. 47 (1883-1886)
Vol. 48 (1887-1890)
Vol. 49 (1890-1892)
Vol. 50 (1892-1895)
This collection is also available on the Internet Archive .
Files
MECW_01.pdf (30.07 MB)
MECW_02.pdf (30.05 MB)
MECW_03.pdf (20.94 MB)
MECW_04.pdf (31.55 MB)
MECW_05.pdf (18.93 MB)
MECW_06.pdf (29.68 MB)
MECW_07.pdf (24.89 MB)
MECW_08.pdf (22.1 MB)
MECW_09.pdf (23.98 MB)
MECW_10.pdf (28.15 MB)
MECW_11.pdf (31.56 MB)
MECW_12.pdf (31.27 MB)
MECW_13.pdf (29.89 MB)
MECW_14.pdf (30.06 MB)
MECW_15.pdf (30.85 MB)
MECW_16.pdf (29.72 MB)
MECW_17.pdf (19.52 MB)
MECW_18.pdf (16.88 MB)
MECW_19.pdf (21.89 MB)
MECW_20.pdf (28.81 MB)
MECW_21.pdf (30.81 MB)
MECW_22.pdf (30.36 MB)
MECW_23.pdf (29.83 MB)
MECW_24.pdf (19.95 MB)
MECW_25.pdf (31.21 MB)
MECW_26.pdf (31.61 MB)
MECW_27.pdf (19.12 MB)
MECW_28.pdf (31.79 MB)
MECW_29.pdf (25.19 MB)
MECW_30.pdf (28.26 MB)
MECW_31.pdf (26.62 MB)
MECW_32.pdf (25.59 MB)
MECW_33.pdf (23.16 MB)
MECW_34.pdf (23.29 MB)
MECW_35.pdf (26.48 MB)
MECW_36.pdf (20.16 MB)
MECW_37.pdf (29.46 MB)
MECW_38.pdf (29.68 MB)
MECW_39.pdf (28.19 MB)
MECW_40.pdf (31.48 MB)
MECW_41.pdf (30.21 MB)
MECW_42.pdf (31.75 MB)
MECW_43.pdf (31.85 MB)
MECW_44.pdf (28.17 MB)
MECW_45.pdf (23.37 MB)
MECW_46.pdf (23.68 MB)
MECW_47.pdf (28.3 MB)
MECW_48.pdf (24.61 MB)
MECW_49.pdf (26.82 MB)
MECW_50.pdf (3.58 MB)
Karl Marx
Marxism
Friedrich Engels
anthologies
PDF
publications
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17/128-01:31:02.537 ON ON ON ON ON | https://lasp.colorado.edu/maven/sdc/public/data/sites/site-20190820T214730/anc/eng/sasm1/sci_anc_sasm117_126_130.drf |
Biodegradation of 2,4-dinitroanisole (DNAN) by Nocardioides sp. JS1661 in water, soil and bioreactors | Request PDF
Request PDF | Biodegradation of 2,4-dinitroanisole (DNAN) by Nocardioides sp. JS1661 in water, soil and bioreactors | 2,4-Dinitroanisole (DNAN), a low sensitivity replacement for TNT, is a key component of a new class of melt cast formulations designed for use in... | Find, read and cite all the research you need on ResearchGate
Biodegradation of 2,4-dinitroanisole (DNAN) by Nocardioides sp. JS1661 in water, soil and bioreactors
March 2016
Journal of Hazardous Materials 312
DOI: 10.1016/j.jhazmat.2016.03.029
Abstract
2,4-Dinitroanisole (DNAN), a low sensitivity replacement for TNT, is a key component of a new class of melt cast formulations designed for use in insensitive munitions. It is therefore essential that its fate and transport in the environment be assessed before its large scale implementation. Several recent studies have described reductive biotransformation pathways leading to dead-end products. Recently a Nocardioides strain, JS1661 was isolated based on its ability to mineralize DNAN via the 2,4-dinitrophenol (DNP) pathway. However, its potential for degrading DNAN under environmentally relevant conditions was not examined. Therefore we evaluated the aerobic biodegradation of DNAN by JS1661 in non-sterile soil, aqueous media and in a fluidized bed bioreactor over a wide range of DNAN concentrations. DNAN was completely degraded under all tested conditions with little or no accumulation of DNP and almost stoichiometric release of nitrite. Furthermore, when DNAN was used as the sole carbon and nitrogen source, the accumulation of nitrite was dramatically reduced. The results of the study revealed the robustness of the strain over a range of loading rates in various physical environments suggesting that it could provide the basis for waste treatment, bioremediation and bioaugmentation applications.
... However, widespread DNAN-mineralizing capability by indigenous soil microorganisms has not been found to date. 6,9,14,
15
Instead, aromatic amines are the primary products observed from DNAN in soils, 6,9 which lead to complex oligomer mixtures. 6 Elucidation of DNAN biotransformation products has been accomplished using nontargeted mass spectrometry, 6,9,12 but a large gap remains to quantify the distribution of these products across the different matrices (i.e., soil, aqueous medium, gas phase). ...
... O-Demethylation of DNAN bioconversion products has been detected in soils. 6,9,
15
Overall, the recovery of the 14 C label was satisfactory, with generally >95% recovery of the radiolabel added. However, the recovery decreased at longer incubation times, resulting in 76− 78% label recovery in both soils. ...
Environmental fate of 14 C radiolabeled 2,4-dinitroanisole (DNAN) in soil microcosms
Camila Leite Madeira
Reyes Sierra-Alvarez
Jim Field
2,4-dinitrosanisole (DNAN) is an insensitive munitions component that is replacing conventional explosives. While DNAN is known to biotransform in soils to aromatic amines and azo-dimers, it is seldom mineralized by indigenous soil bacteria. Incorporation of DNAN biotransformation products into soil as humus-bound material could serve as a plausible remediation strategy. The present work studied DNAN biotransformation in ¹⁴C-ring labeled soil and sludge microcosms to quantify the distribution of label in soil, aqueous, and gaseous phases. Electron donor amendments, different redox conditions (anaerobic, aerobic, sequential anaerobic-aerobic), and the extracellular oxidoreductase enzyme horseradish peroxidase (HRP) were evaluated to maximize incorporation of DNAN biotransformation products into the non-extractable soil humus fraction, humin. Irreversible humin incorporation of ¹⁴C-DNAN occurred at higher rates in anaerobic conditions, with a moderate increase when pyruvate was added. Additionally, a single dose of HRP resulted in an instantaneous increased incorporation of ¹⁴C-DNAN into the humin fraction. ¹⁴C-DNAN incorporation to the humin fraction was strongly correlated (R²=0.93) by the soil organic carbon (OC) amount present (either intrinsic or amended). Globally, our results suggest that DNAN biotransformation products can be irreversibly bound to humin in soils as a remediation strategy, which can be enhanced by adding soil OC.
... DNAN, although slightly more water soluble than TNT, is expected to remain in soils tainted with the explosives for years, while other ingredients in IM formulations are expected to dissolve faster (3). Therefore, biotic and abiotic reactions, such as biotransformation (4)(5)
(6)
and photolysis (7), are expected to be the main mechanisms affecting the fate of DNAN in the environment. ...
... The reduction of DNAN to its transformation products increases the compound mobility because MENA and DAAN are more hydrophilic than DNAN, the parent compound (9). Moreover, during the course of nitroreduction, reduced amino metabolites can couple forming azo-dimers, that are expected to be long-term end-products in most natural soil scenarios (5,
6)
. ...
Identifying Toxic Biotransformation Products of the Insensitive Munitions Compound, 2,4-Dinitroanisole (DNAN), Using Liquid Chromatography Coupled to Quadrupole Time-of-Flight Mass Spectrometry (LC-QToF-MS)
Chapter
Christopher Olivares
Leif Abrell
Jon Chorover
Jim Field
As insensitive munitions (IMs) replace conventional explosives, releases of 2,4-dinitronanisole (DNAN) -an IM compound- are expected to increase in the environment. DNAN is readily biotransformed in soils, and while toxicity studies have evaluated DNAN, little attention has been given to its biotransformation products. In this work, we elucidated and semiquantitated product mixtures formed during anaerobic biotransformation of DNAN using high-resolution mass spectrometry techniques. DNAN underwent nitroreduction, and at later bioconversion stages, formed azo-dimers, accounting for the majority of end-products from DNAN anaerobic biotransformation. The chemical analyses were complemented by microbial (methanogenesis and Aliivibrio fischeri bioluminescence) and zebrafish embryo toxicity assays on mixtures of products formed, as well as individual compounds (biotransformation products and model azo-oligomers). Methanogens were severely inhibited during nitroreduction stages, but recovered at longer incubation times when azo-dimers were predominant. On the other hand, A. fischeri bioluminescence decreased at later biotransformation stages. When tested individually, the most toxic products to the microbial targets were the azo-oligomer models, while the least toxic species were 2,4-diaminoanisole and its N-acetylated analog. Zebrafish embryos showed few active developmental endpoints for the individual compounds tested, but 3-nitro-4-methoxyaniline and the model azo-dimer 2,2 Œ-dimethoxy-4,4 Œ-azodianiline had a lowest observable adverse effect level (LOAEL) of 6.4 ÊM. Overall, the interdisciplinary experimental design allowed to identify key transformation processes and products that alter toxicity beyond the parent compound.
... For these smaller sizes, there was more transport and dissolution meaning greater potential for contamination of nearby waterways or uptake by plants (Dodard et al., 2013;Kiiskila et al., 2015;Price et al., 2011;Schroer et al., 2017;Yoon et al., 2002). The concern for the larger particles that are less common is that they have very low transport and we would expect the less soluble constituents (DNAN, HMX, RDX) to remain on the surface and slowly dissolve (Arthur et al., 2018;Dontsova et al., 2014;Morley et al., 2006;Richard and Weidhaas, 2014) and biodegrade (Indest et al., 2017;
Karthikeyan and Spain, 2016)
, whereas the more soluble NTO would remain on the surface longer but still dissolve with rainfall events and enter solution easily (Richard and Weidhaas, 2014). However, given a high enough flow rate, these particles that reside on the surface can be transported with the overland flow bringing greater instantaneous concentrations to nearby surface waters. ...
A laboratory rill study of IMX-104 transport in overland flow
Oct 2022
CHEMOSPHERE
Benjamin Karls
Stephen Mercer Meding
Li Li
Katerina Dontsova
The deposition of explosive contaminants in particulate form onto the soil surface during low-order detonations can lead to ground and surface water contamination. The vertical fate and transport of insensitive munitions formulation IMX-104 through soil has been thoroughly studied, however the lateral transport of explosive particles on the surface is less known. The objective of this research was to understand the impact of overland flow on the transport of IMX-104 constituent compounds 3-nitro-1,2,4-triazol-5-one (NTO), 2,4-dinitroanisole (DNAN), hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX), and octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine (HMX). The effect of overland flow was examined in a rill flume using several flow rates (165-, 265-, and 300-mL min-1) and IMX-104 particle sizes (4.75-9.51 mm, 2.83-4.75 mm, 2-2.83 mm, and <2 mm). We found that the smaller particles were transported more in solution and with the sediment compared to the larger particles, which had a higher percent mass remaining on the surface. As flow rate increased, there was an increase in the percent mass found in solution and sediment and a decrease in the percent mass remaining on the surface. NTO fate was dominated by transport in solution, while DNAN, RDX and HMX were predominantly transported with the sediment. This research provides evidence of the role of overland flow in the fate of energetic compounds.
... Bioreactors have been used to successfully degrade DNAN and NTO in synthetic wastewater with aerobic removal efficiencies of 58 AE 22% and 45 AE 24%, respectively when using purely aerobic methods (Weidhaas et al., 2018). In addition, specific strains of microbial organism have been identified that are able to degrade DNAN completely despite the presence of other IHE
(Karthikeyan and Spain, 2016)
. There have also been reports of DNAN, NTO and nitroguanadine (NQ) being degraded from mixed solution (Richard and Weidhaas, 2014). ...
A review of treatment methods for insensitive high explosive contaminated wastewater
Tracey J. Temple
Melissa Ladyman
Frédéric Coulon
Insensitive high explosive materials (IHE) such as 3-nitro-1,2,4-triazol-5-one (NTO) and 2,4-dinitroanisole (DNAN) are increasingly being used in formulations of insensitive munitions alongside 1,3,5-trinitroperhydro-1,3,5-triazine (RDX). Load, assembly and packing (LAP) facilities that process munitions produce wastewater contaminated with IHE which must be treated before discharge. Some facilities can produce as much as 90,000 L of contaminated wastewater per day. In this review, methods of wastewater treatment are assessed in terms of their strengths, weaknesses, opportunities and threats for their use in production of IHE munitions including their limitations and how they could be applied to industrial scale LAP facilities. Adsorption is identified as a suitable treatment method, however the high solubility of NTO, up to 16.6 g.L⁻¹ which is 180 times higher that of TNT, has the potential to exceed the adsorptive capacity of carbon adsorption systems. The key properties of the adsorptive materials along the selection of adsorption models are highlighted and recommendations on how the limitations of carbon adsorption systems for IHE wastewater can be overcome are offered, including the modification of carbons to increase adsorptive capacity or reduce costs.
... 2,4-Dinitroanisole (DNAN) is being used as a substitute for 2,4,6-trinitrotoluene in the formula for insensitive munitions [1][2][3]. Its behavior and fate in the environment continue to be evaluated [4][5][6]
[7]
[8][9][10][11]. As a nitroaromatic compound, DNAN may be transformed through alkaline or enzymatic hydrolysis and abiotic or enzymatic reduction in groundwater [10,[12][13][14][15][16][17]. ...
Alkaline Hydrolysis Pathway of 2,4-Dinitroanisole Verified by 18O Tracer Experiment
Article
Apr 2020
J HAZARD MATER
Chunlei Wang
Adam F. Wallace
Linnea J Heraty
Neil C Sturchio
The environmental fate of insensitive munitions compounds, such as 2,4-dinitroanisole (DNAN), has drawn increasing attention because of their growing use in military activities. One of the main attenuation mechanisms of DNAN degradation in aqueous environments is alkaline hydrolysis. We investigated the pathway for alkaline hydrolysis of DNAN at pH 12 by a combined approach of experiment and theory. An experiment using ¹⁸O-labeled water was performed to verify the reaction pathway. Calculated free energies for two putative reaction pathways by density-functional theory optimized at the SMD(Pauling)/M06-2X/6-311++G(2d,2p) level including explicit solvation of DNAN by 10 H2O molecules and one OH- ion gave a prediction in agreement with the experimental result. The verified reaction pathway for alkaline hydrolysis of DNAN is a SN2Ar nucleophilic aromatic substitution with a methoxy leaving group (-OCH3) at the C1 site.
... In a soil microcosm study for evaluating biodegradation of DNAN by Nocardioides sp, nitrite content was monitored colorimetrically. Nitrite accumulation was found to increase indicating the role of nitrite oxidizing bacteria
[84]
an important reductive step during the process of bioremediation. Monitoring nitrite formation thus served as an indicator of reductive transformation of explosive chemicals. ...
Environmental monitoring approaches used during bioremediation of soils contaminated with hazardous explosive chemicals
Article
Mar 2020
S. Mary Celin
Sandeep Sahai
Anchita Kalsi
Pallvi Bhanot
Defense sites are contaminated with explosives, which are released during manufacturing, firing, testing and training operations; loading, assembly and packing activities; and demilitarization operations. Explosive chemicals are hazardous in nature. Contamination of the soil and the underlying groundwater by explosives pose serious threat to human and animal health and the eco-system. Bioremediation is an eco-friendly technology as it exploits nature’s own agents- the microbes in degrading the contaminant of interest. This waste treatment technology has been extensively studied for degrading the explosive pollutant. Environmental monitoring, a process of systematic collection of data and analysis is essential in performance evaluation of any waste treatment system. This paper gives a comprehensive overview on the environmental monitoring approaches used during bioremediation of explosives contaminated soil. Biogeochemical factors viz., presence and survivability of microbes, bioavailability of the contaminant, pH, temperature, moisture content, redox conditions, presence/addition of substrate and nutrients and presence of intermediates/co-contaminants in the soil environment that are reported to affect the bioremediation of explosives are highlighted. Details on physical, chemical and biological parameters monitored during bioremediation are included. Advancements in instrumental techniques are evolving rapidly and its application in bioremediation approaches promise an enhanced understanding of the mineralization of explosive in the soil environment. Recent developments in application of advanced analytical instrumentation techniques, future research insights with recommendations, which will illuminate the selection of appropriate monitoring tool for evaluating bioremediation are also summarized.
... Research into DNAN has shown that it undergoes rapid aerobic biodegradation with complete mineralisation to nitrites possible within 100 h in culture
[52]
. In soil environments, DNAN has been shown to be degraded by both anaerobic and aerobic processes [53]. ...
Scientific principles of environmental management
Chapter
Dec 2019
Imma Bortone
Frédéric Coulon
William Gilroy-Hirst
Tracey J. Temple
... Known DNAN degradation or transformation processes include both biotic
(Karthikeyan and Spain 2016;
Olivares et al. 2016;Perreault et al. 2012) and abiotic methods such as photolysis (Rao et al. 2013;Taylor et al. 2017), chemical reduction/oxidation (Liu et al. 2015;Ahn et al. 2011;Shen et al. 2013;Koutsospyros et al. 2012;Kitcher et al. 2016;Hadnagy et al. 2018), and alkaline hydrolysis (Hill et al. 2012;Sviatenko et al. 2014). Recent work using an abiotic reductive process relies on zero-valent iron (ZVI) used to successfully treat the energetic compound hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) (Terracciano et al. 2018). ...
Kinetics of Reductive Degradation of 2,4-dinitroanisole (DNAN) Using Mg-Based Bimetals
Article
Full-text available
Dec 2019
Andrew Mai
Emese Hadnagy
Stanley Menacherry
Agamemnon Koutsospyros
Technology advancements and modern use of explosives have led to the development of insensitive munitions such as 2,4-dinitroanisole (DNAN). Treatment systems using zero-valent iron (ZVI) and Fe-based bimetals are well-known, however, Mg-based bimetals can be advantageous over iron because of the more negative reduction potential and relative insensitivity to pH conditions. This work reports on the use of ZVMg and Mg-bimetals (Mg/Cu, Mg/Ni, Mg/Zn) to treat pure compound aqueous solutions and wastewater containing DNAN. Kinetic experiments were carried out in bench-scale batch reactors at unadjusted initial pH, 0.5% solids-to-liquid ratio (S/L), and 10:1 Mg to catalytic metal ratio. The results, modelled with a pseudo-first order kinetic expression, are used to determine reaction rate constants via nonlinear regression. For pure DNAN aqueous solutions, the pseudo-first order kinetic rate constants are 0.119, 0.102, 0.020, and 0.009 min⁻¹ for Mg/Cu, Mg/Zn, Mg/Ni, and ZVMg, respectively. Reaction rate constants for DNAN wastewater are 0.114, 0.046, and 0.021 min⁻¹ for Mg/Cu, Mg/Zn and Mg/Ni, respectively. Parametric studies investigated the impact of catalytic metal, reagent dose, and initial pH on DNAN degradation. Reagent dose levels tested were 0.25, 0.50 and 0.75% S/L. Initial pH, lowered with acetic acid (pH range 3.3–4.0), significantly enhanced reaction rates of all bimetal pairs and ZVMg yielding half-lives between 0.7–1.4 min. The bimetal pair showing the fastest kinetics at unadjusted initial pH, Mg/Cu, was characterized in constant temperature experiments. Under identical conditions (unadjusted initial pH, 0.5% S/L, 10:1 Mg: Cu), the activation energy of DNAN degradation by Mg/Cu is 8.47 kJ/mol.
... A 1.5 L jacketed FBR was used in the continuous mode with 750 g of sand and a 1.0 L working volume as described previously
[22]
. Media consisted of either 1/10 strength MSB (for minimal inorganic nutrients and buffer) or tap water with phosphate buffer (2.0 mM) at flow rates ranging from 1.0 to 15.0 L/day. ...
Aerobic biodegradation of 2,3- and 3,4-dichloronitrobenzene
Article
J HAZARD MATER
Mallory L. Palatucci
Lisa A Waidner
Elizabeth Erin Mack
Jim c Spain
Dichloronitrobenzenes (DCNB) are intermediates in the production of dichloroanilines, which are key feedstocks for synthesis of diuron and other herbicides. Although DCNB is a major contaminant at certain chemical manufacturing sites, aerobic DCNB biodegradation is poorly understood and such sites have not been candidates for bioremediation. When a bench-scale aerobic fluidized- bed bioreactor was inoculated with samples from a DCNB contaminated site in Brazil 2,3-DCNB, 3,4-DCNB, 1,2-dichlorobenzene (o-DCB), and chlorobenzene (CB) were biodegraded simultaneously. Biodegradation of the mixture was complete even when the reactor was operated at high flow rates (1.6 h hydraulic residence time), and bacteria able to degrade the individual contaminants were isolated from the reactor by selective enrichment. The enrichments yielded 2 strains of bacteria able to degrade 3,4-DCNB and one able to degrade 2,3-DCNB. The isolates released nitrite during growth on the respective DCNB isomers under aerobic conditions. The draft genome sequence of Diaphorobacter sp. JS3050, which grew on 3,4-DCNB, revealed the presence of putative nitroarene dioxygenase genes, which is consistent with initial attack by a dioxygenase analogous to the initial steps in degradation of nitrobenzene and dinitrotoluenes. The results indicate clearly that the DCNB isomers are biodegradable under aerobic conditions and thus are candidates for natural attenuation/bioremediation.
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... strain JS1661 has been isolated from activated sludge based on its ability to grow on DNAN as the sole source of carbon and energy. JS1661 is able to degrade DNAN in non-sterile soil, aqueous media and in a fluidized bed bioreactor (Fida et al. 2014;
Karthikeyan and Spain 2016)
. To achieve this, an existing hydrolase has evolved the ability to catalyze the hydrolytic release of methanol from DNAN to form 2,4dinitrophenol, as shown in Figure 3. Degradation then occurs through an established pathway involving hydride-Meisenheimer complex formation, denitration then metabolism by the TCA cycle (Fida et al. 2014). ...
Right on target: using plants and microbes to remediate explosives
Article
Full-text available
May 2019
Elizabeth L Rylott
Neil C Bruce
While the immediate effect of explosives in armed conflicts is frequently in the public eye, until recently, the insidious, longer-term corollaries of these toxic compounds in the environment have gone largely unnoticed. Now, increased public awareness and concern are factors behind calls for more effective remediation solutions to these global pollutants. Scientists have been working on bioremediation projects in this area for several decades, characterizing genes, biochemical detoxification pathways, and field-applicable plant species. This review covers the progress made in understanding the fundamental biochemistry behind the detoxification of explosives, including new shock-insensitive explosive compounds; how field-relevant plant species have been characterized and genetically engineered; and the major roles that endophytic and rhizospheric microorganisms play in the detoxification of organic pollutants such as explosives.
... Once the DNT degradation pathway was established, the genes responsible for this pathway were studied (Spanggord et al. 1991;Suen and Spain 1993;
Karthikeyan and Spain 2016)
. The DNT-degrading genes were localized on three plasmids, pJS1, pJS2, and pJS3, which are 180 Kb, 50 Kb, and 2.1 Kb, respectively. ...
Tendency of using different aromatic compounds as substrates by 2,4-DNT dioxygenase expressed by pJS39 carrying the gene dntA from Burkholderia sp. strain DNT
Full-text available
Nov 2018
Khaled Khleifat
Muhamad Allimoun
Khalid Y. Al-sharafa
The substrate range of 2,4-dinitrotoluene (DNT) dioxygenase was investigated by measuring substrate-dependent O2 uptake and maximum growth (expressed in A600) on substrate-containing minimal medium. The control for each strain had no added particular substrate. The following aromatic compounds: catechol, α-naphthalene acetic acid, β-dimethylaminobenzaldehyde, 3,4-dinitrosalicylic acid, p-nitrophenol, naphthanol, o-anisic acid, salicylic acid, toluene, and benzoic acid, were tried as possible substrates. Considering all substrates used, only p-nitrophenol showed zero oxygen uptake rate and zero growth. This indicates that it was rather unlikely that p-nitrophenol is a substrate analog for 2,4-DNT. Catechol was clearly used as a sole carbon source by both wild-type Escherichia. coli (JM103) and the dnt transformant (JS39). Using α-naphthalene acetic acid and β-dimethylaminobenzaldehyde as substrates resulted in DNT dioxygenase oxygen uptake rates of 11.8 and 14 μM/hr/mg protein, respectively. However, using both compounds as a carbon source, JS39 had twice the growth rate of E. coli JM103. For the remaining six substrates tested (3, 4-dinitrosalicylic acid, p-nitrophenol, o-anisic acid, salicylic acid, toluene, and benzoic acid), there appeared to be growth advantages for JS39 (even though the growth in the presence of substrate was less than the controls) suggesting a situation similar to that described for α-naphthalene and β-dimethylaminobenzaldehyde above. Combining results from our assay with respirometry and growth-based experiments will allow a better understanding of the biochemical consequences of these interactions. These results suggest that DNT dioxygenase gene, dntA carried by JS39, and those potential genes for substrates-degraded enzyme(s) system could have a common root.
... Identification of byproducts is critical for unveiling the contaminant degradation pathway and establishing that transformed products are toxicologically and environmentally more benign than the parent contaminant. Treatment methods such as photodegradation (Rao et al. 2013;Hawari et al. 2015;Taylor et al. 2017) and aerobic biodegradation (Fida et al. 2014;
Karthikeyan and Spain 2016)
are typically oxidative. Conversely, typical transformation pathways in treatment with ZVI, ZVMg, or Fe-and Mg-based bimetals indicate reductive chemistry, as observed, for example, in the reduction of nitrate to nitrite (Ileri et al. 2015;Khalil et al. 2016), Cr(VI) to Cr(III) (Rivero-Huguet and Marshall 2009), and the reductive dechlorination of PCBs (Hadnagy et al. 2007;Agarwal et al. 2009a, b;Coutts et al. 2011). ...
Characterization of Mg-based bimetal treatment of insensitive munition 2,4-dinitroanisole
The manufacturing of insensitive munition 2,4-dinitroanisole (DNAN) generates waste streams that require treatment. DNAN has been treated previously with zero-valent iron (ZVI) and Fe-based bimetals. Use of Mg-based bimetals offers certain advantages including potential higher reactivity and relative insensitivity to pH conditions. This work reports preliminary findings of DNAN degradation by three Mg-based bimetals: Mg/Cu, Mg/Ni, and Mg/Zn. Treatment of DNAN by all three bimetals is highly effective in aqueous solutions (> 89% removal) and wastewater (> 91% removal) in comparison with treatment solely with zero-valent magnesium (ZVMg; 35% removal). Investigation of reaction byproducts supports a partial degradation pathway involving reduction of the ortho or para nitro to amino group, leading to 2-amino-4-nitroanisole (2-ANAN) and 4-amino-2-nitroanisole (4-ANAN). Further reduction of the second nitro group leads to 2,4-diaminoanisole (DAAN). These byproducts are detected in small quantities in the aqueous phase. Carbon mass balance analysis suggests near-complete closure (91%) with 12.4 and 78.4% of the total organic carbon (TOC) distributed in the aqueous and mineral bimetal phases, respectively. Post-treatment surface mineral phase analysis indicates Mg(OH)2 as the main oxidized species; oxide formation does not appear to impair treatment.
... JS1661, both of which form the same product, 2,4-dinitrophenol (DNP). 20,
21
Therefore, assessing the extent and predominant routes of DNAN degradation will be challenging because the initial products are not only identical but also transient. 15,22,23 Compound-specific stable isotope analysis (CSIA) offers a strategy for distinguishing between degradation processes without an explicit need to monitor the concentration dynamics and therefore may be especially well suited for assessing DNAN degradation. ...
Different Mechanisms of Alkaline and Enzymatic Hydrolysis of the Insensitive Munition Component 2,4-Dinitroanisole Lead to Identical Products
13,
The biodegradation potential of insensitive munition melt cast formulations IMX101 and IMX104 was investigated in two unamended training range soils under aerobic and anaerobic growth conditions. Changes in community profiles in soil microcosms were monitored via high-throughput 16S rRNA sequencing over the course of the experiments to infer key microbial phylotypes that may be linked to IMX degradation. Complete anaerobic biotransformation occurred for IMX101 and IMX104 constituents 2,4-dinitroanisole (DNAN) and 3-nitro-1,2,4-triazol-5-one during the 30-day incubation period with Camp Shelby (CS) soil. By comparison, soil from Umatilla chemical depot demonstrated incomplete DNAN degradation with reduced transformation rates for both IMX101 and IMX104. Aerobic soil microcosms for both soils demonstrated reduced transformation rates compared to anaerobic degradation for all IMX constituents with DNAN the most susceptible to biotransformation by CS soil. Overall, IMX constituents hexahydro-1,3,5-trinitro-1,3,5-triazine and 1-nitroguanidine did not undergo significant transformation. In CS soil, organisms that have been associated with explosives degradation, namely members of the Burkholderiaceae, Bacillaceae, and Paenibacillaceae phylotypes increased significantly in anaerobic treatments whereas Sphingomonadaceae increased significantly in aerobic treatments. Collectively, these data may be used to populate fate and transport models to provide more accurate estimates for assessing environmental costs associated with release of IMX101 and IMX104.
... At the time of writing, the genus Nocardioides comprised 81 species with validly published names (www.bacterio.net/nocardioides.html). In recent years, members of the genus Nocardioides have attracted more and more attention, because they are able to degrade various xenobiotic compounds [15][16][17]
[18]
Insensitive munitions compounds (IMCs), such as 2,4‐dinitroanisole (DNAN) and 3‐nitro‐1,2,4‐triazol‐5‐one (NTO), are replacing conventional explosives in munitions formulations. Manufacture and use of IMCs generate waste streams in manufacturing plants and load/assemble/pack facilities. There is a lack of practical experience in executing biodegradation strategies to treat IMCs waste streams. This study establishes a proof of concept that bacterial consortia can be designed to mineralize IMCs and co‐occurring nitroaromatics in waste streams. First, DNAN, 4‐nitroanisole (4‐NA), and 4‐chloronitrobenzene (4‐CNB) in a synthetic DNAN‐manufacturing waste stream were biodegraded using an aerobic fluidized‐bed reactor (FBR) inoculated with Nocardioides sp. JS 1661 (DNAN degrader), Rhodococcus sp. JS 3073 (4‐NA degrader), and Comamonadaceae sp. LW1 (4‐CNB degrader). No biodegradation was detected when the FBR was operated under anoxic conditions. Second, DNAN and NTO were biodegraded in a synthetic load/assemble/pack waste stream during a sequential treatment comprising: (i) aerobic DNAN biodegradation in the FBR; (ii) anaerobic NTO biotransformation to 3‐amino‐1,2,4‐triazol‐5‐one (ATO) by an NTO‐respiring enrichment; and (iii) aerobic ATO mineralization by an ATO‐oxidizing enrichment. Complete biodegradation relied on switching redox conditions. The results provide the basis for designing consortia to treat mixtures of IMCs and related waste products by incorporating microbes with the required catabolic capabilities. This article is protected by copyright. All rights reserved.
| https://www.researchgate.net/publication/297891661_Biodegradation_of_24-dinitroanisole_DNAN_by_Nocardioides_sp_JS1661_in_water_soil_and_bioreactors |
OBM Integrative and Complementary Medicine | An Initial Investigation of Neural Changes in Overweight Adults with Food Cravings after Emotional Freedom Techniques
Background: This pilot randomised clinical trial investigated the effect of an Emotional Freedom Techniques (EFT) intervention on brain activation in response to food craving stimuli using functional magnetic resonance imaging. EFT is a brief stress reduction technique which involves stating a cognitive statement with somatic tapping on acupressure points. Method: Fifteen overweight/obese adults were allocated to a four-week group EFT treatment or control condition. Random repeating images of high-calorie food designed to engage parts of the brain were presented during the pre and post scans. Results: Marked reduction in the BOLD response in Superior Temporal Gyrus and lateral orbito-frontal cortex occurred for the EFT treatment group only. The control group showed continued activation in these areas. Conclusion: The findings indicated EFT may decrease limbic region brain activity and reduce food related symptoms in overweight/obese individuals. Recommendations for more comprehensive trials are discussed.
OBM Integrative and Complementary Medicine
(ISSN 2573-4393)
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An Initial Investigation of Neural Changes in Overweight Adults with Food Cravings after Emotional Freedom Techniques
Peta Stapleton 1, *, Craig Buchan 2, Ian Mitchell 3, Yasmin McGrath 2, Paul Gorton 2, Brett Carter 1
School of Psychology, Bond University, Gold Coast, Queensland, 4229, Australia
Queensland Diagnostic Imaging, Gold Coast, Queensland, Australia
Siemens Healthcare Pty Ltd, Healthcare Sector, Brisbane, Australia
*Correspondence:Peta Stapleton
Academic Editor:Gerhard Litscher
Received:December 11, 2018 |Accepted:February 12, 2019 |Published:February 15, 2019
OBM Integrative and Complementary Medicine2019, Volume 4, Issue 1 doi:10.21926/obm.icm.1901010
Recommended citation:Stapleton P, Buchan C, Mitchell I, McGrath Y, Gorton P, Carter B. An Initial Investigation of Neural Changes in Overweight Adults with Food Cravings after Emotional Freedom Techniques. OBM Integrative and Complementary Medicine2019; 4(1): 010; doi:10.21926/obm.icm.1901010.
© 2019 by the authors. This is an open access article distributed under the conditions of the Creative Commons by Attribution License, which permits unrestricted use, distribution, and reproduction in any medium or format, provided the original work is correctly cited.
Abstract
Background: This pilot randomised clinical trial investigated the effect of Clinical Emotional Freedom Techniques (EFT) on brain activation in response to food craving stimuli using functional magnetic resonance imaging. EFT is a brief stress reduction technique which involves stating a cognitive statement with stimulation of acupressure points with a tapping technique. Method: Fifteen overweight/obese adults were allocated to a four-week group EFT treatment or control condition and completed a measure of food craving. Random repeating images of high-calorie food designed to engage parts of the brain were presented during the pre and post fMRI scans. Results: The Group x Time interaction for food cravings were significant for the EFT group when compared to the controls. Participant mean scores decreased by 18% for the EFT group and 5% for the control group. Brain activity was mapped using fMRI measures, and there was relative deactivation in the Superior Temporal Gyrus and lateral orbito-frontal cortex for the EFT treatment group only. The control group however, showed continued activation in these areas. Conclusion: The findings indicated EFT may decrease limbic region brain activity and reduce food related symptoms in overweight/obese individuals. This study also illuminates the neurological mechanisms at work behind the many successful outcome studies of EFT for weight loss. Recommendations for more comprehensive trials are discussed.
Keywords
Food cravings; overweight; obesity; emotional freedom technique; fMRI; brain
1. Introduction
Obesity is a chronic disease, with an aetiology typically purported to result from a range of causes including metabolic [ 1], excessive consumption of obesogenic foods [ 2], genetics [ 3], environmental contributions that have resulted in more sedentary behaviour such as increased use of transport (e.g. cars), and obesogenic foods being more easily accessible to lower socioeconomic groups because of decreased costs [ 2]. The likely explanation may well be a combination of these complex, and often interacting processes. What is known is that a five to 10% decrease in body weight for obese adults is associated with significant improvements in blood pressure, serum lipid levels, glucose tolerance [ 4], and reductions in diabetes [ 5] and hypertension [ 6, 7]. Existing approaches to addressing the obesity epidemic have included combined dietary and physical activity approaches [ 8, 9] and of late, behavioural or motivation strategies to influence the weight loss process [ 10, 11, 12]. Weight loss and weight maintenance, however, are complex issues.
Research suggests dieting regularly results in weight loss in the short term [ 13] yet, meta-analyses indicate the more time that elapses between the end of a diet and the follow-up period, the more weight is regained [ 14]. Weight instability has been related to lower health satisfaction and self-esteem and higher body dissatisfaction, dieting, and binge eating [ 15]. Unfortunately, it is clear that dieting alone does not lead to sustained weight loss and individuals who diet are more likely to gain back more weight than they lost [ 14].
Adults who are overweight or obese do experience enhanced weight reductions from psychological interventions as well as behavioural approaches [ 16]. A Cochrane review [ 16] suggested Cognitive Behaviour Therapy (CBT) and Behaviour Therapy (BT) significantly improved the success of weight loss for overweight and obese adults, but cognitive therapy alone was not found to be effective as a weight loss treatment. The evidence available for other strategies such as relaxation therapy and hypnotherapy also indicated that these might be beneficial in improving weight loss [ 16].
Energy Psychology (EP) strategies are emerging as techniques which can change emotional, behavioural, and cognitive concerns by combining physical somatic interventions with a cognitive element [ 17]. Emotional Freedom Techniques (EFT) [ 18] is one such EP strategy; a type of exposure therapy that includes a somatic and cognitive component for altering the cognitive, behavioural, and neurochemical foundations of psychological problems. Likened to a version of psychological acupuncture, but without the use of fine needles, EFT combines components of traditional approaches (including cognitive and exposure therapy) with acupoint stimulation [ 18].
Research has found EFT for to be extremely successful and durable over time for treatment of food cravings in overweight and obese adults [ 19, 20, 21]. A randomised clinical trial which originally offered a 4-week EFT treatment program to 96 overweight and obese participants with severe food cravings, and then assessed their progress six- and 12-months after treatment ended [ 19, 20] found Body Mass Index (BMI), degree of food craving, individual’s perceived power of food, restraint capabilities and psychological symptoms significantly improved. Weight loss over the 12 months was significant from the start of treatment (mean difference, -5.05 kilograms or 11.1 pounds, p<.05) and the decrease in BMI was also significant (mean difference, -2.28, p<.05; (Stapleton, Sheldon, & Porter, 2012b).
EFT has also been compared to a gold standard therapy. In an overweight/obese sample of adults, EFT and CBT demonstrated comparable efficacy in reducing food cravings, individuals’ responsiveness to food in the environment (power of food), and dietary restraint, with Cohen’s effect size values suggesting moderate to high practical significance for both interventions [ 22]. Significant decreases in anxiety and depression scores were also reported for subjects in both the EFT and CBT treatment groups, and these benefits were maintained at 12-month follow-up.
These results revealed that EFT was capable of producing treatment effects that were clinically meaningful and comparable to a gold standard approach. Notably, EFT lasted longer over time than CBT for improvements in food cravings and anxious symptomology and subjects’ food cravings, power over food choices, and dieting mentality at the 12-month follow-up [ 21, 22].
For general psychological conditions outside food cravings, several meta analyses have found a very large treatment effect for anxiety (d = 1.23 95% CI: 0.82-1.64, p < 0.001), a very large effect size in the treatment of depression (Cohen's d across all studies was 1.31) [ 23], and a large treatment effect (weighted Cohen’s d = 2.96, 95% CI 1.96-3.97; p < 0.001) for post-traumatic stress disorder [ 24]. Research has also indicated treatment gains persist over time [ 25, 26, 27, 28, 29].
Performing the EFT technique while vocalising aspects of a targeted problem (the cognitive element) has been hypothesized to decrease hyperarousal in the amygdala (the stress response area of the brain) and hippocampus (the memory area) [ 30], alter dopamine and serotonin ratios [ 17], produce connective tissue transmission of piezoelectric signals [ 31], and increase HPA axis regulation, which among other benefits reduces stress-related cortisol secretion [ 32]. Recent research in a sample of veterans with PTSD indicated regulation of six genes associated with inflammation and immunity after 10 EFT sessions, with downregulation of inflammation and stress markers and upregulation of immune markers found [ 33]. However, despite these studies, it has not been unambiguously established how brain activation and neural mechanisms might be affected by EFT.
1.1 Functional Magnetic Resonance Imaging (fMRI)
Functional Magnetic Resonance Imaging (fMRI) is widely used to map brain activity. fMRI exploits the local increase in blood flow and hence blood volume and blood oxygenation that occur to support the resulting increase in metabolic demand, instead of detecting neuronal activity directly [ 34]. Brain imaging is a powerful technique that is enhancing neuroscience research. Most conventional fMRI studies are based on the BOLD effect, which is the term used to describe the increase in fMRI signal due to the change in blood oxygenation and blood volume secondary to the increase in blood flow.
Therefore, tracking brain activity with fMRI does not involve direct measurement of neuronal activity. With fMRI, attention is paid to changes in blood flow, blood volume, and blood oxygenation, features of metabolic demand affected by changes in brain activity. Measuring brain activity indirectly is the basic for the BOLD system where changes in brain activity are defined as increases or decreases in blood oxygenation and blood volume secondary to changes in blood flow. Changes in fMRI signal, then, are presumed to be evidence of changes in neural activity.
BOLD fMRI has been used to map the primary cortical representation of taste and odour in humans and to study responses to pleasant and aversive stimuli. Previous neuroimaging studies have shown that emotional distress increases the reward value of palatable food in the brain of restrained eaters [ 35, 36, 37]. Studies have also indicated individuals with, versus without substance dependence, show greater activation in brain areas related to reward [ 38, 39] and obese, versus lean adults, show similar activation in response to food cues [ 40, 41].
Due to the emerging evidence indicating EFT can have an immediate and lasting effect on food cravings in obese adults, and given food cravings frequently lead to consumption of the craved food [ 42], are positively correlated with body mass index (BMI) [ 39, 43] and obese adults report preferences for high fat foods [ 44], this feasibility study focussed on extending this research further. Subsequently, the study had two objectives:
1. To determine brain activation (using fMRI) in response to high calorie food image stimuli in overweight/obese adults, and 2. To investigate neural mechanisms of symptom improvements in overweight/obese adults following EFT treatment, compared to controls, in order to conduct a larger trial.
2. Materials and Methods
Ethical Approval was provided by the Bond University Human Research Ethics Committee and the trial was registered under the Australia New Zealand Clinical Trials Registry.
2.1 Participants
Ethical Approval was provided by the Bond University Human Research Ethics Committee and the trial was registered under the Australia New Zealand Clinical Trials Registry. The inclusion criteria were: at least 18 years of age, both genders, overweight (i.e. Body Mass Index; BMI; between 25-29) or obese (BMI greater than 30), and not currently receiving treatment (psychological or medical) for their food cravings. Participants who were pregnant, and known sufferers of diabetes (Type I and II) and hypoglycaemia were excluded due to possible craving confound. Because of the fMRI aspect of the study, participants could not have any metal implants (e.g. pace maker) and completed a MRI head safety questionnaire prior to the scan.
After screening, eligible overweight/obese adults were randomly assigned to either the fMRI treatment (N=10) or control group (N=5). All participants completed a pre-survey battery of measures via an electronic link (data not presented here), and underwent a brain scan (fMRI) at a local radiology facility; once for the control group and twice (pre-and post) for the EFT treatment group.
The majority of participants were female (86%), and chocolate was the most commonly chosen food craving to address in the EFT treatment group. The mean age of the EFT group was 48 years and 39 years for the controls; and the average BMI was 37 for the EFT group and 39 for the controls. Results of chi-square analyses revealed there were no significant differences between the EFT and control conditions in baseline sociodemographic characteristics (p>0.05).
2.2 Measures
Anthropometric Measures.Height and weight measurements were obtained to calculate BMI, which is defined as weight in kilograms divided by height in meters squared (kg/m²). BMI categories utilised for the present study included: underweight (< 18.5), healthy weight (18.5 to 24.9), overweight (25.0 to 29.9), or obese (≥ 30.0).
The Food Craving Inventoryis a reliable and valid measure for the assessment of cravings for specific types of foods (White et al., 2002). The FCI measures cravings for specific types of foods, namely: High Fats, Sweets, Carbohydrates/Starches, and Fast Food Fats, all of which comprise the higher order construct of “food craving” or the FCI Total score (White & Grilo, 2005). Higher numbers for each of the subscales reflect greater cravings for that food type with the highest score being 185.
2.3 fMRI Paradigm
All participants had an initial (pre) brain scanning session and 5-weeks later at the end of the 4-week EFT intervention. Participants were asked to refrain from eating or drinking prior to the scan (water excepted) and were asked to consume a caffeinated beverage 30-minutes prior (e.g. coffee) to capture the hunger state that most individuals feel prior to their next meal. All scans were completed between 8:00 a.m. and 11:00 a.m., with all participants changed into a gown and presented with safety questions prior to the scan.
The fMRI scans were examined for intracranial structural abnormalities by the Radiologist partner in the study (second author) and the third author interpreted pre-and post-effect differences due to the EFT intervention. During the fMRI scanning the participants were presented with six random repeating images of high-calorie food designed to engage parts of the brain which respond to food stimuli. They were passive during the procedure, except for paying attention to the food images, and this was to minimise engagement of other cognitive systems.
Participants were scanned on a Skyra 3T system on NUMARIS/4 Version Syngo MR E11A, using a 20ch head neck coil combination. A 6:35 mins ep2d_pace_moco sequence was used. This is a single shot Echo planar sequence that has prospective motion correction built within the sequence to correct in real time for motion. In addition, real time monitoring of the amount of motion is possible via the 3D neuro card utilizing the inline features. Block design was used for paradigm creation, and the total number of measurements was 120, with paradigm size being 20 Threshold or T-score was set at 3 for the sequence acquisition. The TR 3200 TE 30 total scan time for sequence was 6:29 minutes, however the use of dummy scans and IPAT calibration accounted for the 6 second disparity. No other filtering was used; synchronization with the scanner ensured that baseline did present until after this period. The Voxel size was 2 x 2 x 3 slices 36 dist factor 0 GRAPPA 2. Block design resulted in baseline, activation, baseline for the duration of test BABA. The paradigm was designed to examine activation in response and anticipated consumption of six food items (seeFigure 2). Images were presented via digital projector located outside of the scan room but able to project to a MRI compatible screen. Test subjects were then able to see images via a head mounted mirror.
Activation and baseline periods for the test were 30 seconds. This meant the randomized images were visible for 5.4 seconds each time they were viewed by the subject. When participants saw images, they were advised to imagine tasting and eating each food item as it was presented to them. The duration of each block was designed to be short enough to prevent habituation in the amygdala [ 45]. In the rest or baseline section a ‘checker board’ image was shown and participates were asked to relax.
Post processing was completed on the scanner using the Neuro 3D platform. Whilst the threshold had been applied on the creation of the paradigm. Final processing of threshold was applied to patient for both data sets to ensure clear visualization of activation area (this gave a threshold of 3.2-4 for all volunteers in cohort). This ensured clarity of data sets for comparison on completion of data collection.
2.4 EFT Treatment
The intervention used in the current trial was ‘Clinical EFT’; the approach has been validated in more than 100 clinical trials. The research supporting Clinical EFT has utilized a protocol which has remained stable through three editions of the EFT Manual [ 18].
The EFT treatment was offered for two hours per week, for the 4-week period, to the treatment group, while the control group did not engage in any treatment. A trained EFT practitioner counsellor skilled in delivery clinical trials delivered the intervention and all sessions were based on standardised protocols and adhered to the EFT manual [ 18]. Acupressure points on the eyebrow, side of eye, under eye, under nose, chin, collarbone, under arm, and the top of the head were used.
The procedure of EFT begins by the individual stating a difficulty they are experiencing, followed by an opposing, but positive affirming statement. For example, an individual may state “Even though I am nervous right now, I accept myself and this problem”. Researchers have long found that when positive and negative thoughts are combined, the individual reports a decrease of the negative experience [ 46]. This combination of positive affirmation and negative thoughts is typically used in Systematic Desensitization, a behaviour modification therapy [ 46].
Stimulation of specific acupoints then involves tapping on them with two fingers while saying a shorter reminder phrase e.g. “nervous”. The subject rates their level of the problem (nervousness) out of 10 (0 = completely calm, 10 = highest level possible of the issue) before beginning, and re-rates this every time they complete the eight tapping points. The process is repeated until the discomfort score is zero. The EFT treatment sessions involved direct exposure to craved foods with full adherence to protocols and safeguards occurring [ 18, 47]. The group spent two hours using EFT on their food cravings, and were encouraged to self-administer EFT outside of treatment sessions in response to cravings e.g. in the moment of in anticipation). Weekly short message reminders were sent in between sessions to encourage adherence.
3. Results
3.1 Food Craving Analyses
The self-report data was analysed using SPSS (Version 23). An alpha level of .05 was utilised to determine the statistical significance of all results. Inspection of boxplots revealed no extreme outliers.
The test of within subjects effects revealed there was a significant main effect of time for participant total FCI scores, Wilk’s Λ= .485, F (1, 13) = 13.778, p = .003, partial η 2= .515. Participant mean scores decreased by 18% for the EFT group (M = 101.1) to post (M = 67.3) and 5% for the control group (M = 83.75 pre; M = 73.25 post). The main effect of group revealed FCI total scores were not significantly different between the EFT (M = 84.300; SE = 3.512) and control (M = 76.400; SE = 4.967) groups, p > .05. The Group x Time interaction for FCI was however significant, revealing the food craving difference scores over time decreased significantly for the EFT group when compared to the controls, Wilk’s Λ= .690, F (1, 13) = 5.830, p = .031, partial η 2= .310 (seeTable 1).
Table 1Associated means, standard deviations, and mean differences for the food craving inventory.
Table 1Associated means, standard deviations, and mean differences for the food craving inventory.
Variable EFT Control Pre (SD) Post (SD) Diff Pre (SD) Post (SD) Diff FCI Total101.10(17.62)67.30(12.52)33.80(22.69)83.75(19.94)73.25(8.50)10.50(14.20)
3.2 fMRI Analysis
The fMRI scans were analysed as a between-groups whole-brain contrast analysis to identify brain regions activated by anticipation of food. A ‘threshold’ was set to reduce the ‘noisy’ or areas showing activation that were not of interest. Typically with emotive responses the BOLD response is very small so the threshold was set at a level to ensure the areas in question were able to be analysed. The threshold or T-score was set at approximately 2-2.6 (patient dependent). This was then used for all their scans so that comparison could be made with all the tests.
The areas of emotive responses to food and other stimuli have been documented in previous papers and it is noted that there does not appear to be one single area that is definitively identified as the primary response to food. However, in the present study for all the pre-scans, there was relative activation in the superior temporal gyrus (associated with cognition) and lateral orbito-frontal cortex (associated with reward). The post scans for the treatment group only were relatively deactivated in both these areas; there was marked reduction in the BOLD response (seeFigure 1as an example). Post scanning of a control group who did not receive the EFT treatment showed continued activation in these areas (seeFigure 2).
Figure 1Pre and post fMRI for subject in EFT treatment condition.
Note: the yellow, orange and red areas active on the pre scan are relatively deactivated in the post scan of the EFT group.
Figure 2Control group example fMRI scan.
Note: the yellow, orange and red areas active on the pre scan that are still relatively activated in the control group.
4. Discussion
This study represents the first to initially explore neural changes after EFT treatment in overweight/obese adults and was designed to develop a fMRI protocol for future investigations. Our fMRI results were also consistent with those obtained by previous studies and met the first objective. As expected, food images presentation increased activation in the brain and were largest in the superior temporal gyrus and orbitofrontal cortex (left cortical regions). Research suggests even if someone is not hungry, seeing food or thinking about food can stimulate eating [ 48, 49], and cortical regions responsive to food images in previous studies have included the limbic and paralimbic areas [ 50] and the prefrontal cortex [ 51].
It has also been noted that while the orbitofrontal cortex is typically associated with reward, it is also activated when non-reward, or loss occurs, and this may be relevant if a subject is imagining being deprived of a food (e.g., a diet or treatment program to target this). The orbitofrontal cortex is the first place where olfactory information and taste information converge [ 52], therefore, given participants in the present study were explicitly told to imagine eating the food they were viewing, this was not unexpected. Other functional imaging studies have found similar high-calorie items result in more activation than low-calorie control items in the same orbitofrontal cortex region [ 53, 54]. Further, obese participants characteristically show greater neural activation in these brain regions implicated in reward, when compared to lean participants [ 41, 55].
The activation in the superior temporal gyrus in the present study has been noted in other studies. The superior temporal gyrus is significantly activated to a greater extent during the presentation of food items compared to non-food items [ 56]. Television viewing studies also highlight that food and non-food commercials result in greater activation in neural regions associated with similar attention, focus and language areas [ 57]. Food images significantly increase activation in healthy controls in this brain area too [ 58].
The second objective of this study was to compare the EFT treatment group to the controls and ascertain any differences in neural activity after therapy. There were differences between the EFT group on their pre-and post fMRI scans, as well as differences to the control group. The EFT group achieved a marked reduction in activation post their EFT treatment in both the superior temporal gyrus and orbitofrontal cortex, whereas the control group remained the same.
While speculatively, the neural changes indicated in this pilot study appear to compare to the self-reported food craving decreases in the current trial as well as previous EFT and food craving trials [ 19, 20, 21, 22]. The lack of engagement in homework activities reported by participants (addressed next) and the relative deactivation of the brain activity during the post scans while viewing high caloric food images, suggests a correlation worth examining in larger future trials.
Finally and worthy of note is that while the EFT participants were encouraged to engage in the technique outside sessions, and reminder messages were sent by the lead therapist between sessions every week. However, they typically did not do so via self-report and this was also indicated in previous trials [ 19, 20, 21, 22]. A recent two year follow-up of an 8-week online intervention program for overweight or obese adults found participants’ food craving, perceived power of food, dietary restraint capabilities and all psychological distress symptoms (i.e. anxiety, depression and somatic) remained significantly reduced from the end of treatment to two-year follow-up [ 59] with no further treatment and a distinct lack of in-between session homework. This study suggested that using EFT in the sessions alone resulted in a reduction of cravings that did not require any further intervention from the end of the 8-week program.
It is true a common strategy in the gold standard cognitive and behaviour therapies is utilizing homework assignments as a mechanism to produce and strengthen beneficial treatment outcomes. Practicing skills outside the therapy session for permanent and long-term change is essential. Indeed, engaging in homework activities to produce positive therapy outcomes has been examined in meta-analyses and results indicate that greater compliance with homework is associated with more beneficial treatment outcomes [ 60, 61].
However, one of the top cited reasons for therapy failure in CBT is homework noncompliance [ 62]. In adult clients, the rates of nonadherence range from 20 to 50 percent [ 63]. As mentioned, EFT’s physical component is more than tapping on the skin (indeed meta-analysis indicates that the acupressure component is an active ingredient and outcomes are not due solely to placebo, nonspecific effects of any therapy, or nonacupressure components [ 64]). EFT results in changes in the brain, DNA expression, hormone production, brain waves, and blood flow; and is it remarkably swift. This stimulation of acupressure points is indeed a “health promoting activity” that occurs in session, and does not necessarily rely on homework tasks being completed outside this.
It has been suggested that there are three factors common to all successful psychotherapies: the therapist and the client have a strong bond and effective working relationship; the therapist and client both have an expectation that therapy will be successful; and the therapy approach includes the client engaging in health-promoting, beneficial actions [ 65]. The stimulation of specific acupoints in EFT has been suggested to bethis “health promoting activity” and thus does not necessarily rely on homework tasks being completed outside the session [ 66]. This may answer why the treatment effects last over time, although further research is warranted
4.1 Limitations
This research served as a pilot study for further explorations of brain activation after EFT treatment. Clearly participant numbers were relatively low and restrictive on the inferences that can be drawn. In order to draw direct conclusions future studies should be larger and longer in follow-up periods and individuals perhaps be able to pick the most appropriate food images that they would like to consume at the specific moment of the scan. Subjects in the current study were scanned while fasting; thus, they were hungry during the protocol, which may have enhanced the appeal of high calorie food items. This study examined findings at an individual level because of sample size and to retain individualities in brain structure, however it is recommended that future studies include group brain analyses. Further research may also benefit from investigating the issue of engaging in homework (e.g. further tapping) to ascertain the impact of compliance and longevity of the technique.
4.2 Implications and Future Recommendations
Despite the limitations, this initial study did demonstrate that the viewing of high calorie food items by fasting overweight adults activated brain areas associated with focus and attention (superior temporal gyrus) and reward (orbitofrontal cortex). Furthermore, eight hours of EFT treatment resulted in a relative deactivation of neural activity for those adults and may be a useful adjunct for adults in weight loss and maintenance programs.
Author Contributions
The first author designed and oversaw the clinical trial and wrote the publication with the research assistant sixth author. The second author investigated the fMRI scans for intracranial structural abnormalities and was the Radiologist partner in the study. The third author interpreted pre-and post-effect fMRI scan differences due to the EFT intervention, while the fourth and fifth authors were technical staff present during all scans.
Acknowledgements
This study wishes to acknowledge the EFT practitioner Brett Porter who delivered the intervention for the trial.
Funding
This study acknowledges the private donations of several benefactors (Mrs Pamela Thomas and Alina Frank/Craig Weiner) and Faculty funding from Bond University, as well as the Association of Comprehensive Energy Psychology, USA.
Competing Interests
The first author may derive income from delivering presentations or trainings using the technique investigated in this paper. The remaining authors have declared that no competing interests exist.
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Setting up the Cardiovascular Work Force for the Care of Oncolog
https://www.scholarsresearchlibrary.com/articles/setting-up-the-cardiovascular-work-force-for-the-care-of-oncology-patients-73425.html
Setting up the Cardiovascular Work Force for the Care of Oncology Patients
Ana Barac
Department of Epidemiology, Biostatistics and Informatics, University of Pennsylvania, Philadelphia, United States
* Corresponding Author:
Ana Barac, Department of Epidemiology, Biostatistics and Informatics, University of Pennsylvania,
Philadelphia,
United States,
Email:
[email protected]
Description
Cardiovascular sickness and malignant growth cross on numerous levels, and Cardio-oncology is an arising discipline zeroed in on the anticipation, early discovery and ideal therapy of CV infection in patients treated for disease. A developing number of focuses in the United States are giving freedoms to prepare in cardio-oncology; which requires an expansive however specific information on CV illness related to a profound comprehension of malignancy treatments. The development and accomplishment of the control in propelling the consideration of malignant growth patients is intrinsically reliant upon the nearby cooperation with Oncologists, a vigorous examination endeavor, and the help of expert social orders and promotion gatherings.
Near 5,000 new instances of disease are analyzed every day in the United States, and more than 15 million people with a background marked by malignant growth are alive today. Advances in early location and therapy have prompted a decline in malignant growth related mortality and an exceptional ascent in the quantity of disease survivors. By 2026, there will be an expected 20 million survivors, of which practically half would be old enough 70 years or more established. A maturing populace with a background marked by malignancy and co-dismal cardiovascular (CV) infection.
The field of cardio-oncology initially emerged with the expanded use of anthracyclines in the therapeutic regimens of various cancers, and the rise in cardio toxicity exemplified by doxorubicin-induced cardiomyopathy. The explosion in the number of novel therapies in recent years has led to a paradigm shift in the approach to the treatment of cancer from the use of standard regimens to targeted therapies based on individualized susceptibility. The beneficial effects of these therapies has however been offset by adverse CV effects, of which the mechanisms are poorly understood, and clinical manifestations include heart failure, coronary, peripheral and pulmonary vascular disease, arrhythmias, hypertension and thrombosis. Valvular disease and premature atherosclerosis of the coronaries occur as long-term consequences of radiation therapy.
To characterize the general number and topographical circulation of cardio-oncology preparing programs and better describe whether and how CV Disease preparing programs give openness to cardio-oncology, we directed a cross country review of Accreditation Council for Graduate Medical Education (ACGME)- authorize General Cardiology cooperation. An email containing a connection to an electronic study was sent in November 2017 to CV cooperation program chiefs. Starting non-responders were reached by telephone in July 2018 and urged to finish the review. Of 206 projects reached, 104 (half) got to the overview and 81 (39%) gave essentially incomplete reactions. Near half (n=37, 46%) of CV preparing programs joined customary instructive themes relating to the oncology patients, incorporating disease treatment related cardio toxicity, difficulties of radiation treatment, hazard delineation, thromboembolism and the board of malignancy survivors, with 39% devoting no less than 3-5 talks to cardio-oncology. The preparation programs in focuses that give cardio-oncology administrations were more probable (55% versus 27%) to remember related instructive themes for their central subjects.
The requirement for experts in cardio-oncology reaches out past the United States, and exceptionally specific focuses across the world are beginning to offer types of assistance. The quantity of formal preparing open doors in the Americas and Europe are developing quickly. At present, most freedoms offered are as workshops and courses. Others have molded projects like that of the United States. For instance, the University of Ottawa offers a Cardiac Oncology Research association which incorporates a clinical part, going to both oncology and cardiovascular facilities. In Sao Paolo, Brazil, the Instituto do Cancer do Estado de Sao Paolo (ICESP) has presented to 3 association preparing positions each year. The Royal Brompton Hospital in the United Kingdom comparably gives freedoms to an expert to join a multidisciplinary group overseeing both inpatient and outpatient cardio-oncology administrations. Italy has countless clinics of different sizes offering cardio-oncology administrations, and Associazione Nazionale Medici Cardiologi Ospedalieri (ANMCO) in a joint effort with other European Societies have given clinical and theexecutives pathways.
Disease is analyzed in 15,700 patients <20-years old every year in the US. While this number is fundamentally lower than that for grown-ups, with current 5-year endurance at 80% for a wide range of pediatric and youthful adulthood malignancies, there are ~450,000 overcomers of pediatric disease in the US alone. Survivors are 5-6 times almost certain than kin controls to foster cardiovascular infection of different etiologies. Shockingly, information and practice rules in pediatric patients are missing, especially for those effectively going through and as of late finishing treatment rather than grown-up survivors.
| https://www.scholarsresearchlibrary.com/articles/setting-up-the-cardiovascular-work-force-for-the-care-of-oncology-patients-73425.html |
My sick chicken. This stuff came out of his eyes | BackYard Chickens - Learn How to Raise Chickens
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Thread starter debilorrah Start date Apr 26, 2011
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Apr 26, 2011 #1
debilorrah
The Great Guru of Yap
Premium Feather Member 11 Years
Aug 25, 2008 39,693 163 423 The Carpal Tunnel Rehab Center
Help?
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Apr 26, 2011 #2
PepsNick
Back to Business 9 Years
May 9, 2010 5,212 23 241 Egglanta, GA
So sorry, Deb! How about a picture of the eye?
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Apr 26, 2011 #3
benjoycei
Songster 11 Years
Mar 4, 2011 1,332 50 231 Wilmington
eeeeeeeeeeeeeewwwwwwwwwww!!!
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Apr 26, 2011 Thread starter #4
debilorrah
The Great Guru of Yap
Premium Feather Member 11 Years
Aug 25, 2008 39,693 163 423 The Carpal Tunnel Rehab Center
His eyes are glued shut. Swollen too, no smell.
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Apr 26, 2011 #5
M Mrs MIA
Chick Magnet 11 Years
Mar 3, 2008 7,988 70 303
Looks like an infection of some sort...
If you haven't already, take a soft warm wet towel and clean his eyes - get them open to see if the eye is ok. Keep it clean, trim any feathers away so they don't compound the problem. I don't know enough about eye problems to know what generic stuff works (other than saline solutions), but they do make antibiotic gels for the eyes. You just put a small amount in the eyelid and gently rub it to spread it.
Make sure you keep your hands clean...
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Apr 26, 2011 #6
Matt A NC
Crowing 14 Years
Feb 22, 2007 3,092 93 349 Morganton, NC
That is solidified infection. You have to keep the eye free of it. If the eye stays glued shut with that in it, it will lead to blindness. This can be from an upper respiratory infection. Daily injections of Tylan 50 in a muscle or a daily capsule of Amoxicillin(sold as Fish-Mox) for 5-7 days.
Matt
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Apr 26, 2011 #7
Nikkumz
Songster 8 Years
Mar 24, 2011 394 0 109 Spanaway,WA
I used bacitracin ointment when my chicky had yucky stuff in his eyes. I just cleaned around the eye so it could open and close then put the ointment around as close to the eye as i could get without getting in it....Poor chicky
Last edited: Apr 26, 2011
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Apr 26, 2011 #8
Celtic Chick
Crowing 8 Years
Apr 7, 2011 4,075 124 280 SE Wis
I sure hope it isn't anything serious. I found these.
http://www.raising-chickens.org/poultry-ailments.html
Check chronic cholera or Infectious Coryza?????
Cholera (chronic):
Incidence: common poultry ailment worldwide, but less common than acute.
System/organ affected: primarily respiratory
Symptoms: in birds at least 6-weeks old: cheesy nasal discharge, loss of appetite, rapid weight loss, increased thirst, lameness and swelling of leg joints, wing joints, foot pads, wattles, and sinuses; swollen sticky eyes, sometimes breathing difficulties. In hens: loss of egg production. In cocks: loss of aggression and desire to crow.
Cause: bacteria.
Transmission: contagious; much like acute.
Prevention: Vaccination is not effective. You must not introduce possibly infected birds into flock and use good sanitation and management practices.
Treatment: none effective. Isolate and dispose of infected flock.
Infectious Coryza
Incidence: common chicken ailment worldwide, especially in fall and winter in tropical and temperate environments.
System/organ affected: respiratory
Symptoms: in chicks: nasal discharge, facial swelling, one or both eyes closed, death. In growing birds: watery eyes, eyelids stuck together, reddish bad smelling discharge from nose, drop in feed consumption.
Cause: bacteria: it does not survive long in environment and is easily destroyed with disinfectants.
Transmission: contagious; contact with infected birds and their nasal discharge.
Prevention: avoid mixing birds from different flocks. Remove the infected birds and disinfect and leave the housing vacant for at least three weeks. Vaccinate only if the disease is positively identified.
Treatment: different drugs. Culling is preferred since survivors may be carriers.
Reply
Apr 27, 2011 #9
mccabe
In the Brooder 8 Years
Apr 26, 2011 32 0 21
Aloha. I am assuming you live in a tropical setting as that is eyeworm. I live on a half acre and my chickens free range during the day. It is impossible to prevent the occasional eyeworm. But I have a treatment I developed that is successful. Over the last four years I have lost no birds, and only one hen lost sight in one eye. Meanwhile, the wild island chickens succumb to it.
First, I take a quick look at my flock every morning. Eyeworm is identified early by a discharge or a bit of white in the inner or outer corner. The eye swells and the chicken scratches at it. Quickly separate the sick bird and gently stick your finger in the indention at each eye corner. Gently, very gently, apply pressure toward the eyeball. Often, worms will spill out. Carefully wipe them away. Put one or two drops of bio-active hydrosol, (silver) an inexpensive, natural antibiotic available in health food stores, into both eyes. Yes, both. Then give her a dropperful to swallow. The taste is not bad and she will sip it from the dropper. If she is listless, pry her beak open just a bit and squeeze in the liquid. Then go back to gently massaging and pushing in around the eye, pushing toward the eyeball. You are trying to dislodge that sac in your photo. If it does not float into view, leave the eye until the evening. I finish by coating the entire eye area (and beyond if there are cuts or bumps) with aloe vera. Now, it grows in great quantity here. I peel all the rough edges and wipe her face with the inner gel. Again, this is not painful. I have tasted and used both of these natural medicines. If you do not grow aloe, it can be purchased. In the evening, repeat all of the above, but work diligently to remove that larvae sac. It should be dying by then, will not adhere, and it will slide from some deep recess and over her eye, like a big white contac lens. Work the eyelids, press and gently squeeze until it pops out. I put the chicken back in with the general population at this time but continue the treatments for 2 or 3 days. The eye should be clear, the hen should be perky, and any self-inflicted wounds dry and healed before you cease the regimen. If you find her as late as you have, there is a lot of damage. She will probably be blind in that eye, but if you start right away you can save her life. If she loses sight the eye will turn opaque. My one hen has no trouble navigating with one eye, but her lack of depth perception and sight made her a less than stellar mother. If this one loses her eye I would hesitate to let her hatch a brood. I hope this helps. I was seeking more information on the origin of this disease and ran across this site. Best of luck.
Help?
Reply
Apr 27, 2011 #10
M Mrs MIA
Chick Magnet 11 Years
Mar 3, 2008 7,988 70 303
She's in California...
just curious, what about it makes you assume it's eyeworm?
Reply
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The Oxford Oratory
A sanctuary in the midst of the city
The Oxford Oratory is a vibrant centre of Catholic life. Our church is open every day: join us for Mass, pop in for some quiet prayer, or come and discover more at one of our groups. Our historic church of St Aloysius has been a key feature in the lives of the city’s Catholics for 150 years, attracting people of all ages and from every walk of life. We use beauty to raise hearts and minds to God, faithful to the traditions of St Philip Neri and St John Henry Newman.
Two relics of his are displayed this month in our relic chapel, including a letter bearing his signature.
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Flos paradisi
Today we celebrate the great solemnity of the patron of our church: St Aloysius Gonzaga of the Society of Jesus. St Aloysius is, together with St Gabriel Possenti, patron of young people, students, and seminarians and thus was a natural choice as patron for our church in this university city. He is also the patron of our parish school and we entrust to his loving intercession all our children who are able to learn the love of God from his example. We have his shrine in the chapel of Our Lady of Oxford, his statue is there on the reredos, and his initials guide our eyes towards his heavenly home as we look up at the sanctuary ceiling. Our patrons are important — St Aloysius has been given to us in this parish by God, through his Church, to watch over us in a particular manner, to intercede for all those who live and worship here, and to encourage us in our own quest for holiness.
Born the eldest son of the Marquis of Castiglione, St Aloysius seemed destined for a life of political intrigue and secular affairs, but, as with St Ignatius before him, it was the lives of the saints that really captivated him and placed in his heart the desire to strive for something better. This was not some childish caprice; he had seen the reality of life at court with its violence, frivolity, and degradation of human dignity, and desired not only to turn his back on it, but to embrace with all his heart a life given wholly to God. He began in earnest, adopting severe penances and teaching the local children their catechism. Hearing about the missions of St Francis Xavier, he set his heart on becoming a Jesuit — much to the horror of his family.
Eventually, having not overcome family opposition but at least its concrete obstacles, and having renounced his rights of inheritance, he entered the Jesuit novitiate in Rome in 1585. He had much to learn and much to which to adapt himself, but whatever he had to do he simply did it with all his heart — trusting in the sure knowledge that God was at work. Would he have met St Philip in Rome? Concrete evidence is hard to find, though these two saints of Rome are often depicted in art. We know they had mutual friends and these no doubt would have told them of Rome’s Third Apostle and of the holy Jesuit novice. One can imagine St Aloysius on a novitiate walk popping in to the Chiesa Nuovato see Mister Father Philip whom all Rome spoke of and revered or of St Philip blessing a crowd of passing Jesuit novices and knowing the heart of one of them that would see them both in glory.
St Aloysius’ real work in Rome was that which St Philip had embarked upon at the beginning — the care of the sick and the destitute. When plague broke out he volunteered to go with the other novices to pick people off the streets, to wash them, to prepare them for the sacraments and care for their souls. At first, he admitted to his director St Robert Bellarmine, this revolted him, but he soon learnt to see the image of Christ in these people, and to love them, not only in caring for them, but in seeing Christ in them. Never one to enjoy good health, Aloysius himself fell ill of plague, and died at the age of 23 on 21 June 1591, just a few years before St Philip’s death.
When we look at images of St Aloysius we normally see a rather pale young man who looks like so many other sickly young saints, distinguished perhaps only by the great ruff that he wears about his neck. But he was more than that. He was a young man who bothered about God and thus about other people. He was not yet in his mid-twenties, when he had discovered that real freedom comes from serving God with all ones heart; that Christian love has to be lived in the real, strength-sapping, heart-breaking, service of others; that there is joy in taking people off the streets, washing them, bandaging their wounds and restoring them to the dignity that is theirs as children of God.
The image attached to these words is a depiction of St Aloysius in Milan in the Chiesa di Santa Maria presso San Satiro. The saint looks rather weak and malnourished, but what strength he has is used to hold up a man who is either dying or dead, with St Aloysius pressing the Cross to him and holding the man’s head up with his hands. The look on St Aloysius’ face is one, simply, of love — of love for God and neighbour, and of joy found in bringing the love of God to others. How much this young man, St Aloysius, still has left to teach us…
Heart of Jesus, all-holy! Fountain of all blessings, I adore thee, I love thee, and with a lively sorrow for my sins, I offer thee this poor heart of mine. Make me humble, patient, pure, and wholly obedient to thy will. Good Jesus, grant that I may live in thee and for thee. Protect me in the midst of danger; comfort me in my afflictions; give me health of body, assistance in my temporal needs, thy blessing on all that I do, and the grace of a holy death. Amen.
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A photo from Sunday’s Solemn Mass for Corpus Christi.
June Music
Sunday 4 JuneSolemn Mass 11:00The Most Holy TrinityKyrie MundyMissa Euge bone TyeLibera nos SheppardHonor, virtus et potestas Tallis
Sunday 11 JuneSolemn Mass 11:00Corpus ChristiMissa Pange lingua JosquinLauda Sion PalestrinaOculi omnium Byrd
Friday 16 JuneSolemn Mass 18:00The Most Sacred Heart of JesusMissa Dormendo un giorno GuerreroImproperium PalestrinaSancte Deus Tallis
Sunday 18 JuneSolemn Mass 11:0011th Sunday of the YearMissa Brevis in F Op.117 RheinbergerBenedicam Dominum VictoriaSalve Regina Poulenc
Wednesday 21 JuneSolemn Mass 18:00St Aloysius GonzagaMissa O quam gloriosum VictoriaJustitiae Domini A ScarlattiO bone Jesu Anchieta
Sunday 25 JuneSolemn Mass 11:0012th Sunday of the YearMissa Repleatur os meum PalestrinaPerfice gressus meos LassusHomo quidam fecit coenam magnam Mouton
Thursday 29 JuneSolemn Mass 18:00St Peter and St PaulMissa Petre ego pro te rogavi LoboPetre ego pro te rogavi GuerreroJanitor caeli Ortiz
The Sacred Heart
Love is a funny thing. Materialists will tell us that it is purely the result of a series of electro-chemical responses in the brain, and yet others will tell us that it is the result of fate, the conspiracy of the alignment of the planets or the times we find ourselves in. The heart has long been understood as the centre of a person, a place of knowledge as much as will. It makes us do unreasonable things like acts of unwarranted kindness and altruism and by the edge of its blade we can be hurt in ways that we just can’t speak about. And yet none of these express what love is in itself — only God does that.
On Friday we venerate the Heart of our Lord as the symbol of his human love in which God’s divine love is revealed to us. In most of the prayers to or the meditations on the Sacred Heart, even those very ancient prayers, the woundedness of our Lord’s heart comes to the fore. That heart pierced with a lance and bruised with outrages and blasphemies is a stark and realistic image of the extent to which Christ loves us. Christ, who is the image of the unseen God, the Icon of the Father, shows us precisely what God’s love for us looks like. And it looks like a heart pierced and bruised on account of our sins, yet burning with ardent love for you and for me. This divine love is not for softies.
The time when we celebrate this feast is very fitting. We have come to the end of the Church’s celebration of the mysteries of our redemption: the Passion, the Cross, the Resurrection, the Ascension, Pentecost, the Feast of the Blessed Trinity and Corpus Christi. But today we commemorate the divine-human love which motivated them all. In adoring the Sacred Heart, we adore the totality of Christ’s saving work — it represents the way in which God holds nothing back from us. And in order to share his divine life with us, he reaches down into the very depths of our life, even — and especially — where it is painful, difficult to speak of, hidden. By taking it all and joining it to himself, he scoops us up, he enables us to become like him. By sharing our life, and by sharing our pains, he heals us, he sanctifies us, and he strengthens us.
It is also true that his heart welcomes us precisely so that we might become like it. The whole thrust of our Christian life is that we might be conformed to our Saviour, that we might resemble him, and in this sense, in the life of faith, we should ask ourselves continually whether our heart resembles his. His Sacred Heart is both the example and the cause of our becoming like him. His love is attractive. The more we consider the love with which Jesus acted, and spoke and gave of himself for us, the more we can begin, by his grace, to imitate him — it is truly the school of Christian perfection.
And we begin in that school by prayer. When St John Henry Newman, our Cardinal, chose his motto, he looked to St Francis de Sales’ Treatise on the Love of God. The phrase he chose and paraphrased, Cor ad Cor loquiturrepresents for us the central mystery of the prayer that can begin to transform us. St Francis de Sales wrote:
Truly the chief exercise in mystical theology is to speak to God and to hear God speak in the bottom of the heart; and because this discourse passes in most secret aspirations and inspirations, we term it a silent conversing. Eyes speak to eyes, and heart to heart, and none understand what passes save those who speak.
We may be no great shakes at the spiritual life, or prayer, or we may feel that excelling in virtue is beyond us, but if we can in the simplest of ways open our poor heart to his Sacred Heart, and speak to him as to a friend, if we can entrust our lives to him and ask him devoutly and sincerely to shape us after the model of his Heart, then our Christian life will be all the more graced.
The Corpus Christi procession concluded with Benediction at the University Chaplaincy. #oxfordoratory
The procession finished at the University’s Catholic Chaplaincy. #oxfordoratory
The numbers caught the attention of the local media:
https://www.oxfordmail.co.uk/news/23582016.oxfords-catholic-congregations-take-part-corpus-christi-procession/
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Children scattered flower petals before the Blessed Sacrament all the way. #oxfordoratory
Our route now passes through the city in a straight line, taking us directly through the busiest shopping areas. #oxfordoratory
The canopy was carried by members of the University of Oxford wearing their academic dress. #oxfordoratory
Tuesday 13 June 2023
Fr Robert Ombres OP preached a sermon. #oxfordoratory
We paused at Blackfriars. #oxfordoratory
We were joined by local clergy and religious orders as we processed through the streets to the Dominican Priory at Blackfriars. #oxfordoratory
The processions sets off… #oxfordoratory
We had record numbers for the procession this year. There wasn’t space in church for everyone at the beginning! There were more people outside too. #oxfordoratory
The beginning of our Corpus Christi procession last Sunday.#oxfordoratory
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We’ve made it even easier to buy the Oratory Prayer Book from anywhere in the world.
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Worship
What does it actually mean to worship God? In the New Testament, the word we most often translate as ‘worship’ doesn’t mean to reverence another in some abstract sense. It always involves some kind of bodily action. When we think about the magi visiting the Holy Family, we sometimes convey this motion by describing them — after they fall to their knees — as ‘doing homage’. But it’s actually that same word here we might translate elsewhere as ‘worship’. It’s just that we recognise the need to describe the bodily sign of their submission and adoration of the new born King with something that sounds a bit more physical.
The word we usually translate as ‘worship’ ( proskuneo) comes literally from a root meaning ‘to make yourself like a dog before the other person’. It originally meant prostrating yourself on the floor to show your humble submission before another. By the time of the New Testament, people wouldn’t necessarily have had the root of this word in mind whenever they used it,* but the word still carries with it the idea of doing something with your body to express your worship.
The feast of Corpus Christi is all about this kind of bodily worship. It’s tied to the fact that we are not pure spirits, but that we are human beings, body and soul. To worship God is not just a spiritual act. The right worship of God does not consist in simply having the right kinds of thoughts towards him. But the worship of God involves the humble submission of our entire human being, body and soul, before the God who is greater than all of us.
And ever since the Incarnation, we do this not just before an abstract spirit. Because, from the moment of the Incarnation, God really does have a human body, that we can worship, that we fall down on our knees before, like the magi and the Canaanite woman, and so many others in the Gospel who kneel down and worship Christ. When we worship God, we kneel before God who is present in the flesh, under the appearances of bread and wine, in our churches all over the world.
Corpus Christi is a joyful celebration of Christ’s presence among us, and it gives us an opportunity to think about how we respond to that gift. All this talk of kneeling and worship might not sound so joyful, but one of the great paradoxes of Christianity is that we find our greatest freedom in the humble service of God. Our greatest joy really should be found in finding ways to express this loving worship. So at least once a year, it is no bad thing to think about how we express with our own bodies that worship of God’s body, and what ways we can find to worship him even more perfectly.
This Sunday, we will carry Christ’s Body through the streets of our city. We have a chance to demonstrate to the world our love, our joyful service, our worship of him, through our presence. The procession leaves our church at 2:30pm. Make sure you are there.
But we should also think about the more ordinary things, like making sure we show that worship whenever we are in his presence. We should show through our behaviour in church that we believe him to be there: by genuflecting before him in the tabernacle of the church, and by keeping the church quiet and prayerful.
We show our worship above all by kneeling down before him — like all those people in the Gospel — for the moment of Holy Communion. And we allow the priest to place the Host on our tongues, so that we don’t handle unnecessarily what is holy and precious, and no particles of Our Lord’s Body are ever dropped or lost through carelessness.
We continue that worship in our prayers of thanksgiving after Communion and once the Mass has ended. We certainly never leave church during Communion. And we might think of ways of extending the time we spend with Christ present in the Blessed Sacrament: by attending Mass during the week sometimes, or visiting him during the times each week when his Body is exposed solemnly on the altar for Adoration, or even just by visiting an empty church, where he is waiting for us to show him our worship.
Our Lord is hidden there, waiting for us to come and visit him, and make our request to him. See how good he is! He is there in the Sacrament of his love, sighing and interceding incessantly with his Father for sinners. To what outrages does he not expose himself, that he may remain in the midst of us! He is there to console us; and therefore we ought often to visit him. How pleasing to him is the short quarter of an hour that we steal from our occupations, from something of no use, to come and pray to him, to visit him, to console him for all the outrages he receives! When he sees pure souls coming eagerly to him, he smiles upon them. They come with that simplicity which pleases him so much, to ask his pardon for all sinners, for the outrages of so many ungrateful men. What happiness do we not feel in the presence of God, when we find ourselves alone at his feet before the holy tabernacles! ‘Come, my soul, redouble thy fervour; thou art alone adoring thy God. His eyes rest upon thee alone.’
— St John Mary Vianney
* One exception is that I do think Christ had this root meaning in mind when he spoke to the Canaanite woman in Matthew 15:21–28. He wasn’t randomly insulting her by comparing her to a dog, but drawing attention to the fact that she was making herself like a dog before him — i.e. worshipping him — because she recognised him to be God. In other words, he was acknowledging her worship as proof of her faith and humility.
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Chebyshev Spectral Collocation Method for Magneto Micro-Polar Convective Flow Through Vertical Porous Pipe Using Local Thermal Non-equilibrium Approach | Request PDF
Request PDF | Chebyshev Spectral Collocation Method for Magneto Micro-Polar Convective Flow Through Vertical Porous Pipe Using Local Thermal Non-equilibrium Approach | The influence of thermal non-equilibrium condition on the mixed convective flow of a magneto-micro-polar fluid in a vertical pipe filled with... | Find, read and cite all the research you need on ResearchGate
Chebyshev Spectral Collocation Method for Magneto Micro-Polar Convective Flow Through Vertical Porous Pipe Using Local Thermal Non-equilibrium Approach
June 2021
International Journal of Applied and Computational Mathematics 7(3)
DOI: 10.1007/s40819-021-01052-z
Authors:
Km. Renu
Graphic Era Hill University
To read the full-text of this research, you can request a copy directly from the authors.
Read publisher preview
Abstract and Figures
The influence of thermal non-equilibrium condition on the mixed convective flow of a magneto-micro-polar fluid in a vertical pipe filled with porous media along with the heat source is investigated in this article. The Chebyshev spectral collocation method has been used to numerically solve the governing equations and it shows excellent agreement with the earlier published results obtained by FEM and network simulation method. The non-Darcy–Brinkman—Forchheimer extended model is used in the momentum equations. In this extensive study, the rigorous impact of physical parameters inter-phase heat transfer coefficient (H) and thermal conductivity ratio \((\gamma )\) on the fluid flow, both solid and fluid temperature profiles, micro-rotation, and shear stress are especially investigated. The comprehensive investigation indicates that velocity, micro-rotation, and fluid temperature are decreased on increasing H, but, the behavior of solid temperature is a reversal to the fluid temperature for the case of heat generated by fluid. While in the case of heat-generating due to solid all the results indicate opposite behavior to the case of heat generated by fluid. The notable finding is that the velocity, micro-rotation, fluid, and solid temperature are increased on enhancing \(\gamma \) up to 100. There exist an small interval \([0, H_0]\) of H in which the velocity gradient is decreased and increased for \(\alpha =1\) and \(\alpha =-1\) at \(\gamma \le 1\) respectively. While, the impact of \(\beta \) on the velocity gradient is reverse to the effect of \(\alpha \). The velocity gradient is increased on increasing Gr for heat generation/absorption by fluid and solid phases and it is increased on increasing Darcy number (Da) for all value of \(\gamma \). In the entire study, we have observed that the behavior of heat generation/absorption by fluid was similar to the heat absorption/generation by solid zone with different magnitude.
Physical model and coordinate system …
The shear stress i.e. velocity gradient as a function of H for the case of heat generation aα=1\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\alpha =1$$\end{document}, β=0\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\beta =0$$\end{document} and heat absorption bα=-1\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\alpha =-1$$\end{document}, β=0\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\beta =0$$\end{document}, by fluid at Ha=1\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$Ha=1$$\end{document}, and Gr=1\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$Gr=1$$\end{document}, γ=0.01\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\gamma =0.01$$\end{document} for different value of Da …
Variation of a velocity (f) and b micro-rotation (g) for various heat source/sink parameter α\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\alpha $$\end{document} with Ha=0\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$Ha=0$$\end{document}, Da=∞\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$Da= \infty $$\end{document}, H=0\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$H=0$$\end{document}, γ=0\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\gamma =0$$\end{document}, β=0\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\beta =0$$\end{document}Er=3\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$Er=3$$\end{document}, and Gr=1\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$Gr=1$$\end{document} …
Influence of H on a velocity, b micro-rotation, c fluid temperature and d solid temperature profiles, for γ=0.01\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\gamma =0.01$$\end{document} at Da=0.1\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$Da= 0.1$$\end{document}, α=1\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\alpha =1$$\end{document}, β=0\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\beta =0$$\end{document} and Gr=1\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$Gr=1$$\end{document} …
Effect of heat source/sink when heat is generated by fluid phase (a)–(b); and when heat generated by solid phase (c)–(d); at Da=0.1\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$Da= 0.1$$\end{document}, H=1\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$H=1$$\end{document}, γ=1\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\gamma =1$$\end{document} and Gr=1\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$Gr=1$$\end{document} …
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Int. J. Appl. Comput. Math (2021) 7:117
https://doi.org/10.1007/s40819-021-01052-z
ORIGINAL PAPER
Chebyshev Spectral Collocation Method for Magneto
Micro-Polar Convective Flow Through Vertical Porous Pipe
Using Local Thermal Non-equilibrium Approach
Km. Renu 1 · Ashok Kumar 1 · Anup Singh Negi 1
Accepted: 9 May 2021 / Published online: 28 May 2021
© The Author(s), under exclusive licence to Springer Nature India Private Limited 2021
Abstract
The influence of thermal non-equilibrium condition on the mixed convecti ve flow of a
magneto-micro-polar fluid in a vertical pipe filled with porous media along with the heat
source is investigated in this article. The Chebyshev spectral collocation method has been
used to numerically solve the governing equations and it shows e xcellent agreement with
the earlier published results obtained by FEM and network simulation method. The non-
Darcy–Brinkman—Forchheimer extended model is used in the momentum equations. In
this extensive study , the rigorous impact of physical parameters inter-phase heat transfer
coefficient ( H ) and thermal conductivity ratio (γ ) on the fluid flow , both solid and fluid
temperature profiles, micro-rotation, and shear stress are especially investigated. The com-
prehensive in vestigation indicates that velocity , micro-rotation, and fluid temperature are
decreased on increasing H , but, the behavior of solid temperature is a reversal to the fluid
temperature for the case of heat generated by fluid. While in the case of heat-generating due
to solid all the results indicate opposite behavior to the case of heat generated by fluid. The
notable finding is that the velocity , micro-rotation, fluid, and solid temperature are increased
on enhancing γ up to 100. There exist an small interval [ 0 , H 0 ] of H in which the velocity
gradient is decreased and increased for α = 1a n d α =− 1a t γ ≤ 1 respecti vely . While,
the impact of β on the velocity gradient is reverse to the ef fect of α . The velocity gradient
is increased on increasing Gr for heat generation/absorption by fluid and solid phases and
it is increased on increasing Darcy number ( Da ) for all value of γ . In the entire study, we
have observed that the behavior of heat generation/absorption by fluid w as similar to the heat
absorption/generation by solid zone with different magnitude.
B Ashok Kumar
[email protected]
Km. Renu
[email protected]
Anup Singh Negi
[email protected]
1 Department of Mathematics, H. N. B. Garhwal University (A Central University), Srinagar 246174,
India
123
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Convergence and stability of spectral collocation method for hyperbolic partial differential equation with piecewise continuous arguments
Article
Nov 2022
Yongtang Chen
Qi Wang
This paper deals with the convergence and stability of the spectral collocation method for a hyperbolic partial differential equation with piecewise continuous arguments. Firstly, the convergence of continuous-time and discrete-time collocation methods is analyzed by means of equivalent schemes with \(L^2\)-norm rigorously. We obtain the order of convergence of the continuous-time collocation method is \(O(h^4)\) and the discrete-time collocation method is \(O(h^4+p)\), where h and p are spatial step and temporal step, respectively. Secondly, the stability of two numerical schemes is analyzed by Fourier analysis method. It is proven that the continuous-time collocation method is unconditionally stable. The stability conditions for the discrete-time collocation method are derived under which the analytic solution is asymptotically stable. Finally, some numerical experiments are carried out to demonstrate our theoretical results.
Heat transfer and thermal conductivity of magneto micropolar fluid with thermal non-equilibrium condition passing through the vertical porous medium
Article
Jul 2022
WAVE RANDOM COMPLEX
Naveed Ahmad Khan
Muhammad Sulaiman
This paper investigates the incompressible mixed convection flow of electrically conductive micropolar fluid with a thermal non-equilibrium condition that passes through the vertical circular (pipe) porous medium. The extension of the non-Darcy–Brinkman–Forchheimer model is considered to formulate the governing non-linear system of differential equations for the problem. Furthermore, the rigorous impact of different parameters such as thermal conductivity ratio (γ), inter-phase heat transfer coefficient (H), Darcy number (Da), Grashof number (Gr), Eringen micro-polar parameter (Er), Hartmann number (Ha), solid-heat generation (β), and fluid heat generation parameter (α) on velocity profile (f∗), micro-rotational (angular velocity) (g∗), temperature of solid (Θf∗) and fluid (Θs∗) has been investigated by using the computational strength of artificial intelligence based Elman neural networks (ENN) and Levenberg–Marquardt algorithm (LMA). We have compared the solutions calculated by the designed ENN-LM algorithm with the Cuckoo Search Algorithm (CSA), Chebyshev spectral collocation method (CSCM), particle swarm optimization (PSO) algorithm, and Runge–Kutta method. The convergence rate and stability of the ENN-LM technique show that it can be applied to solving complex models involving partial and fractional differential equations.
Lie similarity analysis of MHD flow past a stretching surface embedded in porous medium along with imposed heat source/sink and variable viscosity
Article
Jul 2020
Priyanka Agrawal
Praveen Kumar Dadheech
R N Jat
Ilyas Khan
Porous medium Stretching surface Heat generation/absorption and MHD a b s t r a c t The present examination is centered around the transfer of heat for the flow of a boundary layer free convective incompressible fluid, past a stretching porous surface, assuming viscosity dependent on temperature linearly along with heat source and sink with imposed magnetic field. Lie group similarity transformation is used to obtain the symmetric graphs of the given problem. Solutions for velocity and heat profile are encountered numerically with fourth-order Runga-Kutta shooting technique and graphically presented and explained the impact on velocity profile and temperature profile of several physical parameters as temperature-dependent parameter of viscosity A, k 1 as parameter of permeability, Prandtl number, as parameter of heat generation and absorption and M as parameter of magnetic field. We observed that the thermal boundary layer thickness can be reduced by increasing viscosity parameter A and heat sink parameter. As we give increment in k 1 we find a decrement in the horizontal velocity profile, which leads to the enhanced deceleration of the flow and, hence, the velocity decreases.
Numerical simulations of unsteady flows in a rotating channel using a novel eigenfunction expansion method
Article
Full-text available
Jun 2020
Q. Rubbab
Y. Mahsud
Sohail Irshad
Massimiliano Ferrara
Starting flows of a viscous incompressible fluid, modeled by the time-fractional derivatives, within a rotating channel due to an impulsive pressure gradient are studied. Using the eigenfunction expansion, the analytic solutions in series form are obtained. The flow of the ordinary fluid is studied as a special case of the time-fractional problem. The convergence of series solutions is proved. In addition, using the classical analytical method, coupled with the Laplace transform and Stehfest’s algorithm, an approximate solution is found. The flow rates in x- and y-directions are determined. In the case of the ordinary fluid, the steady-state and transient components of velocities are obtained. The numerical calculations are carried out by using the Mathcad software. It is found that, for fractional fluids, the reversal flow is much attenuated if the values of the fractional parameter are less than 1.
Entropy Generation and Consequences of MHD in Darcy–Forchheimer Nanofluid Flow Bounded by Non-Linearly Stretching Surface
Article
Mar 2020
Ghulam Rasool
Anum Shafiq
Ilyas Khan
Gullnaz Shahzadi
Present communication aims to inspect the entropy optimization, heat and mass transport in Darcy-Forchheimer nanofluid flow surrounded by a non-linearly stretching surface. Navier-Stokes model based governing equations for non-Newtonian nanofluids having symmetric components in various terms are considered. Non-linear stretching is assumed to be the driving force whereas influence of thermal radiation, Brownian diffusion, dissipation and thermophoresis is considered. Importantly, entropy optimization is performed using second law of thermodynamics. Governing problems are converted into nonlinear ordinary problems (ODEs) using suitably adjusted transformations. RK-45 based built-in shooting mechanism is used to solve the problems. Final outcomes are plotted graphically. In addition to velocity, temperature, concentration and Bejan number, the stream lines, contour graphs and density graphs have been prepared. For their industrial and engineering importance, results for wall-drag force, heat flux (Nusselt) rate and mass flux (Sherwood) rate are also given in tabular data form. Outputs indicate that velocity reduces for Forchheimer number as well as for the porosity factor. However, a rise is noted in temperature distribution for elevated values of thermal radiation. Entropy optimization shows enhancement for larger values of temperature difference ratio. Skin-friction enhances for all relevant parameters involved in momentum equation.
MHD Slip Flow of Casson Fluid along a Nonlinear Permeable Stretching Cylinder Saturated in a Porous Medium with Chemical Reaction, Viscous Dissipation, and Heat Generation/Absorption
Article
Apr 2019
Imran Ullah
Abdullah Alkanhal
Sharidan Shafie
Waqar Khan
The aim of the present analysis is to provide local similarity solutions of Casson fluid over a non-isothermal cylinder subject to suction/blowing. The cylinder is placed inside a porous medium and stretched in a nonlinear way. Further, the impact of chemical reaction, viscous dissipation, and heat generation/absorption on flow fields is also investigated. Similarity transformations are employed to convert the nonlinear governing equations to nonlinear ordinary differential equations, and then solved via the Keller box method. Findings demonstrate that the magnitude of the friction factor and mass transfer rate are suppressed with increment in Casson parameter, whereas heat transfer rate is found to be intensified. Increase in the curvature parameter enhanced the flow field distributions. The magnitude of wall shear stress is noticed to be higher with an increase in porosity and suction/blowing parameters.
A novel algorithm based on the Legendre wavelets spectral technique for solving the Lane–Emden equations
Article
Mar 2020
APPL NUMER MATH
A. Karimi Dizicheh
Soheil Salahshour
Ali Ahmadian
Dumitru Baleanu
In this research, we present an iterative spectral method for the approximate solution of a class of Lane–Emden equations. In this procedure, we initially extend the Legendre wavelet which is appropriate for any time interval. Thereafter, the Guass-Legendre collection points of the Legendre wavelet are acquired. Employing this new approach, the iterative spectral technique converts the differential equation to a set of algebraic equations which diminishes the computational costs effectively. By solving the obtained algebraic equations, an accurate approximate solution for the assumed Lane–Emden equation is achieved. The present technique is validated by solving a number of Lane–Emden problems and are compared with other existing methods. The numerical simulations demonstrate that the new algorithm is simple and it has highly accuracy.
Effect of Radiation On Hydromagnetic Mixed Convective Flow in a Vertical Channel Filled with Porous Media: A Thermal Non-Equilibrium Approach
Article
Apr 2020
J HEAT TRANS-T ASME
Km. Renu
The present work addresses the magnetic and radiation effect on the fully developed mixed convective flow in a vertical channel occupied by a porous medium with the thermal non-equilibrium state. The assumption that the fluid is electrically conducted is taken into account and permitted by uniform transversal magnetic field while the temperature of the wall is changing linearly with the direction of the fluid flow. The spectral collocation technique is used to solve governing differential equation numerically, whereas the analytical solution is governed for the special case when (F*) and the ratio of porosity-scaled thermal conductivity are zero. The aim of this study is to understand the impact of radiation and the magnetic field with thermal non-equilibrium parameter (H) on fluid flow and on the (Nuf). Obtained results are described in terms of Nusselt numbers, Hartmann number(M), Darcy number, Radiation perimeter, Rayleigh number, inter-phase heat transfer coefficient, and the ratio of porosity-scaled thermal conductivity for both buoyancy assisted and opposed cases. This investigation demonstrated, that in the buoyancy assisted case the fluid flow for Ra<102, (Nuf) is increase near to the wall with increasing (M). Beyond this when Ra >= 102, (Nuf) is decreased with increasing (M). There also exists an interval [0, H_0] in which (Nuf) increases with increasing M, furthermore beyond the value of H_0, Nuf decreasing asymptotically. While for the buoyancy opposed case the flow separation and inflection point appear in the velocity profile for different value of M.
MHD Flow and Heat Transfer of Immiscible Micropolar and Newtonian Fluids Through a Pipe: A Numerical Approach: Select Proceedings of NHTFF 2018
Chapter
| https://www.researchgate.net/publication/351955108_Chebyshev_Spectral_Collocation_Method_for_Magneto_Micro-Polar_Convective_Flow_Through_Vertical_Porous_Pipe_Using_Local_Thermal_Non-equilibrium_Approach |
Maloney v. Rincon - New York - Case Law - VLEX 885586414
0: [object Object]. 1: [object Object]. 2: [object Object]. 3: [object Object]. 4: [object Object]
Maloney v. Rincon
<table><tbody><tr><td> Court</td><td> New York City Court</td></tr><tr><td> Writing for the Court</td><td> MICHAEL D. STALLMAN</td></tr><tr><td> Citation</td><td> 581 N.Y.S.2d 120,153 Misc.2d 162</td></tr><tr><td> Decision Date</td><td> 22 January 1992</td></tr><tr><td> Parties</td><td> Michael MALONEY, Plaintiff, v. E. RINCON, d/b/a Eddy Auto Repair, Inc., Defendant.</td></tr></tbody></table>
Page 120
581 N.Y.S.2d 120
153 Misc.2d 162
Michael MALONEY, Plaintiff,
v.
E. RINCON, d/b/a Eddy Auto Repair, Inc., Defendant.
Civil Court of the City of New York,
New York County, Special Term,
Part I.
Jan. 22, 1992.
Page 121
Macleon & Maloney (Michael M. Maloney, of counsel), for plaintiff.
Jose A. Quinones, Bronx, for defendant.
MICHAEL D. STALLMAN, Judge.
This motion for a stay raises an important question concerning the subject matter jurisdiction of the Civil Court and its capacity to deal with an apparent statutory gap. Specifically, [153 Misc.2d 163] does the Civil Court have the subject matter jurisdiction to enjoin a lien sale pendente lite within a proceeding challenging the validity of a lien?
Petitioner moves for an order staying the sale of an automobile, and, by a special proceeding simultaneously commenced moves to cancel a garage owner's lien. Petitioner alleges that he is the owner of a 1984 Mercedes Benz which he asserts respondent had agreed to store without charge, and that respondent had performed various repairs without petitioner's consent. Petitioner further asserts that respondent served petitioner with a notice of sale to foreclose an asserted $3,300 repair lien, without either demanding payment or giving other notice. Respondent answered by denying petitioner's allegations, including ownership, and asserts that he surrendered the vehicle to a third party who had allegedly exhibited a New Jersey certificate of title. Because the factual issues are in dispute and because respondent did not bring a formal motion to dismiss, the issues of standing and mootness cannot be summarily determined. This motion, however, was submitted on default, upon respondent's failure to appear on the submission date. 1
A court's subject matter jurisdiction embraces the categories of litigation which it is empowered to adjudicate and the types of remedies which it is authorized to grant. Unlike personal jurisdiction, it cannot be waived by a party's failure to object. See Gager v. White,53 N.Y.2d 475, 485 n. 2,442 N.Y.S.2d 463,425 N.E.2d 851. Thus, respondent's default cannot prevent this Court from questioning subject matter jurisdiction, since any judgment rendered without subject matter jurisdiction would be void ab initio.
The Civil Court has been statutorily granted subject matter jurisdiction over this type of special proceeding.
Lien Law Section 201-a provides that a special proceeding to determine the validity of a lien "may be brought in any court which would have jurisdiction to render a judgment for a sum equal to the amount of the lien." It is a logical complement to Civil Court Act Section 202 which grants the Civil Court jurisdiction over actions and proceedings to foreclose liens on personal property where the amount sought does not exceed $25,000. Since the amount sought by respondent-lienor is $3,300, this Court clearly has subject matter jurisdiction over the proceeding itself.
[153 Misc.2d 164] Petitioner here seeks not only a determination of the validity of the lien, but injunctive relief staying the sale.
Petitioner has incorrectly moved for a stay under CPLR 2201. CPLR 2201 codifies a court's inherent power to stay, i.e., to suspend, its own proceedings in a pending
Page 122
case, within its discretion, on a proper showing. For example, a court may stay the entry of a judgment pending determination of a motion to vacate judgment. In so doing, a court may stay execution of the judgment, since execution is done pursuant to its mandate. Thus, it may stay supplementary proceedings to enforce a judgment and stay the sheriff or marshal and attorneys, who are agents or officers of the Court.
In contrast, a lien sale, while considered an aspect of state action, is not a function of the court's own process. Cf. Sharrock v. Dell Buick-Cadillac, Inc.,45 N.Y.2d 152, 408 N.Y.S.2d...
7 practice notes
J.B. v. 110 Auto Body Repair Inc., CV-009951-20/QU United States New York Civil Court August 26, 2020 ...Plaintiff OSC No. 4, "since any judgement rendered without subject matter jurisdiction would be void ab initio " ( Maloney v. Rincon , 153 Misc. 2d 162, 581 N.Y.S.2d 120 [1992] ) and the subject matter jurisdiction, "unlike personal jurisdiction, cannot be waived by a party's failure to obj......
Spinnell v. Doris L. Sassower, P.C. United States New York City Court June 16, 1992 ...jurisdiction, not subject matter jurisdiction (see Gager v. White, 53 N.Y.2d 475, 442 N.Y.S.2d 463, 425 N.E.2d 851; Maloney v. Rincon, 153 Misc.2d 162, 581 N.Y.S.2d 120), as recognized by the statute's drafters. A fortiori, the Civil Court is not empowered to exercise the full statewide per......
Mongelli v. Cabral United States New York City Court July 17, 1995 ...upon being ordered to return Peaches, this Court must still consider its subject matter jurisdiction [see e.g., Maloney v. Rincon, 153 Misc.2d 162, 163, 581 N.Y.S.2d 120, 121 (1992) ("A court's subject matter jurisdiction embraces the categories of litigation which it is empowered to adjudi......
Katz Park Ave. Corp. v. Olden United States New York City Court May 18, 1993 ...and the action can continue, provided that the court is empowered to grant some of the Page 760 relief sought. See Maloney v. Rincon, 153 Misc.2d 162, 581 N.Y.S.2d 120 (motion for preliminary injunction improperly brought in properly pending Civil Court action). [158 Misc.2d 545] In contras......
7 cases
J.B. v. 110 Auto Body Repair Inc., CV-009951-20/QU United States New York Civil Court August 26, 2020 ...Plaintiff OSC No. 4, "since any judgement rendered without subject matter jurisdiction would be void ab initio " ( Maloney v. Rincon , 153 Misc. 2d 162, 581 N.Y.S.2d 120 [1992] ) and the subject matter jurisdiction, "unlike personal jurisdiction, cannot be waived by a party's failure to obj......
Spinnell v. Doris L. Sassower, P.C. United States New York City Court June 16, 1992 ...jurisdiction, not subject matter jurisdiction (see Gager v. White, 53 N.Y.2d 475, 442 N.Y.S.2d 463, 425 N.E.2d 851; Maloney v. Rincon, 153 Misc.2d 162, 581 N.Y.S.2d 120), as recognized by the statute's drafters. A fortiori, the Civil Court is not empowered to exercise the full statewide per......
Mongelli v. Cabral United States New York City Court July 17, 1995 ...upon being ordered to return Peaches, this Court must still consider its subject matter jurisdiction [see e.g., Maloney v. Rincon, 153 Misc.2d 162, 163, 581 N.Y.S.2d 120, 121 (1992) ("A court's subject matter jurisdiction embraces the categories of litigation which it is empowered to adjudi......
Katz Park Ave. Corp. v. Olden United States New York City Court May 18, 1993 ...and the action can continue, provided that the court is empowered to grant some of the Page 760 relief sought. See Maloney v. Rincon, 153 Misc.2d 162, 581 N.Y.S.2d 120 (motion for preliminary injunction improperly brought in properly pending Civil Court action). [158 Misc.2d 545] In contras......
| https://case-law.vlex.com/vid/maloney-v-rincon-885586414 |
Determining the Benefits of Improving Communication in BPAP/CPAP Users - Full Text View - ClinicalTrials.gov
Determining the Benefits of Improving Communication in BPAP/CPAP Users
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government.
Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT03795753 Recruitment Status :
Completed First Posted : January 8, 2019 Results First Posted : September 18, 2020 Last Update Posted : September 18, 2020
Sponsor:
Emory University
Information provided by (Responsible Party):
Nancy Abbey Collop, MD, Emory University
Study Details
Study Description
Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information
Brief Summary:
The purpose of this study is to determine the effectiveness of a non-invasive communication aid for BPAP/CPAP masks. This study also looks to determine the potential impact of the device on patients with obstructive sleep apnea (OSA) and the individuals that interact with the device.
Condition or disease Intervention/treatment Phase Positive-Pressure Respiration Communication Device: F2S Communicator Other: Non-functioning Communicator Not Applicable
Detailed Description:
Noninvasive positive pressure ventilation (NIPPV) is a crucial tool used to treat respiratory distress and failure, especially when patients have acute worsening (also called exacerbations) of emphysema or chronic obstructive pulmonary disease (COPD). This study will randomize patients who use Noninvasive positive pressure ventilation (NIPPV) to a control (non-functioning) and intervention (functioning) device to determine how well speech can be understood while wearing the device.
The purpose of this study is to determine the effectiveness of a non-invasive communication aid for BPAP/CPAP masks. This study also looks to determine the potential impact of the device on patients with obstructive sleep apnea (OSA) and the individuals that interact with the device.
Study Design
Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information
Layout table for study information Study Type : Interventional
(Clinical Trial) Actual Enrollment : 36 participants Allocation: Randomized Intervention Model: Parallel Assignment Masking: Single (Outcomes Assessor) Primary Purpose: Treatment Official Title: Determining the Benefits of Improving Communication in BPAP/CPAP Users Actual Study Start Date : March 22, 2019 Actual Primary Completion Date : July 8, 2019 Actual Study Completion Date : July 8, 2019
Resource links provided by the National Library of Medicine
Genetic and Rare Diseases Information Center resources: Chronic Graft Versus Host Disease
U.S. FDA Resources
Arms and Interventions
Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information
Arm Intervention/treatment Experimental: F2S Communicator The F2S Communication System is a communication aid for use with a noninvasive ventilation (NIV) mask covering at least the mouth. It is a two-component system consisting of (1) a disposable, single patient use patch and signal cable and (2) a reusable communicator with power cable.The non-invasive aid for patients receiving BPAP/CPAP therapy delivers communication between the patient and medical personnel. Device: F2S Communicator The communicator will be attached to the BPAP/CPAP mask. The study coordinator will ENABLE the communicator. A list of single words and 5-word through 15-word sentences will be provided to the patient. Each single word may be read aloud up to two times. The partner must then select the read word out of a list of twelve possible words. Each sentence may be read aloud up to two times. The partner must transcribe each sentence on a standardized form. A survey will be provided to evaluate the "mask on, communicator on" period. Other Name: BPAP/CPAP communicator Sham Comparator: Non-functioning Communicator Non-functioning study communication device is used. Other: Non-functioning Communicator The communicator will be attached to the BPAP/CPAP mask. The study coordinator will DISABLE the communicator. A list of single words and 5-word through 15-word sentences will be provided to the patient. Each single word may be read aloud up to two times. The partner must then select the read word out of a list of twelve possible words. Each sentence may be read aloud up to two times. The partner must transcribe each sentence on a standardized form. A survey will be provided to evaluate the "mask on, communicator on" period.
Outcome Measures
Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information
Primary Outcome Measures
:
Accuracy of Single Word Selection (Proportion of Right Words From Total) [ Time Frame: Mask on-communicator on-20 minutes ]
Data will be collected using audio recording - accuracy of single word selection (spoken by patient -> selected by partner). The communicator will be attached to the BPAP/CPAP mask. A list of single words will be provided to the patient. Each single word may be read aloud by patient up to two times. The partner must then select the read word out of a list of twelve possible words.
Accuracy of Sentence Selection (Proportion of Right Sentences From Total) [ Time Frame: Mask on-communicator on-20 minutes ]
Data will be collected using audio recording - accuracy of sentence selection (spoken by patient -> transcribed by partner). The communicator will be attached to the BPAP/CPAP mask. A list of 5-word through 15-word sentences will be provided to the patient. Each sentence may be read aloud by patient up to two times. The partner must transcribe each sentence on a standardized form.
Secondary Outcome Measures
:
Speech Transmission Index (STI) [ Time Frame: Mask on with communicator on (20 min) ]
STI is a numeric representation measure of communication channel characteristics whose value varies from 0 = bad to 1 = excellent.On this scale, an STI of at least 0.5 is desirable for most applications.
Number of Subjects That Found That the Device Significantly Improved Noninvasive Ventilation (NIV) Comfort [ Time Frame: Mask on-communicator on-20 minutes ]
Number of subjects that found that the device significantly improved noninvasive ventilation (NIV) comfort was calculated and reported. Assessment of noninvasive ventilation (NIV) comfort was conducted using Likert Scale Score on clarity of communication on a symmetric seven-level agree-disagree scale.
Eligibility Criteria
Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information
Information from the National Library of Medicine
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
Layout table for eligibility information Ages Eligible for Study: 18 Years and older (Adult, Older Adult) Sexes Eligible for Study: All Accepts Healthy Volunteers: No
Criteria
Inclusion Criteria:
Patients must be receiving BPAP/CPAP therapy in the outpatient setting (e.g. clinics, sleep centers).
Exclusion Criteria:
Intubated or have a tracheostomy.
Vulnerable populations (children, pregnant women, decisionally impaired adults, and prisoners).
Speech disabilities, reading disabilities, dyslexia.
Contacts and Locations
Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03795753
Locations
Layout table for location information United States, Georgia Emory Clinic Atlanta, Georgia, United States, 30322 Emory University Hospital Atlanta, Georgia, United States, 30322 Grady Health System Atlanta, Georgia, United States, 30322
Sponsors and Collaborators
Emory University
Investigators
Layout table for investigator information Principal Investigator: Nancy Collop, MD Emory University
Study Documents (Full-Text)
Documents provided by Nancy Abbey Collop, MD, Emory University:
Study Protocol and Statistical Analysis Plan [PDF] March 27, 2019
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Wong AI, Cheung PC, Zhang J, Cotsonis G, Kutner M, Gay PC, Collop NA. Randomized Controlled Trial of a Novel Communication Device Assessed During Noninvasive Ventilation Therapy. Chest. 2021 Apr;159(4):1531-1539. doi: 10.1016/j.chest.2020.09.250. Epub 2020 Oct 1.
Layout table for additonal information Responsible Party: Nancy Abbey Collop, MD, Professor, Emory University ClinicalTrials.gov Identifier: NCT03795753 History of Changes Other Study ID Numbers: IRB00097529 First Posted: January 8, 2019 Key Record Dates Results First Posted: September 18, 2020 Last Update Posted: September 18, 2020 Last Verified: August 2020 Individual Participant Data (IPD) Sharing Statement: Plan to Share IPD: No
Layout table for additional information Studies a U.S. FDA-regulated Drug Product: No Studies a U.S. FDA-regulated Device Product: Yes Device Product Not Approved or Cleared by U.S. FDA: Yes Product Manufactured in and Exported from the U.S.: No
Keywords provided by Nancy Abbey Collop, MD, Emory University:
Emphysema Chronic obstructive pulmonary disease Obstructive sleep apnea
For Study Record Managers
U.S. Department of Health and Human Services
| https://clinicaltrials.gov/show/NCT03795753 |
Publications - Global Disability Innovation Hub
The GDI Hub brings together academic excellence, innovative practice and co-creation; harnessing the power of technology for good.
Type
Conference Paper
Themes
Assistive & Accessible Technology
Culture and Participation
The Social Network: How People with Visual Impairment use Mobile Phones in Kibera, Kenya
Giulia Barbareschi,Catherine Holloway, Katherine Arnold, Grace Magomere, Wycliffe Ambeyi Wetende, Gabriel Ngare, Joyce Olenja
We present the findings of a case study of mobile technology use by People with Visual Impairment (VIPs) in Kibera, an informal settlement in Nairobi. We used contextual interviews, ethnographic observations and a co-design workshop to explore how VIPs use mobile phones in their daily lives, and how this use influences the social infrastructure of VIPs. Our findings suggest that mobile technology supports and shapes the creation of social infrastructure. However, this is only made possible through the existing support networks of the VIPs, which are mediated through four types of interaction: direct, supported, dependent and restricted.
CHI '20: Proceedings of the 2020 CHI Conference; 2020
Abstract
The Social Network: How People with Visual Impairment use Mobile Phones in Kibera, Kenya
Living in an informal settlement with a visual impairment can be very challenging resulting in social exclusion. Mobile phones have been shown to be hugely beneficial to people with sight loss in formal and high-income settings. However, little is known about whether these results hold true for people with visual impairment (VIPs) in informal settlements. We present the findings of a case study of mobile technology use by VIPs in Kibera, an informal settlement in Nairobi. We used contextual interviews, ethnographic observations and a co-design workshop to explore how VIPs use mobile phones in their daily lives, and how this use influences the social infrastructure of VIPs. Our findings suggest that mobile technology supports and shapes the creation of social infrastructure. However, this is only made possible through the existing support networks of the VIPs, which are mediated through four types of interaction: direct, supported, dependent and restricted.
The Social Network: How People with Visual Impairment use Mobile Phones in Kibera, Kenya
Giulia Barbareschi, Catherine Holloway, Katherine Arnold, Grace Magomere, Wycliffe Ambeyi Wetende, Gabriel Ngare, and Joyce Olenja. 2020. The Social Network: How People with Visual Impairment use Mobile Phones in Kibera, Kenya. In Proceedings of the 2020 CHI Conference on Human Factors in Computing Systems (CHI '20). Association for Computing Machinery, New York, NY, USA, 1–15.https://doi.org/10.1145/331383...
The Social Network: How People with Visual Impairment use Mobile Phones in Kibera, Kenya
Type
Editorial
Themes
Culture and Participation
COVID-19 as social disability: the opportunity of social empathy for empowerment
Ikenna D Ebueny, Emma M Smith,Catherine Holloway, Rune Jensen, Lucía D'Arino, Malcolm MacLachlan
Social empathy is ‘the ability to more deeply understand people by perceiving or experiencing their life situations and as a result gain insight into structural inequalities and disparities’. Social empathy comprises three elements: individual empathy, contextual understanding and social responsibility. COVID-19 has created a population-wide experience of exclusion that is only usually experienced by subgroups of the general population. Notably, persons with disability, in their everyday lives, commonly experience many of the phenomena that have only recently been experienced by members of the general population. COVID-19 has conferred new experiential knowledgeon all of us. We have a rare opportunity to understand and better the lives of persons with disabilities for whom some aspects of the COVID- 19 experience are enduring. This allows us greater understanding of the importance of implementing in full a social and human rights model of disability, as outlined in the UNCRPD.
BMJ Global Health; 2020
Abstract
COVID-19 as social disability: the opportunity of social empathy for empowerment
COVID-19 has conferred new experiential knowledge on society and a rare opportunity to better understand the social model of disability and to improve the lives of persons with disabilities.
The COVID-19 experience may offer contextual knowledge of the prepandemic lives of persons with disabilities and foster greater social awareness, responsibility and opportunities for change towards a more inclusive society.
Information, family and social relationships, health protection and healthcare, education, transport and employment should be accessible for all groups of the population. The means must be developed and deployed to ensure equity – the deployment of resources so that people with different types of needs have the same opportunities for living good lives in inclusive communities.
We have learnt from COVID-19 that inclusive healthcare and universal access should be the new normal, that its provision as a social good is both unifying and empowering for society as a whole.
COVID-19 as social disability: the opportunity of social empathy for empowerment
Ebuenyi ID, Smith EM, Holloway C , et alCOVID-19 as social disability: the opportunity of social empathy for empowerment BMJ Global Health2020;5:e003039.
COVID-19 as social disability: the opportunity of social empathy for empowerment
Type
Editorial
Themes
Assistive & Accessible Technology
Research Group
Social Justice
Developing inclusive and resilient systems: COVID-19 and assistive technology
Emma M. Smith, Malcolm MacLachlan, Ikenna D. Ebuenyi,Catherine Holloway&Victoria Austin
While the inadequacies of our existing assistive technology systems, policies, and services have been highlighted by the acute and rapidly changing nature of the COVID-19 pandemic, these failures are also present and important during non-crisis times. Each of these actions, taken together, will not only address needs for more robust and resilient systems for future crises, but also the day-to-day needs of all assistive technology users. We have a responsibility as a global community, and within our respective countries, to address these inadequacies now to ensure an inclusive future.
Disability & Society; 2020
Abstract
Developing inclusive and resilient systems: COVID-19 and assistive technology
Assistive technology is a critical component of maintaining health, wellbeing, and the realization of rights for persons with disabilities. Assistive technologies, and their associated services, are also paramount to ensuring individuals with functional limitations have access to important health and social service information, particularly during a pandemic where they may be at higher risk than the general population. Social isolation and physical distancing have further marginalized many within this population. We have an opportunity to learn from the COVID-19response to develop more inclusive and resilient systems that will serve people with disabilities more effectively in the future. In this Current Issues piece, we present a starting point for discussion, based on our experiences working to promote access to assistive technologies through inclusive and sustainable systems and policies.
Developing inclusive and resilient systems: COVID-19 and assistive technology
Emma M. Smith, Malcolm MacLachlan, Ikenna D. Ebuenyi, Catherine Holloway & Victoria Austin (2021) Developing inclusive and resilient systems: COVID-19 and assistive technology, Disability & Society, 36:1, 151-154, DOI:10.1080/09687599.2020.1829558
Developing inclusive and resilient systems: COVID-19 and assistive technology
Type
Conference Paper
Disability design and innovation in computing research in low resource settings
Dafne Zuleima Morgado-Ramirez,Giulia Barbareschi, Maggie Kate Donovan-Hall, Mohammad Sobuh, Nida' Elayyan, Brenda T Nakandi, Robert Tamale Ssekitoleko, joyce Olenja, Grace Nyachomba Magomere, Sibylle Daymond, Jake Honeywill, Ian Harris, Nancy Mbugua, Laurence Kenney,Catherine Holloway
80% of people with disabilities worldwide live in low resourced settings, rural areas, informal settlements and in multidimensional poverty. ICT4D leverages technological innovations to deliver programs for international development. But very few do so with a focus on and involving people with disabilities in low resource settings. Also, most studies largely focus on publishing the results of the research with a focus on the positive stories and not the learnings and recommendations regarding research processes.
ASSETS '20: Proceedings of the 22nd International ACM SIGACCESS Conference on Computers and Accessibility; 2020
Abstract
Disability design and innovation in computing research in low resource settings
80% of people with disabilities worldwide live in low resourced settings, rural areas, informal settlements and in multidimensional poverty. ICT4D leverages technological innovations to deliver programs for international development. But very few do so with a focus on and involving people with disabilities in low resource settings. Also, most studies largely focus on publishing the results of the research with a focus on the positive stories and not the learnings and recommendations regarding research processes. In short, researchers rarely examine what was challenging in the process of collaboration. We present reflections from the field across four studies. Our contributions are: (1) an overview of past work in computing with a focus on disability in low resource settings and (2) learnings and recommendations from four collaborative projects in Uganda, Jordan and Kenya over the last two years, that are relevant for future HCI studies in low resource settings with communities with disabilities. We do this through a lens of Disability Interaction and ICT4D.
Disability design and innovation in computing research in low resource settings
Dafne Zuleima Morgado-Ramirez, Giulia Barbareschi, Maggie Kate Donovan-Hall, Mohammad Sobuh, Nida' Elayyan, Brenda T Nakandi, Robert Tamale Ssekitoleko, joyce Olenja, Grace Nyachomba Magomere, Sibylle Daymond, Jake Honeywill, Ian Harris, Nancy Mbugua, Laurence Kenney, and Catherine Holloway. 2020. Disability design and innovation in computing research in low resource settings. In Proceedings of the 22nd International ACM SIGACCESS Conference on Computers and Accessibility (ASSETS '20). Association for Computing Machinery, New York, NY, USA, Article 11, 1–7.https://doi.org/10.1145/337362...
Type
Editorial
Research Group
Social Justice
Assistive Technology (AT), for What?
Vicki Austin, Catherine Holloway
This year (2022) has seen the publication of the World’s first Global Report on Assistive Technology (GReAT) [1]. This completes almost a decade of work to ensure assistive technology (AT) access is a core development issue. The lack of access to assistive products (APs), such as wheelchairs, hearing aids, and eyeglasses, as well as less well-referenced products such as incontinence pads, mobile phone applications, or walking sticks, affects as many as 2.5 billion people globally. Furthermore, the provision of APs would reap a 1:9 return on investment [2]. This could result in a family in need netting (or living without) over GBP 100,000 in their lifetime [2] or more, if we count dynamic overspills in the economy such as employment of assistive technology services and manufacturing of devices [3].
Societies; 2021
Abstract
Assistive Technology (AT), for What?
Amartya Sen’s seminal Tanner lecture: Equality of What?began a contestation on social justice and human wellbeing that saw a new human development paradigm emerge—the capability approach (CA)—which has been influential ever since. Following interviews with leading global assistive technology (AT) stakeholders, and users, this paper takes inspiration from Sen’s core question and posits, AT for what?arguing that AT should be understood as a mechanism to achieve the things that AT users’ value. Significantly, our research found no commonly agreed operational global framework for (disability) justice within which leading AT stakeholders were operating. Instead, actors were loosely aligned through funding priorities and the CRPD. We suggest that this raises the possibility for (welcome and needed) incoming actors to diverge from efficiently designed collective action, due to perverse incentives enabled by unanchored interventions. The Global Report on Assistive Technology (GReAT) helps, greatly! However, we find there are still vital gaps in coordination; as technology advances, and AT proliferates, no longer can the device-plus-service approach suffice. Rather, those of us interested in human flourishing might explore locating AT access within an operational global framework for disability justice, which recognizes AT as a mechanism to achieve broader aims, linked to people’s capabilities to choose what they can do and be.
Assistive Technology (AT), for What?
Austin, V.; Holloway, C. Assistive Technology (AT), for What? Societies2022, 12, 169.https://doi.org/10.3390/soc120...
Type
Article
Themes
Assistive & Accessible Technology
These tools help visually impaired scientists read data and journals
Alla Katsnelson
This article was featured in Nature and discusses tools that help visually impaired scientists read data and Journals. Innovation Manager, Daniel Hajas, was interviewed as part of this piece and highlights the need for an ecosystem approach, and access to data / visualisations for blind members of the research and science community.
Nature; 2023
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| Download Table
Download Table | from publication: MRI-Targeted Biopsies versus Systematic Transrectal Ultrasound Guided Biopsies for the Diagnosis of Localized Prostate Cancer in Biopsy Naïve Men | Introduction: To compare, in the same cohort of men, the detection of clinically significant disease in standard (STD) cores versus multiparametric magnetic resonance imaging (mpMRI) targeted (TAR) cores. Material and methods: A prospective study was conducted on 129... | Biopsy, STD and Transrectal Ultrasound | ResearchGate, the professional network for scientists.
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MRI-Targeted Biopsies versus Systematic Transrectal Ultrasound Guided Biopsies for the Diagnosis of Localized Prostate Cancer in Biopsy Naïve Men
Article
Full-text available
[...]
Roland F P van Velthoven
Introduction:
To compare, in the same cohort of men, the detection of clinically significant disease in standard (STD) cores versus multiparametric magnetic resonance imaging (mpMRI) targeted (TAR) cores.
Material and methods:
A prospective study was conducted on 129 biopsy naïve men with clinical suspicion of prostate cancer. These patients und...
Full-text available
Apr 2018
Pingkun Yan
Sheng Xu
Ardeshir Rastinehad
Brad J. Wood
Robust and accurate alignment of multimodal medical images is a very challenging task, which however is very useful for many clinical applications. For example, magnetic resonance (MR) and transrectal ultrasound (TRUS) image registration is a critical component in MR-TRUS fusion guided prostate interventions. However, due to the huge difference bet...
Citations
... [19] В друго проучване Paltier A et al съпоставяйки ефективността между трансперинеална простатна биопсия със систематична трансректанлна биопсия сред 129 мъже, но биопсирани за първи път, установяват значима разлика от 28.9% на открити карциноми при таргетна спрямо 9.8% при ТРУС биопсия (p<0.001)
[20]
В идентично проучване Maxeiner A et al. сред 310 мъже, но включващо както биопсирани за първи път, така и такива с повторна биопсия пациенти, извършват МРТ/УЗ насочена простатна биопсия с последваща систематична биопсия, като доказат наличие на неопластичен процес при 158 пациента (51%). Таргетната биопсия доказва наличието на карцином при 110 пациета (69.7%), като 38% от тях са Gleason score 6, a 28% са с Gleason score ≥ 8, спрямо систематичната биопсия 54% Gleason score 6 и 15% Gleason score ≥ 8. Тези резултати са съпоставими с резултатите от нашето проучване, показващо че таргетната биопсия открива повече случаи на карцином и в по-голям процент на клинично значими карциноми, спрямо систематичната биопсия. ...
Compаrative study: Efficacy and safety of MRI / ultrasound transperineal vs systematic transrectal prostate biopsy in patients with previous negative TRUS biopsy
Article
Nov 2022
Stefan Hristoforov
Ognyan Gatsev
Petar Petrov
Kremena Petkova
Iliya Saltirov
Objective The aim of the study was to compare the efficacy and safety of magnetic resonance imaging / ultrasound-targeted transperineal prostate biopsy versus standard transrectal systemic biopsy, in detection of prostate cancer, in patients with evidence of previous negative systematic transrectal ultrasound prostate biopsy. Material and Methods From February 2019 to February 2021 in the Clinic of Endourology and SWL of the Military Medical Academy – Sofia, in 59 patients repeated prostate biopsy was performed after a previous negative systematic transrectal ultrasound-guided biopsy. In 35/59 patients in the group, MRI / ultrasound transperineal prostate biopsy was performed (group A), and in the remaining 24/59 patients a repeat systemic TRUS biopsy was performed (group B). The main indications for repeat prostate biopsy were persistent elevated PSA values, a finding on rectal digital examination, and / or a suspected area of prostate MRI. Results. Preoperative data were comparable in the two groups of patients, with no statistically significant differences. The mean value of PSA in group A was 17.27 ± 14.6 ng / ml, compared to 25.93 ± 24.19 ng / ml in group B, p = 0.264. MRI / ultrasound transperineal prostate biopsy revealed the presence of prostate cancer in 28 patients (80%) of the study group, compared to 8 patients (33.3%) in the group who underwent systematic TRUS biopsy, p = 0.001. The histopathological results of group A revealed the presence of low-grade prostate cancer in 15 patients (42.9%), compared to 13 patients (37.1%) in whom high-grade cancer was detected. The results show a statistically significant difference compared to patients in group B, where 3 patients (12.5%) showed low-grade prostate cancer, and 5 patients (20.8%) had a high-grade malignant process, p = 0.005. There was no statistically significant difference in intra- and postoperative complications in the two groups. Conclusion. Performing MRI / ultrasound targeted biopsy showed significant higher efficacy and identical safety in diagnosing a prostate neoplastic process compared to standard 12-core transrectal systemic biopsy in patients with previous negative systemic TRUS biopsy.
... In another study [65], cognitive biopsy by the transperineal approach was not associated with a higher rate of detection of csPCa than was transperineal template biopsy, though the rate of detection of insignificant PCa was lower. Three prospective studies have shown that more csPCa and less insignificant PCa are detected with transrectal fusion biopsy than with systematic biopsy [12,
66,
67]. An additional prospective study [68] showed no difference in overall PCa detection between transperineal template saturation systematic biopsy and transperineal fusion biopsy in the overall study sample, though significantly more anterior cancers were detected with transperineal fusion biopsy in patients who underwent repeat biopsy. ...
MRI-Targeted Prostate Biopsy Techniques: AJR Expert Panel Narrative Review
Article
Full-text available
Sangeet Ghai
Chan Kyo Kim
Aytekin Oto
Caroline M. Moore
Prostate cancer is the second most common malignancy in men worldwide. Systematic transrectal prostate biopsy is commonly used to obtain tissue to establish the diagnosis. However, in recent years, MRI-targeted biopsy (based on an MRI examination performed prior to consideration of biopsy) has been shown to detect more clinically significant cancer and less clinically insignificant cancer compared to systematic biopsy. This approach of performing MRI prior to biopsy has become, or is becoming, a standard of practice in centers throughout the world. This growing use of an MRI-directed pathway is leading to performance of a larger volume of MRI-targeted prostate biopsies. The three common MRI-targeted biopsy techniques are cognitive biopsy, MRI-ultrasound software fusion biopsy, and MRI in-bore guided biopsy. These techniques for using MRI information at the time of biopsy can be performed via a transrectal or transperineal approach. This narrative review presents the three MRI-targeted biopsy techniques along with their advantages and shortcomings. Comparisons among the techniques are summarized based on the available evidence. Studies to date have provided heterogeneous results, and the preferred technique remains debated.
... Regarding CDR for csPCa, 20 studies showed higher prevalence of csPCa for the patients biopsied by Fus-TBx, in 8 of them the difference was statistically significant [18,21,[25]
[26]
[27][28]34,35]. Even in a multicenter designed trial, Fus-TBx outperformed SBx for the diagnosis of csPCa [35], while the detection rate for is PCa was lower [21,28,31,[33][34][35]39,42,43]. ...
... In terms of diagnostic efficiency, Radtke et al. showed that even if saturation biopsy outruled Fus-TBx from the perspective of CDR, it still needs twice more cores to detect 1 GS ≥7 (7.4 cores vs 3.4 cores) [23]. On the other hand, PRECISION multicenter trial reported a statistical significant better performance of Fus-TBx for CDR and diagnostic efficiency, while similar efficiency was observed in several other trials [12,16,
26]
. ...
MRI-targeted prostate biopsy: the next step forward!
Article
Full-text available
Nov 2020
Emanuel Darius Cata
Iulia Andras
Teodora Telecan
Atilla Tamas-Szora
Nicolae Crisan
Aim:
For decades, the gold standard technique for diagnosing prostate cancer was the 10 to 12 core systematic transrectal or transperineal biopsy, under ultrasound guidance. Over the past years, an increased rate of false negative results and detection of clinically insignificant prostate cancer has been noted, resulting into overdiagnosis and overtreatment. The purpose of the current study was to evaluate the changes in diagnosis and management of prostate cancer brought by MRI-targeted prostate biopsy.
Methods:
A critical review of literature was carried out using the Medline database through a PubMed search, 37 studies meeting the inclusion criteria: prospective studies published in the past 8 years with at least 100 patients per study, which used multiparametric magnetic resonance imaging as guidance for targeted biopsies.
Results:
In-Bore MRI targeted biopsy and Fusion targeted biopsy outperform standard systematic biopsy both in terms of overall and clinically significant prostate cancer detection, and ensure a lower detection rate of insignificant prostate cancer, with fewer cores needed. In-Bore MRI targeted biopsy performs better than Fusion biopsy especially in cases of apical lesions.
Conclusion:
Targeted biopsy is an emerging and developing technique which offers the needed improvements in diagnosing clinically significant prostate cancer and lowers the incidence of insignificant ones, providing a more accurate selection of the patients for active surveillance and focal therapies.
... With regard to the question of whether or not to perform a systematic biopsy additionally to mpMRI-targeted biopsy, the majority of studies show the highest detection rates of clinically significant prostate cancer in the combination of both modalities [6,[31][32][33]
[34]
[35]. In a prospective multicenter study, Rouvière et al. compared the oncological outcome of systematic ultrasound-guided biopsy versus mpMRI-targeted biopsy performed by two separate operators on the same patient (n = 275). ...
Multiparametric magnetic resonance imaging and multiparametric magnetic resonance imaging-guided biopsy in the diagnostic pathway of prostate cancerMultiparametrische Magnetresonanztomographie (mpMRT) und mpMRT-gesteuerte Biopsie bei der Diagnostik des Prostatakarzinoms
Article
Jul 2020
RADIOLOGE
Michael Chaloupka
Maria Apfelbeck
Paulo Pfitzinger
Robert Bischoff
Dirk‑André Clevert
Multiparametric magnetic resonance imaging (mpMRI) of the prostate and mpMRI-guided biopsy have proved to be a valuable part of the diagnostic pathway for prostate cancer. This review reports on the current results in terms of clinical performance of these diagnostic tools and their role in clinical decision-making.
... The gold standard method still present in the guidelines uses a conventional two-dimensional (2D) transrectal ultrasound (TRUS) guidance for prostate biopsy.
[1,
2] This method is not however standardized, as significant difference in prostate cancer detection rates exists among operators. It has poor detection rates not exceeding 40% at the first biopsy run and 20% at the second biopsy run, due to ineffective sampling. ...
... Many papers have shown that mpMRI/TRUS fusion biopsy of the prostate resulted in increased detection of clinically significant cancer, decreased detection of low-risk cancer, and improvement in patient outcome.
[1]
Our results show a positive correlation between mpMRI findings and pathology results comparable to the previously published series for patients having biopsies performed under Trinity in 15 European centers. Our study sample was however much smaller as we had difficulty to introduce this new modality in our medical environment. ...
Single-Center Experience in Targeted Prostate Biopsy Using Multiparametric Magnetic Resonance Imaging‑Transrectal Ultrasound Elastic Fusion Technique
Article
Full-text available
Raja Ashou
Introduction: Transrectal ultrasound (TRUS)-guided random biopsies are used to be the gold standard when diagnosing prostate cancer. A relatively new system with organ tracking that fuses real-time TRUS images with previously acquired multiparametric magnetic resonance imaging (mpMRI) images for prostate biopsy guidance is presented here. The primary goal of the study is to correlate (1) the mpMRI findings with the Gleason score grading of the prostate biopsies performed under mpMRI-TRUS elastic fusion and (2) the prostate-specific antigen (PSA) levels with the Gleason grading. Materials and Methods: Between January 2017 and August 2018, 58 patients had targeted prostate biopsy using mpMRI-TRUS elastic fusion technique (Urostation). These patients had previously the mpMRI of the prostate at our center using three-dimensional T2-weighted imaging, diffusion-weighted imaging, and dynamic contrast enhanced imaging. Of all 58 patients, 32 patients were classified as having Prostate Imaging-Reporting And Data System (PI-RADS) 4/5, 21 patients as PI-RADS 3, and five as PI-RADS 2. Results: Twenty-seven patients had positive biopsies for prostate cancer. Positive results were found in 25 patients having PI-RADS 4/5 (25 out of 32). Of these patients, 20 had positive specimens from the dominant lesion, four from both the targeted lesion and nontargeted areas, and one from a nontargeted area. Positive results were found in two patients classified as PI-RADS 3 from targeted and nontargeted areas. These results show that 78% of the patients classified by mpMRI as PI-RADS 4/5 and 10% of the patients classified as PI-RADS 3 had positive biopsies for prostate cancer. The results also showed a correlation between the PI-RADS score on mpMRI, the Gleason score, and the PSA levels. Conclusion: mpMRI-TRUS fusion biopsy is a safe and accurate method for targeted prostate biopsies. Our preliminary results are comparable to the published international numbers and show a good correlation between the PI-RADS classification and histopathology, as well as correlation between PI-RADS, Gleason scores, and PSA levels of positive biopsies.
... Multiparametric magnetic resonance imaging (mp-MRI) has been studied as a new tool for early detection of prostate cancer before performing initial biopsies and recent studies confirm its high sensitivity especially for clinically significant cancer [6][7][8]
[9]
. Suspicious foci can be targeted during biopsy and several modalities have been developed for clinical practice, including MRI/ultrasound (MRI/US) image fusion and cognitive techniques [10]. Few prospective studies comparing image fusion and cognitive techniques have not clearly shown a significant difference in terms of cancer detection and grade concordance with final specimen [11][12][13]. ...
A multicentric study on accurate grading of prostate cancer with systematic and MRI/US fusion targeted biopsies: comparison with final histopathology after radical prostatectomy
Article
Full-text available
Oct 2019
WORLD J UROL
R. Diamand
M. Oderda
W. Al Hajj Obeid
S. Albisinni
A. Peltier
Objective
To evaluate the accuracy in histologic grading of MRI/US image fusion biopsy by comparing histopathology between systematic biopsies (SB), targeted biopsies (TB) and the combination of both (SB + TB) with the final histopathologic outcomes of radical prostatectomy specimens.
Materials and methods
Retrospective, multicentric study of 443 patients who underwent SB and TB using MRI/US fusion technique (Urostation® and Trinity®) prior to radical prostatectomy between 2010 and 2017. Cochran’s Q test and McNemar test were conducted as a post hoc test. Uni-multivariable analyses were performed on several clinic-pathological variables to analyze factors predicting histopathological concordance for targeted biopsies.
Results
Concordance in ISUP (International Society of Urological Pathology) grade between SB, TB and SB + TB with final histopathology was 49.4%, 51.2%, and 63.2% for overall prostate cancer and 41.2%, 48.3%, and 56.7% for significant prostate cancer (ISUP grade ≥ 2), respectively. Significant difference in terms of concordance, downgrading and upgrading was found between SB and TB (ISUP grade ≥ 2 only), SB and SB + TB, TB and SB + TB (overall ISUP grade and ISUP grade ≥ 2) (p < 0.001). Total number of cores and previous biopsies were significant independent predictive factors for concordance with TB technique.
Conclusion
In this retrospective study, combination of SB and TB significantly increased concordance with final histopathology despite a limited additional number of cores needed.
... In the setting of standard 14 systematic biopsy, TP and TR approaches have comparable accuracy in detecting PCa but TP 15 route harbored a higher accuracy for tumor located in the anterior zone of the prostate, as 16 well as lower risk of sepsis. 9,
10
However, such findings may not be transferable to the 17 targeted biopsy technique. The diagnostic accuracy of MRI-targeted biopsy using the TP 18 versus TR routes in the detection of PCa, csPCa especially, has yet to be revealed . ...
... 9,28 However, some urologists have stated that TP 26 biopsy detects more positive cores in the transitional zone when the PSA was in a gray zone 27 (4-10 ng/mL), 29 as well as more csPCa in the anterior zone of the prostate.
10,
30,31 Other 28 relevant aspects, including patient comfort and clinical feasibility, were of less concern in 29 clinical practice. 28 As local anesthesia is practical for TP biopsy, there are no major 30 differences between the two approaches for tolerability as well as for the length of each 31 procedure. ...
Transperineal Magnetic Resonance Imaging-Targeted Biopsy May Perform Better Than Transrectal Route in the Detection of Clinically Significant Prostate Cancer: Systematic Review and Meta-analysis
Article
May 2019
CLIN GENITOURIN CANC
Xiang Tu
Zhenhua Liu
Tiancong Chang
Shi Qiu
Qiang Wei
Background
The diagnostic accuracy of magnetic resonance imaging (MRI)-targeted biopsy by using transperineal (TP) versus transrectal (TR) route in the detection of clinically significant prostate cancer (csPCa) has yet to be revealed.
Materials and methods
A systematic search in Pubmed, Embase, Ovid and the Cochrane Library up to April 2019 was conducted. We pooled odds ratio (OR) with 95% confidence intervals (CIs) for csPCa detected by TP and TR MRI-targeted biopsy. The relative sensitivity (or risk ratio, RR) between TP and TR route were synthesized. We also pooled the diagnostic sensitivity of either approach using the combined biopsy results as the reference standard.
Results
A total of 328 patients with positive multiparametric MRI (mpMRI) underwent TP MRI-targeted biopsy and 315 patients underwent TR MRI-targeted biopsy. TP route detected more csPCa with the detection rate of 62.2% (204/328) in comparison with that of 41.3% (130/315) for TR route (OR 2.37, 95% CI 1.71-3.26). After adjusting for differences in cancer prevalence, TP MRI-targeted biopsy detected 91.3% (105/115) of csPCa compared with that of 72.2% (83/115) by using TR route (RR 1.26, 95% CI 1.02-1.54). The pooled diagnostic sensitivity of TP route (86%, 95% CI 77%-96%) was superior than that of TR route (73%, 62%-88%). TR approach missed more csPCa located at anterior zone of the prostate (20 vs. 3).
Conclusions
TP performed better than TR route in MRI-targeted biopsy, especially in detecting csPCa located at anterior prostate. More large, prospective randomized or head-to-head comparison studies comparing the two approaches are warranted.
... Mehrere Studien weisen darauf hin, dass durch die mpMRTgestützte Biopsie häu ger klinisch signi kante PCA detektiert werden als durch die konventionelle systematische Biopsie. Allerdings wird durch beide Verfahren ein nicht vernachlässigbarer Anteil (10-20 %) an klinisch signi kanten PCA übersehen [2,5,
6,
7,8]. Als e ektivster Weg der Maximierung der Detektionsrate von Prostatakarzinomen zeigt sich die Kombination einer systematischen (SBx) und gezielten Prostata biopsie (mpMRT-In-Bore-Biopsie oder mpMRT-FBx). ...
mpMRT-Fusionsbiopsie: Stellenwert und Datenlage
Article
Jan 2019
Lukas Koneval
Ioannis Sokolakis
Annette Thurner
Daniel Lukaszyk
Georgios Hatzichristodoulou
Die konventionelle systematische Prostatastanzbiopsie ist nach wie vor der Goldstandard in der Diagnostik des Prostatakarzinom. Die Zukunft dürfte jedoch der mpMRT-Fusionsbiopsie gehören — einer schon heute wertvollen diagnostischen Methode. Ein Überblick über aktuelle Leitlinienempfehlungen, Publikationsdaten und Erfahrungen aus der Klinik.
... Äëÿ á³îïñ³¿ ÏÇ ï³ä êîíòðîëåì ÒÐÓÇÄ õàðàêòåðíèì º âèÿâëåííÿ ì³êðîôîêàëüíèõ îñåðåäê³â àäåíîêàðöèíîìè (≤ 0,5 cm 3 ), ÿê³ ìîaeóòü áóòè êë³í³÷íî íåçíà÷óùèìè [16]. Íàâ³òü ñàòóðàö³éíà á³îïñ³ÿ (20-38 ïðîá) ëèøå íåçíà÷íî çá³ëüøóº âèÿâëåííÿ êë³í³÷íî çíà÷óùîãî ÐÏÇ
[17]
. ×åðåç âèùå çãàäàí³ ïðè÷èíè âàaeëèâîþ º çàäà÷à óäîñêîíàëåííÿ ìåòîä³â ðàííüî¿ ä³àãíîñòèêè ÐÏÇ. ...
Multiparametric magnetic resonance imaging in prostate cancer diagnostics
Article
Dec 2018
M.P. Меlnychuk
О.О. Lyulko
A.Z. Zhuravchak
... In patients with previous negative biopsies, studies have demonstrated cancer detection rates up to 50% with MRI-guided biopsy, with approximately 30% representing clinically significant disease [19,21,63,64]. On average, MRI-guided biopsy also requires fewer cores and, as would be expected, has a significantly higher cancer detection rate per core [19,31,59,[65][66][67]
[68]
[69][70][71][72]. ...
... One key difference between standard and MRI-guided biopsy is the rate at which clinically significant cancer is detected. Multiple studies have shown that targeted biopsies detect a greater number of clinically significant prostate cancers and fewer insignificant prostate cancers [5,20,25,26,50,57,62,66,
68,
69,76]. These results have been seen in both biopsy naïve men as well as men with previous negative biopsies [25,26,50,57]. ...
... However, it has been shown to have a limited role in detecting localized prostate cancer except as an adjunct to mpMRI [126]. Another such agent,
68
Ga-N,N;-bis [2-hydroxy-5-(carboxyethyl)benzyl] ethylenediamine-N,N -diacetic acid ([ 68 Ga]HBED-CC), has demonstrated sensitivity and specificity superior to other imaging techniques [127]. [ 68 Ga]-HBED-CC PET/CT has been shown to improve accuracy of lymph node staging over conventional imaging in the setting of BCR with a sensitivity of 65.9% and specificity of 98.9% [128]. ...
Imaging as a Personalized Biomarker for Prostate Cancer Risk Stratification
Article
Full-text available
Nov 2018
Kyle H. Gennaro
Kristin K. Porter
Jennifer B. Gordetsky
Samuel J. Galgano
Soroush Rais-Bahrami
Biomarkers provide objective data to guide clinicians in disease management. Prostate-specific antigen serves as a biomarker for screening of prostate cancer but has come under scrutiny for detection of clinically indolent disease. Multiple imaging techniques demonstrate promising results for diagnosing, staging, and determining definitive management of prostate cancer. One such modality, multiparametric magnetic resonance imaging (mpMRI), detects more clinically significant disease while missing lower volume and clinically insignificant disease. It also provides valuable information regarding tumor characteristics such as location and extraprostatic extension to guide surgical planning. Information from mpMRI may also help patients avoid unnecessary biopsies in the future. It can also be incorporated into targeted biopsies as well as following patients on active surveillance. Other novel techniques have also been developed to detect metastatic disease with advantages over traditional computer tomography and magnetic resonance imaging, which primarily rely on defined size criteria. These new techniques take advantage of underlying biological changes in prostate cancer tissue to identify metastatic disease. The purpose of this review is to present literature on imaging as a personalized biomarker for prostate cancer risk stratification.
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| https://www.researchgate.net/figure/46_tbl2_272514195 |
Atia Sahpur Branch Post Office, Hardoi 04, Uttar Pradesh
Get Atia Sahpur post office address, pincode, phone number, Atia Sahpur speed post tracking, saving scheme and location map.
Atia Sahpur Post Office, Hardoi
Atia Sahpur Post Officeis located at Atia Sahpur, Hardoiof Uttar Pradesh state. It is a branch office (B.O.). A Post Office (PO) / Dak Ghar is a facility in charge of sorting, processing, and delivering mail to recipients. POs are usually regulated and funded by the Government of India (GOI). Pin code of Atia Sahpur POis 241204. This Postoffice falls under Hardoi postal division of the Uttar Pradesh postal circle. The related head P.O. for this branch office is Hardoi head post office and the related sub-post office (S.O.) for this branch office is Sandila post office.
Atia Sahpur dak ghar offers all the postal services like delivery of mails & parcels, money transfer, banking, insurance and retail services. It also provides other services including passport applications, P.O. Box distribution, and other delivery services in Atia Sahpur. The official website fo this PO is http://www.indiapost.gov.in.
Types of Post Offices
are basically classified into 3 types, namely – Head Post Office, Sub-Post Office including E.D. Sub-Office and Branch Postoffice. Atia Sahpur P.O. is a Branch Post Office. So far as the public is concerned, there is basically no difference in the character of the service rendered by Sub-Post Offices and Head-Post Offices except in regard to a few Post Office Savings Bank (SB) transactions. Certain Sub Post Offices do not undertake all types of postal business. Facilities are generally provided at Branch Post Offices for the main items of postal work like delivery and dispatch of mails, booking of registered articles and parcels accepting SB deposits and effecting SB withdrawals, and issue and payment of money orders, though in a restricted manner.
Post Office Type Head Post Office Sub-Post Offices including E.D. Sub-Offices Branch Post Office
Atia Sahpur Post Office & Its Pin Code
Branch Office Information
Atia Sahpur Post Office Services
Mail Services
Parcels
Retail Services
Premium Services
Speed Post
India Post Speed Post Tracking
Tracking System
India Post Tracking Number Formats
Express Parcel Post
Media Post
Greetings Post
Logistics Post
ePost Office
Financial Services
Savings Bank (SB) Account
Recurring Deposit (RD) Account
Monthly Income Scheme (MIS)
Monthly Public Provident Fund (PPF)
Time Deposit (TD)
Senior Citizen Saving Scheme (SCSS)
National Savings Certificate (NSC)
Kisan Vikas Patra (KVP)
Sukanya Samriddhi Accounts (SSA)
Post Office Timings
India Post Tracking
Atia Sahpur Post Office Recruitment
Location Map
Contact Details
About India Post
Atia Sahpur Post Office & Its Pin Code
Often Post Offices are named after the town / village / location they serve. The Atia Sahpur Post Office has the Postal Index Number or Pin Code 241204. A Pincode is a 6 digit post code of postal numbering system used by India Post. The first digit indicates one of the regions. The first 2 digits together indicate the sub region or one of the postal circles. The first 3 digits together indicate a sorting / revenue district. The last 3 digits refer to the delivery post office type.
P.O. Name Atia Sahpur PO Pincode 241 204
The first digit of 241204 Pin Code '2' represents the region, to which this Post Office of Atia Sahpur belongs to. The first two digits of the Pincode '24' represent the sub region, i.e, Uttar Pradesh. The first 3 digits '241' represent the post-office revenue district, i.e, Hardoi. The last 3 digits, i.e, '204' represent the Atia Sahpur Delivery Branch Office.
Branch Office Information
The Atia Sahpur Post Office is a branch office. The Delivery Status for this PO is that it has delivery facility. Postal division name for this Dak Ghar is Hardoi, which falls under Bareilly region. The circle name for this PO is Uttar Pradesh and it falls under Hardoi Taluka and Hardoi District. The state in which this Dakghar is situated or located is Uttar Pradesh. The related head postoffice is Hardoi post office and the related sub post office is Sandila post-office. The phone number of Atia Sahpur post office is unavailable at present.
PO Type Branch Office Delivery Status Delivery Postal Division Hardoi Postal Region Bareilly Postal Circle Uttar Pradesh Town / City / Tehsil / Taluka / Mandal Hardoi District Hardoi State Uttar Pradesh Related Sub PO Sandila Sub Office Related Head PO Hardoi Head Post Office
Atia Sahpur Post Office Services
Traditionally the primary function of Atia Sahpur post office was collection, processing, transmission and delivery of mails but as of today, a Post Office offers many other vital services in addition to its traditional services. The additional services provided by a Dak Ghar include – Mail Services, Financial Services, Retail Services and Premium Services.
Mail Services
Mail Services are the basic services provided by Atia Sahpur P.O. Mails and mail services include all or any postal articles whose contents are in the form of message which may include Letters, Postcards, Inland letter cards, packets or parcels, Ordinary mails etc.
Parcels
Mail Service also includes transmission and delivery of Parcels. A parcel can be anything ranging from a single written letter or anything addressed to an addressee. No parcel shall be by any chance be in a shape, way of packing or any other feature, such that it cannot be carried or transmitted by post or cause serious inconvenience or risk. Every parcel (including service parcels) that needs to be transmitted by post must be handed over at the window of the post office. Any parcel found in a letter box will be treated and charged as a registered parcel. Delivery services are provided by some selected delivery and branch post offices. This dakghar have the facility of delivery, thus the people of Atia Sahpur and nearby localities can avail all the types of mail services.
Retail Services
Post offices in India serve in various ways and Atia Sahpur Post Office offer most of the retail services. They offer the facility to accept or collect constomer bills like telephone or mobile bills, electricity bills for Government and private organizations through Retail Post. Some of the aditional agency services that Post offices offers through retail services are as follows - Telephone revenue collection, e-Ticketing for Road Transport Corporations and Airlines, Sale of UPSC forms, university applications, Sale of Passport application forms, Sale of Gold Coins, Forex Services, Sale of SIM and recharge coupons, Sale of India Telephone cards, e-Ticketing of Railway tickets etc. The postal customers of Atia Sahpur can pay their bills and avail other retail services from this Dak Ghar.
Premium Services
Most of the premium services can be availed by the Atia Sahpur peoples and nearby living people. The premium services provided by Atia Sahpur Post Office are - Speed Post, Business Post, Express Parcel Post, Media Post, Greeting Post, and Logistics Post.
Speed Post
Speed Post is a time bound service in express delivery of letters and parcels. The max weight up to which an article or parcel be sent is 35 kgs between any two specified stations in India. Speed Post delivers 'Value for money' to everyone and everywhere, delivering Speed Post upto 50 grams @ INR 35 across the country and local Speed Post upto 50 grams @ INR 15, excluding applicable Service Tax. Kindly check official website for updated Speed Post service charges.
India Post Speed Post Tracking
Speed Post offers a facility of on-line tracking and tracing that guarantees reliability, speed and customer friendly service. Using a 13 digit barcode that makes a Speed Post consignment unique and identifiable. A web-based technology (www.indiapost.gov.in/speednettracking.aspx) helps the Atia Sahpur customers track Speed Post consignments from booking to delivery.
Tracking System
Except Speed Post, India Post also allows people to track their order information for certain products like Parcels, Insured letters, Speed Post, Registered Post, Electronic Money Orders (EMO) and Electronic value payable parcel (EVPPs) etc. The tracking number is available on the receipt given at Atia Sahpur Post Office. Using the tracking number postal customers can find out the date and time of dispatch of an article at various locations. The time of booking and the time of delivery of article.
India Post Tracking Number Formats
Different types of postal service have different kinds of tracking number formats. The tracking number for Express Parcel is a 13 digit alphanumeric format. The format for Express Parcel is XX000000000XX. The tracking number for a Registered Mail is a 13 digit alphanumeric number and its format is RX123456789IN. But a Electronic Money Order (EMO) has a 18 digit tracking number and its format is 000000000000000000. For domestic Speed Post (EMS) there is a 13 digit alphanumeric tracking number with the format EE123456789IN.
Bharatiya Dak Ghar Seva Tracking Number Format Number of Digits Electronic Money Order (eMO) 000000000000000000 18 Express Parcel XX000000000XX 13 International EMS Artilces to be delivered in India EE123456789XX 13 Registered Mail RX123456789IN 13 Speed Post (EMS) Domestic EE123456789IN 13
Express Parcel Post
In Express Parcel Post, the Atia Sahpur postal customer gets time bound delivery of parcels. These parcels will be transmitted through air or any other fastest mean available at that time. Minimum chargeable weight for which Express Parcel consignments will be booked is 0.5 Kg. Maximum weight of Express Parcel consignments which shall be booked across the Post Office counter by a retail customer shall be 20 Kg and maximum weight that can be booked by corporate customer is 35 kgs.
Media Post
India Post offers a unique way or concept to help the Indian corporate organisations and the Government organizations reach potential customers through media post. Through media post people can advertise on postcards, letters, aerogramme, postal stationary etc. Customers get to see the logo or message of the respective corporate or government organizations. The Aerogramme even gives the organizations the opportunity to make their product have a global impact.
Greetings Post
Greeting Post is yet another innovative or unique step by India Post. It consists of a card with an envelope with pre-printed and pre attached postage stamp on the envelope. The stamp on the envelope is a replica of the design that appears upon the card but in miniature form. Thus there is no need affix postage stamps on the envelope implicitly saving your time of going to post offices and standing in the queue. All the rules and that are applicable for the postage dues will also be applicable to the Greeting Post.
Logistics Post
Logistics Post manages the entire transmission and distribution side of the parcels. It deals with collection of goods, storage of goods, carriage and distribution of the various parcels or goods, from order preparation to order fulfilment. And that too at the minimum possible price. Logistics Post services provides the Atia Sahpur postal customer with cost-effective and efficient distribution across the entire country.
ePost Office
The advent of internet made communication very rapid through emails. But, the internet has not yet reached most of the rural parts of India. To change this division between rural & urban life, and to get the benefit of internet technology to Atia Sahpur people's lives, Indian Postal Department has introduced e-post. e-post is a service in which personalized handwritten messages of customers are scanned and sent as email through internet. And at the destination address office, these messages are again printed, enveloped and delivered through postmen at the postal addresses. E-post centres are established in the Post Offices, covering a large geographical area including major cities and districts. These e-post centres are well equipped with internet connection, scanners, printers and other necessary hardware equipment. However, this e-post service doesn’t particularly need a e-post centre, but can this facility can be availed at any normal Post Office or you can visit www.epostoffice.gov.in to access postal services on your desktop, laptop or even on mobile. If a message is booked at Atia Sahpur post office, the post is scanned and sent to an e-post centre by e-mail and a mail received at e-post centre is printed and sent to nearby Post Office for dispatch.
A Atia Sahpur customer can also avail these services of an e-post, at his/ her home. All he/ she has do is to register as a user at www.epostoffice.gov.in website. After registration, a user can use e-post by scanning and sending messages, printing and receive messages. The message to be scanned must not be written in a paper not more A4. There is no limit for sending number of sheets of messages in e-post.
E-Post Office offers certain services like – Philately, Postal Life Insurance, Electronic Indian Postal Order, Information Services, Track & Trace and Complaints & Guidelines services.
Philately
Philately service deals with collection, sale and study of postage stamps. Philately includes lot of services Philately Information, Stamp issue Program, Stamps List and Buy Stamps service.
Postal Life Insurance (PLI)
A service offered by the Government to pay a given amount of money on the death of an individual to his prescribed nominee. The amount may also be paid to the person himself, in case he survives that maturity period. The two services offered under Postal Life Insurance are – Pay Premium service and PLI information.
Electronic Indian Postal Order
eIPO or Electronic Indian Postal Order is a facility to purchase an Indian Postal Order electronically by paying a fee on-line through e-Post Office. This service is launched by the Department of Posts, Ministry of Communications & IT, Government of India.
eIPO can now be used by Indian Citizens living in India for paying online fee, whoever seeks information under the RTI Act, 2005. eIPO offers 2 types of services – eIPO information and payment of online fees.
Information Services
This helps Atia Sahpur customers to get information regarding certain products like – Pin Code search, Speed post, Banking, Insurance, Business Post, Logistics Post, IMTS and many more other services.
Track & Trace
The track & trace service is very helpful as it aids in getting information of our valuables. Track & Trace service offers 5 different services – Pin Code search, EMO tracking, Speed Post tracking, WNX tracking and International mail service.
Complaints & Guidelines
Using e-post office service Atia Sahpur postal costumer can access services based on – complaint registration, complaint status and guidelines on complaints.
ePost Office Website www.epostoffice.gov.in
Financial Services
The customers of Atia Sahpur can enjoy the various savings schemes available in this post office that prove to be highly beneficial for the people living in Atia Sahpur area. The Financial service offered by PO includes Savings and Postal Life Insurance (PLI). There are various options available to save and invest with post-offices. The commonly used ones include - Savings account, Recurring Deposit, Monthly Income Scheme, Monthly Public Provident Fund, Time Deposit, Senior Citizen Saving Scheme, National Savings Certificate, Kisan Vikas Patra and Sukanya Samriddhi Yojana. Post Office also offers Insurance product through Postal Life Insurance (PLI) and Rural Postal Life Insurance (RPLI) schemes that offer low premium and high bonus.
Post Office Financial Services Kisan Vikas Patra (KVP) Monthly Income Scheme (MIS) Monthly Public Provident Fund (PPF) National Savings Certificate (NSC) Recurring Deposit (RD) Account Savings Bank (SB) Account Senior Citizen Saving Scheme (SCSS) Sukanya Samriddhi Accounts (SSA) Time Deposit (TD)
Savings Bank (SB) Account
A Savings bank account serves the need of regular deposits for its customers as well as withdrawals. Cheque facility is also avail by Atia Sahpur postal consumers.
Recurring Deposit (RD) Account
A post office offers a monthly investment option with handsome return at the time period with an option to extend the investment period. Insurance facility is also available with certain conditions.
Monthly Income Scheme (MIS)
MIS offers a fixed investment technique for five or more years with monthly interest payment to the account holder. There is also a facility of automatic crediting of interest to SB account of the Atia Sahpur postal customer.
Monthly Public Provident Fund (PPF)
This service offers intermittent deposits subject to a particular limit for a time period of 15 years with income tax exemptions, on the investment. It also offers loan and withdrawal facilities for the postal customers.
Time Deposit (TD)
Fixed deposit option for periods ranging from one, two, three to five years with facility to draw yearly interest offered at compounded rates. Automatic credit facility of interest to SB account.
Senior Citizen Saving Scheme (SCSS)
Offers fixed investment option for senior citizens for a period of five years, which can be extended, at a higher rate of interest that are paid in quarterly instalments.
National Savings Certificate (NSC)
NSC is offered with a fixed investment for 5 or 10 years on certificates of various denominations. Pledging facility available for availing loan from Banks.
Kisan Vikas Patra (KVP)
Kisan Vikas Patra is a saving certificate scheme in which the amount Invested doubles in 110 months (i.e. 9 years & 2 months). It is available in denominations of Rs 1,000, 5000, 10,000 and Rs 50,000. Minimum deposit is Rs 1000/- and there is no maximum limit. The KVP certificate can be purchased by any adult for himself or on the behalf of a minor. This certificate can also be transferred from one account holder to another and from one post office to another. This certificate can be en-cashed only after 2 and 1/2 years from the date of issue.
Sukanya Samriddhi Accounts (SSA)
Sukanya Samriddhi Account Yojana offers a small deposit investment for the girl children as an initiative under 'Beti Bachao Beti Padhao' campaign. This yojana is to facilitate girl children proper education and carefree marriage expenses. One of the main benefits of this scheme is that it is very affordable and offers one of the highest interest rates. Currently its interest rate is set as 8.6% per annum that is again compounded yearly. The minimum deposit allowed in a financial year is INR. 1000/- and Maximum is INR. 1,50,000/-. Subsequent deposits can be made in multiples of INR 100/-. Deposits can be made all at a time. No limit is set on number of deposits either for a month or a financial year. A legal Guardian can open an account in the name of a Girl Child. Account can be closed only after completion of 21 years of the respective child. The normal Premature closure allowed is after completion of 18 years only if that girl is getting married.
Post Office Timings
The official working hours of Post Offices vary from one another, but the general Post Office opening time starts from 08:00 AM or 09:00 AM or 10:00 AM and the closing time is 04:00 PM or 05:00 PM or 06:00 PM respectively. The working days are from Monday to Saturday, Sunday being a holiday. This doesn't include the public holidays or the extended working hours. You can verify the working hours of Atia Sahpur Branch Post Office from the official resources.
India Post Tracking
Online tracking of India Post allowed Atia Sahpur people to access their postal article tracking information and confirm the delivery of their postal article by using the tracking number assigned to them at the time of Booking. They can find the tracking number on the Postal acknowledgement handed over to them at the Atia Sahpur Branch Post Office counter at the time of postal article booking. Following items can track through the www.indiapost.gov.in/articleTracking.aspx official website.
Business Parcel
Business Parcel COD
Electronic Money Order (e-MO)
Electronic Value Payable Parcel (eVPP)
Express Parcel
Express Parcel COD
Insured Letter
Insured Parcel
Insured Value Payable Letter
Insured Value Payable Parcel
International EMS
Registered Letter
Registered Packets
Registered Parcel
Registered Periodicals
Speed Post
Value Payable Letter
Value Payable Parcel
The India Post tracking system is updated at regular intervals to give the Atia Sahpur postal customers with the most up to date information available about the location and status of their postal article. They'll be able to find out the following:
When their postal article was booked
When their postal article was dispatched at various locations during its Journey
When their postal article was received at various locations during its Journey
When their postal article was delivered, or
When a delivery intimation notice was issued to notify the recipient that the postal article is available for delivery
Atia Sahpur Post Office Recruitment
For latest Atia Sahpur post office recruitment kindly visit www.indiapost.gov.in/recruitment.aspx.
Location Map
Atia Sahpur Branch Post Office is located in Atia Sahpur, Hardoi.
Contact Details
All the queries or complaints regarding Bill Mail Service, Booking Packets, Business Post, Direct Post, Flat Rate Box, Indian Postal Orders, Inland Letters, Instant Money Orders, Insurance of Postal Articles, Insurance of Postal Parcels, Letters, Logistics Posts, MO Videsh, Money Orders, Parcels, Post Office Savings Bank, Postal Life Insurance, Postcards, Registration of Postal Articles, Registration of Postal Parcels, Rural Postal Life Insurance, Saving Certificates, Small Saving Schemes, Speed Post, Value Payable Post etc.services in Atia Sahpur Post Office, can be resolved at Atia Sahpur Branch Post Office. You can send letters to "Postmaster, Atia Sahpur Branch Post Office, Atia Sahpur, Hardoi, Uttar Pradesh, India, Pincode: 241 204". The official website of the Berhampur University Sub Office is http://www.indiapost.gov.in.
Atia Sahpur Branch Office
Address: Atia Sahpur Branch Post Office, Atia Sahpur, Hardoi , Uttar Pradesh , India
Pin Code: 241204
Website: www.indiapost.gov.in
About India Post
India Postis a government-operated postal system, which is part of the Ministry of Communications and Information Technology of the Government of India. It has the largest Postal Network in the Indiawith over 154882 Post Offices. There are around 139182 Post Offices in the rural India and 15700 Post Offices in urban India. The individual post office serves an area of 21.22 Sq. Km. and a population of 8221 people. The slogan of India Post is Dak Seva Jan Seva. There are 25464 departmental post offices and 129418 extra-departmental branch post offices in India.
Atia Sahpur Post Office Summary
Dak Ghar Name Atia Sahpur Branch Post Office Pincode 241204 Dakghar Type Branch Office Post Office Delivery Status Delivery Branch Office Postal Division Hardoi Postal Region Bareilly Postal Circle Uttar Pradesh Location Atia Sahpur District Hardoi State Uttar Pradesh Country India Related Sub Office Sandila Sub Office Related Head Office Hardoi Head Post Office Website www.indiapost.gov.in ePost-office Web Site Address www.epostoffice.gov.in Speed Post Tracking Website www.indiapost.gov.in/speednettracking.aspx Recruitment Web Site Address www.indiapost.gov.in/recruitment.aspx
Other Post Offices
| https://www.postoffices.co.in/uttarpradesh-up/atia-sahpur-hardoi-04/ |
LncRNA136131 Suppresses Apoptosis of Renal Tubular Epithelial Cells in Acute Kidney Injury by Targeting the miR -378a-3p/Rab10 Axis
Download Citation | On Jan 1, 2021, Zhifen Wu and others published LncRNA136131 Suppresses Apoptosis of Renal Tubular Epithelial Cells in Acute Kidney Injury by Targeting the miR -378a-3p/Rab10 Axis | Find, read and cite all the research you need on ResearchGate
LncRNA136131 Suppresses Apoptosis of Renal Tubular Epithelial Cells in Acute Kidney Injury by Targeting the miR -378a-3p/Rab10 Axis
January 2021
SSRN Electronic Journal
DOI: 10.2139/ssrn.3893506
Authors:
Jian Pan
Jurong Yang
To read the full-text of this research,you can request a copy directly from the authors.
The critical role of FXR is associated with the regulation of autophagy and apoptosis in the progression of AKI to CKD
Article
Full-text available
Apr 2021
Dong-hyun Kim
Jung Sun Park
Hoon-In Choi
Soo Wan Kim
Autophagy is important for cells to break down and recycle cellular proteins, remove damaged organelles, and especially, for recovery from acute kidney injury (AKI). Despite research on the role and cellular mechanism of autophagy in AKI, the role of autophagy in the progression to chronic kidney disease (CKD) remains poorly understood. Here, using farnesoid X receptor (FXR) knockout (KO) mice, we determined whether FXR prevents the progression of AKI to CKD after renal ischemic-reperfusion (such as I/R) injury through the regulation of renal autophagy and apoptosis. FXR regulated genes that participate in renal autophagy under feeding and fasting conditions, such as hepatic autophagy, and the activation of FXR by agonists, such as GW4064 and INT-747, attenuated the increased autophagy and apoptosis of hypoxia-induced human renal proximal tubule epithelial (HK2) cells. The expression levels of autophagy-related and apoptosis-related proteins in FXR KO mice were increased compared with those in wild-type (WT) mice. We also showed that the increase in reactive oxidative species (ROS) in hypoxia-treated HK2 cells was attenuated by treatment with FXR agonist or by FXR overexpression, and that the level of ROS was elevated in FXR-deficient cells and mice. At 28 days after I/R injury, the autophagy levels were still elevated in FXR KO mice, and the expression levels of fibrosis-related proteins and ROS deposits were higher than those in WT mice. In conclusion, the regulation of renal autophagy and apoptosis by FXR may be a therapeutic target for the early stages of kidney damage, and the progression of AKI to CKD.
Long Noncoding RNA PRNCR1 Reduces Renal Epithelial Cell Apoptosis in Cisplatin-Induced AKI by Regulating miR-182-5p/EZH1
Article
Full-text available
Mar 2021
KIDNEY BLOOD PRESS R
Jing Li
Xing Fan
Qian Wang
Li Guo
Background/aims:
This study was designed to examine the role of long noncoding RNA PRNCR1 in cisplatin-induced acute kidney injury (AKI) in vitro and in vivo.
Methods:
The expression levels of PRNCR1 and miR-182-5p in cisplatin-induced AKI mice were examined. HK-2 cells were treated with cisplatin to induce cell damage. Then, the effects of PRNCR1 and miR-182-5p on cisplatin-stimulated HK-2 cell viability and apoptosis were detected by the CCK-8 and annexin V-FITC/PI method. Target genes of PRNCR1 and miR-182-5p were analyzed by bioinformatics analysis and luciferase.
Results:
The expression level of PRNCR1 was significantly reduced in cisplatin-induced AKI mice. In addition, overexpression of PRNCR1 attenuated the damage of cisplatin to HK-2. The expression level of miR-182-5p was significantly raised in cisplatin-induced AKI mice. MiR-182-5p was negatively regulated by PRNCR1 and leaded to an upregulation of EZH1 expression. Overexpression of PRNCR1 attenuated cisplatin-induced apoptosis by downregulating the miR-182-5p/EZH1 axis.
Conclusion:
LncPRNCR1 reduced the apoptosis of renal epithelial cells induced by cisplatin by modulating miR-182-5p/EZH1.
miR-182-5p and miR-378a-3p regulate ferroptosis in I/R-induced renal injury
Article
Full-text available
Oct 2020
Chenguang Ding
Xiaoming Ding
Jin Zheng
Wujun Xue
Renal tubular cell death is the key factor of the pathogenesis of ischemia/reperfusion (I/R) kidney injury. Ferroptosis is a type of regulated cell death (RCD) found in various diseases. However, the underlying molecular mechanisms related to ferroptosis in renal I/R injury remain unclear. In the present study, we investigated the regulatory role of microRNAs on ferroptosis in I/R-induced renal injury. We established the I/R-induced renal injury model in rats, and H/R induced HK-2 cells injury in vitro. CCK-8 was used to measure cell viability. Fe ²⁺ and ROS levels were assayed to evaluate the activation of ferroptosis. We performed RNA sequencing to profile the miRNAs expression in H/R-induced injury and ferroptosis. Western blot analysis was used to detect the protein expression. qRT-PCR was used to detect the mRNA and miRNA levels in cells and tissues. We further used luciferase reporter assay to verify the direct targeting effect of miRNA. We found that ischemia/reperfusion-induced ferroptosis in rat’s kidney. We identified that miR-182-5p and miR-378a-3p were upregulated in the ferroptosis and H/R-induced injury, and correlates reversely with glutathione peroxidases 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11) expression in renal I/R injury tissues, respectively. In vitro studies showed that miR-182-5p and miR-378a-3p induced ferroptosis in cells. We further found that miR-182-5p and miR-378a-3p regulated the expression of GPX4 and SLC7A11 negatively by directly binding to the 3′UTR of GPX4 and SLC7A11 mRNA. In vivo study showed that silencing miR-182-5p and miR-378a-3p alleviated the I/R-induced renal injury in rats. In conclusion, we demonstrated that I/R induced upregulation of miR-182-5p and miR-378a-3p, leading to activation of ferroptosis in renal injury through downregulation of GPX4 and SLC7A11.
MBD2-mediates septic AKI through activation of PKCη/ p38MAPK and the ERK1/2 axis
Article
Full-text available
Sep 2020
Yuxin Xie
Bohao Liu
Jian Pan
Dongshan Zhang
Our previous study demonstrated that the Methyl-CpG–binding domain protein 2 (MBD2) mediates vancomycin (VAN)-induced acute kidney injury (AKI). However, the role and regulation of MBD2 in septic AKI is unknown. Herein, MBD2 was induced by LPS in BUMPTs and mice. For both in vitro and in vivo experiments, we showed that inhibition of MBD2 by MBD2 siRNA and MBD2-KO substantially improved the survival rate, and attenuated both LPS and CLP-induced AKI, renal cell apoptosis, and inflammatory factor production. Global genetic expression analyses and in vitro experiments suggest that the expression of PKCη caused by LPS is markedly suppressed in MBD2-KO mice and MBD2 siRNA, respectively. Mechanistically, ChIP analysis indicates that MBD2 directly binds to promoter region CpG islands of PKCη via suppression of promoter methylation. Furthermore, PKCη siRNA improves the survival rate, and attenuates LPS induced BUMPT cell apoptosis and inflammatory factor production via inactivation of p38MAPK and ERK1/2, which was further verified by PKCη siRNA treatment in CLP-induced AKI. Finally, MBD2-KO mice exhibited CLP-induced renal cell apoptosis and inflammatory factor production by inactivation of PKCη/ p38MAPK and ERK1/2 signaling. Taken together, the data indicate that MBD2 mediates septic-induced AKI through the activation of PKCη/ p38MAPK and the ERK1/2 axis. MBD2 represents a potential target for treatment of septic AKI.
DsbA-L mediated renal tubulointerstitial fibrosis in UUO mice
Sep 2020
Xiaozhou Li
Jian Pan
Huiling Li
Dongshan Zhang
Recent studies have reported that upregulation of disulfide-bond A oxidoreductase-like protein (DsbA-L) prevented lipid-induced renal injury in diabetic nephropathy (DN). However , the role and regulation of proximal tubular DsbA-L for renal tubulointerstitial fibrosis (TIF) remains unclear. In current study, we found that a proximal tubules-specific DsbA-L knockout mouse (PT-DsbA-L-KO) attenuated UUO-induced TIF, renal cell apoptosis and inflammation. Mechanistically, the DsbA-L interacted with Hsp90 in mitochondria of BUMPT cells which activated the signaling of Smad3 and p53 to produce connective tissue growth factor (CTGF) and then resulted in accumulation of ECM of BUMPT cells and mouse kidney fibroblasts. In addition, the progression of TIF caused by UUO, ischemic/reperfusion (I/R), aristolochic acid, and repeated acute low-dose cisplatin was also alleviated in PT-DsbA-L-KO mice via the activation of Hsp90 /Smad3 and p53/CTGF axis. Finally, the above molecular changes were verified in the kidney biopsies from patients with obstructive nephropathy (Ob). Together, these results suggest that DsbA-L in proximal tubular cells promotes TIF via activation of the Hsp90 /Smad3 and p53/CTGF axis.
Long Noncoding RNA TCONS_00016406 Attenuates Lipopolysaccharide-Induced Acute Kidney Injury by Regulating the miR-687/PTEN Pathway
Jun 2020
Xuelan Liu
Na Zhu
Bo Zhang
Shao Bo Xu
Acute kidney injury (AKI) is a common and serious complication of sepsis accompanied by kidney dysfunction resulting from various etiologies and pathophysiological processes. Unfortunately, there is currently no ideal therapeutic strategy for AKI. Numerous studies have confirmed that long noncoding RNAs (lncRNAs) play important regulatory roles in the pathogenesis of sepsis-associated AKI. In this study, lncRNA TCONS_00016406 (termed lncRNA 6406), a novel lncRNA identified by using TargetScan, was significantly downregulated in the kidney tissues of mice with sepsis-associated AKI. This study aimed to explore the role of lncRNA 6406 in lipopolysaccharide (LPS)-induced AKI and its potential molecular mechanism. The models of sepsis-induced AKI (called LPS-induced AKI models) in mice and cell lines were established with male C57BL/6 mice and renal tubular epithelial (PTEC) cells, respectively. Twenty-four hours after LPS administration, kidneys and cell samples were collected after various treatments to examine the alterations in the lncRNA 6406 levels and to evaluate the effects on LPS-induced inflammation, oxidative stress, and apoptosis through real-time PCR (RT-PCR) analysis, western blotting, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining. The results revealed that lncRNA 6406 could significantly attenuate LPS-induced AKI, as shown by the alleviation of inflammation, the suppression of oxidative stress and the inhibition of apoptosis. Mechanistically, a luciferase reporter assay and additional research showed that lncRNA 6406 functioned as a ceRNA to sponge miRNA-687, thereby modulating LPS-stimulated AKI by targeting the miR-687/PTEN axis; thus, this study presents a novel therapeutic strategy or sepsis-associated AKI.
miR-378a-3p inhibits ischemia/reperfusion-induced apoptosis in H9C2 cardiomyocytes by targeting TRIM55 via the DUSP1-JNK1/2 signaling pathway
May 2020
Jiaying Tan
Jun Shen
Huigeng Zhu
Tao Sun
MicroRNAs (miRNAs) are involved in many pathological and biological processes, such as ischemia/reperfusion (I/R) injury by modulating gene expression. Increasing evidence indicates that miR-378a-3p might provide a potential cardioprotective effect against ischemic heart disease. Cell apoptosis is a crucial mechanism in I/R injury. As such, this study evaluated the protective effects and underlying mechanisms of action of miR-378a-3p on H9C2 cardiomyocyte apoptosis following I/R injury. We found that I/R-induced H9C2 cardiomyocytes exhibited a decrease in miR-378a-3p expression, while treatment with a miR-378a-3p mimic suppressed cell apoptosis, JNK1/2 activation, cleavage of PARP and caspase-3, and Bax/Bcl-2 ratio but increased DUSP1 expression, which subsequently inhibited JNK1/2 phosphorylation. TRIM55 was shown to be a target of miR-378a-3p and its downregulation inhibited the miR-378a-3p inhibitor-induced increase in cell apoptosis and JNK1/2 activation. TRIM55 inhibited DUSP1 protein expression through ubiquitination of DUSP1. Moreover, DUSP1 overexpression inhibited the TRIM55 overexpression-induced increase in cell apoptosis and JNK1/2 activation. The protective effect of miR-378a-3p was subsequently confirmed in a rat myocardial I/R model, as evidenced by a decrease in cardiomyocyte apoptosis of cardiomyocytes, TRIM55 expression, and JNK1/2 activation. Taken together, these results suggest that miR-378a-3p may protect against I/R-induced cardiomyocyte apoptosis via TRIM55/DUSP1/JNK signaling.
lncRNA HOTAIR Contributes to 5FU Resistance through Suppressing miR-218 and Activating NF-κB/TS Signaling in Colorectal Cancer
Jun 2020
Peilong Li
Xin Tao Zhang
Lili Wang
Chuanxin Wang
microRNA -378a-3p Restrains the Proliferation of Retinoblastoma Cells but Promotes Apoptosis of Retinoblastoma Cells via Inhibition of FOXG1
May 2020
Chao Zhang
Shuai Wu
Purpose:
More recently, literature has emerged providing findings about the novelty of microRNAs (miR)-targeted therapeutics in the treatment of retinoblastoma (RB). The prime objective of this study was to identify the potential role of miR-378a-3p and its regulation in RB cells via forkhead box G1 (FOXG1).
Methods:
The expression of miR-378a-3p and FOXG1 in the clinical RB tissues was determined using RNA quantitation and Western blot assays. The interaction between miR-378a-3p and FOXG1 was identified using dual luciferase reporter gene assay. The potential effects of miR-378a-3p on the RB cell biological processes were evaluated by conducting gain- and loss-of-function studies of miR-378a-3p and FOXG1, followed by cell viability, cell cycle progression, and apoptosis measurements. Furthermore, experiments were performed in nude mice to assess its effects on tumor formation.
Results:
miR-378a-3p was poorly expressed, whereas FOXG1 was highly expressed in RB tissues and cells. miR-378a-3p bound to the FOXG1 3' untranslated region and negatively modulated its expression. The overexpression of miR-378a-3p was found to decrease RB cell viability and to promote cell apoptosis in vitro, whereas overexpressed FOXG1 reversed the regulatory effects of miR-378a-3p on RB cellular behaviors. In nude mice, the restoration of miR-378a-3p by miR-378a-3p agomir was shown to play a role in the reduction of tumor volume and size relative to nude mice injected with negative control-agomir.
Conclusions:
Our findings identified that increased miR-378a-3p exerted an inhibitory effect on RB cell proliferation by targeting FOXG1, suggesting the role of miR-378a-3p as a novel therapeutic target for RB.
microRNA-519d Induces Autophagy and Apoptosis of Human Hepatocellular Carcinoma Cells Through Activation of the AMPK Signaling Pathway via Rab10
Apr 2020
Yi-Jie Zhang
Qi Pan
Yang Yu
Xin-Ping Zhong
Background and aim:
Hepatocellular carcinoma (HCC) is a type of cancer with high mortality rates. The overexpression of microRNA-519d (miR-519d) has been explored in different types of cancers, which could significantly help suppress cancer development. This study aimed to investigate the interaction of miR-519d with its target gene, Rab10, as well as its effects on cell proliferation and autophagy in HCC cells through modulation of the AMPK signaling pathway.
Methods:
Microarray analysis was used to analyze the differentially expressed genes in HCC, and the target genes of the screened-out miRNA were predicted and verified. The expression of miR-519d and Rab10, AMPK signaling pathway-related proteins, apoptosis- and autophagy-related proteins was determined by RT-qPCR and Western blot analysis in HCC tissues and cell lines. Lastly, the effects of miR-519d and Rab10 in HCC cell proliferation, apoptosis, and mouse tumour xenograft in vivo were examined through gain- and loss-of-function experiments.
Results:
MiR-519d was down-regulated and Rab10 was upregulated in HCC tissues and cell lines. Overexpression of miR-519d decreased the expression of Rab10, mTOR, and Bcl-2, but increased the expression of Bax, Beclin1, Atg5, and p53. Upregulated miR-519d and downregulated Rab10 expression suppressed cell proliferation and induced cell apoptosis and autophagy in HCC cells. Finally, upregulation of miR-519d inhibited tumour growth in vivo.
Conclusion:
The result obtained in this study indicates that up-regulation of miR-519d inhibits proliferation and promotes apoptosis and autophagy of HCC cells through activation of the AMPK signaling pathway via downregulating Rab10, which provides a potential target for the treatment of HCC.
The biomarker TCONS_00016233 drives septic AKI by targeting the miR-22-3p/AIFM1 signaling axis
Full-text available
Jan 2020
Pan Zhang
Lei Yi
Siyuan Qu
Dongshan Zhang
The prediction of mortality for septic acute kidney injury (AKI) has been assessed by a number of potential biomarkers, including long noncoding RNAs (lncRNAs). However, the validation of lncRNAs as biomarkers, particularly for the early stages of septic AKI, is still warranted. Our results indicate that the lncRNA TCONS_00016233 is upregulated in plasma of sepsis-associated non-AKI and AKI patients, but a higher cutoff threshold (9.5 × 105, copy number) provided a sensitivity of 71.9% and specificity of 89.6% for the detection of AKI. The plasma TCONS_00016233 was highly correlated with serum creatinine, tissue inhibitor metalloproteinase-2 (TIMP-2), insulin-like growth factor binding protein-7 (IGFBP7), interleukin-1β (IL-1β), tumor necrosis factor α (TNF-α), C-reactive protein (CRP), and urinary TCONS_00016233. Lipopolysaccharide (LPS) induced the expression of lncRNA TCONS_00016233 via the Toll-like receptor 4 (TLR4)/p38 mitogen-activated protein kinase (MAPK) signal pathway in human renal tubular epithelial (HK-2) cells. Furthermore, TCONS_00016233 mediates the LPS-induced HK-2 cell apoptosis and the expression of IL-1β and TNF-α. Mechanistically, TCONS_00016233 acts as a competing endogenous RNA (ceRNA) to prevent microRNA (miR)-22-3p-mediated downregulation of the apoptosis-inducing factor mitochondrion-associated 1 (AIFM1). Finally, overexpression of TCONS_00016233 is capable of aggravating the LPS- and cecal ligation and puncture (CLP)-induced septic AKI by targeting the miR-22-3p/AIFM1 axis. Taken together, our data indicate that TCONS_00016233 may serve as an early diagnosis marker for the septic AKI, possibly acting as a novel therapeutic target for septic AKI.
miR‑378a‑3p inhibits cellular proliferation and migration in glioblastoma multiforme by targeting tetraspanin 17
Aug 2019
Xiao‑Bing Guo
Xiao‑Chao Zhang
Peng Chen
Zhi-Qiang Shen
Glioblastoma multiforme (GBM) is the most common and aggressive brain tumor and patients with this disease tend to have poor clinical outcome. MicroRNAs (miRs) are important regulators of a number of key pathways implicated in tumor pathogenesis. Recently, the expression of miR‑378 was shown to be dysregulated in several different types of cancer, including gastric cancer, colorectal cancer and oral carcinoma. Additional studies have demonstrated that miR‑378 may serve as a potential therapeutic target against human breast cancer. However, the underlying mechanisms and potential targets of miR‑378a‑3p involved in GBM remain unknown. The aim of the present of was to determine the effects of miR‑378a‑3p and its potential targets. Tetraspanin 17 (TSPAN17) is involved in the neoplastic events in GBM and is a member of the tetraspanin family of proteins. The tetraspanins are involved in the regulation of cell growth, migration and invasion of several different types of cancer cell lines, and may potentially act as an oncogene associated with GBM pathology. The results of the present study showed that high miR‑378a‑3p and low TSPAN17 expression levels were associated with improved survival in patients with GBM. Additionally, high levels of TSPAN17 were linked to the poor prognosis of patients with GBM aged 50‑60, larger tumor sizes (≥5 cm) and an advanced World Health Organization stage. TSPAN17 was identified and confirmed as a direct target of miR‑378a‑3p using a luciferase reporter assay in human glioma cell lines. Overexpression of miR‑378a‑3p in either of U87MG or MT‑330 cells decreased the expression of TSPAN17, promoted apoptosis and decreased proliferation, migration and invasion. Overexpression of TSPAN17 attenuated the aforementioned effects induced by miR‑378a‑3p overexpression. The present study indicated that miR‑378a‑3p suppresses the progression of GBM by reducing TSPAN17 expression, and may thus serve as a potential therapeutic target for treating patients with GBM.
LncRNA NR_038323 suppresses renal fibrosis in diabetic nephropathy by targeting miR-324-3p/DUSP1 axis
Jul 2019
Yanni Ge
Dengke Wu
Juan Wang
Dongshan Zhang
Several studies have suggested that long intergenic noncoding RNAs are involved in the progression of diabetic nephropathy (DN). However, the exact role and regulatory mechanism of long noncoding RNA (lncRNA) NR_038323 in diabetic nephropathy (DN) remain largely unclear. In the present study, we found that lncRNA NR_038323 overexpression ameliorated the high glucose (HG)-induced expression levels of collagen I, collagen IV, and fibronectin, whereas lncRNA NR_038323 knockdown exerted the opposite effects. Moreover, the results of bioinformatic prediction, luciferase assay, and fluorescence in situ hybridization (FISH) demonstrated that lncRNA NR_038323 directly interacted with miR-324-3p. Additionally, miR-324-3p mimic aggravated the HG-induced expression levels of collagen I, collagen IV, and fibronectin by dual-specificity protein phosphatase-1 (DUSP1) expression to activate p38 mitogen-activated protein kinase (MAPK) and ERK1/2 pathways. In contrast, overexpression of DUSP1 attenuated the HG-induced expression levels of collagen I, collagen IV, and fibronectin via inactivation of p38 MAPK and ERK1/2 pathways. In addition, lncRNA NR_038323 knockdown increased the expression levels of collagen I, collagen IV, and fibronectin by upregulating DUSP1 expression during HG treatment, which were markedly reversed by miR-324-3p inhibitor. Furthermore, these molecular changes were verified in the human kidney samples of DN patients. Finally, overexpression of lncRNA NR_038323 ameliorated the interstitial fibrosis in STZ-induced diabetic nephrology (DN) rat via miR-324-3p/DUSP1/p38MAPK and ERK1/2 axis. In conclusion, our data indicate that overexpression of lncRNA NR_038323 may suppress HG-induced renal fibrosis via the miR-324-3p/DUSP1/p38MAPK and ERK1/2 axis, which provides new insights into the pathogenesis of DN. Keywords: diabetic nephropathy, lncRNA NR_038323, miR-324-3p, DUSP1
EGFR drives the progression of AKI to CKD through HIPK2 overexpression
Apr 2019
thno
Luyang Xu
Xiaozhou Li
Fei Zhang
Dongshan Zhang
The molecular mechanism underlying the transition of acute kidney injury (AKI) to chronic kidney disease (CKD) induced by vancomycin (VAN) remains largely unknown.
Methods: The mice model of VAN drives AKI to CKD was developed to investigate the role and molecular mechanism of epidermal growth factor receptor (EGFR). The EGF receptor mutant (Wa-2) mice and gefitinib were used to inactivation of EGFR. The homeodomain interacting protein kinase 2 (HIPK2) siRNA was applied to silence of HIPK2. Human proximal tubular epithelial cells (HK-2) were used to explore the molecular regulation methanism of EGFR. ChIp analysis was used to investigate if STAT3 interaction with the promoter of HIPK2.
Results: A novel VAN-induced AKI mouse model was established for the first time. Moreover, the expression levels collagen I&IV, α-SMA, p-EGFR and the expression of HIPK2 proteins were upregulated in this model. Interestingly, AKI caused by VAN was markedly attenuated in waved-2 mice at the early stage, as evidenced by the suppression of renal dysfunction, renal cell apoptosis and caspase3 activation. In the latter stage, renal fibrosis and inflammation were significantly ameliorated in Wa-2 mice, accompanied by the downregulation of profibrotic molecules and F4/80. Besides, the expression levels of HIPK2 and p-STAT3 were suppressed in Wa-2 mice during VAN-induced transition of AKI to CKD. In addition, renal fibrosis and inflammation, profibrotic molecules, and EGFR/STAT3/HIPK2 signaling were ameliorated by gefitinib treatment after VAN-induced AKI. These results were consistent with the findings of Wa-2 mice. EGFR/STAT3 signaling mediated VAN-induced HIPK2 expression in HK-2 cells. ChIp analysis revealed that STAT3 directly bound to the promoter region of HIPK2. Finally, inhibition of HIPK2 attenuated the VAN drove the progression of AKI to CKD.
Conclusion: These data suggest that EGFR plays an important role in VAN-driven progression of AKI to CKD.
RAB10: an Alzheimer’s disease resilience locus and potential drug target
Dec 2018
Clin Interv Aging
Justina P. Tavana
Matthew J Rosene
Nick Jensen
Celeste M Karch
Justina P Tavana,1,* Matthew Rosene,2,* Nick O Jensen,2 Perry G Ridge,1 John SK Kauwe,1,3 Celeste M Karch2,4 1Department of Biology, Brigham Young University, Provo, UT 84602, USA; 2Department of Psychiatry, Washington University in St Louis, St Louis, MO, USA; 3Department of Neuroscience, Brigham Young University, Provo, UT 84602, USA; 4Hope Center for Neurological Disorders, Washington University in St Louis, St Louis, MO, USA *These authors contributed equally to this work Abstract: Alzheimer’s disease (AD) is mainly a late-onset neurodegenerative disorder. Substantial efforts have been made to solve the complex genetic architecture of AD as a means to identify therapeutic targets. Unfortunately, to date, no disease-altering therapeutics have been developed. As therapeutics are likely to be most effective in the early stages of disease (ie, before the onset of symptoms), a recent focus of AD research has been the identification of protective factors that prevent disease. One example is the discovery of a rare variant in the 3'-UTR of RAB10 that is protective for AD. Here, we review the possible genetic, molecular, and functional role of RAB10 in AD and potential therapeutic approaches to target RAB10. Keywords: Alzheimer’s disease, RAB10, retromer, APP, resilience, GTPase
The long noncoding RNA LOC105374325 causes podocyte injury in individuals with focal segmental glomerulosclerosis
Nov 2018
Shuai hu
Runhong Han
Jingsong Shi
Zhihong Liu
Focal segmental glomerulosclerosis (FSGS) is a common kidney disease that results in nephrotic syndrome. FSGS arises from dysfunction and apoptosis of podocytes in the glomerulus of the kidney, leading to podocytopathy. The molecular mechanisms underlying podocyte apoptosis remain incompletely understood. Using an array of gene expression profiling, PCR and in situ hybridization assay, we found here that the levels of the long noncoding RNA LOC105374325 were elevated in the renal podocytes of individuals with FSGS. We also observed that the microRNAs miR-34c and miR-196a/b down-regulated the expression of the apoptosis regulators BCL2-associated X, apoptosis regulator (Bax) and BCL2 antagonist/killer 1 (Bak) in podocytes. Competitive binding between LOC105374325 and miR-34c or miR-196a/b increased Bax and Bak levels and caused podocyte apoptosis. Of note, the mitogen-activated protein kinase P38 and the transcription factor CCAAT enhancer–binding protein β (C/EBPβ) up-regulated LOC105374325 expression. P38 inhibition or C/EBPβ silencing decreased LOC105374325 levels and inhibited apoptosis in Adriamycin-treated podocytes. LOC105374325 overexpression decreased miR-34c and miR-196a/b levels, increased Bax and Bak levels, and induced proteinuria and focal segmental lesions in mice. In conclusion, the activation of the P38/C/EBPβ pathway stimulates the expression of LOC105374325, which, in turn, increases Bax and Bak levels and causes apoptosis by competitively binding to miR-34c and miR-196a/b in the podocytes of individuals with FSGS.
lncRNA GAS5 Reverses EMT and Tumor Stem Cell-Mediated Gemcitabine Resistance and Metastasis by Targeting miR-221/SOCS3 in Pancreatic Cancer
Oct 2018
Bingyan Liu
Shaoqiu Wu
Jun Ma
Aiwu Mao
Dysregulated long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) mediating chemotherapeutic drug effects and metastasis in pancreatic cancer (PC) are key reasons for the poor prognosis of this disease. lncRNA growth arrest-specific 5 (GAS5) is reported to be a tumor suppressor in multiple cancers. However, the functions of GAS5 and its related miRNAs in PC are poorly understood. This study explored the potential functions and mechanisms of GAS5 in PC gemcitabine resistance and metastasis. The results show that overexpression of GAS5 suppressed the proliferation, migration, gemcitabine resistance, stem cell-like properties, and epithelial-mesenchymal transition (EMT) of PC cells by directly binding to and suppressing miR-221 expression and enhancing suppressor of cytokine signaling 3 (SOCS3) expression. The effects of miR-221 overexpression on proliferation, migration, gemcitabine resistance, stem cell-like properties, and EMT inhibition were reversed by SOCS3 overexpression in PC cells. Additionally, GAS5 promoted gemcitabine-induced tumor growth and metastasis inhibition, as determined by Ki-67 staining and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), bioluminescence imaging, and the detection of cell-like properties and EMT in vivo. Thus, lncRNA GAS5 functioned as a competing endogenous RNA for miR-221, and it suppressed cell growth, metastasis, and gemcitabine resistance in PC by regulating the miR-221/SOCS3 pathway mediating EMT and tumor stem cell self-renewal.
lncRNA ZEB1-AS1 Was Suppressed by p53 for Renal Fibrosis in Diabetic Nephropathy
Jul 2018
Juan Wang
Jian Pang
Huiling Li
Dongshan Zhang
The role of p53 in renal fibrosis is still controversial, and its underlying mechanisms remain not clear. Here, we showed that the pharmacological inhibition and genetic deletion of p53 in proximal tubular cells can attenuate renal dysfunction, tubular epithelial disruption, and interstitial fibrosis in db/db and STZ-induced diabetic nephrology (DN) mice. In human renal proximal tubule (human kidney 2 [HK-2]) cells, inhibition of p53 by PIF reduced the high glucose (HG)-induced extracellular matrix (ECM) accumulation and reversed the inhibitory effect of HG on mRNA expression levels of lncRNA zinc finger E-box binding homeobox1-antisense RNA 1 (ZEB1-AS1) and ZEB1. Interestingly, our results demonstrated that both lncRNA ZEB1-AS1 and ZEB1 exhibited an anti-fibrotic role, while ZEB1 is positively regulated by lncRNA ZEB1-AS1 during HG treatment. Mechanistically, lnc ZEB1-AS1 bound directly to H3K4 methyltransferase myeloid and lymphoid or mixed-lineage leukemia 1 (MLL1) and promoted H3K4me3 histone modification on ZEB1 promoter, which was reduced by HG treatment. ChIP analysis indicated the binding of p53 to the promoter region of lnc ZEB1-AS1. Furthermore, the findings were verified by the kidney biopsy samples from patients with DN. Taken all together, our results suggest that p53 may be a therapeutic target for renal fibrosis in DN.
MiR-378a-3p exerts tumor suppressive function on the tumorigenesis of esophageal squamous cell carcinoma by targeting Rab10
Apr 2018
Naixin Ding
Xiujin Sun
Tingting Wang
Yiqin Zhou
Esophageal squamous cell carcinoma (ESCC) is a life‑threatening cancer with increasing incidence worldwide. MicroRNAs (miRs) have been reported to be involved in the progression of various types of cancer. In previous studies, the expression of miR‑378a‑3p was shown to be reduced in ESCC tissues. However, the mechanism underlying the effect of miR‑378a‑3p in ESCC remains to be elucidated. By employing a reverse transcription‑quantitative polymerase chain reaction, miR‑378a‑3p expression was tested in ESCC tissues and cell lines. In addition, the effects of miR‑378a‑3p on cell viability, proliferation, apoptosis, migration and invasion were studied using an MTT assay, an EdU assay, flow cytometry analysis, wound healing analysis and a Transwell assay. In the present study, the level of miR‑378a‑3p was significantly downregulated in ESCC clinical tissues and cell lines (EC109 and KYSE150). In addition, the overexpression of miR‑378a‑3p suppressed the viability, proliferation, migration and invasion of the ESCC cells. The upregulated expression of miR‑378a‑3p also increased the expression levels of B‑cell lymphoma 2‑associated X protein and caspase‑3, and decreased the expression levels of matrix metalloproteinase (MMP)‑2 and MMP‑9, which attenuated ESCC tumorigenesis. Furthermore, Rab10 was confirmed to be a direct target gene of miR‑378a‑3p, and was negatively affected by miR‑378a‑3p. The silencing of Rab10 revealed antitumor effects in ESCC cell lines, and the expression of miR‑378a‑3p was negatively correlated with that of Rab10 in ESCC. Collectively, miR‑378a‑3p may act as a tumor‑suppressor in ESCC cells through negatively regulating Rab10.
LincRNA 1700020I14Rik alleviates cell proliferation and fibrosis in diabetic nephropathy via MIR-34a-5p/Sirt1/HIF-1α signaling
Apr 2018
Ailing Li
Yan Sun
Rui Peng
Zheng Zhang
Long intergenic noncoding RNAs (lincRNAs) have been gradually identified to be functional in a variety of different mechanisms associating with development and epigenetic regulation of cellular homeostasis. However, the study of lincRNAs in diabetic nephropathy (DN) is still in its infancy. Here, we have found dysexpressed long noncoding RNAs (lncRNAs) in renal tissues of db/db DN mice compared with db/m mice by RNA sequencing. In this study, 5 lincRNAs were confirmed to express in a consistent trend among these DN-related lncRNAs both in vivo and in vitro. Particularly, 1700020I14Rik was the downregulated one. Moreover, our data showed overexpression or knockdown of 1700020I14Rik could regulate cell proliferation and fibrosis in mouse mesangial cells (MCs). Furthermore, 1700020I14Rik was found to interact with miR-34a-5p via both the directly targeting way by bioinformatic investigation and luciferase assay and the Ago2-dependent manner by RIP assay. Results also displayed that overexpression of 1700020I14Rik inhibited cell proliferation and expressions of renal fibrosis markers through miR-34a-5p/Sirt1/HIF-1α pathway in MCs under high glucose condition, while knockdown of 1700020I14Rik could increase cell proliferation and expressions of renal fibrosis markers. In conclusion, these results provide new insights into the regulation between 1700020I14Rik and miR-34a-5p/Sirt1/HIF-1α signaling pathway during the progression of DN.
Inhibition of TDP43-Mediated SNHG12-miR-195-SOX5 Feedback Loop Impeded Malignant Biological Behaviors of Glioma Cells
Dec 2017
Xiaobai Liu
Jian Zheng
Yixue Xue
Yunhui Liu
Long non-coding RNA (lncRNA) dysregulation is involved in tumorigenesis and regulation of diverse cellular processes in gliomas. lncRNA SNHG12 is upregulated and promotes cell growth in human osteosarcoma cells. TAR-DNA binding protein 43 (TDP43) functions as an oncogene in various tumors by modulating RNA expression. Downregulation of TDP43 or SNHG12 significantly inhibited malignant biological behaviors of glioma cells. miR-195, downregulated in glioma tissues and cells, significantly impaired the malignant progression of glioma cells. TDP43 upregulated miR-195 in an SNHG12-dependent manner. We further revealed that SNHG12 and miR-195 were in an RNA-induced silencing complex (RISC). Inhibition of SNHG12 combined with restoration of miR-195 robustly reduced tumor growth in vivo. SOX5 was overexpressed in glioma tissues and cells. miR-195 targeted SOX5 3′ UTR in a sequence-specific manner. Gelsolin was activated by SOX5. More importantly, SOX5 activated SNHG12 promoter and upregulated its expression, forming a feedback loop. Dysregulation of SNHG12, miR-195, and SOX5 predicted poor prognosis of glioma patients. The present study demonstrated that SNHG12-miR-195-SOX5 feedback loop exerted a crucial role in the regulation of glioma cells’ malignant progression.
RAB10 overexpression promotes tumor growth and indicates poor prognosis of hepatocellular carcinoma
Wei Wang
Wei-Dong Jia
Bing Hu
Yue-Yin Pan
Hepatocellular carcinoma (HCC), one of the most common and lethal cancers worldwide, has a high recurrence rate with current treatment modalities. Identifying biomarkers for early diagnosis and discovering new sufficient molecular targets for the development of targeted therapies are urgently needed. RAB10, a member of the RAS family, has been shown to be highly expressed in HCC. However, the function of RAB10 in HCC is less studied. Here we report that RAB10 acts as an oncogene in HCC. The shRNA-mediated knockdown of RAB10 significantly reduced the proliferation of HCC cells and colony formation, induced cell cycle arrest at G0/G1 phase and increased apoptosis in vitro. In addition, RAB10 knockdown suppressed HCC growth in nude mice. Moreover, RAB10 silencing decreased the phosphorylation of InsR, Met/HGFR, Ron/MST1R, Ret, c-Kit/SCFR, EphA3, EphB4, Tyro3/Dtk, Axl, Tie2/TEK, VEGFR2/KDR, Akt/PKB/Rac, S6 Ribosomal Protein and c-Abl, while the phosphorylation of HSP27, p38 MAPK, Chk2 and TAK1 increased significantly. These results suggest that RAB10 regulates cell survival and proliferation through multiple oncogenic, cell stress and apoptosis pathways. More importantly, high RAB10 expression levels in HCC cells correlated with a poor prognosis in HCC patients. Therefore, our findings revealed an oncogenic role for RAB10 in the pathogenesis of HCC and that RAB10 is a potential molecular target or a biomarker for HCC.
LincRNA-Gm4419 knockdown ameliorates NF-κB/NLRP3 inflammasome-mediated inflammation in diabetic nephropathy
Hong Yi
Rui Peng
Lu-yu Zhang
Zheng Zhang
Diabetic nephropathy (DN) as the primary cause of end-stage kidney disease is a common complication of diabetes. Recent researches have shown the activation of nuclear factor kappa light-chain enhancer of activated B cells (NF-κB) and NACHT, LRR and PYD domain-containing protein 3 (NLRP3) inflammasome are associated with inflammation in the progression of DN, but the exact mechanism is unclear. Long noncoding RNAs (lncRNAs) have roles in the development of many diseases including DN. However, the relationship between lncRNAs and inflammation in DN remains largely unknown. Our previous study has revealed that 14 lncRNAs are abnormally expressed in DN by RNA sequencing and real-time quantitative PCR (qRT-PCR) in the renal tissues of db/db DN mice. In this study, these lncRNAs were verified their expressions by qRT-PCR in mesangial cells (MCs) cultured under high- and low-glucose conditions. Twelve lncRNAs displayed the same expressional tendencies in both renal tissues and MCs. In particular, long intergenic noncoding RNA (lincRNA)-Gm4419 was the only one associating with NF-κB among these 12 lncRNAs by bioinformatics methods. Moreover, Gm4419 knockdown could obviously inhibit the expressions of pro-inflammatory cytokines and renal fibrosis biomarkers, and reduce cell proliferation in MCs under high-glucose condition, whereas overexpression of Gm4419 could increase the inflammation, fibrosis and cell proliferation in MCs under low-glucose condition. Interestingly, our results showed that Gm4419 could activate the NF-κB pathway by directly interacting with p50, the subunit of NF-κB. In addition, we found that p50 could interact with NLRP3 inflammasome in MCs. In conclusion, our findings suggest lincRNA-Gm4419 may participate in the inflammation, fibrosis and proliferation in MCs under high-glucose condition through NF-κB/NLRP3 inflammasome signaling pathway, and may provide new insights into the regulation of Gm4419 during the progression of DN.
Long non‑coding RNA ASncmtRNA‑2 is upregulated in diabetic kidneys and high glucose‑treated mesangial cells
Jan 2017
Yan Gao
Zhao-Yu Chen
Yan Wang
Yu-kun Li
Diabetic nephropathy (DN) is one of the most frequent complications associated with type I and II diabetes mellitus. Kidneys from patients with DN are characterized by mesangial matrix expansion and increased thickness of the glomerular basement membrane, which are induced by reactive oxygen species (ROS) production. Previous studies have been conducted to investigate this; however, the detailed mechanism of DN progression remains to be elucidated. The present study evaluated the expression of antisense mitochondrial non-coding RNA-2 (ASncmtRNA-2) in an experimental DN model and cultured human mesangial cells. When mice that exhibited genetic type II diabetes developed DN, ASncmtRNA-2 expression was significantly increased (P=0.017) and was positively correlated with pro-fibrotic factor transforming growth factor ?1 (TGF?1) expression and its downstream gene, fibronectin. Inhibition of ROS through administration of the nitric oxide synthase inhibitor, NG-nitro-L-Arginine methylester (L-NAME), significantly reduced (P=0.022) the upregulation of ASncmtRNA-2 in DN. In cultured human renal mesangial cells (HRMCs), ASncmtRNA-2 was upregulated by high glucose stimuli in a time-dependent manner. Glucose-induced upregulation of ASncmtRNA-2 was also reduced by co-incubation of HRMCs with L-NAME. Notably, specific short hairpin RNA against ASncmtRNA-2 significantly downregulated the expression of TGF?1 in HRMCs. The present study suggests that ASncmtRNA-2 is upregulated by ROS and may promote glomerular fibrosis in DN via positively regulating the expression of pro-fibrotic factors. These findings may provide novel potential therapeutic and preventative treatments for DN.
Recognition and management of acute kidney injury in the International Society of Nephrology 0by25 Global Snapshot: A multinational cross-sectional study
Apr 2016
LANCET
Ravindra Mehta
Emmanuel A Burdmann
Jorge Cerdá
Giuseppe Remuzzi
Background:
Epidemiological data for acute kidney injury are scarce, especially in low-income countries (LICs) and lower-middle-income countries (LMICs). We aimed to assess regional differences in acute kidney injury recognition, management, and outcomes.
Methods:
In this multinational cross-sectional study, 322 physicians from 289 centres in 72 countries collected prospective data for paediatric and adult patients with confirmed acute kidney injury in hospital and non-hospital settings who met criteria for acute kidney injury. Signs and symptoms at presentation, comorbidities, risk factors for acute kidney injury, and process-of-care data were obtained at the start of acute kidney injury, and need for dialysis, renal recovery, and mortality recorded at 7 days, and at hospital discharge or death, whichever came earlier. We classified countries into high-income countries (HICs), upper-middle-income countries (UMICs), and combined LICs and LMICs (LLMICs) according to their 2014 gross national income per person.
Findings:
Between Sept 29 and Dec 7, 2014, data were collected from 4018 patients. 2337 (58%) patients developed community-acquired acute kidney injury, with 889 (80%) of 1118 patients in LLMICs, 815 (51%) of 1594 in UMICs, and 663 (51%) of 1241 in HICs (for HICs vs UMICs p=0.33; p<0.0001 for all other comparisons). Hypotension (1615 [40%] patients) and dehydration (1536 [38%] patients) were the most common causes of acute kidney injury. Dehydration was the most frequent cause of acute kidney injury in LLMICs (526 [46%] of 1153 vs 518 [32%] of 1605 in UMICs vs 492 [39%] of 1260 in HICs) and hypotension in HICs (564 [45%] of 1260 vs 611 [38%%] of 1605 in UMICs vs 440 [38%] of 1153 LLMICs). Mortality at 7 days was 423 (11%) of 3855, and was higher in LLMICs (129 [12%] of 1076) than in HICs (125 [10%] of 1230) and UMICs (169 [11%] of 1549).
Interpretation:
We identified common aetiological factors across all countries, which might be amenable to a standardised approach for early recognition and treatment of acute kidney injury. Study limitations include a small number of patients from outpatient settings and LICs, potentially under-representing the true burden of acute kidney injury in these areas. Additional strategies are needed to raise awareness of acute kidney injury in community health-care settings, especially in LICs.
Funding:
International Society of Nephrology.
On the classification of long non-coding RNAs
Apr 2013
RNA BIOL
Lina Ma
Vladimir Bajic
Zhang Zhang
Long non-coding RNAs (lncRNAs) have been found to perform various functions in a wide variety of important biological processes. To make easier interpretation of lncRNA functionality and conduct deep mining on these transcribed sequences, it is convenient to classify lncRNAs into different groups. Here, we summarize classification methods of lncRNAs according to their four major features, namely, genomic location and context, effect exerted on DNA sequences, mechanism of functioning and their targeting mechanism. In combination with the presently available function annotations, we explore potential relationships between different classification categories, and generalize and compare biological features of different lncRNAs within each category. Finally, we present our view on potential further studies. We believe that the classifications of lncRNAs as indicated above are of fundamental importance for lncRNA studies, helpful for further investigation of specific lncRNAs, for formulation of new hypothesis based on different features of lncRNA and for exploration of the underlying lncRNA functional mechanisms.
Acute kidney injury
Nov 2019
Claudio Ronco
Rinaldo Bellomo
John A. Kellum
Acute kidney injury (AKI) is defined by a rapid increase in serum creatinine, decrease in urine output, or both. AKI occurs in approximately 10-15% of patients admitted to hospital, while its incidence in intensive care has been reported in more than 50% of patients. Kidney dysfunction or damage can occur over a longer period or follow AKI in a continuum with acute and chronic kidney disease. Biomarkers of kidney injury or stress are new tools for risk assessment and could possibly guide therapy. AKI is not a single disease but rather a loose collection of syndromes as diverse as sepsis, cardiorenal syndrome, and urinary tract obstruction. The approach to a patient with AKI depends on the clinical context and can also vary by resource availability. Although the effectiveness of several widely applied treatments is still controversial, evidence for several interventions, especially when used together, has increased over the past decade.
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Long noncoding RNA NEAT1 accelerates the proliferation and fibrosis in diabetic nephropathy through activating Akt/mTOR signaling pathway
Shan Huang
Yong Xu
Xiaoxu Ge
Lili Xia
Accumulating evidence has indicated the significant roles of long noncoding RNAs (lncRNAs) in the pathophysiology of diabetic nephropathy (DN). LncRNA nuclear enriched abundant transcript 1 (NEAT1) has been reported to exert a key role in the progression of several diseases including diabetes. However, the role of NEAT1 in the regulation of DP progression remains barely known. Therefore, our study aimed to investigate the role of NEAT1 in a streptozotocin‐induced diabetes model (DM) of rats and glucose‐induced mouse mesangial cell models. Currently, we found that NEAT1 was greatly upregulated in DM rats and glucose‐induced mice mesangial cells, in which a high activation of Akt/mTOR signaling was also observed. Then, it was shown that knockdown of NETA1 was able to reduce renal injury in DM rats obviously. In addition, cell counting kit‐8 assay and 5‐ethynyl‐2′‐deoxyuridine assay were carried out and we observed downregulation of NEAT1 significantly inhibited mesangial cell proliferation. Meanwhile, extracellular matrix proteins and messenger RNA (transforming growth factor β1, fibronectin, and collagen IV) expression was dramatically restrained by silencing of NEAT1 in the high glucose‐induced mesangial cells. Finally, knockdown of NEAT1 greatly reduced the expression of the phosphorylation of Akt and mammalian target of rapamycin (mTOR) in vitro. These findings revealed that the decrease of NEAT1 repressed the proliferation and fibrosis in DN via activating the Akt/mTOR signaling pathway, which might represent a novel pathological mechanism of DN progression. A novel role of nuclear enriched abundant transcript 1 (NEAT1) was reported in DN progression. We proved that NEAT1 was able to induce DN development through activating Akt/mTOR signaling. Taken these together, NEAT1 might serve as a biomarker and therapeutic target for DN.
Circular RNA-100290 promotes cell proliferation and inhibits apoptosis in acute myeloid leukemia cells via sponging miR-203
Hongqiong Fan
Yuying Li
Chunshui Liu
Wei Li
Circular RNA (CirRNA) is a type of noncoding RNA that has been shown to play a unique role in tumor development and other fields in recent years. In this study, we aimed to explore the biological role of hsa_circ_100290 in acute myeloid leukemia (AML). First, we found that the expression of hsa_circ_100290 was increased in human AML samples and cell lines. Down-regulation of hsa_circ_100290 significantly suppressed cell proliferation of AML cells. Silencing hsa_circ_100290 also dramatically induced cell cycle arrest and apoptosis. Bioinformatic prediction and luciferase assay revealed that hsa_circ_100290 and Rab10 were targeted by miR-203. Validation experiments verified that hsa_circ_100290 was co-expressed with Rab10 and was negatively correlated with miR-203 expression. Moreover, rescue experiments demonstrated that miR-203 inhibitor could reverse the role of hsa_circ_100290 knockdown on proliferation and apoptosis in AML cells. Overall, the present study identifies the crucial regulation of hsa_circ_100290 in AML cell proliferation and apoptosis via targeting the miR-203/Rab10 axis.
Long noncoding RNA lnc-TSI inhibits renal fibrogenesis by negatively regulating the TGF-β/Smad3 pathway
Oct 2018
Transforming growth factor–β (TGF-β) is a well-established central mediator of renal fibrosis, a common outcome of almost all progressive chronic kidney diseases. Here, we identified a poorly conserved and kidney-enriched long noncoding RNA in TGF-β1–stimulated human tubular epithelial cells and fibrotic kidneys, which we termed TGF-β/Smad3-interacting long noncoding RNA ( lnc-TSI ). Lnc-TSI was transcriptionally regulated by Smad3 and specifically inhibited TGF-β–induced Smad3 phosphorylation and downstream profibrotic gene expression. Lnc-TSI acted by binding with the MH2 domain of Smad3, blocking the interaction of Smad3 with TGF-β receptor I independent of Smad7. Delivery of human lnc-TSI into unilateral ureteral obstruction (UUO) mice, a well-established model of renal fibrosis, inhibited phosphorylation of Smad3 in the kidney and attenuated renal fibrosis. In a cohort of 58 patients with biopsy-confirmed IgA nephropathy (IgAN), lnc-TSI renal expression negatively correlated with the renal fibrosis index ( r = −0.56, P < 0.001) after adjusting for cofounders. In a longitudinal study, 32 IgAN patients with low expression of renal lnc-TSI at initial biopsy had more pronounced increases in their renal fibrosis index and experienced stronger declines in renal function at repeat biopsy at a mean of 48 months of follow-up. These data suggest that lnc-TSI reduced renal fibrogenesis through negative regulation of the TGF-β/Smad pathway.
miR-378a-3p sensitizes ovarian cancer cells to cisplatin through targeting MAPK1/GRB2
Ovarian cancer has gradually become one of the commonest gynecological tumor in the world. Although various therapies have been developed by researchers, the chemoresistance of ovarian cancer is still a huge challenge. MircroRNAs (miRNAs) have been widely studied due to their anti-oncogenic functions. MiR-378a-3p has been reported to sensitize breast cancer cells to chemotherapy. Here, we hypothesized that miR-378a-3p is a potential chemosensitizer in ovarian cancer. Firstly, miR-378a-3p was uncovered to down-regulated in ovarian cancer tissues and cell lines through using qRT-PCR analysis and northern blot analysis. According to the result of Kaplan Meier analysis, low expression of miR-378a-3p is closely associated with unfavorable prognosis of ovarian cancer patients. Subsequently, gain-of function assays indicated that miR-378a-3p suppressed cell proliferation and promoted cell apoptosis. Moreover, miR-378a-3p was found to enhance cisplatin sensitivity of ovarian cancer cells. Mechanism investigations suggested that MAPK1 and GRB2 are two targets of miR-378a-3p. Finally, rescue assays revealed that MAPK1 and GRB2 can reverse the effects of miR-378a-3p on chemosensitivity of ovarian cancer cells. In conclusion, miR-378a-3p enhanced the sensitivity of ovarian cancer cells to cisplatin through targeting MAPK1 and GRB2.
LncRNA HOX transcript antisense RNA accelerated kidney injury induced by urine-derived sepsis through the miR-22/high mobility group box 1 pathway
Objective:
This study investigated the role of long noncoding RNA (lncRNA) HOX transcript antisense RNA (HOTAIR) in kidney injury induced by urine-derived sepsis (US).
Materials and methods:
An Escherichia coli suspension was injected into the distal ureter of adult male Sprague Dawley rats to establish a US model. Lipopolysaccharides (LPSs) were used to induce an in vitro septic model. The interaction between HOTAIR and microRNA 22 (miR-22) was detected by RNA precipitation and RNA pull-down assays. The expression of HOTAIR, miR-22, and high mobility group box 1 (HMGB1) were detected by quantitative real time polymerase chain reaction (qRT-PCR) and Western blot analyses.
Results:
Compared with a sham group, HOTAIR was upregulated in kidney tissues of the US group. HOTAIR was also upregulated in LPS-induced human renal tubular epithelial cells (HK-2). Furthermore, HOTAIR negatively regulated miR-22 and promoted apoptosis of HK-2 cells. HOTAIR also promoted HMGB1 expression and HK-2 cell apoptosis by inhibiting miR-22. In addition, the miR-22/HMGB1 pathway was involved in LPS-induced HK-2 cell apoptosis. In vivo experiments showed that HOTAIR negatively modulated miR-22 and positively modulated HMGB1 and that HOTAIR knockdown decreased renal function indicators (blood urea nitrogen [BUN] and serum creatinine).
Conclusion:
HOTAIR was upregulated in sepsis-induced kidney injury, which promoted HK-2 cell apoptosis in kidney injury through the miR-22/HMGB1 pathway.
Hyperhomocysteinemia accelerates AKI to CKD progression by downregulating heme oxygenase-1 expression
Aims:
The risk factors promoting acute kidney injury (AKI) to chronic kidney disease (CKD) progression remains largely unknown. The aim of the present study was to investigate whether hyperhomocysteinemia (Hhcy) accelerates the development of renal fibrosis after AKI.
Results:
Hhcy aggravated ischemia-reperfusion-induced AKI and the subsequent development of renal fibrotic lesions characterized by excessive extracellular matrix deposition. Mechanistically, the RNA binding protein human antigen R (HuR) bound to the 3'-untranslated region (3'-UTR) of heme oxygenase-1 (HO-1) mRNA. Hcy downregulated HuR expression, reduced the binding of HuR to the 3'-UTR of HO-1, and thereafter decreased HO-1 expression. Administration of the HO-1 inducer cobalt protoporphyrin-IX significantly hindered Hhcy-augmented ROS production and renal fibrotic lesions. Innovation and Conclusion: These data indicate that Hhcy might be a novel risk factor that promotes AKI to CKD progression. Lowering Hcy level or HO-1 induction might be a potential therapeutic strategy to improve the outcome of AKI.
Rodent models of AKI-CKD transition
Acute kidney injury (AKI) is a contributing factor in the development and progression of chronic kidney disease (CKD). Despite rapid progresses, the mechanism underlying AKI- CKD transition remains largely unclear. Animal models recapitulating this process are crucial to the research of the pathophysiology of AKI-CKD transition and the development of effective therapeutics. In this review, we present the commonly used rodent models of AKI-CKD transition, including bilateral ischemia-reperfusion injury (bIRI), unilateral IRI (uIRI), unilateral IRI with contralateral nephrectomy (uIRIx), multiple episodes of IRI, and repeated treatment of low dose cisplatin, diphtheria toxin, aristolochic acid or folic acid. The main merits and pitfalls of these models are also discussed. This review provides helpful information for establishing reliable and clinically relevant models for studying post-AKI development of chronic renal pathologies and the progression to CKD.
Long non-coding RNAs: An essential emerging field in kidney pathogenesis
Human Genome Project has made it clear that a majority of the genome is transcribed into the non-coding RNAs
including microRNAs as well as long non-coding RNAs (lncRNAs) which both can affect different features of
cells. LncRNAs are long heterogenous RNAs that regulate gene expression and a variety of signaling pathways
involved in cellular homeostasis and development. Studies over the past decade have shown that lncRNAs have a
major role in the kidney pathogenesis. The effective roles of lncRNAs have been recognized in renal ischemia,
injury, inflammation, fibrosis, glomerular diseases, renal transplantation, and renal cell carcinoma. The present
review outlines the role and function of lncRNAs in kidney pathogenesis as novel essential regulators. Molecular
mechanism insights into the functions of lncRNAs in kidney pathophysiological processes may contribute to
effective future therapeutics.
AKI on CKD: Heightened injury, suppressed repair, and the underlying mechanisms
Acute kidney injury (AKI) and chronic kidney disease (CKD) are interconnected. Although AKI-to-CKD transition has been intensively studied, the information of AKI on CKD is very limited. Nonetheless, AKI, when occurring in patients with CKD, is known to be more severe and difficult to recover. CKD is associated with significant changes in cell signaling in kidney tissues, including the activation of transforming growth factor-β, p53, hypoxia-inducible factor, and major developmental pathways. At the cellular level, CKD is characterized by mitochondrial dysfunction, oxidative stress, and aberrant autophagy. At the tissue level, CKD is characterized by chronic inflammation and vascular dysfunction. These pathologic changes may contribute to the heightened sensitivity of, and nonrecovery from, AKI in patients with CKD.
The lncRNA PDIA3P Interacts with miR-185-5p to Modulate Oral Squamous Cell Carcinoma Progression by Targeting Cyclin D2
Long noncoding RNAs (lncRNAs) are emerging as important regulators during tumorigenesis by serveing as competing endogenous RNAs (ceRNAs). In this study, the qRT-PCR results indicated that the lncRNA protein disulfide isomerase family A member 3 pseudogene 1 (PDIA3P) was over-expressed in oral squamous cell carcinoma (OSCC) and decreased the survival rate of OSCC patients. CCK8 and clonal colony formation assays were used to detect the effects of PDIA3P on cell proliferation. Results revealed that silencing PDIA3P by siRNA inhibited OSCC cell proliferation, and repressed tumor growth and reduced the expression of proliferation antigen Ki-67 in vivo. Furthermore, the interaction between PDIA3P and miRNAs was then analyzed by qRT-PCR and luciferase reporter gene assay. We found that PDIA3P negatively regulated miR-185-5p in OSCC cells. Simultaneously, we found that silencing PDIA3P by siRNA suppressed proliferation via miR-185-5p in OSCC cells. Moreover, silencing PDIA3P by siRNA inhibited CCND2 protein (no influence on mRNA levels) expression via miR-185-5p in OSCC cells, and CCND2 facilitated cell proliferation of SCC4 and SCC15 cells induced by sh-PDIA3P#1. Therefore, our study demonstrated that PDIA3P may be a therapeutic target for treatment of OSCC.
Protein Kinase C Suppresses Autophagy to Induce Kidney Cell Apoptosis in Cisplatin Nephrotoxicity
Nephrotoxicity is a major adverse effect in cisplatin chemotherapy, and renoprotective approaches are unavailable. Recent work unveiled a critical role of protein kinase Cδ (PKCδ) in cisplatin nephrotoxicity and further demonstrated that inhibition of PKCδ not only protects kidneys but enhances the chemotherapeutic effect of cisplatin in tumors; however, the underlying mechanisms remain elusive. Here, we show that cisplatin induced rapid activation of autophagy in cultured kidney tubular cells and in the kidneys of injected mice. Cisplatin also induced the phosphorylation of mammalian target of rapamycin (mTOR), p70S6 kinase downstream of mTOR, and serine/threonine-protein kinase ULK1, a component of the autophagy initiating complex. In vitro, pharmacologic inhibition of mTOR, directly or through inhibition of AKT, enhanced autophagy after cisplatin treatment. Notably, in both cells and kidneys, blockade of PKCδ suppressed the cisplatin-induced phosphorylation of AKT, mTOR, p70S6 kinase, and ULK1 resulting in upregulation of autophagy. Furthermore, constitutively active and inactive forms of PKCδ respectively enhanced and suppressed cisplatin-induced apoptosis in cultured cells. In mechanistic studies, we showed coimmunoprecipitation of PKCδ and AKT from lysates of cisplatin-treated cells and direct phosphorylation of AKT at serine-473 by PKCδ in vitro Finally, administration of the PKCδ inhibitor rottlerin with cisplatin protected against cisplatin nephrotoxicity in wild-type mice, but not in renal autophagy-deficient mice. Together, these results reveal a pathway consisting of PKCδ, AKT, mTOR, and ULK1 that inhibits autophagy in cisplatin nephrotoxicity. PKCδ mediates cisplatin nephrotoxicity at least in part by suppressing autophagy, and accordingly, PKCδ inhibition protects kidneys by upregulating autophagy.
Hyperglycemia, p53, and mitochondrial pathway of apoptosis are involved in The susceptibility of diabetic models to ischemic acute kidney injury
| https://www.researchgate.net/publication/353883368_LncRNA136131_Suppresses_Apoptosis_of_Renal_Tubular_Epithelial_Cells_in_Acute_Kidney_Injury_by_Targeting_the_miR_-378a-3pRab10_Axis |
Mud Run Training Guide: Men's Health.com
Scale obstacles in the Tough Mudder, Warrior Dash, or Spartan Race with ease
The Mud Run Training Plan
Scale obstacles in the Tough Mudder, Warrior Dash, or Spartan Race with ease
Media Platforms Design Team
Trudging through mud, hopping over fire, crawling beneath barbed wire? Piece of cake. If you follow this routine from Nathan Trenteseaux—owner of Underground Fitness Revolution, a member of the Fitness Revolution Nation, in Alachua, Florida—you’ll be fully prepared for the obstacles in the Warrior Dash, Tough Mudder, Spartan Race, or a local version of these adventure races sweeping the nation.
Trenteseaux knows from experience what works. In addition to being an expert in metabolic bodyweight training, Trenteseaux says mud runs are his “latest obsession.” He even has a tattoo of the Tough Mudder logo he received after completing the 12-mile race this past December.
“People who struggle with these events spend too much time running and not enough time developing the upper body strength and skills necessary for the obstacles,” says Trenteseaux. “For those already in shape and running on a regular basis, some form of high-intensity total-body resistance training is crucial to provide the other components needed for a mud run.”
Trenteseaux selected these movements because they have the most real-world carryover to the obstacles you’ll see in a typical mud run. The spider lunge, for example, will open up your hips—a notoriously tight spot for men—so you can crawl under barbed wire. Bupees, pushups, and pull-ups will help you scale a wall, climb a cargo net, or swing across monkey bars.
The Plan
Perform this circuit three times a week after your normal training sessions. You can also do it on an off day—just make sure you leave at least one day a week for recovery. If you’re performing the routine after strength training, warm up with a 5-minute jog.
Perform the following number of circuits for your three weekly workouts:Workout 1: Perform 3 circuits (18 minutes)Workout 2: Perform 4 circuits (24 minutes)Workout 3: Perform 2 circuits (12 minutes)
The Moves
Sprint:Run at the fastest pace you can sustain for a full minute.
Pullup:Use an overhand grip, your hands at shoulder width. Raise your body until the top of your chest touches bar, then lower your body until your arms are straight.
Burpee with jump:Begin standing with your feet shoulder-width apart. Lower your body down, bending at the hips and knees, so your hands are on the floor. Thrust out your legs behind you, so that you’re at the start of a pushup position. Do a pushup, then pull your knees toward your chest so your feet are beneath you. Jump up and land softly in a standing position.
Pushup:Your body should stay in a straight line for the entire move. Tuck your elbows so that your upper arms form a 45-degree angle with your torso. Lower your body until your chest nearly touches the floor.
Spider lunge (walk or crawl):From a position in which you are on all fours but only inches off the ground, crawl along the ground keeping your body very low, arms and legs spread as wide as possible.
The Circuit
Sprint 1 minutePullups (overhand grip): 30 secondsSprint 1 minuteBurpees (with jump): 30 secondsSprint 1 minutePushups: 30 secondsSprint 1 minuteSpider lunges: 10 yards
| https://www.menshealth.com/fitness/a19519093/mud-run-training/ |
American Fire Casualty Co v. Finn, No. 252 - Federal Cases - Case Law - VLEX 895545429
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Federal Cases
American Fire Casualty Co v. Finn, No. 252
Court United States Supreme Court Writing for the Court REED Citation 95 L.Ed. 702,71 S.Ct. 534,341 U.S. 6,19 A.L.R.2d 738 Parties AMERICAN FIRE & CASUALTY CO. v. FINN Docket Number No. 252 Decision Date 09 April 1951
341 U.S. 6
71 S.Ct. 534
95 L.Ed. 702
AMERICAN FIRE & CASUALTY CO.
v.
FINN.
No. 252.
Argued Dec. 7, 1950.
Decided April 9, 1951.
Page 7
Mr. David Bland, Houston, Tex., for petitioner.
Mr. Bailey P. Loften, Houston, Tex., for respondent.
Mr. Justice REED delivered the opinion of the Court.
These proceedings present for determination the proper federal rule to be followed on a motion by a defendant to vacate a United States District Court judgment, obtained by a plaintiff after removal from a state court by defendant, and to remand the suit to the state court. Petitioner, the movant, urges that 28 U.S.C. § 1441 , 28 U.S.C.A. § 1441 did not permit this removal and therefore the District Court was without jurisdiction to render the judgment which respondent, the plaintiff below, seeks to retain. The issue arose in this way:
Petitioner, the American Fire and Casualty Company, a Florida corporation, and its codefendant, the Indiana Lumbermens Mutual Insurance Company, an Indiana corporation, removed, in accordance with 28 U.S.C. § 1446 , 28 U.S.C.A. § 1446, a suit brought by respondent Finn in a Texas state court against the two corporations and an individual,
Page 8
Reiss, local agent of both corporations and a resident of Texas. The suit was for a fire loss on Texas property suffered by respondent, a resident of Texas. Respondent tried to have the case remanded before trial but was unsuccessful. After special issues were found by the jury, judgment was entered against petitioner for the amount of insurance claimed and costs, and in favor of the other two defendants. The District Court denied the motion to vacate the judgment and the Court of Appeals affirmed.181 F.2d 845. The latter court concluded there were causes of action against the foreign insurance companies 'separate and independent' from that stated against the resident individual. Since the causes against the companies would have been removable if sued on alone, the entire suit was removable. 28 U.S.C. § 1441(c) , 28 U.S.C.A. § 1441(c). That ruling required consideration of the changes concerning removal made by § 1441(c), which superseded 28 U.S.C. (1946 ed.)§ 71. The Court of Appeals said:
'The difference, if any, between separable controversies under the old statute and separate and independent claims under the new one is in degree, not in kind. It is difficult to distinguish between the two concepts, but it is not necessary to attempt it in a case like this, which would be removable under either statute.'181 F.2d 846.
Consideration of the ruling on the motion to vacate the judgment requires a determination of whether the suit contained separate and independent causes of action under § 1441(c), and, if the conclusion is that it did not, a ruling on the effect of a judgment after a removal without right, initiated by the party against whom the judgment was ultimately rendered. As prompt, economical and sound administration of justice depends to a large degree upon definite and finally accepted principles governing important areas of litigation, such as the respective jurisdictions of federal and state courts, we granted cer-
Page 9
tiorari. 340 U.S. 849, 71 S.Ct.79. See also Mayflower Industries v. Thor Corporation, 3 Cir., 184 F.2d 537 ; Bentley v. Halliburton Oil Well Cementing Co., 5 Cir., 174 F.2d 788 .
I.
The removal took place after September 1, 1948, the effective date of the revision of the laws relating to judicial procedure.62 Stat. 992, 28 U.S.C.A. note preceding § 1. The former provision governing removal, 28 U.S.C. (1946 ed.)§ 71, read:
'And when in any suit mentioned in this section there shall be a controversy which is wholly between citizens of different States, and which can be fully determined as between them, then either one or more of the defendants actually interested in such controversy may remove said suit into the district court of the United States for the proper district.'
The new section, 28 U.S.C. § 1441(c) , 28 U.S.C.A. § 1441(c), states:
'(c) Whenever a separate and independent claim or cause of action, which would be removable if sued upon alone, is joined with one or more otherwise nonremovable claims or causes of action, the entire case may be removed and the district court may determine all issues therein, or, in its discretion, may remand all matters not otherwise within its original jurisdiction.'
One purpose of Congress in adopting the 'separate and independent claim or cause of action' test for removability by § 1441(c) of the 1948 revision in lieu of the provision for removal of 28 U.S.C. (1946 ed.) § 71, was by simplification to avoid the difficulties experienced in determining the meaning of that provision. 1Another and im-
Page 10
portant purpose was to limit removal from state courts. 2 Section 71 allowed removal when a controversy was wholly between citizens of different states and fully determinable between them. Such a controversy was said to be 'separable.' The difficulties inherent in old § 71 show plainly in the majority and concurring opinions in Pullman Co. v. Jenkins, 305 U.S. 534 , 542, 59 S.Ct. 347 , 351, 83 L.Ed. 334 . See note, 41 Harv.L.Rev.1048. Often plaintiffs in state actions joined other state residents as defendants with out-of-state defendants so that removable controversies wholly between citizens of different states would not be pleaded. The effort frequently failed, see Pullman Co. v. Jenkins, 305 U.S. at page 538, 59 S.Ct. at page 349, and removal was allowed. Our consideration of the meaning and effect of 28 U.S.C. § 1441(c) , 28 U.S.C.A. § 1441(c) should be carried out in the light of the congressional intention. Cf. Pullman Co. v. Jenkins, supra, 305 U.S. at page 547, 59 S.Ct. at page 353; Phillips v. United States, 312 U.S. 246 , 250, 61 S.Ct. 480 , 483, 85 L.Ed. 800 .
The Congress, in the revision, carried out its purpose to abridge the right of removal. 3 Under the former provi-
Page 11
sion, 28 U.S.C. (1946 ed.) § 71, separable controversies authorized removal of the suit. 'Controversy' had long been associated in legal thinking with 'case.' It covered all disputes that might come before federal courts for adjudication. In § 71 the removable 'controversy' was interpreted as any possible separate suit that a litigant might properly bring in a federal court so long as it was wholly between citizens of different states. So, before the revision, when a suit in a state court had such a separate federally cognizable controversy, the entire suit might be removed to the federal court. 4
A separable controversy is no longer an adequate ground for removal unless it also constitutes a separate and independent claim or cause of action. Compare Barney v. Latham, 103 U.S. 205 , 212, 26 L.Ed. 514 , with the revised § 1441. Congress has authorized removal now under § 1441(c) only when there is a separate and independent claim or
Page 12
cause of action. 5 Of course, 'separate cause of action' restricts removal more than 'separable controversy.' In a suit covering multiple parties or issues based on a single claim, there may be only one cause of action and yet be separable controversies. 6 The addition of the word 'independent' gives emphasis to congressional intention to require more complete disassociation between the federally cognizable proceedings and those cognizable only in state courts before allowing removal.
The effectiveness of the restrictive policy of Congress against removal depends upon the meaning ascribed to 'separate and independent * * * cause of action'.§ 1441. Although 'controversy' and 'cause of action' are treated as synonymous by the courts in situations where the present considerations are absent, 7 here it is obvious different concepts are involved. 8 We are not unmindful that the phrase 'cause of action' has many meanings. 9 To accomplish its purpose of limiting and simplifying removal, Congress used the phrase 'cause of action' in an accepted meaning to obtain that result. By interpretation we should not defeat that purpose.
In a suit turning on the meaning of 'cause of action,' this Court announced an accepted description.Balti-
Page 13
more S.S. Co. v. Phillips, 274 U.S. 316 , 47 S.Ct. 600 , 71 L.Ed. 1069 . 10 This Court said, 274 U.S. at page 321, 47 S.Ct.at page 602:
'Upon principle, it is perfectly plain that the respondent suffered but one actionable wrong and was entitled to but one recovery, whether his injury was due to one or the other of several distinct acts of alleged negligence or to a combination of some or all of them. In either view, there would be but a single wrongful invasion of a single primary right of the plaintiff, namely, the right of bodily safety, whether the acts constituting such invasion were one or many, simple or complex.
'A cause of action does not consist of facts, but of the unlawful violation of a right which the facts show.'
See Magnolia Petroleum Co. v. Hunt, 320 U.S. 430 , 443, 64 S.Ct. 208 , 215, 88 L.Ed. 149 . 11 Considering the previous history of 'separable controversy,' the broad meaning of 'cause of action,' and the
Page 14
congressional purpose in the revision resulting in 28 U.S.C. § 1441(c) , 28 U.S.C.A. § 1441(c), we conclude that where there is a single wrong to plaintiff, for which relief is sought, arising from an interlocked series of transactions, there is no separate and independent claim or cause of action under § 1441(c). 12
In making this determination we look to the plaintiff's pleading, which controls. Pullman Co. v. Jenkins, 305 U.S. 534 , 538, 59 S.Ct. 347 , 349, 83 L.Ed. 334 . 13 The single wrong for which relief is sought is the failure to pay compensation for the loss on the property. Liability lay among three parties, but it was uncertain which one was responsible. Therefore, all were joined as defendants in one petition. First, facts were stated that made the petitioner, American Fire and Casualty Company, liable. It was alleged that the company, through...
1246 practice notes
Meritcare Inc. v. St. Paul Mercury Ins. Co., No. 98-3032 United States U.S. Court of Appeals — Third Circuit January 25, 1999 ...is not established until the case is on appeal, the judgment of the District Court cannot stand. See American Fire & Casualty Co. v. Finn, 341 U.S. 6 , 17-19, 71 S.Ct. 534, 95 L.Ed. 702 (1951); Knop v. McMahan, 872 F.2d 1132, 1139 (3d Cir.1989). In circumstances where two or more plaintiffs ......
Ramirez v. Humana, Inc., No. 6:00CV1108-ORL-31B. United States United States District Courts. 11th Circuit. United States District Court of Middle District of Florida October 27, 2000 ...jurisdictional grants are not to be expanded by judicial decree. Id. at 377, 114 S.Ct. 1673, (citing American Fire & Casualty Co. v. Finn, 341 U.S. 6 , 71 S.Ct. 534, 95 L.Ed. 702 (1951)). It is to be presumed that a cause lies outside this limited jurisdiction, id. at 377, 114 S.Ct. 1673 (ci......
Fed. Nat'l Mortg. Ass'n v. Morris, Case No. 2:15–cv–0798–JEO. United States United States District Courts. 11th Circuit. United States District Court of Northern District of Alabama July 31, 2015 ...series of transactions, there is no separate and independent claim or cause of action under § 1441(c)." American Fire & Cas. Co. v. Finn, 341 U.S. 6 , 14, 71 S.Ct. 534, 95 L.Ed. 702 (1951). Now, however, the statute authorizes removal when "a civil action includes" both a removable federal c......
Simmons v. State of Cal., Dept. of Indus. Rel., No. Civ. S-89-1347 LKK. United States United States District Courts. 9th Circuit. United States District Courts. 9th Circuit. Eastern District of California June 20, 1990 ...I restate those reasons here. The purpose of section 1441(c) is to limit removal jurisdiction. See American Fire & Casualty Co. v. Finn, 341 U.S. 6 , 10, 71 S.Ct. 534, 538, 95 L.Ed. 702 (1951). The crucial determination under section 1441(c) is whether a truly separate and independent cause ......
1244 cases
Powers v. South Central United Food & Commercial Workers Unions and Employers Health & Welfare Trust, No. 82-2319 United States United States Courts of Appeals. United States Court of Appeals (5th Circuit) October 31, 1983 ...of the congressional intent to restrict the jurisdiction of federal courts on removal. See American Fire & Casualty Co. v. Finn, 341 U.S. 6 , 10, 71 S.Ct. 534, 538, 95 L.Ed. 702 (1951) ("The Congress, in [Sec. 1441], carried out its purpose to abridge the right of removal"); Shamrock Oil & G......
Welch v. Texas Department of Highways and Public Transportation, No. 85-1716 United States United States Supreme Court June 25, 1987 ...Moreover, the courts properly are reluctant to infer that Congress has expanded our jurisdiction. See American Fire & Casualty Co. v. Finn, 341 U.S. 6 , 17, 71 S.Ct. 534, 541-542, 95 L.Ed. 702 (1951) ("The jurisdiction of the federal courts is carefully guarded against expansion by judicial ......
Leathers v. Leathers, No. 15-3264 United States United States Courts of Appeals. United States Court of Appeals (10th Circuit) May 2, 2017 ...the judgment." See Feichko v. Denver & Rio Grande W. R.R. Co., 213 F.3d 586, 590–91 (10th Cir. 2000) (quoting Am. Fire & Cas. Co. v. Finn, 341 U.S. 6 , 16, 71 S.Ct. 534, 95 L.Ed. 702 (1951) ); accord Caterpillar Inc. v. Lewis, 519 U.S. 61, 72–73, 117 S.Ct. 467, 136 L.Ed.2d 437 (1996).14 Even......
Seminole Tribe Florida v. Florida, 9412 United States United States Supreme Court March 27, 1996 ...California v. LaRue, 409 U.S. 109, 112-113, n. 3, 93 S.Ct. 390, 394, n. 3, 34 L.Ed.2d 342 (1972); American Fire & Casualty Co. v. Finn, 341 U.S. 6 , 17-18, and n. 17, 71 S.Ct. 534, 541-542, and n. 17, 95 L.Ed. 702 (1951); Mitchell v. Maurer, 293 U.S. 237, 244, 55 S.Ct. 162, 165, 79 L.Ed. 338......
1 books & journal articles
| https://case-law.vlex.com/vid/american-fire-casualty-co-895545429 |
LCQ10: Strengthening monitoring of performance of contractors for public works
LCQ10: Strengthening monitoring of performance of contractors for public works
Following is a question by the Dr Hon Lau Siu-lai and a written reply by the Secretary for Development, Mr Eric Ma, in the Legislative Council today (June 14):
Question:
Last month, the Independent Commission Against Corruption (ICAC) arrested 21 staff members of a public works laboratory, who were suspected of corruption and having submitted to the Civil Engineering and Development Department (CEDD) falsified concrete compression test reports associated with the works under the Hong Kong-Zhuhai-Macao Bridge Hong Kong (HZMB) and related projects. The laboratory is operated by an outsourced service provider (the contractor concerned) engaged by the CEDD. Moreover, the CEDD suspected in July last year that the testing time recorded in some of the test reports had been tampered with by the staff of that laboratory (report-tampering incident). The contractor concerned admitted to the CEDD in September last year that the reports had been tampered with by its staff in order to make the testing time shown in the records fall within the required timeframe. However, not until the aforesaid arrest was reported did the CEDD make public the incident. In this connection, will the Government inform this Council:
(1) of the reasons why the CEDD did not make public the report-tampering incident during the period from September last year, when the incident was confirmed, to last month;
(2) of the existing mechanisms whereby the various government departments notify each other and make public those accidents, blunders and irregularities which occurred in public works projects (including alleged falsifications by contractors);
(3) whether the contractor concerned has, since 2012, been awarded any contract for conducting concrete tests for other public works projects; if so, set out by year in a table the following information of each contract: (i) contract number, (ii) project title, (iii) tender acceptance date, (iv) works commencement date, (v) anticipated works completion date, (vi) costs involved, and (vii) government department(s) awarding the contract;
(4) whether the authorities will immediately conduct (i) visual inspections, (ii) non-destructive concrete strength tests (commonly known as "Schmidt Hammer Tests"), and (iii) core tests on the structures built under the projects mentioned in (3), so as to allay public concern; if so, of the details; if not, the reasons for that;
(5) how the authorities will handle the uncompleted contracts of the contractor concerned; and
(6) given that after the report-tampering incident had been confirmed, the CEDD did not impose any punishment on the contractor concerned other than the issuance of an adverse Quarterly Consultants' Performance Appraisal Report to it, and the CEDD has not suspended the contractor concerned from tendering for public works and, instead, awarded it a new contract for public works in March this year, whether the authorities will (i) tighten the mechanisms for selecting contractors for public works and evaluating their performance and (ii) increase the penalties for malpractice/default by contractors, so as to enhance the deterrent effect; if so, of the details; if not, the reasons for that?
Reply:
President,
The Government always accords top priority to the safety and quality of infrastructure projects. We will not tolerate any act that puts the safety and quality of works at risk. Indeed, the Government has all along attached great importance to quality assurance in public works projects, including the testing work in laboratories, and has required strict compliance with internationally recognised quality management procedures to ensure the works quality.
The aforementioned quality management procedures were proved effective in the incident as anomalies in the testing records had been identified by the Civil Engineering and Development Department (CEDD). Upon discovery of suspected tampering of testing time in the testing records of the concerned laboratory in mid-2016, the CEDD has taken follow-up actions proactively, including comprehensive review and upgrading of the system of the laboratories under its purview to prevent recurrence of similar incidents. Also, the CEDD has reported the case to the Independent Commission Against Corruption (ICAC) and rendered full assistance to and co-operation with the ICAC during its investigation.
At the Special Meeting of the Panel on Transport held on June 5, 2017, we explained the quality assurance system for use of concrete in the public works projects and reported the latest developments of the follow-up actions by the CEDD into the alleged falsification of concrete test reports in respect of the works under the Hong Kong-Zhuhai-Macao Bridge Hong Kong Section and related projects.
My reply to the Dr Hon Lau Siu-lai's questions is as follows:
(1) and (6) Upon discovery of the suspected tampering of testing time in some concrete testing records of the concerned laboratory in mid-2016, the CEDD immediately commenced an investigation to review and assess the relevant testing records of the concerned laboratory. Its findings revealed that the delays in conducting the tests were relatively short and the rate of gain in compressive strength of concrete would have slowed down and become stable beyond the age of 28 days. As such, the CEDD considered that the effect of the testing time adjustments was insignificant.
In the light of the information obtained at that time, the CEDD immediately gave an adverse report to the consultant concerned in its quarterly performance appraisal and requested the consultant to undertake improvement measures. Such measures included replacing the consultant's staff in charge of the laboratory concerned, deploying additional supervisory staff and upgrading the testing equipment to prevent unauthorised resetting of testing times as well as arranging refresher training on concrete testing for the consultant's staff and reminding them on the essence of integrity management. Under the prevailing mechanism, works departments would consider the information in hand and the seriousness of incidents in determining any appropriate regulating action(s) to take. Having reviewed the overall situation, including the consultant's improvement measures undertaken, the CEDD considered that it was not necessary to take further regulating action (including suspension of the consultant from tendering) since no evidence showing other suspected falsification malpractices of the consultant was revealed at that time. For the sake of prudence, the CEDD subsequently reported the case to the ICAC for further investigation. During the process, the CEDD had to comply with the internal guidelines on confidentiality requirement and refrain from making public the incident to avoid compromising the investigation.
Having been notified by the ICAC about the discovery of suspected falsification malpractice of the consultant involving replacement of test samples during its investigation in May this year, and with the information provided by the ICAC, the CEDD immediately conducted a follow-up investigation to examine the raw data of the concrete testing records of the laboratory concerned for the period from January 2015 to June 2016. About 0.1 per cent of the test records were found to involve suspected falsification by replacement of test samples. In the light of its latest findings, the CEDD immediately issued to the consultant a performance report with an "unacceptable" rating. With the endorsements of the Architectural and Associated Consultants Selection Board and the Engineering and Associated Consultants Selection Board, the CEDD suspended the consultant from tendering for all categories of architectural and engineering consultancy agreements within the jurisdiction of the two Boards for a period of twelve months with effect from June 2, 2017. Depending on the future development of the case, the Government may consider extending the suspension period or taking further regulating action(s) against the consultant when appropriate. In other words, the current regulating mechanism has already empowered the Government to take regulating actions with deterrent effect where necessary. Furthermore, the Development Bureau (DEVB) is conducting a review, with a view to further enhancing the management of architectural and engineering consultants.
(2) In case of major emergency incidents or industrial accidents occurring in public works projects, works departments would notify the government departments concerned and the Works Branch of the DEVB in accordance with the relevant works technical circular (Note 1) and the Construction Site Safety Manual (Note 2). Works departments would upload or access the information about the regulating actions taken against contractors or consultants for public works projects in relation to their contract performance, including suspension from tendering, through the computer systems for the management of contractors and consultants.
In case of any instance of crime or alleged crime, works departments concerned would report it to the appropriate enforcement authority directly in accordance with their internal guidelines. Generally, works departments would not make public these instances after making referral to the enforcement authorities for investigation to avoid hindering or affecting their investigation.
In general, the DEVB and works departments would take into account the seriousness of individual incidents and whether they involve public interest or cause serious impact on the public and possible judicial procedures in considering whether to make them public timely.
(3) to (5)
Since 2012, the consultant concerned has been awarded another two consultancy agreements from the CEDD for management and operation of laboratories. Details are as follows:
Award date Service commencement date Expected service completion date Lump sum fee at award ($ million) Consultancy Agreement 1 June 2014 July 2014 August 2018 57 Consultancy Agreement 2 March 2015 April 2015 July 2019 44
In addition to the laboratory concerned (Note 3), the CEDD has examined the concrete compression test results of other regional laboratories (including the two laboratories in operation as mentioned in the table above) and no anomaly was found. Therefore, there is no need to conduct inspection and testing again for the public works projects served by these two laboratories.
The CEDD has also immediately implemented further improvement measures in all the laboratories under its purview (including the two laboratories in operation as mentioned in the table above). The measures included deployment of additional government staff to monitor the outsourced laboratories, arranging different laboratories to carry out concrete tests for public works projects on a rotational basis, increasing the number of parallel testing which testifies the consistency of the testing performance of different laboratories, strengthening routine auditing check on test records, and arranging installation of additional closed circuit televisions for monitoring concrete tests in detail. The CEDD is currently reviewing its procedures for testing concrete cubes and will introduce other improvement measures as and when necessary.
In addition to the above improvement measures, the DEVB issued a circular memorandum in May this year requesting the works departments to review and step up the monitoring of the performance of the architectural and engineering consultants engaged by them, particularly from the integrity management and quality assurance perspectives. The works departments will continue to closely monitor the services delivered by the consultant concerned and will conduct the necessary technical audits.
Note 1: For the Technical Circular (Works) No. 20/2005 (English version only), please refer to the link below:
www.devb.gov.hk/filemanager/technicalcirculars/en/upload/21/1/C-2005-20-0-1.pdf
Note 2: For the Construction Site Safety Manual (English version only), please refer to the link below:
www.devb.gov.hk/en/publications_and_press_releases/publications/construction_site_safety_manual/index.html
Note 3: The laboratory concerned ceased operation in March 2017.
Ends/Wednesday, June 14, 2017Issued at HKT 17:35NNNN
| http://www.info.gov.hk/gia/general/201706/14/P2017061400742p.htm |
(PDF) Response to “Black Box Warning Did Not Cause Increased Suicides”
PDF | On Mar 11, 2021, Stephen B. Soumerai and others published Response to “Black Box Warning Did Not Cause Increased Suicides” | Find, read and cite all the research you need on ResearchGate
Response to “Black Box Warning Did Not Cause Increased Suicides”
Psychiatric Research and Clinical Practice 3(2)
DOI: 10.1176/appi.prcp.20200039
License
CC BY-NC-ND 4.0
University of Colorado
LETTER TO THE EDITOR
Response to “Black Box Warning Did Not Cause
Increased Suicides”
Stephen B. Soumerai, ScD, Robert B. Penfold, PhD, Anne M. Libby, PhD, Christine Y. Lu, PhD, MSc
In their letter regarding our recent PRCP study ( 1 ), Spiel-
mans et al. demonstrate a lack of familiarity with rigorous
quasi ‐ experimental research designs. Such designs, how-
ever, are essential in studies of health policies, which can
seldom or ever be randomized, for example, one can't issue
national drug safety warnings to a random sample of the
population. Before responding to their specific conclusions,
we would like to refer readers to an informative table of the
hierarchy of strong and weak research designs. Table 1 is
based on 100s of years of science ( 2 ). It shows a hierarchy of
strong research designs that often yield valid results, in
contrast to weak designs without baselines (cited by Spiel-
mans et al.) that are largely untrustworthy (i.e., post ‐ only
designs without baselines cannot control for common bia-
ses, such as history bias and secular trends) ( 3 ).
Further guidance on research design hierarchy is
available ( 4–6 ).
Spielmans et al. critique our strong interrupted time ‐ se-
ries (ITS) with comparison series study (multi ‐ age groups
used as comparisons) by citing uncontrolled post ‐ only de-
signs—which are at the bottom of the hierarchy of research
designs—alleging that our study proved no effects of black
box warnings on antidepressant use. Without a baseline it is
impossible to estimate the counterfactual pre ‐ intervention
trend (what would have happened in the policy's absence).
The simple truth is that it is misleading to attempt to mea-
sure a change occurring after a policy is enacted in the
absence of any baseline (pre ‐ intervention) measure.
Spielmans et al. conclude that treatment of youth
depression has not declined substantially since the warn-
ings, and they defend this statement by a misleading and
selective observation that “Lu et al (our previous study)
found a decrease in …treatment of less than one percentage
point.” This conclusion is false when one simply observes
the sudden and sustained change in trend of antidepressant
use after a substantial increase in trend during the 14 quar-
terly baseline observations before the advisory (Figure 1 ).
What is immediately apparent in Figure 1 is that the “less
than one percentage point” reduction in treatment was from
less than a 2 percent prevalence of treatment just before the
warnings. (The denominator was all adolescents and the
relative reduction was greater than 30 percent. Thus, by
ignoring the relative reduction, Spielmans et al. understate
the effect by more than 30 times.) The difference (effect)
between the counterfactual baseline trend and the actual
observation at the time of the second black box warning is
almost 50% of all adolescents per quarter (approximately 1.1
million adolescents in the 11 US health systems). Failing to
provide both absolute and relative changes in effect esti-
mates is a major bias in both media and scientific reporting of
the effects of health technologies and policies. Such failings
distort findings in ways that adversely affects both science
and health policies, sometimes with patient harms ( 7 , 8 ).
The sudden reduction in the above ITS and comparison
series study is evident to a non ‐ scientist—the tremendous
decrease in both level and slope, controlling for the rising
baseline trend probably persisted for about 7 years
following the initial advisory warning in the fall of 2003.
But we conservatively estimated medication use and sui-
cidality effects only for several years beyond the warnings
because the confidence intervals of ITS effects gradually
become wider over time.
The other studies cited by Spielmans et al. to refute our
results (that the warnings reduced treatment) are weak
post ‐ only designs (Table 1 ) with uninterpretable findings
that violate the basic research design criteria of the
worldwide Cochrane Collaboration's systematic reviews
( 9–11 ). Post ‐ only studies are excluded altogether from any
rigorous Cochrane reviews ( 12 ). Studies with insufficient
baseline trends (pre ‐ post designs) also offer weak, if any,
evidence of causal inference. For example, the Valluri
study has only three monthly data points before the first
advisory (Oct. 2003) and none from prior years. The data
showing the well ‐ known, steep rise in antidepressant use
before the first advisory (see baseline in Figure 1 ) are
missing in the Valluri paper; absent these critical obser-
vations of baseline trends, their data are insufficient.
Moreover, their paper lacks any data occurring during the
[Corrections added on March 16, 2021 after first online publication: The title has been revised.]
Psych Res Clin Pract. xx:0, 2021 prcp.psychiatryonline.org 1
second black box warning in 2007, as well as any other
year after the warning. Effect estimates (change from
before to after) are impossible without reliable measures of
the pre ‐ and post ‐ policy trends. Similarly, Kafali et al
cannot reliably measure pre ‐ advisory counterfactual
trends with only three points. Baseline trends can be ris-
ing, stable or falling; without adequate baseline data, at-
tempts to measure before ‐ to ‐ after changes are biased, and
all too frequently misleading and deceptive.
Speilmans et al. then cite post ‐ only correlations be-
tween antidepressant use and suicide attempts only after
the warnings began, representing ecological fallacies
without any baseline. This claim is based on Ploderl's
study using self ‐ reported antidepressant use and self ‐ re-
ported suicide attempts. Correlations based on self ‐ re-
ported measures are often severely compromised by recall
and social desirability biases.
In their previously published narrative review, Speil-
mans et al. ( 13 ) incorrectly depict our prior ITS study as an
ecological study examining the relationship between an-
tidepressants and suicide attempts. Narrative reviews are
inadequate for informing policy ‐ making because they do
not assess the methodological quality of studies in the field
before summarizing credible results. Our ITS studies and
TABLE 1. Hierarchy of strong designs and weak designs, based on design's capacity to control for most biases
Hierarchy of designs for interventions
Strong designs
Multiple randomized controlled trials The “gold standard” of evidence, incorporating many RCTs of an
intervention
Randomized controlled trials A strong design, but sometimes not feasible or generalizable,
especially for health policies
Interrupted time series with a control series Strong quasi ‐ experimental design that controls for common biases.
This design has two controls: baseline trend and control group to
measure sudden discontinuities in trend soon after an
intervention.
Intermediate designs
Single interrupted time series Measures changes in level or slope of trend controlling for baseline
trend, but has no comparison group
Before and after with comparison group (single observations,
sometimes called “difference in difference” design)
Pre ‐ post changes using single observations. Comparability of
baseline trend often unknown
Weak designs No controls for common biases, excluded from literature syntheses
Uncontrolled before and after (pre ‐ post) Single observation before and after, no baseline trends
Cross ‐ sectional or post ‐ only designs Simple correlation, no baseline, no measure of change from before
intervention
Source: Soumerai SB et al. Prev Chronic Dis. 2015; 12:E101.
FIGURE 1. Rates of antidepressant use per quarter before and after the warnings among adolescents enrolled in 11 health plans in
nationwide mental health research network. BMJ. 2014; 348:g3596.
2 prcp.psychiatryonline.org Psych Res Clin Pract. xx:0, 2021
LETTER TO THE EDITOR
other studies that we cited ( 14–21 ) employed rigorous
quasi ‐ experimental research methods to examine the ef-
fects of FDA warnings on antidepressant use, non ‐ drug
treatments, suicide attempts, and suicides. As shown in
Table 1 and in major research design texts and the
Cochrane Collaboration, research on drug safety policies
require strong quasi ‐ experimental designs (preferably ITS
with comparison series to assess interruptions in trends,
controlling for pre ‐ policy levels and slopes). The ITS de-
signs can control for many biases, such as history, matu-
ration, and selection ( 4 ). Our study measured the
multifactorial effects of risk communications. We did not,
as stated by Spielmans, study “whether a drug causes
suicidality.” Nor did w e measure the adverse effects of
policy ‐ induced reductions in medications alone. Most of
the effects were related to demonstrated reductions in
both drug and non ‐ drug depression treatment rates
following the warnings ( 14–21 ).
The majority of longitudinal ITS studies have demon-
strated, in different large samples (including national), that
the youth antidepressant warnings have almost simulta-
neous, unintended effects on identification of depression,
psychotherapy, antidepressant treatment, suicidal behavior ,
and suicide deaths ( 15–21 ). They cause sudden shifts in the
level and slopes of the trends. A public health policy analysis
cannot ignore this number of simultaneous unintended
outcomes in different datasets. The burden of proof of policy
harms should be on the policymakers creating those pol-
icies, not on the outside scientists who have no or fewer
conflicts of interest ( 22 ).
Together, findings from these ITS studies (including
our own) suggest the boxed warnings may have contrib-
uted to the very thing FDA was trying to prevent: youth
suicidal behavior and suicides. Even before COVID, more
than two thirds of depressed teens did not receive any
depression care ( 23 ), an issue now further exacerbated by
both the pandemic and the continuing barrage of alarming
suicidality warnings contained in all drug labels and TV
advertisements. It is time for the FDA to err on the side of
caution and reduce the severity of the continuing antide-
pressant warnings.
AUTHOR AND ARTICLE INFORMATION
Department of Health Services Research, Kaiser Permanente
Washington Health Research Institute and University of Washington,
Seattle, (Penfold); Department of Emergency Medicine, School of
Medicine, University of Colorado, Anschutz Medical Campus, Denver,
(Libby); Department of Population Medicine, Harvard Medical
School and Harvard Pilgrim Health Care Institute, Boston, Massachu-
setts, (Soumerai, Lu).
Send correspondence to Dr. Soumerai ( [email protected] ).
The authors declare no conflict of interest.
This is a Response to a Letter available here: [ https://doi.org/10.1176/
appi.prcp.20200038 ]. The Article that is the subject of the Letter is
available here: [ 10.1176/appi.prcp.20200012 ].
This is an open access article under the terms of the Creative Commons
Attribution ‐ NonCommercial ‐ NoDerivs License, which permits use and
distribution in any medium, provided the original work is properly cited,
the use is non ‐ commercial and no modifications or adaptations are
made.
© 2021 The Authors. Psychiatric Research and Clinical Practice pub-
lished by Wiley Periodicals LLC. on behalf of the American Psychiatric
Association.
Received December 30, 2020; revised December 30, 2020; accepted
January 3, 2021.
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LETTER TO THE EDITOR
4 prcp.psychiatryonline.org Psych Res Clin Pract. xx:0, 2021
... Strong critiques of these claims argue that arbitrary inferences drawn from convenient measures do not substantiate the long-term data
(Soumerai et al., 2021)
. In a nutshell, there was no change in the overall suicide rates and there is not enough evidence to link these observations with FDA warnings (Henry et al., 2012;Cuffe, n.d.). ...
FDA Black Box Warning for SSRI: Reexamining the Role of High-Functioning Autism as a Confounder
It is two decades since the start of controversy around the FDA’s warnings of SSRI use in children and adolescents. A detailed review of these debates provides information on many serious methodological limitations, omissions, and commissions. In the last decade, the knowledge of highly comorbid conditions with MDD like ASD has grown exponentially. The higher-than-ever prevalence and diagnostic overshadowing in higher functioning ASD are now widely accepted; likewise, late and missed diagnoses are common and more in females with HF-ASD. The FDA signal has clinical implications, and if a small proportion of undiagnosed ASD comorbid with MDD was confounded in the data remains unanswered. A scientific inquiry is needed to understand the relationship between ASD, affective illness, and suicide.
Black Box Warning Did Not Cause Increased Suicides
Increases in Suicide Deaths Among Adolescents and Young Adults Following US Food and Drug Administration Antidepressant Boxed Warnings and Declines in Depression Care
Objective:
Studies show decreased depression diagnosis, psychotherapy, and medications and increased suicide attempts following US Food and Drug Administration antidepressant warnings regarding suicidality risk among youth. Effects on care spilled over to older adults. This study investigated whether suicide deaths increased following the warnings and declines in depression care.
Methods:
We conducted an interrupted time series study of validated death data (1990-2017) to estimate changes in trends of US suicide deaths per 100,000 adolescents (ages 10-19) and young adults (ages 20-24) after the warnings, controlling for baseline trends.
Results:
Before the warnings (1990-2002), suicide deaths decreased markedly. After the warnings (2005-2017) and abrupt declines in treatment, this downward trend reversed. There was an immediate increase of 0.49 suicides per 100,000 adolescents, 95% confidence interval [CI]: 0.12, 0.86) and a trend increase of 0.03 suicides per 100,000 adolescents per year (95% CI: 0.026, 0.031). Similarly, there was an immediate increase of 2.07 suicides per 100,000 young adults (95% CI: 1.04, 3.10) and a trend increase of 0.05 suicides per 100,000 young adults per year (95% CI: 0.04, 0.06). Assuming baseline trends continued, there may have been 5958 excess suicides nationally by 2010 among yearly cohorts of 43 million adolescents and 21 million young adults.
Conclusions:
We observed increases in suicide deaths among youth following the warnings and declines in depression care. Alternative explanations were explored, including substance use, economic recessions, smart phone use, and unintentional injury deaths. Additional factors may have contributed to continued increases in youth suicide during the last decade. Combined with previous research on declining treatment, these results call for re-evaluation of the antidepressant warnings.
Duty to Warn: Antidepressant Black Box Suicidality Warning Is Empirically Justified
| https://www.researchgate.net/publication/350171100_Response_to_Black_Box_Warning_Did_Not_Cause_Increased_Suicides |
Land | Free Full-Text | Impact of Transhumant Livestock Grazing Abandonment on Pseudo-Alpine Grasslands in Greece in the Context of Climatic Change
Pseudo-alpine grassland ecosystems have started to decline during the past few decades. According to many studies, climate change and abandonment of traditional anthropogenic activities are directly linked to this phenomenon. However, the interaction of these two factors with pseudo-alpine grasslands has not been studied in Greece. The aim of this study was to assess the impact of climatic change and abandonment of transhumant livestock grazing on pseudo-alpine grassland ecosystems structure and stability in Mt Vermio and Mt Zireia. Geographic Information System data on land use/land cover from 1945 and 2020, as well as climatological and livestock data, have been examined and presented. Landscape metrics were also used to quantify landscape structure changes. Although both mountains’ pseudo-alpine grasslands have reduced in size, Mt Zireia has experienced an upward treeline shift, which seems to be the result of climate change, while in Mt Vermio, the more severe transhumance abandonment caused horizontal tree expansion. There are strong indications that a rise in temperature is the main driver for the upward increase in treeline.
Impact of Transhumant Livestock Grazing Abandonment on Pseudo-Alpine Grasslands in Greece in the Context of Climatic Change
Laboratory of Rangeland Ecology, School of Forestry and Natural Environment, Aristotle University of Thessaloniki, P.O. Box 286, 54124 Thessaloniki, Greece
2
Laboratory of Mountainous Water Management and Control, School of Forestry and Natural Environment, Aristotle University of Thessaloniki, P.O. Box 268, 54124 Thessaloniki, Greece
*
Author to whom correspondence should be addressed.
Land 2022 , 11 (12), 2126; https://doi.org/10.3390/land11122126
Received: 31 October 2022 / Revised: 16 November 2022 / Accepted: 21 November 2022 / Published: 25 November 2022
(This article belongs to the Special Issue Land Development and Management Strategies for Climate Change Adaptation )
Abstract
Pseudo-alpine grassland ecosystems have started to decline during the past few decades. According to many studies, climate change and abandonment of traditional anthropogenic activities are directly linked to this phenomenon. However, the interaction of these two factors with pseudo-alpine grasslands has not been studied in Greece. The aim of this study was to assess the impact of climatic change and abandonment of transhumant livestock grazing on pseudo-alpine grassland ecosystems structure and stability in Mt Vermio and Mt Zireia. Geographic Information System data on land use/land cover from 1945 and 2020, as well as climatological and livestock data, have been examined and presented. Landscape metrics were also used to quantify landscape structure changes. Although both mountains’ pseudo-alpine grasslands have reduced in size, Mt Zireia has experienced an upward treeline shift, which seems to be the result of climate change, while in Mt Vermio, the more severe transhumance abandonment caused horizontal tree expansion. There are strong indications that a rise in temperature is the main driver for the upward increase in treeline.
Keywords:
Mt Zireia
;
Mt Vermio
;
landscape metrics
;
treeline shift
;
temperature
;
grazing
;
GIS
;
land use/land cover change
1. Introduction
Alpine and pseudo-alpine grasslands are uncultivated areas with natural vegetation, mainly herbaceous plants, managed with ecological principles [ 1 , 2 ] and characterized by harsh climatic conditions that limit the plant growth period to a few months [ 3 ]. In Greece, forest boundaries are between 1700 and 2000 m [ 4 ], however, grasslands over 1200 m are ecologically connected to the pseudo-alpine zone and are therefore considered as pseudo-alpine [ 5 ]. They are among the European regions where conservation is of the utmost importance (Council Directive 92/43/EEC of 21 May 1992) [ 6 ] and they make up most of Greece’s Special Protection Zones for Mountainous Areas [ 7 ].
Alpine and pseudo-alpine grasslands are hotspots for biodiversity and have significant cultural heritage values [ 8 ], supporting numerous rare and/or endangered animals and plants species. They provide many ecosystem services, such as nitrogen (N) and carbon (C) storage [ 6 , 9 ], water purification and retention [ 6 , 10 ], valuable genetic material storage [ 2 ], provision of pharmaceuticals [ 11 ], soil conservation [ 9 , 11 ], nutrient recycling, pollination and climate regulation [ 11 ], forage for animals [ 11 ], and can generate substantial economic value through the production of meat and milk [ 6 ]. They represent areas for recreation, tourism, and cultural heritage [ 6 , 9 , 11 ] and create a sustainable framework that ensures the future of rural areas [ 2 ].
Species diversity, ecosystem function and landscape structure in pseudo-alpine grasslands, like most terrestrial ecosystems, are concurrently affected by global climate change and anthropogenic activities such as livestock grazing, agriculture, urbanization, etc. [ 12 , 13 , 14 , 15 , 16 , 17 , 18 ]. Changes in vegetation pattern and floristic composition are the main effects of livestock grazing on the landscape. The nature and extent of these changes depend on livestock species [ 19 ], grazing period, pressure, and history [ 20 , 21 , 22 ], as well as on abiotic variables such as soil type, temperature, and precipitation [ 15 , 23 ].
Pseudo-alpine grasslands are often referred to as summer grasslands because they are grazed in the summer. For this reason, they were mostly associated with transhumance [ 24 ]. In the past, these grasslands were the hub of summer grazing activities with animals and herders, along with their families, living there for more than five months each year [ 25 ]. The animals arrived at the end of spring and left at the end of the summer, grazing the abundant annual growth of forage species. The herders made efficient use of natural resources and created unique natural landscapes [ 26 , 27 ], while also enhancing the genetic diversity by rearing autochthonous breeds and providing ecosystem services [ 28 , 29 ]. In addition, transhumance protected rural livelihoods, reducing the depopulation of marginal and remote areas, and effectively mitigated climate change effects (e.g., soil carbon stock in rangelands) [ 26 ].
Transhumance during the centuries has had a major impact on landscape structure, vegetation composition, and ecosystem services in the mountainous areas [ 30 , 31 , 32 ] not only in many Mediterranean mountains [ 33 ], but also in high mountains such as the Himalayas [ 34 ]. This kind of animal husbandry has helped conserve the rangelands and open forests—two important types of landscape. The decline in the transhumant livestock system over the last few decades has impacted the structure and composition of grassland ecosystems [ 30 , 35 ] and has reduced their multi-functionality, particularly in regions where grazing was prohibited for an extended period of time [ 35 ]. In addition to livestock grazing, strong evidence suggests that global warming is leading to dramatic shifts in structure, species diversity, and functioning in alpine vegetation communities [ 3 , 15 , 36 , 37 ]. Although climate change is affecting the entire globe, alpine regions are particularly vulnerable to its consequences [ 38 , 39 , 40 ]. The increase in air temperature may change the type of vegetation from grasslands to shrublands and finally to forests [ 41 ]. Most of the uses involving woody species tend to integrate rapidly, now forming a more homogeneous mosaic landscape [ 42 ].
Despite significant regional variations, the majority of Europe has seen temperature rises of roughly 0.8 °C on average this century [ 43 ]. The impact of climate change varies with latitude [ 44 , 45 , 46 ], with southern, drier regions being more affected than northern ones [ 43 , 47 ]. Treeline shifts due to climate change and the cessation of transhumance have significant implications for pseudo-alpine grassland spatial distribution [ 48 ]. In the Central Austrian Alps, for example, treelines that have been impacted by pastoral use for centuries respond to climate change differently than treelines that have not been altered [ 49 ].
Numerous studies demonstrate that grazing increases spatial heterogeneity, mostly because of differences between grazed and ungrazed patches as well as other grazing-related effects such as manuring and trampling [ 50 ]. A shift in treeline results in changes in the edge habitat, which could lead to either landscape fragmentation or homogenization, loss of diversity [ 20 , 51 ], and poses a major threat to the conservation value of grasslands [ 11 ]. Landscape spatial structure changes can be better described and quantified using landscape metrics [ 52 , 53 , 54 , 55 ].
While there have been numerous studies on how climate change affects treeline, there are no studies, as far as we are aware, about alpine grasslands. The changes in both climate and land use pose a threat to the long-term survival of the existing plant mosaic in the pseudo-alpine grasslands [
8
]. This study aimed to investigate the impact of climatic change and abandonment of transhumant livestock grazing system on the pseudo-alpine grassland ecosystem structure and stability of two mountains in Greece. We set out to answer the following question: Does the climate and the abandonment of transhumance affect land use changes in the pseudo-alpine zone, and how?
2. Materials and Methods
2.1. Study Area
The research was conducted on Mt Vermio and Zireia, in the pseudo-alpine zone over 1200 m ( Figure 1 ).
Figure 1. The study areas (red outline) in Mt Vermio (North Greece) and Mt Zireia (South Greece).
Mt Vermio is located in central-western Macedonia and administratively belongs to Imathia, Kozani, and Pella Regional Units. It has a north-south orientation with its tallest peak at 2052 m [ 25 ]. The climate is sub-Mediterranean in the uplands and meso-Mediterranean in the lowlands. The driest months are July and August, but due to the vicinity of archipelagos, the atmosphere is never completely dry [ 56 ]. The climate under the Köppen and Geiger [ 57 ] classification system ranges from Mediterranean-influenced warm-summer humid continental (Dsb) to warm-summer humid continental (Dfb). According to the classification approach of Mavromatis [ 58 ], Mt Vermio belongs to the bioclimatic zone wet with severe winter and to two different bioclimatic character categories: axeric temperate and sub-Mediterranean. Most of Mt Vermio is part of the network of the Natura 2000 protected areas [ 59 ]. Forests and shrublands are found mainly on the eastern part of the mountain.
Vermio is a mountain where transhumant livestock animals used to have a very strong presence in the past. According to Chatzimichali [ 60 ], it accommodated 66% of Macedonia’s goats and sheep. It covered the needs for forage production for almost the whole of Thessaly (Central Greece) and beyond [ 25 , 61 ] because it was easily accessible and had plenty of grasslands with an abundance of forage production during summer [ 62 ]. The entire region served as summer grazing land for flocks owned by an ethnic group known as the “Sarakatsanaioi”. The “Tseligkata” social structure that the Sarakatsanaioi established allowed many small-scale transhumant families to collaborate and work together [ 63 ].
According to Katsaros [ 62 ], in the 1950s there were about 150,000–170,000 sheep and goats grazing in the area, but over the past few decades the number of animals and therefore the grazing pressure has significantly decreased. As in most of Greece, the Tseligkato system today has become almost extinct in Mt Vermio [ 64 ]. Sidiropoulou and co-authors [ 25 ] estimate that there were only 27,532 sheep and goats grazing freely in Mt Vermio in 2011. This declining trend in transhumance has caused changes in the size and distribution of grasslands and forests [ 20 , 65 , 66 ].
Mt Zireia (Kyllini) is southeast of the Corinth Regional Unit in Peloponnese. It is the second highest mountain of the Peloponnese peninsula, with the highest peak at 2374 m. The climate under the Köppen and Geiger [ 57 ] classification system ranges from Mediterranean-influenced warm-summer humid continental (Dsb) to warm-summer Mediterranean (Csb). According to the classification approach of Mavromatis [ 58 ], Mt Zireia belongs to the bioclimatic zone wet with severe winter and to three different bioclimatic character categories: sub-axeric cold with a sub-dry period, sub-Mediterranean and mild meso-mediterranean. The majority of Mt Zireia is protected by the Natura 2000 network [ 67 , 68 ]. The study area’s flora is rich and contains several significant endemic species for the Peloponnese and Greece as a whole [ 67 , 69 ]. Above 800 m there are forests and in the higher elevation zone there are mainly grasslands with thorny shrubs and grasses, many of which are unique and rare endemic and rocky areas [ 67 ]. In Mt Zireia there were about 38,000 transhumant sheep and goats in 1960 [ 70 ]. Families and flocks were moved on foot from different areas of the Peloponnese peninsula or West Attica [ 60 ]. However, in recent years, there was remarkable decrease of transhumant animals. According to Karatassiou and coauthors [ 70 ] in 2020 there were 13,717 transhumant sheep and goats in Mt Zireia.
2.2. Methods
Long-term (1990–2019) time series analysis of annual precipitation, mean annual air temperature, and maximum annual air temperature were based on the TerraClimate dataset [
71
], a high-spatial resolution (1/24°, ~4 km) dataset of monthly climate and climatic water balance for global terrestrial surfaces from 1958 until now. The aridity index of De Martonne (I
dM
) [
72
] was calculated for the same period using the following Formula (1):
I dM = P/(T + 10)
(1)
where P is the average annual precipitation (mm) and T the average mean annual air temperature (℃). The aridity index (I
dM
) is a key environmental component influencing the development of natural vegetation and categorizes climate types in proportion to water availability [
15
] because of its efficiency and relevance in relation to the arid/humid climate classification [
73
,
74
].
Livestock data were collected from Chatzimichali [ 60 ], Katsaros [ 62 ] and the Payment and Control Agency for Guidance and Guarantee Community [ 75 ]. Grazing pressure by transhumant sheep and goats in the pseudo-alpine zone was the quotient of transhumant animals/pseudo-alpine grazing areas (grasslands, shrublands, silvopastoral systems).
Land Use/Land Cover (LULC) data for Mt Vermio and Mt Zireia were obtained for 1945 and 2020, to analyze temporal land use changes in the two study areas:
Aerial orthophotographs (spatial resolution of 1 m) of 1945 provided by the National Cadastre and Mapping Agency S.A. [ 76 ] were used to digitize past LULC (scale 1:5000);
Google Earth satellites images were used to digitize current (2020) LULC types.
The LULC data for 1945 and 2020, for Mt Vermio and Mt Zireia, were classified according to Ref. [ 25 ] into the following six categories: pseudo-alpine grasslands, shrublands, silvopastoral systems, forests, agricultural land, and other land uses (mainly built-up areas and a few water surfaces).
Data was processed within ArcGIS v10.8.1 software [
77
], and the minimum cartographic unit was set to 1 ha. The selected classification method detected various components on aerial orthophotos and Google Earth images using basic photographic keys (tone, texture, pattern, shadow, shape, and size) and feature association [
47
,
78
]. Visual photointerpretation was supported by extensive field sampling verifications from a group of scientists, with more than 20-years of research experience in the specific areas. The pseudo-alpine zone was isolated using the “clip” command and a few peaks that were not part of the main mountain core were excluded. The transition matrix method was used to represent all possible landscape changes between 1945 and 2020 for both study areas.
To examine the slopes and elevation zones of the two mountains, a Digital Elevation Model (ASTER Global DEM) [ 79 ] with a resolution of 30 m (pixel size) was processed.
To assess the extent of forest invasion on grasslands, the temporal variations in altimeter forest distribution were analyzed by merging the elevation zones (100 m altitudinal difference) and forest cover with the “union” command in ArcGIS v10.8.1.
Patch Analyst/Grid Extension for ArcGIS [ 80 ] was used to compute four quantitative metrics for analyzing landscape structure [ 81 , 82 ]. Based on previous multi-temporal landscape studies [ 25 , 55 ] the chosen metrics were Number of patches (NumP), Mean patch size (MPS), Edge density (ED), and Interspersion Juxtaposition index (JI) ( Table 1 ).
Table 1. List and description of the landscape metrics used in the study.
Metrics were calculated for all LULC types at the landscape level and exclusively for grasslands at the class level. Classes corresponded to the different LULC types, and each class consisted of numerous polygons (patches). The cell size for grid analysis was set to 10 m.
3. Results
The average values of mean annual air temperature for both Mt Zireia and Mt Vermio over the last 30 years are shown on Figure 2 . Mt Vermio is substantially cooler compared to Mt Zireia by 1–2 °C and differences were rather consistent throughout the last 30 years.
Figure 2. Mean annual air temperature between 1990 and 2019 for Mt Vermio and Mt Zireia.
The mean annual temperature between 1990 and 2019 was 8.3 °C and 9.8 °C for Mt Vermio and Mt Zireia, respectively, and the max annual temperature for the same period was 13.3 °C and 14.9 °C, respectively ( Table 2 ).
Table 2. Climatological parameters for the study areas between 1990 and 2019. Values present means ± SD (n = 29).
The annual precipitation between 1990 and 2019 was 666.8 mm for Mt Vermio and 917.3 mm for Mt Zireia ( Table 2 ). Similar to temperature, annual precipitation for both Mt Zireia and Mt Vermio during the past 30 years showed considerable year-to-year variation ( Figure 3 ).
Figure 3. Annual precipitation between 1990 and 2019 for Mt Vermio and Mt Zireia.
The aridity index (I dM ) for the same period was 36.3 for Mt Vermio and 46.2 for Mt Zireia ( Table 2 ) and the two study areas were classified as moderately humid and humid [ 74 ].
Transhumance was once prevalent on Mt Vermio, which could hold nearly 170,000 transhumant sheep and goats ( Table 3 ). Currently, there are 22,308 transhumant animals, a dramatic decrease of approximately 86.1%. On the contrary, on Mt Zireia, the number of transhumant animals in the past was much smaller (38,230). However, just like on Mt Vermio, transhumance has declined. Today on Mt Zireia there are only 13,717 transhumant animals, a decrease of 64.1% ( Table 3 ).
Table 3. Number of transhumant animals (sheep, goat) in the entire mountainous zone.
Today, there are fewer than 22,000 transhumant animals in both mountains, however grazing pressure (transhumant animals/pseudo-alpine grazing areas) in the pseudo-alpine zone of Mt Vermio is only 0.69, compared to 0.94 in Mt Zireia ( Table 4 ).
Table 4. Grazing pressure in the pseudo-alpine zone of the study areas.
The spatial distribution of LULC on Mt Vermio between 1945 and 2020 is presented in Figure 4 .
Figure 4. Spatial distribution of Land Use/Land Cover types of Mt Vermio for 1945 and 2020.
In 1945, pseudo-alpine grasslands on Mt Vermio occupied most of the area (28,581.2 ha), followed by silvopastoral systems (6308.5 ha), forests (5568 ha), and shrublands (3623.9 ha) ( Table 5 ). In 2020 there was a significant increase (245.7%) in forest size, while pseudo-alpine grasslands, silvopastoral systems, and shrublands have substantially decreased by −19.8%, −77.9%, and −92.8%, respectively.
Table 5. Temporal evolution of Land Use/Land Cover (LULC) types of Mt Vermio for 1945 and 2020.
The spatial distribution of LULC types on Mt Zireia for 1945 and 2020 is presented in Figure 5 .
Figure 5. Spatial distribution of Land Use/Land Cover (LULC) types of Mt Zireia for 1945 and 2020.
In 1945, most areas of Mt. Zireia were covered by pseudo-alpine grasslands (4712.3 ha), followed by forests (3130.5 ha), shrublands (2504.3 ha), and silvopastoral systems (2300.2 ha) ( Table 6 ). In 2020 there was an increase (54.4%) in forests and shrublands (8.7%), while pseudo-alpine grasslands and silvopastoral systems decreased by −19.8% and −51.7%, respectively.
Table 6. Temporal evolution of Land Use/Land Cover (LULC) types of Mt Zireia for 1945 and 2020.
According to
Table 7
and
Table 8
, between 1945–2020 almost 37% the total landscape area of Mt Vermio and 28% of Mt Zireia changed land use. The most important changes in terms of gain for both mountains were forest expansion and in terms of loss, pseudo-alpine grassland and silvopastoral systems reduction. On Mt Zireia a slight increase was also recorded for shrublands, silvopastoral areas, and pseudo-alpine grasslands (
Table 8
, gain values). Further analysis of the transition data showed that on Mt Vermio, the dominant expansion of forests occurred equally at the expense of silvopastoral systems and pseudo-alpine grasslands, and to a lesser extent at the expense of shrublands. On Mt Zireia however, the growth of forests was mainly done at the expense of silvopastoral systems.
Table 7. Transition matrix for Land Use/Land Cover (LULC) types on Mt Vermio between 1945 and 2020 (% from total area).
Table 8. Transition matrix for Land Use/Land Cover (LULC) types on Mt Zireia between 1945 and 2020 (% from total area).
According to the analysis of the Digital Elevation Model, Mt Vermio had primarily moderate slopes (16–30%), whereas Mt Zireia had primarily very steep slopes (>46%). As per the analysis of changes in forest cover (%) per altitudinal zone between 2020 and 1945 for the two mountains, Mt Zireia had an increase in forest cover in higher altitudes, indicating an upward shift in treeline, whereas Mt Vermio showed the opposite trend ( Figure 6 ). On Mt Vermio, forest expansion was higher at 1200 m while in Mt Zireia it was at 1700 m.
Figure 6. Change (%) in forest area per altitudinal zone between 1945 and 2020 for Mt Zireia and Mt Vermio.
On Mt Vermio, although the spread of the forest was intense and dynamic, it happened horizontally rather than vertically, as the treeline did not shift upwards ( Figure 7 ).
Figure 7. Treeline shifts between 1945 and 2020 in relation to the slopes on Mt Vermio.
Between 1945 and 2020, the forest area on Mt. Zireia had expanded upward, primarily on the mountain’s northeast side where the slopes were gentle ( Figure 8 ).
Figure 8. Treeline shifts between 1945 and 2020 in relation to the slopes on Mt Zireia.
The values of the landscape metrics, which constitute the most effective technique to measure and analyze changes in land uses, for Mt Vermio and Mt Zireia from 1945 to 2020, are presented in Table 9 .
Table 9. The landscape level metric values for Mt Vermio and Mt Zireia for 1945 and 2020.
The NumP increased (32.2%) over the study period on Mt Vermio suggesting that larger vegetation areas had been divided up into smaller pieces. The MPS, which has reduced from 123.1 hectares in 1945 to 93.1 ha in 2020, also serves as a proxy for the degree of vegetation fragmentation. The decrease in IJI by 35% suggests that landscape patches have clumped, and they are interspersed disproportionally.
On Mt Zireia on the contrary, the NumP has substantially decreased (41.3%), while MPS dramatically increased from 65.3 ha in 1945 to 111.3 ha in 2020. This indicates that the landscape is less subdivided and fragmented.
For 1945 and 2020, a class level analysis focused on the grasslands of Mt Vermio and Mt Zireia revealed similar tendencies ( Table 10 ).
Table 10. Class level metric values for the pseudo-alpine grasslands of Mt Vermio and Mt Zireia for 1945 and 2020.
On Mt Vermio, during the period 1945–2020, NumP increased significantly (51.1%) while MPS decreased from 317.6 ha in 1945 to 168.6 ha in 2020. The 45.6% decline in IJI values suggests that grasslands are less equally adjacent to each other.
On Mt Zireia, during the period from 1945 to 2020, NumP decreased by 41.7% while MPS increased from 56.1 ha in 1945 to 77.1 ha in 2020. Grasslands appear less fragmented and more united. In addition, grassland edges (ED) showed a reduction (−31.5%), indicating a negative impact of the changes to landscape patches to the ecotones and therefore in biodiversity.
4. Discussion
Our findings suggest that the climate and the abandonment of transhumance may have had a substantial impact on land use changes in the pseudo-alpine zone of the two mountains in the current study. Forests expanded at the expense of other land uses, mainly pseudo-alpine grasslands, shrublands, and silvopastoral systems. In the meantime, higher mean annual air temperature led to an upward shift in treeline and a subsequent retreat of pseudo-alpine grasslands.
In the past, grazing pressure of transhumant animals and the harvest of timber and firewood, maintained an open, mosaic-like landscape, and created openings and corridors in forests [ 25 ]. This way, not only the expansion of invasive or colonizing grass species [ 50 ], but also of trees, was prevented. Today, transhumance has declined in Greece, following a pattern that has been observed across Europe [ 83 ]. The reasons are agricultural reform, World War II, rural depopulation, and the restriction on grazing in mountainous areas [ 25 , 61 , 84 ]. On Mt Vermio and Mt Zireia, this trend led to the abandonment or underutilization of pseudo-alpine grasslands [ 85 ]. On Mt Vermio the number of transhumant animals decreased dramatically ( Table 3 ), and the entire mountain was abandoned. The changes in landscape structure are depicted in the values of landscape metrics. Trees started to penetrate former unified, large grassland patches, creating a more fragmented landscape (NumP, MPS, IJI) ( Table 9 ). This fragmentation reduced the habitat area and increased the spatial discontinuity [ 51 ] leading to a reduction in species richness and biodiversity, impeding the possibilities of dispersion and an increase of vulnerability that is associated with risk of extinction [ 11 ].
On Mt Zireia, grazing pressure was higher (0.94 animals/ha) than Mt Vermio (0.69 animals/ha) and it was constant in lower altitudes, thus preventing the expansion of forest over 1700 m. The abandonment of transhumance on higher altitudes seems to have affected mainly the small grassland patches inside the forest that began to disappear. This phenomenon led to a more cohesive and homogenized landscape (NumP, MPS, ED).
Overall, Mt. Vermio appears to be at an advanced stage of abandonment, where the trees have invaded the grasslands and broken their coherence, whereas Mt. Zireia is in an earlier stage of abandonment where the grassland gaps in the forest started to close. This result is consistent with the claims of many researchers [ 86 , 87 , 88 , 89 ] who suggest that variation in grazing pressure could be the driver of land use changes in the pseudo-alpine zone.
Similar to the rest of Europe, Mt. Vermio and Mt. Zireia’s temperature and precipitation have risen during the past 30 years [ 71 , 90 ]. However, Mt Zireia had higher mean annual air temperature and annual precipitation ( Table 2 ) and therefore different water balance [ 91 ], plant growth period [ 92 ], and annual above-ground productivity [ 93 ]. The differences in climatic conditions were expected due to the influence of orography and spatial climate variability [ 94 ], but mainly due to the geographical location of the two mountains.
The higher mean annual air temperature in Mt Zireia could have led to the upward shift in treeline ( Figure 7 ) since most researchers agree that it is the main driver of upward expansion of the treeline [ 8 , 95 , 96 , 97 , 98 , 99 , 100 , 101 ]. Particularly young trees respond to environmental change by closing the forest gaps [ 100 , 102 ]. Furthermore, the increase in annual precipitation over the past 30 years in Mt. Zireia ( Figure 3 ) facilitated treeline upward elevation.
On the island of Crete’s Samaria National Park, Beloiu and colleagues [
103
] noted that despite a drop in precipitation over the previous 70 years, there had been no treeline change. A combination of meteorological and topographic conditions, such as decreased precipitation with rising warmth and the absence of a sheltering effect because of high topographic wind exposure, are the main causes of the absence of treeline shift in Crete. Even though changes in temperature and precipitation may intensify shifts in treeline, temperature increases and precipitation drop may interact unpredictable as far as an effect on the treeline is regarded. Precipitation restricts the growth of trees, especially in semi-arid regions with little water storage, where it raises evapotranspiration and aggravates moisture stress [
104
]. On the other hand, topographic factors, such as the lack of shelter due to high topographic wind exposure may interact with temperature and precipitation and regulate the trends in treeline shifts in Crete [
105
]. However, Zindros and coauthors [
101
] concluded that treeline shift results from the significant temperature increase during the growing season in National Park of Mt Olympus, Greece.
Today, on Mt Zireia, forests have replaced pseudo-alpine grasslands primarily in the northeast region, where the conditions were more favorable for forests to intrude (lower inclination) ( Figure 7 ). Lundbäck and coauthors [ 105 ] estimate that 82% of the world’s forests grow on slopes <15°. The amount of solar radiation in mountainous or hilly environments is impacted by the slope aspect, which has an immediate impact on species distribution and tree growth [ 106 ]. At mid-latitudes in the Northern Hemisphere, south-facing slopes receive significantly more direct solar radiation than comparable northern slopes [ 107 ]. Thus, it is anticipated that treeline elevation will be higher on south-facing, warmer slopes than on their north-facing, cooler equivalents. However, in the Mediterranean region, south-facing slopes can be more vulnerable to dryness than north-facing slopes [ 107 , 108 ]. As a result, the elevation of the treeline can be significantly lowered. With a few exceptions, seasonal root temperatures globally coincide with treeline height [ 109 ]. Given that they are found in regions with warmer temperatures than indicated by the global distribution pattern, Mediterranean treelines serve as an example of one of these outliers. This has been explained by the absence of cold-resistant treeline taxa or by the prevalence of treelines that have been affected by anthropogenic use in the past [ 110 ]. Most mountainous regions of the world anticipate considerable increases in air temperatures in the future decades, but it is unclear how local characteristics (such as elevation, aspect, and soil) will affect how trees near treelines react to the warming. Because different bio-geographical patterns of tree development respond to temperature differently, a warmer climate may have distinct effects on treeline dynamics [ 111 ].
In our case study, we found the following trends considering forest expansion. Trees either moved up the mountain to a higher elevation (upward/vertical shift = elevational expansion) or expanded horizontally (latitudinal expansion). On Mt Vermio, the spread of the forest was intense and dynamic (245% increase) but happened horizontally rather than vertically (
Figure 8
). This is in accordance with a review study related to treelines in the world [
112
], where the majority of treeline sites (92%) addressed elevational treeline advances while 8% addressed the latitudinal advances. Hansson and coauthors [
112
], suggest that this is likely due to easier horizontal dispersal of trees across landscapes, because the elevational gradient acts as a barrier for seedling dispersal and the temperature remains consistent within the same altitudinal zone.
According to the values of gains and losses of forests and pseudo-alpine grasslands for the two mountains (
Table 7
), the “forest increase vs. pseudo-alpine grasslands reduction” trend was less extensive on Mt Zireia. The expansion of forests over grasslands was less than 3% of the total landscape and was limited on the northeast side. This may be explained by the “mountain effect”, which states that higher mountains face less abandonment than medium ones [
113
]. Simultaneously on Mt Zireia, there was an upward shift of treeline. As mentioned earlier, most researchers agree that treeline position is limited by the average temperatures, however, according to Piper and coauthors [
108
], in the Mediterranean region, the absence of an elevational trend in tree growth shows the presence of other abiotic factors than temperature, including drought, which towards the end of the growing season may overwhelm the temperature-driven elevational increase. Increased temperatures may have an impact on tree development, although Hansson and colleagues [
112
] report that it also depends on the topography and water availability of the area.
5. Conclusions
Pseudo-alpine grasslands on both mountains have reduced. The abandonment of the transhumant livestock grazing system on Mt Vermio has resulted in the horizontal expansion of the forest. However, this is not enough to cause a corresponding upward increase in treeline. The main driver for the latter seems to be climate change, specifically a rise in temperature, as in the case of Mt Zireia.
Pseudo-alpine grasslands have been significantly impacted by both climate change and transhumance abandonment. Given the importance of these areas, more field-based research is required. Long-term monitoring of landscape spatial patterns and climatic conditions could help prevent drastic changes in high-mountain ecosystems such as Mt Vermio and Mt Zireia.
Author Contributions
Conceptualization, A.S., D.C., K.M., S.S. and M.K.; methodology, A.S., D.C., K.M. and M.K.; software, A.S., D.C. and S.S.; validation, A.S., D.C., K.M., S.S. and M.K.; formal analysis, A.S. and D.C.; investigation, A.S., D.C., K.M., S.S. and M.K.; resources, M.K.; data curation, A.S., D.C., K.M., S.S. and M.K.; writing—original draft preparation, A.S., D.C., K.M. and M.K.; writing—review and editing, A.S., D.C., K.M., S.S. and M.K.; visualization, A.S., D.C., K.M. and M.K.; supervision, M.K.; project administration, M.K.; funding acquisition, M.K. All authors have read and agreed to the published version of the manuscript.
Funding
This research was part of the project «PACTORES» and was co-funded by the European Union (European Social Fund, ERANETMED2-72-303) and General Secretariat for Research and Innovation (GSRI, Τ8ΕΡA2-00022) through the Action “ERA-Net”.
Institutional Review Board Statement
Not applicable.
Informed Consent Statement
Not applicable.
Data Availability Statement
The data presented in this study are available in the Figures and Tables provided in the manuscript.
Conflicts of Interest
The authors declare no conflict of interest.
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Figure 1. The study areas (red outline) in Mt Vermio (North Greece) and Mt Zireia (South Greece).
Figure 2. Mean annual air temperature between 1990 and 2019 for Mt Vermio and Mt Zireia.
Figure 3. Annual precipitation between 1990 and 2019 for Mt Vermio and Mt Zireia.
Figure 4. Spatial distribution of Land Use/Land Cover types of Mt Vermio for 1945 and 2020.
Figure 5. Spatial distribution of Land Use/Land Cover (LULC) types of Mt Zireia for 1945 and 2020.
Figure 6. Change (%) in forest area per altitudinal zone between 1945 and 2020 for Mt Zireia and Mt Vermio.
Figure 7. Treeline shifts between 1945 and 2020 in relation to the slopes on Mt Vermio.
Figure 8. Treeline shifts between 1945 and 2020 in relation to the slopes on Mt Zireia.
Table 1. List and description of the landscape metrics used in the study.
Landscape Metrics Abbreviation Description Unit Number of Patches NumP Total number of patches - Mean Patch Size MPS Average patch size ha Edge Density ED Amount of edge relative to the landscape m/ha Interspersion Juxtaposition Index IJI Spatial intermixing of different patch types %
Table 2. Climatological parameters for the study areas between 1990 and 2019. Values present means ± SD (n = 29).
Climatological Parameters Mt Vermio Mt Zireia Mean Annual Temperature (°C) 8.3 ± 0.58 9.8 ± 0.54 Max Annual Temperature (°C) 13.3 ± 0.65 14.9 ± 0.55 Annual Precipitation (mm) 666.8 ± 121.54 917.3 ± 170.48 De Martonne Aridity Index 36.3 46.2
Table 3. Number of transhumant animals (sheep, goat) in the entire mountainous zone.
Mountain 1950–1960 2020 Vermio 150,000–170,000 22,308 Zireia 38,230 13,717
Table 4. Grazing pressure in the pseudo-alpine zone of the study areas.
Mt Vermio Mt Zireia Transhumant animals 16,841 7124 Pseudo-alpine area (ha) 24,585.2 7611.4 Grazing pressure 0.69 0.94
Table 5. Temporal evolution of Land Use/Land Cover (LULC) types of Mt Vermio for 1945 and 2020.
LULC 1945 (ha) 2020 (ha) 2020–1945 (%) Silvopastoral systems 6308.5 1397.1 −77.9 Agricultural land 585.7 659.6 12.6 Forests 5568.0 19,247.0 245.7 Shrublands 3623.9 261.7 −92.8 Pseudo-alpine grasslands 28,581.2 22,926.3 −19.8 Other land uses 23.0 198.5 764.5 Total 44,690.3 44,690.3
Table 6. Temporal evolution of Land Use/Land Cover (LULC) types of Mt Zireia for 1945 and 2020.
LULC 1945 (ha) 2020 (ha) 2020–1945 (%) Silvopastoral systems 2300.2 1111.6 −51.7 Agricultural land 156.4 75.5 −51.7 Forests 3130.5 4833.8 54.4 Shrublands 2504.3 2721.3 8.7 Pseudo-alpine grasslands 4712.3 3778.5 −19.8 Other land uses 0.0 283.1 Total 12,803.8 12,803.8
Table 7. Transition matrix for Land Use/Land Cover (LULC) types on Mt Vermio between 1945 and 2020 (% from total area).
LULC 2020 LULC 1945 For Sil Shr Psa Agr Oth Total 1945 Loss For * 12.27 0.06 0.00 0.12 0.01 0.00 12.46 0.19 Sil 12.26 0.95 0.00 0.85 0.04 0.01 14.11 13.16 Shr 6.10 0.31 0.37 1.33 0.01 0.00 8.12 7.75 Psa 12.26 1.79 0.21 48.67 0.66 0.36 63.95 15.28 Agr 0.19 0.01 0.00 0.32 0.76 0.03 1.31 0.55 Oth 0.00 0.00 0.00 0.00 0.00 0.05 0.05 0.00 Total 2020 43.08 3.12 0.58 51.29 1.48 0.45 100 0 Gain 30.81 2.17 0.21 2.62 0.72 0.40 0 36.93
* For: Forest; Sil: Silvopastoral systems; Shr: Shrublands; Psa: Pseudo-alpine grasslands; Agr: Agricultural land; Oth: Other land uses. Cells filled with a gray background display the percentage of each land use that remained unchanged.
Table 8. Transition matrix for Land Use/Land Cover (LULC) types on Mt Zireia between 1945 and 2020 (% from total area).
LULC 2020 LULC 1945 For Sil Shr Psa Agr Total 1945 Loss For * 23.31 0.79 0.02 0.90 0.00 25.02 1.71 Sil 10.75 5.49 1.07 1.06 0.00 18.37 12.88 Shr 1.72 0.38 16.34 1.56 0.00 20.00 3.66 Psa 2.66 2.22 4.07 26.33 0.10 35.38 9.05 Agr 0.17 0.00 0.23 0.33 0.50 1.23 0.73 Total 2020 38.61 8.88 21.73 30.18 0.60 100 0 Gain 15.30 3.39 5.39 3.85 0.10 0 28.03
* For: Forest; Sil: Silvopastoral systems; Shr: Shrublands; Psa: Pseudo-alpine grasslands; Agr: Agricultural land. Cells filled with a gray background display the percentage of each land use that remained unchanged.
Table 9. The landscape level metric values for Mt Vermio and Mt Zireia for 1945 and 2020.
Mt Vermio Mt Zireia 1945 2020 2020–1945% 1945 2020 2020–1945% NumP * 363.0 480.0 32.2 196.0 115.0 −41.3 MPS (ha) 123.1 93.1 −24.4 65.3 111.3 70.4 ED (m/ha) 40.0 44.5 11.1 90.1 56.9 −36.8 IJI (%) 69.1 44.9 −35.0 75.4 70.5 −6.5
* NumP: Number of Patches, MPS: Mean Patch Size, ED: Edge Density, IJI: Interspersion Juxtaposition Index.
Table 10. Class level metric values for the pseudo-alpine grasslands of Mt Vermio and Mt Zireia for 1945 and 2020.
Mt Vermio Mt Zireia 1945 2020 2020–1945% 1945 2020 2020–1945% NumP * 90.0 136.0 51.1 84.0 49.0 −41.7 MPS (ha) 317.6 168.6 −46.9 56.1 77.1 37.4 ED (m/ha) 15.0 17.2 14.7 26.7 18.3 −31.5 CA 28581.2 22926.3 −19.8 4712.3 3778.5 −19.8 IJI (%) 81.4 44.3 −45.6 81.8 82.2 0.5
* NumP: Number of Patches, MPS: Mean Patch Size, ED: Edge Density, IJI: Interspersion Juxtaposition Index.
MDPI and ACS Style
Sidiropoulou, A.; Chouvardas, D.; Mantzanas, K.; Stefanidis, S.; Karatassiou, M. Impact of Transhumant Livestock Grazing Abandonment on Pseudo-Alpine Grasslands in Greece in the Context of Climatic Change. Land 2022, 11, 2126.
https://doi.org/10.3390/land11122126
AMA Style
Sidiropoulou A, Chouvardas D, Mantzanas K, Stefanidis S, Karatassiou M. Impact of Transhumant Livestock Grazing Abandonment on Pseudo-Alpine Grasslands in Greece in the Context of Climatic Change. Land. 2022; 11(12):2126.
https://doi.org/10.3390/land11122126
Chicago/Turabian Style
Sidiropoulou, Anna, Dimitrios Chouvardas, Konstantinos Mantzanas, Stefanos Stefanidis, and Maria Karatassiou. 2022. "Impact of Transhumant Livestock Grazing Abandonment on Pseudo-Alpine Grasslands in Greece in the Context of Climatic Change" Land11, no. 12: 2126.
https://doi.org/10.3390/land11122126
Article Metrics
| https://www.mdpi.com/2073-445X/11/12/2126 |
HUMANGGP:011698 - FACTA Search
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Target Concepts:
Query: HUMANGGP:011698 (
PECAM-1
)
1,092
The CD31 antigen ( PECAM-1 ) has been reported to be a stable marker for a human CD4 T-cell subpopulation unable to produce interleukin-4 (IL-4). We show here that CD31 expression is not stable inasmuch as CD4 T-cell lines and clones derived from cell-sorted neonatal CD31+ cells lose CD31 upon repetitive cycles of stimulation and IL-2 expansion. Moreover, various cytokines (IL-1 alpha, IL-4, IL-6 , transforming growth factor-beta) fail to reinduce CD31 on CD31- clones. Whereas all CD31+ CD4 T cells rapidly express high levels of the CD45RO antigen and down-regulate the L-selectin antigen after priming, CD31 disappears more slowly because only part of the cells lose CD31 expression upon each cycle of stimulation. Loss of CD31 reflects a functional maturation of CD45RO+ cells since, in a system which favours the development of Th2 effectors, IL-4 is produced by CD31- but not CD31+ effector T cells, whereas interferon-gamma is produced by both types of cells. However, CD31 is not a Th1 marker since it is not expressed on several Th1 antigen-specific clones. We conclude that CD31 is a maturation marker expressed on the great majority of naive CD45RO- CD4 T cells and on a subset of CD45RO+ CD4 T cells that are at an intermediate stage of maturation.
...
PMID:CD31 (PECAM-1) is a differentiation antigen lost during human CD4 T-cell maturation into Th1 or Th2 effector cells. 870 35
The effect of different expansion protocols on the expression levels of CD49dw/CD29 (VLA-4), CD11a/CD18 (LFA-1), CD31 ( PECAM-1 ), CD44, and CD34 was determined after cord blood CD34+ cells were cultured for defined periods with the following: 1) A growth factor mix (GFmix) containing interleukin (IL)-1, IL-3, IL-6 , kit ligand (KL), G-CSF, GM-CSF, and erythropoietin (Epo); 2) IL-3 + KL; and 3) HS-5 (a human stromal cell line supernatant) + KL. Before culturing, cord blood CD34+ cells (> 95% purity) were 94 +/- 5% CD31+, 98 +/- 1% CD44+, 66 +/- 29% VLA-4+, and 68 +/- 18% LFA-1+ (mean +/- SEM). Immunophenotyping and morphological examination of pre- and post-cultured cells indicated that GFmix preferentially supported erythroid development, while IL-3+KL and HS-5+KL preferentially supported myeloid development. Similar to what other investigators have reported, there was an absolute increase in CD34+ cell numbers as well as clonogenic precursors with ex vivo expansion. However, the majority of clonogenic precursors post-expansion expressed CD34 antigen at reduced levels. Examination of adhesion molecules indicated that a majority of cells cultured with GFmix expressed PECAM-1 and LFA-1 at undetectable levels, but PECAM-1 and LFA-1 levels remained essentially unchanged when cells were cultured with IL-3+KL and HS-5+KL. Overall VLA-4 expression levels slightly increased and CD44 expression levels were more heterogeneous with ex vivo expansion. Nevertheless, LFA-1, VLA-4, PECAM-1 , and CD44 expression levels remained essentially unchanged on cultured progeny retaining a CD34 phenotype, independent of the culture system used. Together these results indicate that differential modulation of adhesion markers occur with different culture conditions, yet adhesion receptor expression levels on progeny cells retaining a CD34 phenotype are essentially maintained independent of the culture conditions. And although there is an absolute increase in CD34+ cells after ex vivo expansion, a majority of clonogenic precursors have reduced levels of CD34 antigen.
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PMID:Differential modulation of adhesion markers with ex vivo expansion of human umbilical CD34+ progenitor cells. 931 Jan 90
Endothelial cell dysfunction is a classic consequence of radiation damage. Bone marrow endothelial cells (BMEC) are a critical component of the stroma in the regulation of haemopoiesis. In animal models, radiation-induced injury of BMEC has been described and a role for BMEC in haemopoietic regeneration after irradiation has been suggested. However, functions of BMEC involved in the haemopoietic regeneration have not been assessed. Therefore we studied the functional response of human BMEC to irradiation using the transformed human BMEC line (TrHBMEC) irradiated with 2. 5 or 10Gy. Our results showed a time- and a dose-dependent increase in damage to irradiated TrHBMEC measured by a decreased number of adherent cells which correlated with increased apoptosis and augmented release of soluble ICAM-1 and von Willebrand factor. 2 Gy irradiated TrHBMEC expressed more ICAM-1 on their surface than non-irradiated cells, whereas no change in VCAM-1, E-selectin and PECAM-1 expression was observed. An increased production of G-CSF, GM-CSF, IL-8, IL-6 , IL-1alpha, IL-11, MIP-1alpha and SCF and no production of LIF, TNF-alpha, TPO and IL-3 by 2 Gy irradiated TrHBMEC was observed. The haemopoietic supportive function of TrHBMEC was not altered after a 2 Gy exposure. These results suggest that although radiation induces endothelial cell damage, irradiated cells still support the proliferation and the differentiation of CD34+ haemopoietic cells.
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PMID:Characterization of the response of human bone marrow endothelial cells to in vitro irradiation. 988 9
The application of hyperthermia (HT) and tumour necrosis factor alpha (TNF) in isolation perfusion of the limb or liver results in regression of advanced cancers confined to these regions of the body in most patients and are thought to exert anti-tumour effects primarily on tumour neovasculature. However, the individual contribution of either treatment factor on endothelial cells (EC) are not known. In this study, we investigated the in vitro effects of moderate and severe HT on human umbilical vein EC (HUVEC) with and without TNF in clinically relevant doses. HUVEC were exposed to normothermia (37 degrees C) or moderate (39 degrees C) and severe (41 degrees C) HT for 90 or 180 min with or without TNF (1 microg/ml). Cell viability, cytokine secretion ( IL-6 , IL-8, VEGF, ICAM-1, VCAM-1, RANTES, E-selectin, P-selectin, L-selectin, and PECAM-1 ), and induction of procoagulant activity as reflected in tissue factor (TF) production were assessed at the end of the treatment period and at several time points thereafter. Neither HT nor TNF exerted significant cytotoxic effects on EC at the doses and temperatures used. HT resulted in increased production of PECAM-1 with little or no additional effect when combined with TNF. TNF caused increased secretion of IL-6 , IL-8, ICAM-1, and VCAM-1 with little or no additional effect from HT. Increased E-selectin and RANTES levels were observed with TNF and HT only at 24 h after treatment. HT and TNF had mainly antagonistic effects on VEGF secretion with HT causing primarily decreased production and TNF causing increased VEGF secretion under all temperatures. Most notably, there was a rapid, prolonged and synergistic peak increase in procoagulant activity when TNF and HT were used in combination compared to TNF or HT treatment alone. These results indicate that TNF and HT exert primarily independent effects on inflammatory cytokine production in EC but synergistically increase procoagulant activity as reflected in TF production. These data provide a possible mechanism for the thrombotic effects in tumour neovasculature seen following isolation perfusion with these agents and provide a rationale for their combined use in this treatment setting.
...
PMID:Effects of hyperthermia and tumour necrosis factor on inflammatory cytokine secretion and procoagulant activity in endothelial cells. 1080 14
Migration of blood-borne lymphocytes into lymphoid tissues and sites of inflammation is initiated by vascular adhesion molecules and proinflammatory cytokines. Previous in vivo studies have shown that febrile temperatures dynamically stimulate adhesion in differentiated high endothelial venules (HEV), which are portals for lymphocyte extravasation. This report examines the direct effect of fever-range hyperthermia on the expression of adhesion molecules and cytokines by primary cultured endothelial cells. In both macrovascular (HUVEC) and microvascular (HMVEC) endothelial cells, fever-range hyperthermia (40 degrees C for 6-12 h) did not affect expression of adhesion molecules (ICAM-1, E-selectin, VCAM-1, P-selectin, PECAM-1 , PNAd, MAdCAM-1), cytokine release (IL-1beta, TNF-alpha, IFN-gamma, IL-6 , IL-11, IL-12, IL-13), or chemokine secretion (IL-8, RANTES, MCP-1, MIP-1beta, MIG). This is in contrast to the stimulatory effects of TNF-alpha or 43 degrees C heat shock. However, a novel role for fever-range hyperthermia was identified in augmenting actin polymerization in cultured endothelial cells and enhancing the ability of endothelial-derived factors to transactivate the alpha4beta7 integrin lymphocyte homing receptor. These findings provide insight into the tightly regulated effects of fever-range hyperthermia that exclude induction of adhesion in non-activated endothelium of normal blood vessels. Through these mechanisms, it is proposed that febrile temperatures associated with infection or clinical hyperthermia avoid the unproductive exodus of lymphocytes to non-involved extralymphoid tissues while simultaneously promoting lymphocyte delivery to sites of immune activation.
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PMID:Cytokine and adhesion molecule expression in primary human endothelial cells stimulated with fever-range hyperthermia. 1253 53
Ischemia reperfusion (I-R)-induced renal damage is reduced by systemic administration of the NO-dependent vasodilator molsidomine. The aim of this study was to estimate the effect of direct intrarenal molsidomine administration on renal dysfunction and inflammatory reaction after experimental I-R in rats, in order to assess only renal NO effects and to obviate its systemic hemodynamic action. Ischemia was induced by renal pedicle ligation (60 min) followed by reperfusion and contralateral nephrectomy. Molsidomine (4 mg/kg) was infused into the renal artery 15 min before reperfusion and its effects were compared with those of the NO-independent vasodilator hydralazine (2 mg/kg). Survival rates after 7 days were 100% in the sham-operated group and 75% in the I-R rats. Molsidomine treatment almost completely prevented the I-R-induced renal dysfunction, and survival reached 100%. Molsidomine prevented an I-R-induced increase in superoxide anion and reduced plasma levels of pro-inflammatory cytokines (TNF-alpha, IL-1beta and IFN-gamma), whereas it enhanced anti-inflammatory cytokines ( IL-6 and IL-10). Inflammatory cell infiltration and cell-adhesion molecules (ICAM-1, PECAM-1 , VCAM-1 and P-selectin) were lower in the molsidomine-treated kidneys than in the untreated animals. All these protective effects were not observed after hydralazine administration. In conclusion, intrarenal administration of molsidomine before reperfusion improved renal function and decreased inflammatory responses after I-R.
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PMID:Intrarenal administration of molsidomine, a molecule releasing nitric oxide, reduces renal ischemia-reperfusion injury in rats. 1536 15
Platelet endothelial cell adhesion molecule-1 ( PECAM-1 , CD31), an adhesion molecule expressed on hematopoietic and endothelial cells, mediates apoptosis, cell proliferation, and migration and maintains endothelial integrity in addition to its roles as a modulator of lymphocyte and platelet signaling and facilitator of neutrophil transmigration. Recent data suggest that CD31 functions as a scaffolding protein to regulate phosphorylation of the signal transducers and activators of transcription (STAT) family of signaling molecules, particularly STAT3 and STAT5. STAT3 regulates the acute phase response to innate immune stimuli such as lipopolysaccharide (LPS) and promotes recovery from LPS-induced septic shock. Here we demonstrate that CD31-deficient mice have reduced survival during endotoxic LPS-induced shock. As compared to wild-type controls, CD31-deficient mice showed enhanced vascular permeability; increased apoptotic cell death in liver, kidney, and spleen; and elevated levels of serum tumor necrosis factor alpha (TNF-alpha), interferon gamma (IFNgamma), MCP-1, MCP-5, sTNRF, and IL-6 . In response to LPS in vivo and in vitro, splenocytes and endothelial cells from knockout mice had reduced levels of phosphorylated STAT3. These results suggest that CD31 is necessary for maintenance of endothelial integrity and prevention of apoptosis during septic shock and for STAT3-mediated acute phase responses that promote survival during septic shock.
...
PMID:Enhanced susceptibility to endotoxic shock and impaired STAT3 signaling in CD31-deficient mice. 1563 11
The placental-umbilical unit in sickle cell disease (SCD) pregnancy was used to explore hypoxia in vivo, an important factor in the pathophysiology of this disease. Gross examination and microscopic analysis of the placentas, taken immediately after delivery, indicate good concordance between maturity and term as controls, but higher frequency of vascular injuries such as excess syncytial knots, excess fibrin deposits, congestion and villous necroses. Unexpectedly, neither leukocyte recruitment nor alteration in extraplacental membrane was observed, suggesting the absence of inflammation. Additionally, interleukin (IL)-6 and IL-8 concentrations, measured by enzyme-linked immunosorbent assay (ELISA), were similar in the placental maternal blood from controls and SCD. There were also no significant differences found in IL-6 vein blood concentrations between controls and SCD, IL-8 being not detected. Immunostaining of umbilical vein endothelium in SCD pregnancies showed redistribution of PECAM-1 (CD31), von Willebrand factor (vWF), and P-selectin to the cell surface, controls exhibiting the classical pattern. Staining quantification indicated increases in vWF (+36.2%; P=.006) and vascular endothelial growth factor (VEGF) expression (+96.0%; P=.006) over control, but a reduction in endothelial nitric oxide synthase (eNOS) (-45.5%; P=.029). These results document, for the first time, direct functional adjustments in response to hypoxia in human in vivo. The mechanism for these changes has not been clearly established, but it may reflect increased tolerance to SCD hypoxic conditions and hypoxia in general.
...
PMID:The placental-umbilical unit in sickle cell disease pregnancy: a model for studying in vivo functional adjustments to hypoxia in humans. 1566 92
The inflammatory events induced in the peritoneal cavity of mice by two PLA2s isolated from Bothrops asper snake venom were investigated. MT-III, an Asp-49 catalytically active enzyme and MT-II, a catalytically inactive Lys-49 variant induced increase in vascular permeability. Inhibition of enzymatic activity of MT-III with p-bromophenacyl bromide reduced this effect. MT-III induced a larger neutrophil infiltrate than MT-II. This activity was significantly reduced after inhibition of catalytic activity. Reduction in the number of neutrophils was observed when antibodies against L-selectin, CD18 or LFA-1 were used, suggesting the involvement of these adhesion molecules in the effects of both PLA2s. There was no effect with antibodies against ICAM-1 and PECAM-1 . Increase in the levels of LTB4 and TXA2, as well as of IL-1, IL-6 and TNF-alpha, were observed in the peritoneal exudates induced by MT-III. MT-II did not enhance levels of eicosanoids but increased those of cytokines. It is concluded that both PLA2s induce inflammatory events in this model. Since MT-III exerts a stronger proinflammatory effect, the enzymatic phospholipid hydrolysis may be relevant for these phenomena. However, the fact that MT-II induced inflammation suggests that molecular regions distinct from the catalytic site elicit inflammatory events perhaps by interacting with specific cell membrane acceptors.
...
PMID:Inflammatory events induced by Lys-49 and Asp-49 phospholipases A2 isolated from Bothrops asper snake venom: role of catalytic activity. 1568 72
Bothrops asper venom (BaV) causes systemic and local effects characterized by an acute inflammatory reaction with accumulation of leukocytes and release of endogenous mediators. In this study, the effects of BaV on the release of the cytokines IL-1, IL-6 and TNF-alpha and the eicosanoids LTB4 and TXA2 in the peritoneal cavity of mice were analyzed. We also investigated the participation of beta2 integrin chain, l-selectin, LFA-1, ICAM-1 and PECAM-1 adhesion molecules in the BaV-induced leukocyte accumulation. Levels of proinflammatory cytokines IL-6 and TNF-alpha, as well as eicosanoids LTB4 and TXA2 were significantly increased after BaV injection (250 microg/kg), whereas no increment in IL-1 was observed. Anti-mouse l-selectin, LFA-1, ICAM-1, PECAM-1 and beta2 integrin chain monoclonal antibodies resulted in a reduction of neutrophil accumulation induced by BaV injection compared with isotype-matched control injected animals. These data suggest that BaV is able to induce the activation of leukocytes and endothelium to express adhesion molecules involved in the recruitment of neutrophils into the inflammed site. Furthermore, these results showed that BaV induces the release of cytokines and eicosanoids in the local of the venom injection; these inflammatory mediators may be important for the initiation and amplification of the inflammatory reaction characteristic from Bothrops sp envenomation.
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PMID:Inflammation induced by Bothrops asper venom: release of proinflammatory cytokines and eicosanoids, and role of adhesion molecules in leukocyte infiltration. 1619 89
| http://www.nactem.ac.uk/facta/cgi-bin/facta3.cgi?query=HUMANGGP%3A011698%7C111111%7C0%7C0%7C21489%7C0%7C10 |
JFK Assassination Records - 2018 Additional Documents Release | National Archives
Have a question about JFK Assassination Records? Ask it on HistoryHub! The National Archives is releasing documents previously withheld in accordance with the JFK Assassination Records Collection Act. The vast majority of the Collection (88%) has been open in full and released to the public since the late 1990s. The records at issue are documents previously identified as
JFK Assassination Records - 2018 Additional Documents Release
The National Archives is releasing documents previously withheld in accordance with the JFK Assassination Records Collection Act. The vast majority of the Collection (88%) has been open in full and released to the public since the late 1990s. The records at issue are documents previously identified as assassination records, but withheld in full or withheld in part.Learn more
These releases include FBI, CIA, and other agency documents (both formerly withheld in part and formerly withheld in full) identified by the Assassination Records Review Board as assassination records. The releases to date are as follows:
July 24, 2017: 3,810 documents (read press release )
October 26, 2017: 2,891 documents (read press release )
November 3, 2017: 676 documents (read press release )
November 9, 2017: 13,213 documents (read press release )
December 15, 2017: 3,539 documents * (read press release )
April 26, 2018: 18,731 documents * (read press release )
* Note: There are instances where multiple record identification numbers are associated with the same pdf. This is due to the fact that the files were scanned in batches.
Accessing the Release Files
The table below displays metadata about all the released documents. You can alsodownload the spreadsheet as an Excel file(4.7MB).
To view or download a specific document, follow the link in the "Doc Date" column. The files are sorted by NARA Release Date, with the most recent files appearing first. The previous withholding status (i.e., formerly withheld in part or formerly withheld in full) is identified in the “Formerly Withheld Status” column.
JFK Table
Row Num Record Num NARA Release Date Formerly Withheld Agency Doc Date Doc Type File Num To Name From Name Title Num Pages Originator Record Series Review Date Comments Pages Released 54551 104-10168-10015 11/09/2017 In Part CIA 01/02/1962 [ PDF ] PAPER - TEXTUAL DOCUMENT 80T01357A WF FINANCE ZOGBY, G. J., C/WH/4 RE-IMBURSEMENT TO U.S. BUREAU OF CUSTOMS. 1 CIA JFK 11/09/2017 JFK64-6 : F14 : 1998.02.07.09:15:08:856031 : 1 54552 104-10168-10015 04/26/2018 Redact CIA 01/02/1962 [ PDF ] PAPER-TEXTUAL DOCUMENT 80T01357A WF FINANCE ZOGBY, G. J., C/WH/4 RE-IMBURSEMENT TO U.S. BUREAU OF CUSTOMS. 1 CIA JFK 03/12/2018 JFK64-6 : F14 : 1998.02.07.09:15:08:856031 : 1 54553 198-10006-10011 04/26/2018 Redact 03/07/1963 [ PDF ] PAPER-TEXTUAL DOCUMENT CALIFANO, JOSEPH ZUMWALT, E.R. INTERDEPARTMENTAL COORDINATING COMMITTEE OF CUBAN AFFAIRS: MOVEMENT OF SUBVERSIVES 27 OASD 03/16/2018 Califano Papers, Box 3, Folder 12. ISA comments on the Krulak Committee's paper on the movement of Cuban subversives. 54554 104-10012-10089 11/09/2017 In Part CIA 06/07/1968 [ PDF ] PAPER - TEXTUAL DOCUMENT 201-289248 WITHHELD [DIRECTOR STAFF CABLE RE RICHARD CASE NAGELL, AKA JOE CRAMER, JOE KRANE AND ROBERT C. NOLAN. 1 CIA JFK 11/09/2017 OSW16 : V56 : 1993.06.25.13:42:22:590800 : 1 54555 104-10012-10089 04/26/2018 Redact CIA 06/07/1968 [ PDF ] PAPER-TEXTUAL DOCUMENT 201-289248 WITHHELD [DIRECTOR STAFF CABLE RE RICHARD CASE NAGELL, AKA JOE CRAMER, JOE KRANE AND ROBERT C. NOLAN. 1 CIA JFK 03/16/2018 OSW16 : V56 : 1993.06.25.13:42:22:590800 : 1 54556 104-10003-10180 11/09/2017 In Part CIA 03/17/1964 [ PDF ] PAPER - TEXTUAL DOCUMENT 201-289248 MEMO FOR THE RECORD [[DELETED]] SR/CI/R REPORT OF PHONE CONVERSATION WITH [[DELETED]] DO/OS - OPERATIONS SUPPORT BRANCH. 1 CIA JFK 11/09/2017 OSW9 : V35B : 1993.06.11.14:22:28:180000 : 1 54557 104-10003-10180 04/26/2018 Redact CIA 03/17/1964 [ PDF ] PAPER-TEXTUAL DOCUMENT 201-289248 MEMO FOR THE RECORD [[DELETED]] SR/CI/R REPORT OF PHONE CONVERSATION WITH [[DELETED]] DO/OS - OPERATIONS SUPPORT BRANCH. 1 CIA JFK 03/12/2018 OSW9 : V35B : 1993.06.11.14:22:28:180000 : 1 54558 104-10003-10179 11/09/2017 In Part CIA 03/19/1964 [ PDF ] PAPER - TEXTUAL DOCUMENT 201-289248 MEMO FOR THE RECORD [[DELETE]], SR/CI/R REPORT OF TELEPHONE CONVERSATION. 1 CIA JFK 11/09/2017 OSW9 : V35B : 1993.06.11.14:12:38:250000 : 2OF3 1 54559 104-10003-10179 04/26/2018 Redact CIA 03/19/1964 [ PDF ] PAPER-TEXTUAL DOCUMENT 201-289248 MEMO FOR THE RECORD [[DELETE]], SR/CI/R REPORT OF TELEPHONE CONVERSATION. 1 CIA JFK 03/12/2018 OSW9 : V35B : 1993.06.11.14:12:38:250000 : 2OF3 1 54560 104-10113-10391 11/09/2017 In Part CIA 10/25/1977 [ PDF ] PAPER - TEXTUAL DOCUMENT 80T01357A [[DELETE]]CI/R&A/E ROUTING AND RECORD SHEET. 1 CIA JFK 11/09/2017 JFK41 : F29 : 1993.08.09.18:02:43:000058 : 1 54561 104-10113-10391 04/26/2018 Redact CIA 10/25/1977 [ PDF ] PAPER-TEXTUAL DOCUMENT 80T01357A [[DELETE]]CI/R&A/E ROUTING AND RECORD SHEET. 1 CIA JFK 03/12/2018 JFK41 : F29 : 1993.08.09.18:02:43:000058 : 1 54562 104-10105-10211 11/09/2017 In Part CIA 09/09/0000 [ PDF ] OFFICE PAPER, ROUTING SHEET, PHONE MESSAGES 80T01357A OGC ATTN: LLOYD, WALTER [[DELETIONL]] C/DDO/PIC/AL ROUTING SLIP WITH NOTES RE WERBELL. 3 CIA JFK 11/09/2017 JFK37 : F23 : 1993.08.11.14:16:33:090005 : 3 54563 104-10105-10211 04/26/2018 Redact CIA 09/09/0000 [ PDF ] PAPER-TEXTUAL DOCUMENT 80T01357A OGC ATTN: LLOYD, WALTER [[DELETIONL]] C/DDO/PIC/AL ROUTING SLIP WITH NOTES RE WERBELL. 3 CIA JFK 03/12/2018 JFK37 : F23 : 1993.08.11.14:16:33:090005 : 3 54564 104-10012-10038 11/09/2017 In Part CIA 12/04/1976 [ PDF ] PAPER - TEXTUAL DOCUMENT 201-289248 DIRECTOR [[DELETION]] CABLE RE LEE HARVEY OSWALD CONVERSATION WITH OBYRDKOV. 5 CIA JFK 11/09/2017 OSW16 : V57 : 1993.06.24.14:28:56:150800 : 5 54565 104-10066-10233 11/09/2017 In Part CIA 06/02/1978 [ PDF ] PAPER - TEXTUAL DOCUMENT 80T01357A ((DELETION)) [[DELETION]] CABLE RE: REF A RECEIVED AFTER HSCA STAFFERS HAD ALREADY CONDUCTED INTERVIEW. 2 CIA JFK 11/09/2017 JFK11 : F10 : 1993.07.19.10:35:01:650410 : 2 54566 104-10066-10235 11/09/2017 In Part CIA 06/02/1978 [ PDF ] PAPER - TEXTUAL DOCUMENT 80T01357A ((DELETION)) [[DELETION]] CABLE RE: REALIZE STAFFERS FONZI ANGD GONZALES GIVEN LATITUDE. 1 CIA JFK 11/09/2017 JFK11 : F10 : 1993.07.19.10:41:36:930410 : 1 54567 104-10066-10236 11/09/2017 In Part CIA 06/02/1978 [ PDF ] PAPER - TEXTUAL DOCUMENT 80T01357A ((DELETION)) [[DELETION]] CABLE RE: ASSUME THE SUBJECT OF REF A . 1 CIA JFK 11/09/2017 JFK11 : F10 : 1993.07.19.10:44:27:460410 : 1 54568 104-10066-10245 11/09/2017 In Part CIA 06/01/1978 [ PDF ] PAPER - TEXTUAL DOCUMENT 80T01357A ((DELETION)) [[DELETION]] CABLE RE: REF C WAS PASSED FBIS UPON RECEIPT BY COMMO. 1 CIA JFK 11/09/2017 JFK11 : F10 : 1993.07.19.11:08:16:840410 : 1 54569 104-10103-10327 11/09/2017 In Part CIA 06/03/1965 [ PDF ] PAPER - TEXTUAL DOCUMENT 80T01357A [[DELETION]] MEMO: MR. PAPICH TELEPHONED TO REPORT. 2 CIA JFK 11/09/2017 JFK36 : F32 : 1993.07.22.15:21:47:180410 : 2 54570 104-10103-10330 11/09/2017 In Part CIA 06/04/1965 [ PDF ] PAPER - TEXTUAL DOCUMENT 80T01357A DIRECTOR [[DELETION]] CABLE: SUBJ REFS CONTACTED. 3 CIA JFK 11/09/2017 JFK36 : F32 : 1993.07.22.15:24:43:780410 : 3 54571 104-10103-10331 11/09/2017 In Part CIA 06/04/1965 [ PDF ] PAPER - TEXTUAL DOCUMENT 80T01357A DIRECTOR [[DELETION]] CABLE: ESPINOSA ACTIVITIES SPAIN NOT KNOWN. 1 CIA JFK 11/09/2017 JFK36 : F32 : 1993.07.22.15:29:14:560410 : 1 54572 104-10103-10339 11/09/2017 In Part CIA 06/19/1965 [ PDF ] PAPER - TEXTUAL DOCUMENT 80T01357A DIRECTOR [[DELETION]] CABLE: AMLASH/2 TOLD ((DELETION)) 2 CIA JFK 11/09/2017 JFK36 : F32 : 1993.07.22.16:05:52:150410 : 2 54573 104-10105-10223 11/09/2017 In Part CIA 11/12/1971 [ PDF ] PAPER - TEXTUAL DOCUMENT 80T01357A DIRECTOR [[DELETION]] CABLE RE WERBELL'S WHEREABOUTS. 3 CIA JFK 11/09/2017 JFK37 : F23 : 1993.08.11.15:31:50:900005 : 3 54574 104-10106-10068 11/09/2017 In Part CIA 01/11/1977 [ PDF ] PAPER - TEXTUAL DOCUMENT 80T01357A CHIEF, SE DIVISION [[DELETION]] APPEARANCE AS WITNESS IN BEHALF OF THE UNITED STATES GOVERNMENT. 7 CIA JFK 11/09/2017 JFK38 : F16 : 1993.07.20.16:55:50:840380 : 7 54575 104-10113-10109 11/09/2017 In Part CIA 01/01/0000 [ PDF ] OFFICE PAPER, ROUTING SHEET, PHONE MESSAGES 80T01357A MEMORANDUM FOR THE RECORD [[DELETION]] DUQUE MIYAR, EVELIO 1 CIA JFK 11/09/2017 JFK41 : F26 : 1993.07.24.09:09:44:340440 : 1 54576 104-10143-10219 11/09/2017 In Part CIA 03/11/1965 [ PDF ] PAPER - TEXTUAL DOCUMENT 80T01357A [[DELETION]] MEMO: AMMUG-1 DEBRIEFING REPORT #278 (LUISA RODRIGUEZ. 1 CIA JFK 11/09/2017 JFK58 : F8 : 1993.07.29.08:10:44:680410 : 1 54577 104-10012-10038 04/26/2018 Redact CIA 12/04/1976 [ PDF ] PAPER-TEXTUAL DOCUMENT 201-289248 DIRECTOR [[DELETION]] CABLE RE LEE HARVEY OSWALD CONVERSATION WITH OBYRDKOV. 5 CIA JFK 03/12/2018 OSW16 : V57 : 1993.06.24.14:28:56:150800 : 5 54578 104-10066-10233 04/26/2018 Redact CIA 06/02/1978 [ PDF ] PAPER-TEXTUAL DOCUMENT 80T01357A ((DELETION)) [[DELETION]] CABLE RE: REF A RECEIVED AFTER HSCA STAFFERS HAD ALREADY CONDUCTED INTERVIEW. 2 CIA JFK 03/12/2018 JFK11 : F10 : 1993.07.19.10:35:01:650410 : 2 54579 104-10066-10235 04/26/2018 Redact CIA 06/02/1978 [ PDF ] PAPER-TEXTUAL DOCUMENT 80T01357A ((DELETION)) [[DELETION]] CABLE RE: REALIZE STAFFERS FONZI ANGD GONZALES GIVEN LATITUDE. 1 CIA JFK 03/12/2018 JFK11 : F10 : 1993.07.19.10:41:36:930410 : 1 54580 104-10066-10236 04/26/2018 Redact CIA 06/02/1978 [ PDF ] PAPER-TEXTUAL DOCUMENT 80T01357A ((DELETION)) [[DELETION]] CABLE RE: ASSUME THE SUBJECT OF REF A . 1 CIA JFK 03/12/2018 JFK11 : F10 : 1993.07.19.10:44:27:460410 : 1 54581 104-10066-10245 04/26/2018 Redact CIA 06/01/1978 [ PDF ] PAPER-TEXTUAL DOCUMENT 80T01357A ((DELETION)) [[DELETION]] CABLE RE: REF C WAS PASSED FBIS UPON RECEIPT BY COMMO. 1 CIA JFK 03/12/2018 JFK11 : F10 : 1993.07.19.11:08:16:840410 : 1 54582 104-10073-10279 04/26/2018 Redact 10/06/1976 [ PDF ] PAPER-TEXTUAL DOCUMENT 80T01357A CHIEF, SOV BLOC DIV; CHIEF, FE DIV [[DELETION]] DISPATCH OF MEMORANDUM TO WALT ROSTOW ON BEHEIREN AND FOUR US NAVY DESERTERS 16 CIA 03/12/2018 JFK16 : F60 : 1993.07.15.19:08:42:560620 : 54583 104-10073-10279 04/26/2018 Redact 10/06/1976 [ PDF ] PAPER-TEXTUAL DOCUMENT 80T01357A CHIEF, SOV BLOC DIV; CHIEF, FE DIV [[DELETION]] DISPATCH OF MEMORANDUM TO WALT ROSTOW ON BEHEIREN AND FOUR US NAVY DESERTERS 16 CIA 03/12/2018 JFK16 : F60 : 1993.07.15.19:08:42:560620 : 54584 104-10103-10327 04/26/2018 Redact CIA 06/03/1965 [ PDF ] PAPER-TEXTUAL DOCUMENT 80T01357A [[DELETION]] MEMO: MR. PAPICH TELEPHONED TO REPORT. 2 CIA JFK 03/12/2018 JFK36 : F32 : 1993.07.22.15:21:47:180410 : 2 54585 104-10103-10330 04/26/2018 Redact CIA 06/04/1965 [ PDF ] PAPER-TEXTUAL DOCUMENT 80T01357A DIRECTOR [[DELETION]] CABLE: SUBJ REFS CONTACTED. 3 CIA JFK 03/16/2018 JFK36 : F32 : 1993.07.22.15:24:43:780410 : 3 54586 104-10103-10331 04/26/2018 Redact CIA 06/04/1965 [ PDF ] PAPER-TEXTUAL DOCUMENT 80T01357A DIRECTOR [[DELETION]] CABLE: ESPINOSA ACTIVITIES SPAIN NOT KNOWN. 1 CIA JFK 03/16/2018 JFK36 : F32 : 1993.07.22.15:29:14:560410 : 1 54587 104-10103-10339 04/26/2018 Redact CIA 06/19/1965 [ PDF ] PAPER-TEXTUAL DOCUMENT 80T01357A DIRECTOR [[DELETION]] CABLE: AMLASH/2 TOLD ((DELETION)) 2 CIA JFK 03/16/2018 JFK36 : F32 : 1993.07.22.16:05:52:150410 : 2 54588 104-10105-10223 04/26/2018 Redact CIA 11/12/1971 [ PDF ] PAPER-TEXTUAL DOCUMENT 80T01357A DIRECTOR [[DELETION]] CABLE RE WERBELL'S WHEREABOUTS. 3 CIA JFK 03/12/2018 JFK37 : F23 : 1993.08.11.15:31:50:900005 : 3 54589 104-10106-10068 04/26/2018 Redact CIA 01/11/1977 [ PDF ] PAPER-TEXTUAL DOCUMENT 80T01357A CHIEF, SE DIVISION [[DELETION]] APPEARANCE AS WITNESS IN BEHALF OF THE UNITED DOSS GOVERNMENT. 7 CIA JFK 03/12/2018 JFK38 : F16 : 1993.07.20.16:55:50:840380 : 7 54590 104-10113-10109 04/26/2018 Redact CIA 01/01/0000 [ PDF ] PAPER-TEXTUAL DOCUMENT 80T01357A MEMORANDUM FOR THE RECORD [[DELETION]] DUQUE MIYAR, EVELIO 1 CIA JFK 03/12/2018 JFK41 : F26 : 1993.07.24.09:09:44:340440 : 1 54591 104-10143-10219 04/26/2018 Redact CIA 03/11/1965 [ PDF ] PAPER-TEXTUAL DOCUMENT 80T01357A [[DELETION]] MEMO: AMMUG-1 DEBRIEFING REPORT #278 (LUISA RODRIGUEZ. 1 CIA JFK 03/12/2018 JFK58 : F8 : 1993.07.29.08:10:44:680410 : 1 54592 104-10003-10204 11/09/2017 In Part CIA 03/19/1964 [ PDF ] PAPER - TEXTUAL DOCUMENT 201-289248 SR/CI ATTN: [[DELETION]] [[DELETION]] CD/DO/SUPPORT ROUTING AND RECORD SHEET WITH NOTE "PER OUR TELECON." 1 CIA JFK 11/09/2017 OSW9 : V35B : 1993.06.14.16:36:32:710000 : 1OF3 1 54593 104-10003-10204 04/26/2018 Redact CIA 03/19/1964 [ PDF ] PAPER-TEXTUAL DOCUMENT 201-289248 SR/CI ATTN: [[DELETION]] [[DELETION]] CD/DO/SUPPORT ROUTING AND RECORD SHEET WITH NOTE "PER OUR TELECON." 1 CIA JFK 03/12/2018 OSW9 : V35B : 1993.06.14.16:36:32:710000 : 1OF3 1 54594 104-10012-10055 11/09/2017 In Part CIA 07/31/1975 [ PDF ] PAPER - TEXTUAL DOCUMENT 201-289248 STURBITTS, WILLIAM, LA/EICO [[DELETION]], C/LA/MEXICO REVIEW OF LEE HARVEY OSWALD 201 FILE FOR FOIA REQUEST 2 CIA JFK 11/09/2017 OSW16 : V57 : 1993.06.24.15:43:04:620800 : 2 54595 104-10012-10055 04/26/2018 Redact CIA 07/31/1975 [ PDF ] PAPER-TEXTUAL DOCUMENT 201-289248 STURBITTS, WILLIAM, LA/EICO [[DELETION]], C/LA/MEXICO REVIEW OF LEE HARVEY OSWALD 21 FILE FOR FOIA REQUEST 2 CIA JFK 03/12/2018 OSW16 : V57 : 1993.06.24.15:43:04:620800 : 2 54596 104-10062-10244 11/09/2017 In Part CIA 03/01/1977 [ PDF ] PAPER - TEXTUAL DOCUMENT 80T01357A APPEALS COORDINATOR, FOIA STAFF [[DELETION]], DDO APPEALS OFFICER FOIA APPEAL -- ROBERT SIBLEY (F 76-455) 4 CIA JFK 11/09/2017 JFK9 : F74 : 1993.08.05.17:00:48:870006 : 4 54597 104-10062-10244 04/26/2018 Redact CIA 03/01/1977 [ PDF ] PAPER-TEXTUAL DOCUMENT 80T01357A APPEALS COORDINATOR, FOIA STAFF [[DELETION]], DDO APPEALS OFFICER FOIA APPEAL -- ROBERT SIBLEY (F 76-455) 4 CIA JFK 03/12/2018 JFK9 : F74 : 1993.08.05.17:00:48:870006 : 4 54598 104-10122-10118 11/09/2017 In Part CIA 09/10/1952 [ PDF ] PAPER - TEXTUAL DOCUMENT 80T01357A [[DELETION]], SPECIAL AGENT NOTE RE WILLIAM D. PAWLEY 1 CIA JFK 11/09/2017 JFK44 : F40 : 1993.08.04.10:35:49:930006 : 1 54599 104-10122-10118 04/26/2018 Redact CIA 09/10/1952 [ PDF ] PAPER-TEXTUAL DOCUMENT 80T01357A [[DELETION]], SPECIAL AGENT NOTE RE WILLIAM D. PAWLEY 1 CIA JFK 03/12/2018 JFK44 : F40 : 1993.08.04.10:35:49:930006 : 1 54600 104-10106-10223 11/09/2017 In Part CIA 02/28/1977 [ PDF ] PAPER - TEXTUAL DOCUMENT 80T01357A CHIEF, SE DIVISION {{DELETION}}, SE/X/LA APPEARANCE AS WITNESS IN BEHALF OF THE UNITED STATES GOVERNMENT. 2 CIA JFK 11/09/2017 JFK38 : F16 : 1993.07.20.19:26:50:000380 : 2
| https://www.archives.gov/research/jfk/release?order=From%20Name&page=1091&sort=asc&width=320 |
'When This Old Hat Was New' in 'Songs for the People, or Tippecanoe Melodies' | Northern Illinois University Digital Library
When This Old Hat Was New.
12
TUNE -- " John Anderson my Jo, John."
Song performed by: Chad Sheridan, Leslie Beukelman (vocals) and Tara Dirst (banjo and guitar). Recording engineer: Matt Dotson.
When this old hat was new, the people used to say,The best among the Democrats were Harrison and Clay;The Locos now assume the name, a title most untrue,And most unlike their party name, when this old hat was new.
13
When this old hat was new, Van Burenwas a Fed,An enemy to every man who labored for his bread;And if the people of New York have kept their records true,He voted 'gainst the poor man's rights when this old hat was new.
When this old hat was new, Buchananwas the manBest fitted in the Keystone State to lead the Fed'ral clan;He swore "if Democratic blood should make his veins look blue,He'd cure them by Phlebotomy," when this old hat was new.
When this old hat was new, ('twas eighteen hundred eleven,) Charles Ingersolldid then declare, by all his hopes of heaven,"Had he been able to reflect, he'd been a Tory true,And ne'er have thought it a reproach," when this old hat was new.
When this old hat was new, of Richard Rush'twas said,To figure well among the Feds, he wore a black cockade;Deny this Locos, if you please, for every word is true,I knew full well old Dickey Rush, when this old hat was new.
When this old hat was new, the Senator from Maine,Destroyed by fire an effigy, t' immortalize his name;The effigy was Madison's, if common fame be true,So Ruel Williamswas a Fed when this old hat was new.
When this old hat was new, 'twas in the Granite State,That Henry Hubbardasked each town to send a delegate,To meet in council at the time when Federalism blueMade Hartford look like indigo, when this old hat was new.
When this old hat was new, Sam Cushmandid declare,"That should a soldier cross the lines, he hoped he'd perish there,
14
And leave his bones in Canada for enemies to view;"
So much for his Democracy, when this old hat was new.
When this old hat was new, old Governor ProvostThe States invaded, at the head of a numerous British host,Then mark, ye Locos, what did Martin Chittendenthen do?Forbid Green Mountains Boys to fight! when this old hat was new.
When this old hat was new, Woodburyand Van Ness, E. Allen Brown, and Stephen Haightwere of the Federal mess, A. H. Everett, Martin Field,and Sam. C. Allentoo,New Patent Democrats, were Feds, when this old hat was new.
When this old hat was new, these worthies did opposeThe cause and friends of liberty, and stood among their foes;Not so with "Granny" Harrison, for at Tippecanoe,He bravely fought the savage foes, when this old hat was new.
When this old hat was new, the friends of LibertyKnew well the merits of Old Tip, while fighting at Maumee;Come now, huzza for Harrison, just as we used to do,When first we heard of Proctor's fall, when this old hat was new.
Details
Title
'When This Old Hat Was New' in 'Songs for the People, or Tippecanoe Melodies'
Resource Type
textsound recording-musical
Genre/Form
bookssongs (document genre)
Date Issued
1840
Owning Institution
Newberry Library
Subject
Religion and CulturePolitical DevelopmentPresidential CampaignsLincoln1818--1860Presidents--United States--HistoryPolitical campaigns--United States--HistoryPresidential candidates--United States--HistoryUnited States--Politics and government--History
Identifier
SP:OldHat
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| https://digital.lib.niu.edu/islandora/object/niu-lincoln:35699 |
420462http://detroit1967.detroithistorical.org/files/original/4442021a65db9b33b813a3ed6964a788.jpg75ae214b4d14fe425c6262d4910b4509Dublin CoreThe Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/.TitleA name given to the resourceDetroit 67: Looking Back to Move ForwardSubjectThe topic of the resourceStories gathered to commemorate the summer of 1967 in Detroit.PublisherAn entity responsible for making the resource availableDetroit Historical SocietyRightsInformation about rights held in and over the resourceDetroit Historical Society, Detroit, MILanguageA language of the resourceen-usDateA point or period of time associated with an event in the lifecycle of the resource10/20/2019Oral HistoryAn audio or video resource containing historical information obtained in interviews with persons having firsthand knowledge.Narrator/Interviewee's NameThe current first and last name of the person speaking or being interviewed.Cecile JensonBrief BiographyA short biography of the IntervieweeCecile Jensen was born in Detroit in 1950 and grew up on the west side of Detroit where she lived during the 1967 disturbance. Jensen worked as a school teacher for Rochester Hills for thirty years. She currently lives in Rochester Hills, MI with her husband.Interviewer's NameThe first and last name of the interviewer.Noah LevinsonInterview PlaceThe place where the interview was conducted.West Bloomfield, MIDateThe date of the interview in MM/DD/YYYY format.07/16/2016Interview LengthThe total length of the interview in HH:MM:SS format.00:38:03TranscriptionistThe first and last name of the transcriptionist.Hannah SabalTranscription DateThe date of the transcription in MM/DD/YYYY format.6/01/2016TranscriptionAny written text transcribed from a sound< p> NL: Today is July 17< sup> th< /sup> , 2015. This is the interview of Cecile Jensen by Noah Levinson. We are at the Polish Mission located at Orchard Lake School’s campus in West Bloomfield, Michigan. This interview is for the Detroit Historical Society and the Detroit 1967 Oral History Project. Cecile, thanks for taking the time to meet with us today. Could you first tell me where and when were you born?< /p> < p> CJ: I was born in Detroit in 1950, at Crittenton Hospital.< /p> < p> NL: Do you recall where that was?< /p> < p> CJ: Well, it was the old one. It was along the expressway and it was the forerunner to the one that’s in Rochester today.< /p> < p> NL: What neighborhood do you first remember living in?< /p> < p> CJ: I only lived in one, for the first 18 years of my life. It was on the west side of Detroit. West Chicago and Wyoming were the cross streets. And when I was growing up, as a Catholic school girl, we would never really ask somebody, “What neighborhood are you from?” We would say, “Which parish are you from?” So that was the way we organized our life, by the parish we were in, and we had an elementary school as well.< /p> < p> NL: Was there a correlation that was understood by most people that certain parishes correspond to certain parts of the city or people just went to different ones they liked for various reasons?< /p> < p> CJ: There was a guidance map throughout the diocese of metro Detroit, so if you lived on certain streets, then there was a designated parish for you to belong to and support.< /p> < p> NL: Were you allowed to support a different one if you chose to, or was it pretty strictly adhered to?< /p> < p> CJ: It was pretty strictly adhered to. We have stories of families who got into a discussion with the pastor because they wanted to go somewhere else and that was being allowed. But this was the fifties, now I think a pastor would be very happy with a new parishioner.< /p> < p> NL: I would think so as well. Can you describe that neighborhood, Chicago and Wyoming, where you were growing up?< /p> < p> CJ: Sure. I think now when we look back, it’s sort of like one of those dream sequences. You could walk up to the grocery store, you could walk up to the drug store. If you went in the other direction on Wyoming, there was a toy store. I was always sent up to the German meat market to go to buy the lunchmeat for the family. There were five kids in our family, and I was sort of like the grocery girl. Get on my bike, and go through the neighborhood. So it was close-knit. Not only did we know our neighbors well, but my aunt and uncle lived around the block, and my grandparents lived two blocks away, and down the street from them was yet another aunt and uncle. So we all congregated& nbsp; in that neighborhood because right after World War II, when the expressway went through, our family homes were condemned, and our family had to resettle. So they had been at, like, Michigan and more into a Polish community when they were growing up. And then after World War II, they condemned the houses so they could put in the expressway, and so a new neighborhood was sought. So there are a lot of Poles in our parish, but there were also Irish folks, and other ethnicities as well.< /p> < p> NL: At that time, to the best of your memory, was the Polish community pretty well-spread around the city of Detroit?< /p> < p> CJ: Yes, the Polish community in metro Detroit really started on the east side. Then it went to the west side, and then eventually to Hamtramck, which people are more familiar with. But the core parishes first started on the east side and the west side.< /p> < p> NL: And when did that—I would be part of that camp, the association between here and Hamtramck, the Polish community, they’re synonymous—when did that transition start happening from the neighborhoods more closer to downtown up toward Hamtramck?< /p> < p> CJ: I would say maybe when the plants opened, so maybe around 1910 or so? When I’m talking about the first parishes, I’m talking about the 1880s, so our seminary was actually part of the very core, first Polish community in Detroit, at Canfield and St. Aubin. So St. Albertus church still stands. There had been our seminary; that building does not stand there anymore. And there was also a mother house for the Polish nuns—the Felician sisters—and that really was like a transplanted village from Europe, and then they transplanted that same type of community into Detroit.< /p> < p> NL: You mentioned that you were one of five growing up. Where were you in the pecking order?< /p> < p> CJ: I am the middle girl, but I’m the fourth of five. So I think when I do my Facebook quizzes, I don’t think that gives me any badge.< /p> < p> NL: And what were your parents’ occupations when you were growing up?< /p> < p> CJ: When I was growing up, my mother was a bookkeeper by trade, or by training. She raised us as a stay-at-home mom, and once it was time to go back into the workforce, she became a controller at Mercy School of Nursing on the boulevard. My father was the first generation born in the United States for his family, and one of the things I love so much, I see one of the documents his mother signed with an X, and then my father became a lawyer for the City of Detroit. So I like to see that progress.< /p> < p> NL: Do you know what type of work, more specifically, he handled for the city of Detroit?< /p> < p> CJ: Yes, condemnation. He would start taking down neighborhoods. They would condemn part of the neighborhood, whether it was for the highway that his own family was impacted by, but also for other areas so they could build factories or thoroughfares, so he went to court a lot, to be able to settle those matters on behalf of the city.< /p> < p> NL: What do you remember about Detroit in general, beyond the neighborhood you grew up in, in the fifties and sixties?< /p> < p> CJ: Well, I thought it was pretty exciting to be able to take my dad to work, because first he was at the city hall, over where Kennedy center is right now, and then eventually he did have an office in the Coleman Young building. We used to call it the city-county building. That was super special. When he would take his daughter to work, and I would get to go into the law offices, I’d get to see all the mimeograph machines, all the high-tech that they were creating things with. And then, I got to go into the City of Detroit Chamber, I got to meet the mayor, I got to meet some of the council people, and that really impressed me, that my father would have that level of access to people. So I really loved going downtown. As we approached the city hall, when I was very young, they still had trolleys in the street, so you would see the little snaps of electricity in the overhead, so that had to be in the early fifties. Then my dad died in 1964, I had said goodbye to him and went to Girl Scout camp, and he died when I was at camp. So for me, my idea of Detroit in the sixties, first of all, cozy neighborhood, excellent going down to the city county building, getting to enjoy everything that was on Woodward, walking, enjoying Freedom Festival with Windsor and Detroit, and then all of a sudden, it started falling apart. Being a& nbsp; Catholic, one of the things that happened was the pope died. Then in the sixties, JFK was assassinated. Then Robert Kennedy was assassinated. And then Martin Luther King was assassinated. It’s like, we’re always in mourning, in the early sixties, we’re in mourning! And my own father’s death, and then the riots! So everything that had a beautiful, strong foundation for me was crumbling.< /p> < p> NL: Speaking of the riots, could you tell me where you were and how you first heard of that in late July 1967?< /p> < p> CJ: I was selling snacks at Tiger Stadium. I was at stand 22, and I wasn’t selling beer—I wasn’t old enough—but we were selling hot dogs, and filling the ketchup, and reconstituting the dry onions, and making sure we had enough for everybody, and it was a pretty exciting day. I didn’t first hear about it, I first smelled it, because I could smell things burning around Tiger Stadium. And then we got the word that the city was burning, and I was with some older women, I didn’t have a car, I relied on them to drive me to work and back, and at first we were kind of panicked, and we thought, “What are we going to do? How are we going to get home?” And so at first, we went, “Why don’t we turn off the freezer and hide in the freezer?” Because, you know, it would warm up pretty quickly, and we would have a pretty good defense, but who would know we were there? So that’s how I first—I smelled it.< /p> < p> NL: And how was your commute home, eventually, that day? How did that take place?< /p> < p> CJ: I talked her into driving—I think there were three or four of us that were all carpooling. And we had to get back to the west side, of course, and so we were taking Grand River, and we started to see all the looting going on—shop windows were being shattered, and people were walking out with washing machines, radios, record players, stereo record players. We saw a lot of that that was going on. We just tried to watch and move forward. I also noticed a car that was next to us, and they were calling so many firemen that there weren’t enough vehicles for them, so these were firemen in full uniform but they were driving around in a private car. So that kind of put the panic in us.< /p> < p> NL: As you saw that looting there on Grand River, were there police, other members of law enforcement starting to help tone down the looting and the violence?< /p> < p> CJ: The only thing that I saw were those firemen that were going by, and I don’t know what their destination was, so no, I did not see any law and order out on the streets.< /p> < p> NL: How did you spend your next few days while the looting and the violence continued?< /p> < p> CJ: I got back home on Orange Lawn and nobody was home. So one of my older brothers was at our family cottage on Lake St. Clair in Canada. Another brother was out of state for his summer job. My widowed mother and my younger sister were also out at the cottage, and then my older sister was at Michigan State. So I gave her a call asking her what she thought I should do. I was most concerned, what if mother and Margot start coming across the bridge? And then end up right in the middle of it? So her advice to me was only tears. She started crying. And I was sort of like, “But you’re in East Lansing, and I’m in Detroit! So actually that day made me start to believe in my own judgement, because I was 17, and I had to try to get a message to my family. I did know that there was one phone—I mean nowadays, what are we going to do? We’re going to text somebody, send it by our smartphone—but at that point, it was a rural beach community, and there was only one permanent resident that had a telephone. So I was trying to find that phone number so I would be able to warn them not to come home. But in hindsight, I found out that they didn’t need me to tell them that because they could see flames across the lake. They could already see the burning that was going on.< /p> < p> NL: You said this was on Lake St. Clair, on the Canadian side. What town or area is that?< /p> < p> CJ: Stony Point. The French is [unknown]. It’s nearby Tillberry, nearby Chatham—well Chatham is pretty far away, but it’s outside Windsor.< /p> < p> NL: Okay. How long did they remain there past what they expected?< /p> < p> CJ: That night, I got ahold of my cousins that lived around the block. And my cousin Gordon said, “You know what, we’re going to all go out to the cottage. We’re going to go to our summer homes, and we’ll do that by going through Port Huron.” So I got to leave the neighborhood shortly thereafter, so I spent a week in Canada, at the cottage.< /p> < p> NL: And you were able to drive from your neighborhood, which was not too far away from the nexus of a lot of the violence—you were able to drive on the expressway out of the city that way without being impeded by the curfews or law enforcement personnel with no-drive orders?< /p> < p> CJ: Right. Well, we left the next day. So a lot of those curfews and patrols, I don’t think, were quite in place yet. Because I did hear additional stories that my older brother that had stayed, kind of went snooping around in the daytime with my grandfather. They would go down to see where the National Guard was at, gawking a little bit. He denies it now. I was telling him I was going to tell that story. “No! No! It had to be another cousin!” But I think that they were able to go out a bit, but I was very grateful that my cousin who was just a couple years older than me would agree to drive us out. I think we used back roads to get up to Port Huron.< /p> < p> NL: How long, approximately, did you stay at the cottage?< /p> < p> CJ: I would say a good week.< /p> < p> NL: What do you remember about coming back, crossing the border, and re-entering the city? What did you notice?< /p> < p> CJ: Looked like a very different place. We were noticing all the boarded up buildings. I think people were a little more fearful as we drove. Myself, I was concerned about my younger sister and my mother as well, because she worked on the boulevard.& nbsp; She worked very close to that area, and I’m not sure how long the nursing school stayed closed. Because they had a running school, but maybe because it was in the summer, maybe they didn’t have a session running at the time.< /p> < p> NL: Do you remember anything unusual about the border crossing on the way back?< /p> < p> CJ: No, that’s a good question. I think we just had the regular questions, you know, like, “Where were you? Where are you going? How long were you there? Do you have any meat in the car?”< /p> < p> NL: Did you feel that your neighborhood was affected—which is to say physically was it affected? Obviously all the residents of Detroit were affected in a number of ways, but the actual neighborhood, was that affected at all by the violence?< /p> < p> CJ: No, not immediately. I didn’t see that any of our storefronts were broken into. I saw that more further toward the stadium and along Grand River, even though Grand River was one of our main thoroughfares. I don’t remember our neighborhood specifically suffering. Eventually it did because there was white flight, because so many people wanted to get out of the neighborhood, and that had already started with people going into the suburbs. But that, I think, did eventually take our neighborhood down.< /p> < p> NL: Can you talk a little bit more about that transition in the neighborhood?< /p> < p> CJ: Yes, I mentioned how my family had to relocate from Detroit, from Michigan and Fullerton—well, Fullerton that was later, but Michigan Avenue and Warren, that kind of area, the Polish parish. So they had to relocate. So in the late forties, they relocated in this west side community, we called in Epiphany parish. That was stable, into the sixties, but then people started moving. They started moving—they now had expressways to get faster, they could communicate on them. Some of the areas of choice were Livonia and Dearborn. Some of my classmates, their families started moving out.< /p> < p> NL: Where did you first live after your family residence where you grew up in?< /p> < p> CJ: I graduated from high school in 1968, and we were still living on Orange Lawn at that time. And then, in the course of the next two years, I went to Michigan State, I was in college, and my mother bought a new home in Troy. And she picked that neighborhood because there was some extended family out there, we were still doing that tradition.< /p> < p> NL: And after your time in East Lansing, where did you live?< /p> < p> CJ: Then I came home for short semesters, but I got married in 1972 and so, we were finishing our education—my husband and I were finishing our educations at Michigan State, so we lived in Lansing and East Lansing, eventually coming back to metro Detroit five years later.< /p> < p> NL: And what part of the metro area did you come to?< /p> < p> CJ: We bunked up at my mom’s house for a little while in Troy, and then we bought our own home in Huntington Woods, and we were there for a number of years. And now—you know, we’re really not the regular American demographic because we really stayed put for a long time—we’re probably in Huntington Woods for fifteen years, and I think we’re surpassing twenty years now in Rochester Hills.< /p> < p> NL: Wow. What do you recall about your time in those neighborhoods? Anything specific?< /p> < p> CJ: Well, I like them both very much. I loved Huntington Woods because it had that old neighborhood feel again. You could walk to the library, you could walk to the doctors, you could walk up to the drug store. We had great neighbors, and everything’s on Woodward. Who doesn’t love Woodward? So Huntington Woods was great, and it was halfway between my husband’s job at a brokerage house in Detroit, and halfway between my job teaching in Rochester Hills. We each left in the morning and went different directions. And then, in Rochester Hills, I’m devoted to that community because I spent thirty years teaching in that school district. And so even today, when I go up to the market, even though I’ve been retired for twelve, thirteen years, I still see my old students. I’m lucky that I still have a sense of community, but it’s a different community. It’s not all those kids I went to school with, but it’s children I schooled.< /p> < p> NL: In the years that you’ve lived in the various cities and suburbs of the metro area, do you frequent the city of Detroit?< /p> < p> CJ: I’m a big fan of the city. In fact, when I had the opportunity to take an early retirement, I thought, “What shall I do?” and I had gotten that genealogy bug very early on in my life. My dad had shown me that document when I was fourteen when I was doing a school project, and they said, “Interview one of your parents about their family history.” So I interviewed him, he showed me these very cool documents, but they’re written in German, and I thought, “But we’re Polish! What’s that all about?” But he died two months later, so that really got me interested. I wanted to start asking questions of aunts, uncles, and grandparents. “How did we end up in Detroit? Why did we end up in Detroit?” I began that when I was very young, and when there was an opportunity to take early retirement, I said, “I’m going to do what I can for Poles in Detroit.” So one of my first projects was doing one of these arcadia pictorial histories and I did that on Detroit’s Palonia, so it was wonderful to go back to the Reuther library at Wayne State and look at their negative morgue and start picking out images that would relate to the polish story. Then after we had that one published, so many people were enthusiastic. “Tell my ancestors’ story! Use my picture!” that we started working on two other books, again related to Detroit. One of the oldest active cemeteries in Detroit, Mt. Elliot Cemetery, and also Mt. Olivet Cemetery. That was great fun—yeah, I do like cemeteries. It was great finding the depth of information and compiling it because everyone had a unique, individual story, and just like you’re doing, you’re going to make a greater whole of everyone’s individual story. So we were able to do that with the arcadia books and I go back to the old neighborhoods—not the safest place to drive around—but yes, I’m still devoted to Detroit. Every fall, the burton collection has a genealogy fair, and we always encourage people to document their Detroit history as well.< /p> < p> NL: The project, the Detroit’s Palonia, that was your first involvement with the Mission here? Or was that a separate group?< /p> < p> CJ: This was before I joined the mission. So it was just the art teacher and history teacher and me coming out, and I saw they didn’t have a title that dealt with Detroit—they had some ethnic groups, they had some sections of Detroit, so I had to write up a proposal, and I worked with a number of colleagues in the genealogy group here in metro Detroit. Ran around, met people at different libraries, took my scanner, made big old .tiff images so they would be published, and then turned all that digital information and all the captions over to Arcadia.< /p> < p> NL: What are your observations of the city in the last fifty years compared to your observations pre-1967?< /p> < p> CJ: I’ve been very lucky that my husband has a good eye for travel. And so, I’ve been able to visit many major cities throughout the world, and I always think, you know, we have the essence of a lot of these other cities right here in Detroit, and I really wish it would shine more. But we have a very interesting history, and I think there are core pieces that are just waiting to be harvested and rejuvenated. I guess that’s one of the benefits of travel, that I see the rough jewel that Detroit is and can be again.< /p> < p> NL: Well put. Could you elaborate a little bit about what you mean by that we here in Detroit have that essence that you see abroad? Could you describe that?< /p> < p> CJ: Well sure, we have a mixture of cultures, we have many different cultures. We can explore different ethnic groups, different food waves, different arts in our community. We have that lively mix that generates a lot of energy. We’re not homogenized. We’re still inviting and we’re still getting a lot of immigrants to come into our community. We might have 21< sup> st< /sup> century minorities now, and the people that came in the 20< sup> th< /sup> century are now assimilated, better assimilated, but that is part of the energy, I think, that will move us forward. And I’m not a Pollyanna.< /p> < p> NL: Why do you think it’s been so difficult then for the city to capitalize on that essence and that hotbed of cultures colliding and making for interesting things?< /p> < p> CJ: Well, we have to talk about some leadership issues that have happened to us in the past. People that would rather redline than look for a way to merge things. Maybe all the communities needed to mature a little bit more, and realize this is a good spot on the mitten to be. We still have the water resources, we still have roadways. I just saw that that one defunct factory by the river has been opened to look like a nature reserve from up north—I think it just opened this week. And that’s a cool thing, look at Belle Isle, as well: what a beautiful sanctuary for everybody as well, with the Botanical Gardens, with the aquarium there, and some of my other colleagues and I, we were remembering when there was a petting zoo there as well. That has been, why can’t it be revived? I mean 21< sup> st< /sup> century people want that in their lives, as well as 20< sup> th< /sup> century people.< /p> < p> NL: Absolutely. Where do you live now?< /p> < p> CJ: I live in Rochester Hills.< /p> < p> NL: Still in Rochester Hills. Are you working here in West Bloomfield, regularly, every day?< /p> < p> CJ: I’m here three days a week. My Monday-Wednesday-Friday.< /p> < p> NL: Do you notice a difference in the ability or just the end result of people living in the Oakland, Macomb, suburban communities collaborating together for the types of projects that you do here, is that any different than collaborating with people in the city?< /p> < p> CJ: I would have to say yes, because one thing, we’re one ethnic group here on campus. So there’s a demographic that’s going to come here. But I will say that the prep school does have a number of Asian students as well, we have black students here. Our Chaldean neighbors are sending their boys here. We have a mix at the high school, at the prep school. I would say we probably don’t—we’re not going to necessarily avail ourselves to the ethnic mix that you’re going to find if you go in Detroit. And maybe you have to go to Dearborn for some of that, but let’s also think about the beauty of going to Eastern market, because that’s a pretty nice level field for everyone, I’d say.< /p> < p> NL: For your personal life, what has been the largest lasting impact of the events of July 1967?< /p> < p> CJ: Well, as a teenager, it was a turning point where I couldn’t find an adult to give me direction, and I had to rely on whatever I had been instructed throughout my life to make some decisions about how to stay safe. And then, watching the neighborhood kind of dissolve. That was sad. And it’s only in the last few years because of Facebook that I have actually found elementary school friends! Because everybody scattered! And I tell people, what’s very interesting is that I cannot go back to my grandparent’s parish in Detroit, I cannot go back to my parents’, and I cannot go back to mine but ironically, I can go back to all four of my ancestral villages in Poland, and they’ve been in existence for 750 years. And you would think it would be the exact opposite, you would say, “How can you go back to anything in Poland? They’ve had two major wars!” And yet, I have been able to trace back to 1690 of my European heritage, but no vestiges, really. And that’s why, we actually think of ourselves—Poland talks about a nest, that you want to be in your group, your community, so we actually say, we’re the Polish nest for the metro Detroit because your parishes are gone, or they’ve merged, they’ve vanished, but you can come back here and look at our shelves, and find your history books, find vintage photos, and find someone to tell your story to.< /p> < p> NL: I had just a couple other questions. Backtracking a little bit in our conversation, that day at Tiger stadium, you mentioned the smell as what really stood out to you. What do you remember visually? I’m wondering, was there enough knowledge of the events of that time, do you remember the crowd? There were maybe almost 50,000 people there that day. Was there a big reaction in the crowd?< /p> < p> CJ: There wasn’t, no. I don’t even remember an announcement being made, that it’s time to leave the stadium. I don’t think they swept the stadium of people. I would have to go back and do a little research on that. But I think people just left at the end of the game, and then we were there cleaning up and realized what’s happened. That’s a good point, I would really have to go back and read a news report about, “It’s a great day for a Tiger game!” and see what’s written up that way.< /p> < p> NL: For the events of that day, that week, July 1967, historians and people who lived through it are often calling it a riot, the Detroit Riots of 1967, the Twelfth Street Riots. In your estimation, in your experience is that the most accurate word to describe the events of that week?< /p> < p> CJ: That was our vernacular at that time. That’s how we spoke about it. “Upheaval,” “Crisis,” “Cataclysmic event,” all of those would be good, because it did have that huge of an impact on the tri-county area. Because where did a lot of these people go? They went into Oakland County, or they went into Macomb County, and left the neighborhoods behind.< /p> < p> NL: Lastly, if you could leave a general message for the city of Detroit, going forward on what is soon to be the fiftieth anniversary of these events, what might that be?< /p> < p> CJ: Might be a turning point to change the tide. Might be a day to remember and say, “Well, let’s see what we can go forward with.” Not forgetting our history, but talking about those good elements we do have, I mean a rich history. Look at the flag of Detroit. You have the British influence, you have the French influence, you have the American. We have a lot to talk about. We have a lot of things to be pleased about. Maybe a little more positive and a whole lot less negative.< /p> < p> NL: Well, thank you so much for sharing your stories and memories with us. Is there anything else that we did not touch on that you would like to share?< /p> < p> CJ: I think I told you earlier today of the sad news report I was watching. They said, “Alert! The police have never found a 500-pound pig in the basement in metro Detroit! But now we have.” So there was all day coverage of trying to get this poor porker out of the basement that had two feet of refuse around his feet and the staircase was gone from the basement, there was only a ladder. Unfortunately it was the home of a hoarder who had died like a week before. So I’m watching it, and they say west side Detroit, and I go, “Oooh, I’m going to watch this!” And they go and say, Orange Lawn, I’m like, “Oh my!” And then they show the visuals, and I’m looking at the Shuckle’s house, which was our next-door neighbors in Detroit, and I actually felt very, very sad, not only for the pig, but to see that that now is the condition of my old neighborhood. It was a very sad feeling. Everybody else is like, “The pig! The pig!” and when I saw the video, it’s like, “That’s the Shuckle’s house, that’s the lot our home stood on, that’s where the McClays lived,” and I don’t know what to make of it, but it’s like, what an ending to that neighborhood.< /p> < p> NL: Could you see your house at any parts of that report?< /p> < p> CJ: Our home is not standing anymore, but I could see the neighbors on the other side. I mean, I could tell everybody’s house. I could still recognize their homes and then all of a sudden, I started getting text messages from friends: “What do you now about Orange Lawn? What do you know about the pig?” and the happy ending is that the pig was removed safely and is now at a shelter, a barn, shelter-barn for animals outside Monroe.< /p> < p> NL: Now with that behind us, the city of Detroit can finally move forward, I think. Thanks for sharing your time and your stories with us today, Cecile.< /p> < p> CJ: My pleasure. Thank you.& nbsp;< /p>InterviewerThe person(s) performing the interviewNoah LevinsonIntervieweeThe person(s) being interviewedCecile JensonLocationThe location of the interviewWest Bloomfield, MIVideoA link to the video< iframe width="560" height="315" src="https://www.youtube.com/embed/KtTc6PE8dmQ" frameborder="0" allowfullscreen="">< /iframe>Dublin CoreThe Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/.TitleA name given to the resourceCecile Jenson, July 16th, 2015DescriptionAn account of the resourceIn this interview, Cecile discusses growing up in a tight-knit, Polish community on the west side of Detroit and her recollections 1967 disturbance, including the ensuing white flight. She also discusses her work in the Polish community of metro Detroit and the degradation of the neighborhood in which she grew up.PublisherAn entity responsible for making the resource availableDetroit Historical Society, Detroit, MIDateA point or period of time associated with an event in the lifecycle of the resource6/01/2016RightsInformation about rights held in and over the resourceDetroit Historical Society, Detroit, MILanguageA language of the resourceen-US1967 riot—Detroit—MichiganArsonCatholicDetroit TigersLootingMichigan State UniversityPolish-American communityRochester Hills-MichiganTeenagershttp://detroit1967.detroithistorical.org/files/original/9f9882802a7b894da5674315a3f3953e.jpga1af5fc6830e3cb021c88546b07e18edDublin CoreThe Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/.TitleA name given to the resourceDetroit 67: Looking Back to Move ForwardSubjectThe topic of the resourceStories gathered to commemorate the summer of 1967 in Detroit.PublisherAn entity responsible for making the resource availableDetroit Historical SocietyRightsInformation about rights held in and over the resourceDetroit Historical Society, Detroit, MILanguageA language of the resourceen-usDateA point or period of time associated with an event in the lifecycle of the resource10/20/2019Written StoryA written account or story submitted by an individual.TextAny textual data included in the documentOne of my first jobs as a teenager was selling hot dogs at Stand 22 in Tiger Stadium. I learned a lot from the vendors and enjoyed meeting people from a variety of neighborhoods and different walks of life in Detroit. The strongest memory of the job was not the Tiger's near miss of the World Series pennant in 1967, but the day the Detroit Riots broke out. We were trapped at our booth in the stadium, wondering if we should lock ourselves in the (unplugged) freezer for safety. I convinced the older women that we should try and head home. We had to take Grand River back to the west-side, and saw shattered store windows, the result of the looting of stereo systems and washing machines, etc. The firemen were in civilian clothes with helmets, driving in their own cars. We could hear sirens wailing and the air was filled with the acrid smell of burning buildings. When I arrived home, I found an empty house. My widowed mother and younger sister were still in Canada, and I had to somehow find a way to warn them not to come home via the tunnel nor the Ambassador Bridge. I called my older sister at college and told her about the riots. She cried. I learned to trust my instincts and judgment that day.Original FormatThe type of object, such as painting, sculpture, paper, photo, and additional dataEmail MessageSubmitter's NameThe first and last name of the submitter.Ceil JensenSubmission DateThe date the story was submitted in MM/DD/YYYY format.03/23/2015Search TermsTopics mentioned in the story which may be of larger social interest. Put general search terms in plural form (e.g. horses not horse). All items should have: "1967 riots, riots, interviews, oral history (or written history)". Some possible additional terms might be: "Detroit Police Department, police officers, Detroit Fire Department, firefighters, mayors, Clairmount Street, 12th Street, looting".Tiger Stadium, Canadian, Grand River Ave, Detroit Fire DepartmentDublin CoreThe Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/.TitleA name given to the resourceCeil JensenDescriptionAn account of the resourceCeil Jensen was a teenager who worked the hot dog stands at Tiger Stadium in July 1967.PublisherAn entity responsible for making the resource availableDetroit Historical SocietyDateA point or period of time associated with an event in the lifecycle of the resource07/06/2015RightsInformation about rights held in and over the resourceDetroit Historical Society, Detroit, MIFormatThe file format, physical medium, or dimensions of the resourceTextLanguageA language of the resourceen-USTypeThe nature or genre of the resourceWritten StoryCoverageThe spatial or temporal topic of the resource, the spatial applicability of the resource, or the jurisdiction under which the resource is relevant||||osm West side of Detroit, MI1967 riot—Detroit—MichiganDetroit Fire DepartmentGrand River AvenueTeenagersTiger Stadiumhttp://detroit1967.detroithistorical.org/files/original/71cba11329ca0bd6be8c56314f690b5f.png74cfa0598b985561f375664723a8a0f9Dublin CoreThe Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/.TitleA name given to the resourceDetroit 67 Reflections: Presented By ComcastSubjectThe topic of the resourceDetroit 1967CreatorAn entity primarily responsible for making the resourceDetroit Historical SocietyPublisherAn entity responsible for making the resource availableDetroit Historical SocietyDateA point or period of time associated with an event in the lifecycle of the resource6/19/2017RightsInformation about rights held in and over the resourceDetroit Historical Society, Detroit, MIFormatThe file format, physical medium, or dimensions of the resourceVideo/Mp4LanguageA language of the resourceen-USTypeThe nature or genre of the resourceOral HistoryOral HistoryAn audio or video resource containing historical information obtained in interviews with persons having firsthand knowledge.VideoA link to the video< iframe width="560" height="315" src="https://www.youtube.com/embed/igA_u5ID1e4?list=PLkBC3_1XKHBFww5vN_FbegQUOpk75GU-j" frameborder="0" allowfullscreen="">< /iframe>Narrator/Interviewee's NameThe current first and last name of the person speaking or being interviewed.Charles Ezra FerrellBrief BiographyA short biography of the IntervieweeDirector, Public Programs-Charles H. Wright Museum of African American HistoryInterviewer's NameThe first and last name of the interviewer.William WinkelInterview PlaceThe place where the interview was conducted.Southfield, MIInterview LengthThe total length of the interview in HH:MM:SS format.00:04:20Original FormatThe type of object, such as painting, sculpture, paper, photo, and additional dataAudioDurationLength of time involved (seconds, minutes, hours, days, class periods, etc.)4min 20secDublin CoreThe Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/.TitleA name given to the resourceCharles Ezra FerrellPublisherAn entity responsible for making the resource availableDetroit Historical SocietyDateA point or period of time associated with an event in the lifecycle of the resource6/19/2017RightsInformation about rights held in and over the resourceDetroit Historical Society, Detroit, MIFormatThe file format, physical medium, or dimensions of the resourceVideo/Mp4LanguageA language of the resourceen-USTypeThe nature or genre of the resourceOral History1967 riot—Detroit—Michiganhttp://detroit1967.detroithistorical.org/files/original/188e07d1826ac9083b5b630c84fd3c02.png2fa2a74f8795feff5781e15f7cdfe88aDublin CoreThe Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/.TitleA name given to the resourceDetroit 67 In ConversationPublisherAn entity responsible for making the resource availableDetroit Historical SocietyDateA point or period of time associated with an event in the lifecycle of the resource6/20/2017RightsInformation about rights held in and over the resourceDetroit Historical Society, Detroit, MIFormatThe file format, physical medium, or dimensions of the resourceVideo/Mp4LanguageA language of the resourceen-USTypeThe nature or genre of the resourceOral HistoryOral HistoryAn audio or video resource containing historical information obtained in interviews with persons having firsthand knowledge.VideoA link to the video< iframe width="560" height="315" src="https://www.youtube.com/embed/oCB5ntnlF0c" frameborder="0" allowfullscreen="">< /iframe>Narrator/Interviewee's NameThe current first and last name of the person speaking or being interviewed.Charlie BeckhamInterviewer's NameThe first and last name of the interviewer.Bob BuryInterview LengthThe total length of the interview in HH:MM:SS format.00:53:15Original FormatThe type of object, such as painting, sculpture, paper, photo, and additional dataVideoDurationLength of time involved (seconds, minutes, hours, days, class periods, etc.)53min 15secDublin CoreThe Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/.TitleA name given to the resourceCharlie BeckhamPublisherAn entity responsible for making the resource availableDetroit Historical SocietyDateA point or period of time associated with an event in the lifecycle of the resource6/20/2017RightsInformation about rights held in and over the resourceDetroit Historical Society, Detroit, MIFormatThe file format, physical medium, or dimensions of the resourceVideo/Mp4LanguageA language of the resourceen-USTypeThe nature or genre of the resourceOral History1967 riot—Detroit—Michiganhttp://detroit1967.detroithistorical.org/files/original/3562bce44edfbd5bb50e33eae8394ec4.JPGe29eef1aa48d1c1ecdc6a273874474f0http://detroit1967.detroithistorical.org/files/original/f777a36ae4f8abdd23dc536fad686af7.jpgb3037e1ba38b7e7b287fd23db2e91c80Dublin CoreThe Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/.TitleA name given to the resourceDetroit 67: Looking Back to Move ForwardSubjectThe topic of the resourceStories gathered to commemorate the summer of 1967 in Detroit.PublisherAn entity responsible for making the resource availableDetroit Historical SocietyRightsInformation about rights held in and over the resourceDetroit Historical Society, Detroit, MILanguageA language of the resourceen-usDateA point or period of time associated with an event in the lifecycle of the resource10/20/2019Oral HistoryAn audio or video resource containing historical information obtained in interviews with persons having firsthand knowledge.Narrator/Interviewee's NameThe current first and last name of the person speaking or being interviewed.Cheryl Pierce-ReidBrief BiographyA short biography of the IntervieweeCheryl Pierce-Reid was born in Detroit August 1, 1944 at Edith K. Thomas Hospital. During the summer of 1967 she was living with her husband, young child and father and law on Edison right between LaSalle and Fourteenth. She was working at Detroit Receiving Hospital on the midnight shift. She attended Homer G. Phillips in St. Louis for nursing.Interviewer's NameThe first and last name of the interviewer.Lillian WilsonInterview PlaceThe place where the interview was conducted.Detroit Historical Museum, Detroit, MIDateThe date of the interview in MM/DD/YYYY format.07/25/2015Interview LengthThe total length of the interview in HH:MM:SS format.32:16TranscriptionistThe first and last name of the transcriptionist.Melissa KingTranscription DateThe date of the transcription in MM/DD/YYYY format.10/15/2015TranscriptionAny written text transcribed from a sound< p class="Normal1"> LW: Today is July 25, 2015 this is the interview of Cheryl Pierce-Reid by Lily Wilson. We are at the Detroit Historical Museum in Detroit, Michigan. This interview is for the Detroit 1967 Oral History Project and the Detroit Historical Museum. Cheryl can you tell me, where and when were you born?< /p> < p class="Normal1"> CPR: I was born in Detroit in Edith K. Thomas Hospital August 1, 1944.< /p> < p class="Normal1"> LW: What neighborhood did you live in growing up?< /p> < p class="Normal1"> CPR: Growing up until 1960, my family lived on Beaver Street on the west side of Detroit.< /p> < p class="Normal1"> LW: What was the neighborhood like when you were growing up?< /p> < p class="Normal1"> CPR: It was a nice neighborhood. It was still people moving up from down South, so there were people moving in and moving out. My grandparents actually purchased that house in the 1920s when they moved here from Tennessee and it was actually it was all Polish at the time. So I think they were the only blacks on the block. And my grandfather worked at, there was a name before Hygrade, it was a Hygrade meat packing place on Michigan Avenue, he worked there, my father worked there for a while. He eventually became a city of Detroit employee and that is where he stayed until he died. So I was influenced by that and that’s why I ended up at Receiving, I was a city employee.< /p> < p class="Normal1"> LW: Wow. So tell me what you were doing in July of 1967?< /p> < p class="Normal1"> CPR: July of 1967 by this time I was married. I had finished nursing school the year before and I was working at Receiving Hospital, midnights in the emergency room. I was living with my husband, with my father-in-law at 2252 Edison which was right between LaSalle and Fourteenth, and my mother and father were at Russell Woods on Sturtevant between Broadstreet and Livernois. So, I was going to cross all of the areas that were affected by it. So that particular day, I remember it being a very hot warm night, I don’t remember I don’t think we had air conditioning in the house, so I put my son in the car and we went out for a little ride. And my husband at the time was in school and was, I believe he was working midnights at Ford Motor Company and so we went out for a cruise I had a little convertible and we went out for a cruise.< /p> < p class="Normal1"> LW: Sunday?< /p> < p class="Normal1"> CPR: That night. Sunday night. That was the first night of the riot, I don’t remember what day it was, I do remember some of the events. But anyway we came through Twelfth Street on our way home about 12:30 and I remember seeing people standing around and I just thought to myself this is kind of odd because there were so many people out that time of night and there was nothing happening they were just milling around. So we went home and went to bed. My husband came in the next morning and he had to go back out to get something for the baby and he came back and when he came back he said someone had approached him and told him not to be out on the street. So I don’t know if they knew whether something was going to happen or not. I didn’t have the TV on so he went on, went to bed and then he went later on that day, he went to study or whatever he was doing I don’t remember now. But I kind of hung out at home until it was time to go to my parents' house because my mother kept the baby when I went to work. I got in the car packed up the car and I went Edison to Linwood. When I got to Linwood, I looked to my left and all I could see was smoke and fire trucks. I had no clue what was going on. So I went down Joy Road to Broadstreet, cut over Broadstreet to my mother’s house and I got there and nobody seemed to really know what was happening. So my brother and I, & nbsp;and I can’t remember if my sister was there, but my brother was still a teenager, he was still home, we jumped in his car and went down on Dexter which was two, three blocks away to see what was happening. There were a lot of people standing around, and we were there just as the bricks started going through the glass and we looked up in the rear view mirror my dad was there, "Get home now." So we had to turn around and go back. So didn’t know what else was going on. I got myself dressed later on that night and went to work, it was no big deal.< /p> < p class="Normal1"> LW: To work midnights?< /p> < p class="Normal1"> CPR: Midnights at Receiving.< /p> < p class="Normal1"> LW: So tell me about that.< /p> < p class="Normal1"> CPR: The first night I don’t remember anything too terrible. & nbsp;I do remember, I thought it was just a disturbance because this type of thing was happening everywhere. & nbsp;It was not common in just Detroit. The whole country was going nuts at that time; this was just one more incident, okay? And so I didn’t think too much of it. It was maybe two, three days into it that things were not resolving and by this time they had called in the National Guard and stuff and I remember I went down Lodge Freeway to downtown and having to stop at the check points and these were kids – & nbsp;I was about almost 23 – these were kids the same age I was, okay? But they were nice, they stopped me they asked me what I was doing I said, I was probably in a white uniform so they could see it, I said I was on my way to work and so they just let me go. I was young and stupid. It never occurred to me that there were snipers and things in the area that, you know I could have had my head blown off. & nbsp;Never thought about it. But anyway went to work. & nbsp;There were always a lot of – whenever you have an incident you have more police, you have more city officials, and I didn’t know who was who at that point. Subsequently I kind of got the gist of how things work. But at that time I couldn’t identify who was what, but there were people there. I remember people being injured during that week, more self inflicted injuries, seriously, than other stuff, because people were paranoid. There were people still going to work, they were pulling their guns out of the closet and leaving them out and subsequently getting injured. Well this is what we were getting in the ER because I never, when I tell you there’s conflict, with what I saw, and what I hear built up in the news was a little bit different.< /p> < p class="Normal1"> LW: Okay.< /p> < p class="Normal1"> I saw, I did see or had a couple of reports of bayonet injuries. There were a couple of guys that they brought in sometime during the week that shot at a tank – and these were white guys and the tank from what I understand blew up the house, they fell out of the house so they brought them in for us to put them back together. I just remember thinking, How stupid, how do you shoot at a tank? But anyway they did. I know that we were, this was the old Receiving that was across from Frank Murphy, I think it’s a parking lot now or something. But the front end of the hospital that faced Frank Murphy had big huge glass windows and we had blinds up there, and so police would call us periodically and tell us don’t look out the window, keep the blinds closed cause there would be snipers in the area.< /p> < p class="Normal1"> LW: Oh wow.< /p> < p class="Normal1"> CPR: But I remember more than anything the buses that were across the street full of people all night long. They would arrest anybody who was out on the street without a good reason and that’s where they’d house them, and so they had city buses and whatever else lined with people.< /p> < p class="Normal1"> LW: Outside of the hospital?< /p> < p class="Normal1"> CPR: No it was at Frank Murphy, it was across the street. Across the street at the court house or police headquarters, whatever is over there.< /p> < p class="Normal1"> LW: So when you talk about self-inflicted things that you saw can you elaborate on that?< /p> < p class="Normal1"> CPR: Accidental gunshot wounds, people shooting themselves in the foot, cutting themselves. I just – I remember the paranoia and the fear, everybody was afraid. Now I have to tell you about my neighborhood though. The neighborhoods that I was associated with, these were your middle class neighborhoods, these were not ghettos whatsoever. Twelfth Street, because I knew the fathers of some of my friends who owned businesses there, the businesses were destroyed. Same thing on Dexter, these were black owned businesses gutted, okay? Russell Woods, where I lived, was still probably 40% percent Jewish at the time. Most of my neighbors were Jewish and the rest were black; we had one Chinese family across the street. But these were doctors, lawyers other folks, they were not – and business owners and so you know this was the population that was effected because their offices and things were in this area. Now I do remember rallies, I do remember that there were rallies because I attended a couple of them against my parents wishes down there but it talked about economics, the condition of black people, what we needed to do to improve our state. & nbsp;There was no violent anything that I can remember and I just -- didn’t even know what triggered it for a long time. I thought it was just an uprising because of the heat, there was a lot of police brutality in the neighborhood up to this and I thought it was related to that. I didn’t know about this blind pig stuff for years, really, and I said, “Is that the trigger? Really? I never knew that.” & nbsp;So I had heard about some policemen and some sheriffs who played cards together, and things got ugly. Now whether that was the same incident, these were guys I work with at Receiving, they were through there all the time, you know so I was exposed to them all the time. But like I said there was just so much going on.< /p> < p class="Normal1"> LW: Now I wonder, most of the people that you were treating at Receiving during those few days in July, would you say that there were more black patients, more white patients, same?< /p> < p class="Normal1"> CPR: It was about the same. I would say that— because I do remember one guy who shot himself in the foot, he was a little frustrated but like I said there was a lot of paranoia. Everybody was nervous. It wasn’t just white people, everybody was nervous. And people – especially the older generation – they really didn’t know what was going on; they didn’t necessarily agree with what was happening but they were living in it. And so consequently people were setting their guns out; self-inflicted gunshot wounds, kids getting accidently shot, because these are people who don’t normally use firearms, and so when you set them out and no one knows the dangers of them somebody is going to get hurt or if you’re afraid that someone’s going to hurt you and you’re not used to using it you are going to hurt yourself and that’s what I saw outside a couple of bayonet stabs that came in. But I didn’t see any dead bodies. I know – I looked at something before I came in, I said, "Oh, that many people died?" Well maybe they brought them in on a different shift or maybe they went to a different hospital I don’t know what they did. But during my week there, I didn’t see a lot of that.< /p> < p class="Normal1"> LW: Okay. So thinking about the neighborhood that you and your parents were living in you mentioned that it was predominantly a middle class neighborhood--< /p> < p class="Normal1"> CPR: Very middle class.< /p> < p class="Normal1"> LW: --hard working people, like yourself that were just trying to go to work and that didn’t really even understand maybe what was going on, so I wonder who do you think was sort of to blame them for the upheaval in those neighborhoods?< /p> < p class="Normal1"> CPR: You know I don’t know. And I don’t want to influence what I say because I’m supposed to be saying from that point I was almost 23 I really wasn’t paying a lot of attention to the politics and stuff.& nbsp; I’ve read a lot since so I don’t want that to color what I say. Because I had my own theories but I do remember rallies, there were live rallies on Dexter in which there were people my age and younger out there, and I think there was a moment when H. Rap Brown came to the city there was a rally and shortly after some of the stuff took place.& nbsp;& nbsp;< /p> < p class="Normal1"> LW: Now the rallies that you attended, those were going on leading up to?< /p> < p class="Normal1"> CPR: Leading up to.< /p> < p class="Normal1"> LW: And tell me where those took place.< /p> < p class="Normal1"> CPR: Those were on Dexter, as I said there were a lot of establishments. & nbsp;I couldn’t tell you exactly where it was now, and they weren’t “ra ra ra” pep rally type things, it was more like a session where you go in, it was like a learning thing. We had a speaker and they would be speaking, but again it would be about economics and the state of African-Americans in this country basically and what you need to do: we need to own businesses, dah-dah-dah-dah-dah, but I understood. I was aware, because I did lose, I’m not sure what year he died, a classmate that went to high school with me on Wayne State. This was during the time with the [Black] Panthers were very active, I was very sympathetic with the Panthers and what they were trying to do at the time, until they started executing them like crazy and then I wore my hair in a big fro and I had a Wayne County Sheriff approach me one day and told& nbsp; me I looked a lot like Angela Davis and so my mother was freaking out, so I had to change my hair style, you know, I mean because, because my neighbor three doors down, we had driven to high school together. & nbsp;We went to Cass Tech and he was killed, mistaken identity. You see during that time that’s what was happening. People were getting killed and then they find out later oh, it wasn’t the right person. And so he was a victim of that so you’re aware but not aware. I wasn’t participating in the active stuff, I was defiantly sympathetic but I was married with a small child. I couldn’t do all of that stuff with a job, and my family was pretty conservative so you’re kind of caught in the middle, so if my mother and father found out I was participating in stuff that wouldn’t have gone over too well, so, you know.< /p> < p class="Normal1"> LW: When you were in the hospital July of '67 at Detroit Receiving, what were you being told if anything by the doctors and the patients that were coming in?< /p> < p class="Normal1"> CPR: Nothing. Nothing, that was the trauma hospital, we were used to trauma so you go in, you get your room and your equipment set up for whatever may come through the door, and so we really didn’t talk about politics or what was going on; it’s like, you know, we would joke well you know, wonder what it’s going to be like tonight? you know, but in the processes you’re getting your IVs together, you’re getting everything set up so that whatever comes through the door, you’re ready. And that’s basically it. I don’t ever remember having any conversations with anybody because that was secondary, you know, we were just in a state of readiness all the time is what I remember.< /p> < p class="Normal1"> LW: What else do you want to share about 67’ or about Detroit since then?< /p> < p class="Normal1"> CPR: Um, Detroit since then - I think we are headed back that way, seriously.< /p> < p class="Normal1"> LW: Back toward civil disturbance?< /p> < p class="Normal1"> CPR: Yeah, I see some of the same conditions that triggered a lot of the unrest happening again not necessarily in the city but yes in the city, you know, indirectly.& nbsp;< /p> < p class="Normal1"> LW: So like what?< /p> < p class="Normal1"> CPR: I see some of the things like the tax issues, people losing their houses, the water being turned off, you know money going downtown not to the neighborhoods, but that’s not new that’s been going on. I feel an effort to move people further and further away from the city so that they can convert the city into this metropolitan area like some of the other cities, but the neighborhoods are not included in that, I just don’t see that happening. And I feel like you have people that are trying to fix it, people who are trying to organize. But since that time, we didn’t have the gangs and stuff 50 years ago like they have now, you’ve got another whole subculture out there that you’re dealing with. They’re not political, they’re not - they’re just there and I don’t understand the mentality of them. Maybe it’s a generation thing, but they’ll hurt anybody because you see an equal amount of black on black crime, which is wrong. I don’t know-- I feel bad about what happened in '67 because it was my neighborhood that was hurt; you go through there now it’s a wasteland. You know, all of those businesses, those men lost their business - these were my neighbors, these were my friends' fathers who owned those things and so they were the losers in this, you know and they were never able to recover.< /p> < p class="Normal1"> LW: What happened to some of them do you remember?< /p> < p class="Normal1"> CPR: Yes, they just folded up they couldn’t go back in business.< /p> < p class="Normal1"> LW: Did they keep their homes?< /p> < p class="Normal1"> CPR: Oh yeah they kept their homes. Many of them, many who could afford it moved. There was, they talk about white flight, there was black flight. When I say that my neighborhood was a mixture of-- I mean like ok, Dr. Lionel Swan lived across the street from me we went to the same, he did his internship where I went to nursing school so I got to know them, they packed up and moved out of the city.< /p> < p class="Normal1"> LW: Where did they go do you know?< /p> < p class="Normal1"> CPR: Well, I won’t say out of the city, I take that back because we were not allowed to move too far. They went to northwest Detroit over by Sherwood Forest and then the next stop would have been Southfield and then beyond. So we’re in Bloomfield and places like that now but they weren’t yet.< /p> < p class="Normal1"> LW: You say that you weren’t allowed to move too far what do you mean?< /p> < p class="Normal1"> CPR: You know this was the sixties, there were scandals about housing and stuff back then, I was, listen, I bought a house on Rutherford off of Puritan in 1969-ish, somewhere back in there, I bought it. My husband and I had separated so I bought my own house. They used me, the real-estate agent, to blockbust on that, I didn’t know, I was the only black on the block and so they used me there and then I started watching my neighbors move, they moved out one by one, they were gone. I even had one guy come over and said, “I’m not selling my house because of you.” And I’m like really? It was the kid across the street was horrible and he would terrorize the neighborhood, it was a white kid. And so he said “I can’t deal with him anymore.”& nbsp; Because there was a night we had to call the police he used a BB gun to shoot in several windows and so the parents would go out and leave this kid alone and he would terrorize the neighborhood. So my neighbor, his next door neighbor came and said, “I don’t want you to think I’m selling my house because of you, I’m selling because I can’t stand that kid anymore.” But there were still a lot of restrictions on where you could move to. And so Southfield, I don’t think Southfield was an option yet and I said my neighborhood was 40 percent Jewish at the time. Synagogues were up on Dexter. So they were in the middle of this mess. So they left and then the people who could afford it left, so we had like I said doctors, lawyers, Indian chiefs there and they started to migrate further north.& nbsp; And so that Palmer Woods, Sherwood Forest, places like that was the next jumping ground before Southfield and then after Southfield came Bloomfield and all the others.& nbsp; Because we weren’t allowed to get housing there because somewhere in there, HUD [US Department of Housing] was sued, somewhere between the late sixties and seventies, they were sued and then it opened up more things. Yeah.< /p> < p class="Normal1"> LW: Wow.< /p> < p class="Normal1"> CPR: Yeah.< /p> < p class="Normal1"> LW:& nbsp; And where do you live today?< /p> < p class="Normal1"> CPR: I’m in Southfield. I moved back to Southfield from Canton. I had moved to Canton in '78. '77,'78, we built a house. & nbsp;By this time I had remarried; me and my first husband had split up and I remarried, and my husband had lived somewhere around Chicago and Dexter in there. & nbsp;He had been robbed. & nbsp;He had spent some time in New York. & nbsp;In Harlem, he managed a supermarket and then came back. He said, “I’m not going into the city. I will not move there, we will go somewhere else.” So that’s why we ended up in Westland first and then we moved to Canton. We built a house there and I lived there for 22 years, raised my children there. Then I decided, he had passed away, I decided I didn’t need the subdivision anymore. & nbsp;I was still working midnights, my neighbors religiously cut their grass when I’m trying to sleep and stuff and the houses are close together, I said, “I have to go.” And so after he passed away my son and I actually flipped houses. I moved into - so he had restored this house in Southfield on an acre with trees, it’s all retirees around me, it’s quiet and then he took his wife and children out to Canton and that’s where they went to school out there.< /p> < p class="Normal1"> LW: So you’ve lived all over Metro Detroit.< /p> < p class="Normal1"> CPR: Yeah. I started out on the west side. I went to, I guess I don’t know if you call it northwest Detroit on Rutherford, it’s kind of northwest, then from there we went to Westland and then Canton and then I moved back to Southfield and that’s where I am now.< /p> < p class="Normal1"> LW: Well I really appreciate you talking with me about your experiences especially in the sixties. Is there anything else you want to add?< /p> < p class="Normal1"> CPR: Let me see. & nbsp;You know I went to nursing school in St. Louis, Missouri because I could not get in here.< /p> < p class="Normal1"> LW: Oh, tell me about that.< /p> < p class="Normal1"> CPR: I went to Cass Technical High School, pre-nursing. I was accepted at Highland Park General Hospital School of Nursing. Then I got a D and I was grateful for it my last year in high school, my graduating semester and so they sent me a letter and said that I would have to go to Junior College half way through the summer and said that I could not come there to their school. I applied at Henry Ford, we had to attach a photograph, and so that was an automatic, you know, Sorry, and I met a nurse from there who was in at the same time that I would have been there and said they were accepting their first Jewish students so they were struggling with that, let alone a black student, they weren’t ready for that. So, I tried Wayne State as a Cass Tech graduate with science and math behind me it was Greek to me, the entrance exam. It was Greek, and all I remember is this one problem they wanted me to calculate some weather and I said, Wow.& nbsp; So needless to say I didn’t get into Wayne State. So anyway, at that point, midway through the summer, too late to apply for anyplace right, I get this letter saying that Highland Park says no you have to go to the Junior College, so I’m heartbroken. My dad knew a graduate of Homer G. Phillips, he spoke to her, she called the school. They sent an entrance exam to her brother who was a teacher. & nbsp;I went to his home, took the exam, which was full of anatomy and physiology, and about two weeks later I got a telegram saying that I’d been accepted. So that is how I ended up in St. Louis in an all-black school.< /p> < p class="Normal1"> LW: That was Homer G. Phillips?< /p> < p class="Normal1"> CPR: Homer G. Philips, city No. 2. St. Louis Municipal Hospital No. 2. They had a No.1 and No.2. No.1 was the white hospital, No. 2 was the black hospital or the Negro hospital back then. Seriously, you’re looking at me like, “Really, for real?” It was.< /p> < p class="Normal1"> LW: I believe you.< /p> < p class="Normal1"> CPR: So a lot, well I don’t want to say a lot, some of the black doctors that I knew here had gone there to do their internship. I wanted to go to Maherity [unknown] and they stopped their nursing school the year that I graduated.& nbsp; While I was here, I did work at Kirwood General Hospital, you know about that one?< /p> < p class="Normal1"> LW: No.< /p> < p class="Normal1"> CPR: Kirwood General was a black owned and operated hospital right on Davison, used to be a Jewish Community Center and they converted it into a hospital, so I worked there for a while so I got to meet a lot of the black doctors, most of them are dead now, but Coleman Young was one of ours, all of your who’s who: James Del Rio was a congressmen I think I remember him as a patient, Dr. Claude Young was the physician for the mayor and he practiced there. All of the black physicians we’re connected in some way, so I got a chance to see some of them.< /p> < p class="Normal1"> LW: How interesting.& nbsp;< /p> < p class="Normal1"> CPR: It was.< /p> < p class="Normal1"> LW: And you graduated from Homer G. Philips in what year?< /p> < p class="Normal1"> CPR: 1965 was my graduation year and I actually finished in - I had to go back to finish up some time so I came out in '66. So I got my license in '66.< /p> < p class="Normal1"> LW: And came right back to Detroit.< /p> < p class="Normal1"> CPR: Oh yeah. I was married, got married my senior year and so my husband did not want to go to St. Louis and so I came back here. But you know he had gone to Fisk. He was at Fisk during the sit-ins and stuff. And something he told me that I didn’t know until his mother passed away a few years ago was that he had an incident with the Ku Klux Klan and that brought him back to the city. He had gone to a rally.< /p> < p class="Normal1"> LW: Where?< /p> < p class="Normal1"> CPR: In Nashville, and somehow was separated from his group and was walking back to the school at night when a pickup truck with some guys pulled up and he thought he was going to die and they let him go. And I know he went down there for one year, he came back, I never knew why he came back, that probably scared him to death. & nbsp;But I heard about it maybe four years ago at his mother’s funeral.& nbsp; Never discussed it with me. So yeah, those were some interesting times, so yeah.< /p> < p class="Normal1"> LW: Well thank you so much for sharing this with me.< /p> < p class="Normal1"> CPR: You are so welcome!< /p> < p class="Normal1"> LW: Yes, it’s great, thanks a lot.< /p> **PeopleList any relevant people (interviewers, interviewees, important people mentioned, etc). Please use "Lastname, Firstname".Brown, H. Rap Davis, Angela Wilson, Lily Pierce-Reid, Cheryl Young, ColemanSearch TermsTopics mentioned in the story which may be of larger social interest. Put general search terms in plural form (e.g. horses not horse). All items should have: "1967 riots, riots, interviews, oral history (or written history)". Some possible additional terms might be: "Detroit Police Department, police officers, Detroit Fire Department, firefighters, mayors, Clairmount Street, 12th Street, looting".1967, Detroit, rioting, hospital,VideoA link to the video< iframe width="560" height="315" src="https://www.youtube.com/embed/YTg_cjrQNXs" frameborder="0" allowfullscreen="">< /iframe>Dublin CoreThe Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/.TitleA name given to the resourceCheryl Pierce-Reid, July 25th, 2015DescriptionAn account of the resourceIn this interview Cheryl speaks of her upbringing in Detroit and her early years as a nurse at Detroit Receiving and Kirwood Hospital. She also recalls her time at nursing school and seeing the events of 1967 first hand.PublisherAn entity responsible for making the resource availableDetroit Historical Society, Detroit, MIDateA point or period of time associated with an event in the lifecycle of the resource11/04/2015RightsInformation about rights held in and over the resourceDetroit Historical Society, Detroit, MIFormatThe file format, physical medium, or dimensions of the resourceaudio/WAVLanguageA language of the resourceen-USTypeThe nature or genre of the resourceSoundCoverageThe spatial or temporal topic of the resource, the spatial applicability of the resource, or the jurisdiction under which the resource is relevant||||osm Detroit, 19671967 riot—Detroit—MichiganBlack Panther PartyCantonCass Technical High SchoolDetroit Police DepartmentDetroit Receiving HospitalH. Rap BrownHomer G. PhillipsKirwood HospitalMedicalMedical StaffSnipershttp://detroit1967.detroithistorical.org/files/original/b64142fb8ede4d1e334d15bdab4896e9.png8053453f990cabb5ed05d0bc55fda031Dublin CoreThe Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/.TitleA name given to the resourceDetroit 67 In ConversationPublisherAn entity responsible for making the resource availableDetroit Historical SocietyDateA point or period of time associated with an event in the lifecycle of the resource6/20/2017RightsInformation about rights held in and over the resourceDetroit Historical Society, Detroit, MIFormatThe file format, physical medium, or dimensions of the resourceVideo/Mp4LanguageA language of the resourceen-USTypeThe nature or genre of the resourceOral HistoryOral HistoryAn audio or video resource containing historical information obtained in interviews with persons having firsthand knowledge.VideoA link to the video< iframe width="560" height="315" src="https://www.youtube.com/embed/dj8Sp_R8XCc" frameborder="0" allowfullscreen="">< /iframe>Narrator/Interviewee's NameThe current first and last name of the person speaking or being interviewed.Chief James CraigBrief BiographyA short biography of the IntervieweeChief, Detroit Police DepartmentInterviewer's NameThe first and last name of the interviewer.Bob BuryInterview LengthThe total length of the interview in HH:MM:SS format.00:31:55Original FormatThe type of object, such as painting, sculpture, paper, photo, and additional dataVideoDurationLength of time involved (seconds, minutes, hours, days, class periods, etc.)31min 55secDublin CoreThe Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/.TitleA name given to the resourceChief James CraigPublisherAn entity responsible for making the resource availableDetroit Historical SocietyDateA point or period of time associated with an event in the lifecycle of the resource6/20/2017RightsInformation about rights held in and over the resourceDetroit Historical Society, Detroit, MIFormatThe file format, physical medium, or dimensions of the resourceVideo/Mp4LanguageA language of the resourceen-USTypeThe nature or genre of the resourceOral History1967 riot—Detroit—Michiganhttp://detroit1967.detroithistorical.org/files/original/d251ded745daca0f87e4562f15caf3e7.jpga1af5fc6830e3cb021c88546b07e18edDublin CoreThe Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/.TitleA name given to the resourceDetroit 67: Looking Back to Move ForwardSubjectThe topic of the resourceStories gathered to commemorate the summer of 1967 in Detroit.PublisherAn entity responsible for making the resource availableDetroit Historical SocietyRightsInformation about rights held in and over the resourceDetroit Historical Society, Detroit, MILanguageA language of the resourceen-usDateA point or period of time associated with an event in the lifecycle of the resource10/20/2019Written StoryA written account or story submitted by an individual.TextAny textual data included in the documentWhat I remember of the riots in July of 1967 is watching the tanks roll past our corner store from the City Airport across the street. Listening for the latest updates on the news of which streets the rioting and looting had reached. Seeing the fear in my mother's eyes and watching the police car take her to our store to turn off the automatic lighted sign that glared brightly on the otherwise dark Gratiot street corner that our store had LIQUOR! We were lucky. The ri | http://detroit1967.detroithistorical.org/items/browse?output=omeka-xml&page=4&sort_dir=a&sort_field=Dublin+Core%2CTitle&tags=1967+riot%E2%80%94Detroit%E2%80%94Michigan |
Bill Seurer (POWER6) - Results for 9.0.0 20181016 (experimental) [trunk revision 265192] (GCC)
Results for 9.0.0 20181016 (experimental) [trunk revision 265192] (GCC) testsuite on powerpc64-unknown-linux-gnu
From : "Bill Seurer (POWER6)" <seurer at linux dot ibm dot com>
To : gcc-testresults at gcc dot gnu dot org
Date : Tue, 16 Oct 2018 09:21:13 -0500
Subject : Results for 9.0.0 20181016 (experimental) [trunk revision 265192] (GCC) testsuite on powerpc64-unknown-linux-gnu
Linux 4.18.12-200.fc28.ppc64 ppc64
GNU ld version 2.29.1-23.fc28
GNU assembler version 2.29.1-23.fc28
GNU Make 4.2.1
DejaGnu:
DejaGnu version 1.6.1
Expect version 5.45.4
Tcl version 8.6
64-bit
LAST_UPDATED: Tue Oct 16 12:45:42 UTC 2018 (revision 265192)
Native configuration is powerpc64-unknown-linux-gnu
=== gcc tests ===
Running target unix
FAIL: c-c++-common/asan/null-deref-1.c -O2 output pattern test
FAIL: c-c++-common/asan/null-deref-1.c -O3 -g output pattern test
FAIL: gcc.dg/sms-4.c scan-rtl-dump-times sms "SMS succeeded" 1
FAIL: gcc.dg/gomp/pr82374.c scan-tree-dump-times vect "vectorized 1 loops" 2
XPASS: gcc.dg/guality/example.c -O0 execution test
XPASS: gcc.dg/guality/example.c -O1 -DPREVENT_OPTIMIZATION execution test
XPASS: gcc.dg/guality/example.c -Og -DPREVENT_OPTIMIZATION execution test
XPASS: gcc.dg/guality/guality.c -O0 execution test
XPASS: gcc.dg/guality/guality.c -O1 -DPREVENT_OPTIMIZATION execution test
XPASS: gcc.dg/guality/guality.c -O2 -DPREVENT_OPTIMIZATION execution test
XPASS: gcc.dg/guality/guality.c -O2 -flto -fno-use-linker-plugin -flto-partition=none -DPREVENT_OPTIMIZATION execution test
XPASS: gcc.dg/guality/guality.c -O2 -flto -fuse-linker-plugin -fno-fat-lto-objects -DPREVENT_OPTIMIZATION execution test
XPASS: gcc.dg/guality/guality.c -O3 -g -DPREVENT_OPTIMIZATION execution test
XPASS: gcc.dg/guality/guality.c -Os -DPREVENT_OPTIMIZATION execution test
XPASS: gcc.dg/guality/guality.c -Og -DPREVENT_OPTIMIZATION execution test
XPASS: gcc.dg/guality/inline-params.c -O2 -DPREVENT_OPTIMIZATION execution test
XPASS: gcc.dg/guality/inline-params.c -O2 -flto -fno-use-linker-plugin -flto-partition=none -DPREVENT_OPTIMIZATION execution test
XPASS: gcc.dg/guality/inline-params.c -O2 -flto -fuse-linker-plugin -fno-fat-lto-objects -DPREVENT_OPTIMIZATION execution test
XPASS: gcc.dg/guality/inline-params.c -O3 -g -DPREVENT_OPTIMIZATION execution test
XPASS: gcc.dg/guality/inline-params.c -Os -DPREVENT_OPTIMIZATION execution test
FAIL: gcc.dg/guality/pr36728-1.c -O2 -flto -fuse-linker-plugin -fno-fat-lto-objects -DPREVENT_OPTIMIZATION line 16 y == 2
FAIL: gcc.dg/guality/pr36728-2.c -O2 -flto -fuse-linker-plugin -fno-fat-lto-objects -DPREVENT_OPTIMIZATION line 16 arg1 == 1
FAIL: gcc.dg/guality/pr36728-2.c -O2 -flto -fuse-linker-plugin -fno-fat-lto-objects -DPREVENT_OPTIMIZATION line 16 arg2 == 2
FAIL: gcc.dg/guality/pr36728-2.c -O2 -flto -fuse-linker-plugin -fno-fat-lto-objects -DPREVENT_OPTIMIZATION line 16 arg3 == 3
FAIL: gcc.dg/guality/pr36728-2.c -O2 -flto -fuse-linker-plugin -fno-fat-lto-objects -DPREVENT_OPTIMIZATION line 16 arg4 == 4
FAIL: gcc.dg/guality/pr36728-2.c -O2 -flto -fuse-linker-plugin -fno-fat-lto-objects -DPREVENT_OPTIMIZATION line 16 arg5 == 5
FAIL: gcc.dg/guality/pr36728-2.c -O2 -flto -fuse-linker-plugin -fno-fat-lto-objects -DPREVENT_OPTIMIZATION line 16 arg6 == 6
FAIL: gcc.dg/guality/pr36728-2.c -O2 -flto -fuse-linker-plugin -fno-fat-lto-objects -DPREVENT_OPTIMIZATION line 16 arg7 == 30
FAIL: gcc.dg/guality/pr36728-2.c -O2 -flto -fuse-linker-plugin -fno-fat-lto-objects -DPREVENT_OPTIMIZATION line 18 arg1 == 1
FAIL: gcc.dg/guality/pr36728-2.c -O2 -flto -fuse-linker-plugin -fno-fat-lto-objects -DPREVENT_OPTIMIZATION line 18 arg2 == 2
FAIL: gcc.dg/guality/pr36728-2.c -O2 -flto -fuse-linker-plugin -fno-fat-lto-objects -DPREVENT_OPTIMIZATION line 18 arg3 == 3
FAIL: gcc.dg/guality/pr36728-2.c -O2 -flto -fuse-linker-plugin -fno-fat-lto-objects -DPREVENT_OPTIMIZATION line 18 arg4 == 4
FAIL: gcc.dg/guality/pr36728-2.c -O2 -flto -fuse-linker-plugin -fno-fat-lto-objects -DPREVENT_OPTIMIZATION line 18 arg5 == 5
FAIL: gcc.dg/guality/pr36728-2.c -O2 -flto -fuse-linker-plugin -fno-fat-lto-objects -DPREVENT_OPTIMIZATION line 18 arg6 == 6
FAIL: gcc.dg/guality/pr36728-2.c -O2 -flto -fuse-linker-plugin -fno-fat-lto-objects -DPREVENT_OPTIMIZATION line 18 arg7 == 30
FAIL: gcc.dg/guality/pr36728-2.c -O2 -flto -fuse-linker-plugin -fno-fat-lto-objects -DPREVENT_OPTIMIZATION line 18 y == 2
FAIL: gcc.dg/guality/pr36728-2.c -O3 -g -DPREVENT_OPTIMIZATION line 16 arg1 == 1
FAIL: gcc.dg/guality/pr36728-2.c -O3 -g -DPREVENT_OPTIMIZATION line 16 arg2 == 2
FAIL: gcc.dg/guality/pr36728-2.c -O3 -g -DPREVENT_OPTIMIZATION line 16 arg3 == 3
FAIL: gcc.dg/guality/pr36728-2.c -O3 -g -DPREVENT_OPTIMIZATION line 16 arg4 == 4
FAIL: gcc.dg/guality/pr36728-2.c -O3 -g -DPREVENT_OPTIMIZATION line 16 arg5 == 5
FAIL: gcc.dg/guality/pr36728-2.c -O3 -g -DPREVENT_OPTIMIZATION line 16 arg6 == 6
FAIL: gcc.dg/guality/pr36728-2.c -O3 -g -DPREVENT_OPTIMIZATION line 16 arg7 == 30
FAIL: gcc.dg/guality/pr36728-2.c -O3 -g -DPREVENT_OPTIMIZATION line 18 arg1 == 1
FAIL: gcc.dg/guality/pr36728-2.c -O3 -g -DPREVENT_OPTIMIZATION line 18 arg2 == 2
FAIL: gcc.dg/guality/pr36728-2.c -O3 -g -DPREVENT_OPTIMIZATION line 18 arg3 == 3
FAIL: gcc.dg/guality/pr36728-2.c -O3 -g -DPREVENT_OPTIMIZATION line 18 arg4 == 4
FAIL: gcc.dg/guality/pr36728-2.c -O3 -g -DPREVENT_OPTIMIZATION line 18 arg5 == 5
FAIL: gcc.dg/guality/pr36728-2.c -O3 -g -DPREVENT_OPTIMIZATION line 18 arg6 == 6
FAIL: gcc.dg/guality/pr36728-2.c -O3 -g -DPREVENT_OPTIMIZATION line 18 arg7 == 30
XPASS: gcc.dg/guality/pr41353-1.c -O0 line 28 j == 28 + 37
FAIL: gcc.dg/guality/pr41353-1.c -Og -DPREVENT_OPTIMIZATION line 28 i == 37
FAIL: gcc.dg/guality/pr41353-1.c -Og -DPREVENT_OPTIMIZATION line 28 i1 == 2 * 37
FAIL: gcc.dg/guality/pr41353-1.c -Og -DPREVENT_OPTIMIZATION line 28 i2 == 3 * 37
XPASS: gcc.dg/guality/pr41353-1.c -Og -DPREVENT_OPTIMIZATION line 28 j == 28 + 37
FAIL: gcc.dg/guality/pr41616-1.c -O2 -DPREVENT_OPTIMIZATION execution test
FAIL: gcc.dg/guality/pr41616-1.c -O2 -flto -fno-use-linker-plugin -flto-partition=none -DPREVENT_OPTIMIZATION execution test
FAIL: gcc.dg/guality/pr41616-1.c -O2 -flto -fuse-linker-plugin -fno-fat-lto-objects -DPREVENT_OPTIMIZATION execution test
FAIL: gcc.dg/guality/pr41616-1.c -O3 -g -DPREVENT_OPTIMIZATION execution test
FAIL: gcc.dg/guality/pr43051-1.c -O1 -DPREVENT_OPTIMIZATION line 35 v == 1
FAIL: gcc.dg/guality/pr43051-1.c -O1 -DPREVENT_OPTIMIZATION line 40 v == 1
FAIL: gcc.dg/guality/pr43051-1.c -O2 -DPREVENT_OPTIMIZATION line 35 v == 1
FAIL: gcc.dg/guality/pr43051-1.c -O2 -DPREVENT_OPTIMIZATION line 40 v == 1
FAIL: gcc.dg/guality/pr43051-1.c -O2 -flto -fno-use-linker-plugin -flto-partition=none -DPREVENT_OPTIMIZATION line 35 v == 1
FAIL: gcc.dg/guality/pr43051-1.c -O2 -flto -fno-use-linker-plugin -flto-partition=none -DPREVENT_OPTIMIZATION line 40 v == 1
FAIL: gcc.dg/guality/pr43051-1.c -O2 -flto -fuse-linker-plugin -fno-fat-lto-objects -DPREVENT_OPTIMIZATION line 35 v == 1
FAIL: gcc.dg/guality/pr43051-1.c -O2 -flto -fuse-linker-plugin -fno-fat-lto-objects -DPREVENT_OPTIMIZATION line 40 v == 1
FAIL: gcc.dg/guality/pr43051-1.c -O3 -fomit-frame-pointer -funroll-loops -fpeel-loops -ftracer -finline-functions -DPREVENT_OPTIMIZATION line 35 v == 1
FAIL: gcc.dg/guality/pr43051-1.c -O3 -fomit-frame-pointer -funroll-loops -fpeel-loops -ftracer -finline-functions -DPREVENT_OPTIMIZATION line 40 v == 1
FAIL: gcc.dg/guality/pr43051-1.c -O3 -g -DPREVENT_OPTIMIZATION line 35 v == 1
FAIL: gcc.dg/guality/pr43051-1.c -O3 -g -DPREVENT_OPTIMIZATION line 40 v == 1
FAIL: gcc.dg/guality/pr43051-1.c -Os -DPREVENT_OPTIMIZATION line 35 v == 1
FAIL: gcc.dg/guality/pr43051-1.c -Os -DPREVENT_OPTIMIZATION line 40 v == 1
FAIL: gcc.dg/guality/pr43051-1.c -Og -DPREVENT_OPTIMIZATION line 35 v == 1
FAIL: gcc.dg/guality/pr43051-1.c -Og -DPREVENT_OPTIMIZATION line 40 v == 1
FAIL: gcc.dg/guality/pr54200.c -O1 -DPREVENT_OPTIMIZATION line 20 z == 3
FAIL: gcc.dg/guality/pr54200.c -O2 -DPREVENT_OPTIMIZATION line 20 z == 3
FAIL: gcc.dg/guality/pr54200.c -O2 -flto -fno-use-linker-plugin -flto-partition=none -DPREVENT_OPTIMIZATION line 20 z == 3
FAIL: gcc.dg/guality/pr54200.c -O3 -g -DPREVENT_OPTIMIZATION line 20 z == 3
FAIL: gcc.dg/guality/pr54200.c -Os -DPREVENT_OPTIMIZATION line 20 z == 3
FAIL: gcc.dg/guality/pr54200.c -Og -DPREVENT_OPTIMIZATION line 20 z == 3
FAIL: gcc.dg/guality/pr54519-1.c -O1 -DPREVENT_OPTIMIZATION line 20 x == 36
FAIL: gcc.dg/guality/pr54519-1.c -O1 -DPREVENT_OPTIMIZATION line 20 y == 25
FAIL: gcc.dg/guality/pr54519-1.c -O1 -DPREVENT_OPTIMIZATION line 23 x == 98
FAIL: gcc.dg/guality/pr54519-1.c -O1 -DPREVENT_OPTIMIZATION line 23 y == 117
FAIL: gcc.dg/guality/pr54519-1.c -O2 -DPREVENT_OPTIMIZATION line 20 x == 36
FAIL: gcc.dg/guality/pr54519-1.c -O2 -DPREVENT_OPTIMIZATION line 23 x == 98
FAIL: gcc.dg/guality/pr54519-1.c -O2 -flto -fno-use-linker-plugin -flto-partition=none -DPREVENT_OPTIMIZATION line 20 x == 36
FAIL: gcc.dg/guality/pr54519-1.c -O2 -flto -fno-use-linker-plugin -flto-partition=none -DPREVENT_OPTIMIZATION line 20 y == 25
FAIL: gcc.dg/guality/pr54519-1.c -O2 -flto -fno-use-linker-plugin -flto-partition=none -DPREVENT_OPTIMIZATION line 20 z == 6
FAIL: gcc.dg/guality/pr54519-1.c -O2 -flto -fno-use-linker-plugin -flto-partition=none -DPREVENT_OPTIMIZATION line 23 x == 98
FAIL: gcc.dg/guality/pr54519-1.c -O2 -flto -fno-use-linker-plugin -flto-partition=none -DPREVENT_OPTIMIZATION line 23 y == 117
FAIL: gcc.dg/guality/pr54519-1.c -O2 -flto -fno-use-linker-plugin -flto-partition=none -DPREVENT_OPTIMIZATION line 23 z == 8
FAIL: gcc.dg/guality/pr54519-1.c -O2 -flto -fuse-linker-plugin -fno-fat-lto-objects -DPREVENT_OPTIMIZATION line 20 y == 25
FAIL: gcc.dg/guality/pr54519-1.c -O2 -flto -fuse-linker-plugin -fno-fat-lto-objects -DPREVENT_OPTIMIZATION line 20 z == 6
FAIL: gcc.dg/guality/pr54519-1.c -O2 -flto -fuse-linker-plugin -fno-fat-lto-objects -DPREVENT_OPTIMIZATION line 23 y == 117
FAIL: gcc.dg/guality/pr54519-1.c -O2 -flto -fuse-linker-plugin -fno-fat-lto-objects -DPREVENT_OPTIMIZATION line 23 z == 8
FAIL: gcc.dg/guality/pr54519-1.c -Os -DPREVENT_OPTIMIZATION line 20 x == 36
FAIL: gcc.dg/guality/pr54519-1.c -Os -DPREVENT_OPTIMIZATION line 23 x == 98
FAIL: gcc.dg/guality/pr54519-1.c -Og -DPREVENT_OPTIMIZATION line 20 x == 36
FAIL: gcc.dg/guality/pr54519-1.c -Og -DPREVENT_OPTIMIZATION line 20 y == 25
FAIL: gcc.dg/guality/pr54519-1.c -Og -DPREVENT_OPTIMIZATION line 23 x == 98
FAIL: gcc.dg/guality/pr54519-1.c -Og -DPREVENT_OPTIMIZATION line 23 y == 117
FAIL: gcc.dg/guality/pr54519-2.c -O1 -DPREVENT_OPTIMIZATION line 17 x == 6
FAIL: gcc.dg/guality/pr54519-2.c -O2 -DPREVENT_OPTIMIZATION line 17 x == 6
FAIL: gcc.dg/guality/pr54519-2.c -O2 -flto -fno-use-linker-plugin -flto-partition=none -DPREVENT_OPTIMIZATION line 17 x == 6
FAIL: gcc.dg/guality/pr54519-2.c -O2 -flto -fno-use-linker-plugin -flto-partition=none -DPREVENT_OPTIMIZATION line 17 y == 25
FAIL: gcc.dg/guality/pr54519-2.c -O2 -flto -fuse-linker-plugin -fno-fat-lto-objects -DPREVENT_OPTIMIZATION line 17 y == 25
FAIL: gcc.dg/guality/pr54519-2.c -Og -DPREVENT_OPTIMIZATION line 17 x == 6
FAIL: gcc.dg/guality/pr54519-3.c -O1 -DPREVENT_OPTIMIZATION line 20 x == 36
FAIL: gcc.dg/guality/pr54519-3.c -O1 -DPREVENT_OPTIMIZATION line 20 y == 25
FAIL: gcc.dg/guality/pr54519-3.c -O1 -DPREVENT_OPTIMIZATION line 20 z == 6
FAIL: gcc.dg/guality/pr54519-3.c -O1 -DPREVENT_OPTIMIZATION line 23 x == 98
FAIL: gcc.dg/guality/pr54519-3.c -O1 -DPREVENT_OPTIMIZATION line 23 y == 117
FAIL: gcc.dg/guality/pr54519-3.c -O1 -DPREVENT_OPTIMIZATION line 23 z == 8
FAIL: gcc.dg/guality/pr54519-3.c -O2 -DPREVENT_OPTIMIZATION line 20 z == 6
FAIL: gcc.dg/guality/pr54519-3.c -O2 -DPREVENT_OPTIMIZATION line 23 z == 8
FAIL: gcc.dg/guality/pr54519-3.c -O2 -flto -fno-use-linker-plugin -flto-partition=none -DPREVENT_OPTIMIZATION line 20 y == 25
FAIL: gcc.dg/guality/pr54519-3.c -O2 -flto -fno-use-linker-plugin -flto-partition=none -DPREVENT_OPTIMIZATION line 20 z == 6
FAIL: gcc.dg/guality/pr54519-3.c -O2 -flto -fno-use-linker-plugin -flto-partition=none -DPREVENT_OPTIMIZATION line 23 y == 117
FAIL: gcc.dg/guality/pr54519-3.c -O2 -flto -fno-use-linker-plugin -flto-partition=none -DPREVENT_OPTIMIZATION line 23 z == 8
FAIL: gcc.dg/guality/pr54519-3.c -O2 -flto -fuse-linker-plugin -fno-fat-lto-objects -DPREVENT_OPTIMIZATION line 20 y == 25
FAIL: gcc.dg/guality/pr54519-3.c -O2 -flto -fuse-linker-plugin -fno-fat-lto-objects -DPREVENT_OPTIMIZATION line 20 z == 6
FAIL: gcc.dg/guality/pr54519-3.c -O2 -flto -fuse-linker-plugin -fno-fat-lto-objects -DPREVENT_OPTIMIZATION line 23 y == 117
FAIL: gcc.dg/guality/pr54519-3.c -O2 -flto -fuse-linker-plugin -fno-fat-lto-objects -DPREVENT_OPTIMIZATION line 23 z == 8
FAIL: gcc.dg/guality/pr54519-3.c -O3 -g -DPREVENT_OPTIMIZATION line 20 z == 6
FAIL: gcc.dg/guality/pr54519-3.c -O3 -g -DPREVENT_OPTIMIZATION line 23 z == 8
FAIL: gcc.dg/guality/pr54519-3.c -Os -DPREVENT_OPTIMIZATION line 20 z == 6
FAIL: gcc.dg/guality/pr54519-3.c -Os -DPREVENT_OPTIMIZATION line 23 z == 8
FAIL: gcc.dg/guality/pr54519-3.c -Og -DPREVENT_OPTIMIZATION line 20 x == 36
FAIL: gcc.dg/guality/pr54519-3.c -Og -DPREVENT_OPTIMIZATION line 20 y == 25
FAIL: gcc.dg/guality/pr54519-3.c -Og -DPREVENT_OPTIMIZATION line 20 z == 6
FAIL: gcc.dg/guality/pr54519-3.c -Og -DPREVENT_OPTIMIZATION line 23 x == 98
FAIL: gcc.dg/guality/pr54519-3.c -Og -DPREVENT_OPTIMIZATION line 23 y == 117
FAIL: gcc.dg/guality/pr54519-3.c -Og -DPREVENT_OPTIMIZATION line 23 z == 8
FAIL: gcc.dg/guality/pr54519-4.c -O1 -DPREVENT_OPTIMIZATION line 17 x == 6
FAIL: gcc.dg/guality/pr54519-4.c -O1 -DPREVENT_OPTIMIZATION line 17 y == 25
FAIL: gcc.dg/guality/pr54519-4.c -O2 -DPREVENT_OPTIMIZATION line 17 y == 25
FAIL: gcc.dg/guality/pr54519-4.c -O2 -flto -fno-use-linker-plugin -flto-partition=none -DPREVENT_OPTIMIZATION line 17 y == 25
FAIL: gcc.dg/guality/pr54519-4.c -O2 -flto -fuse-linker-plugin -fno-fat-lto-objects -DPREVENT_OPTIMIZATION line 17 y == 25
FAIL: gcc.dg/guality/pr54519-4.c -O3 -g -DPREVENT_OPTIMIZATION line 17 y == 25
FAIL: gcc.dg/guality/pr54519-4.c -Os -DPREVENT_OPTIMIZATION line 17 y == 25
FAIL: gcc.dg/guality/pr54519-4.c -Og -DPREVENT_OPTIMIZATION line 17 x == 6
FAIL: gcc.dg/guality/pr54519-4.c -Og -DPREVENT_OPTIMIZATION line 17 y == 25
FAIL: gcc.dg/guality/pr54519-5.c -O1 -DPREVENT_OPTIMIZATION line 17 x == 6
FAIL: gcc.dg/guality/pr54519-5.c -O1 -DPREVENT_OPTIMIZATION line 17 y == 25
FAIL: gcc.dg/guality/pr54519-5.c -O2 -DPREVENT_OPTIMIZATION line 17 x == 6
FAIL: gcc.dg/guality/pr54519-5.c -O2 -DPREVENT_OPTIMIZATION line 17 y == 25
FAIL: gcc.dg/guality/pr54519-5.c -O2 -flto -fno-use-linker-plugin -flto-partition=none -DPREVENT_OPTIMIZATION line 17 x == 6
FAIL: gcc.dg/guality/pr54519-5.c -O2 -flto -fno-use-linker-plugin -flto-partition=none -DPREVENT_OPTIMIZATION line 17 y == 25
FAIL: gcc.dg/guality/pr54519-5.c -O2 -flto -fuse-linker-plugin -fno-fat-lto-objects -DPREVENT_OPTIMIZATION line 17 y == 25
FAIL: gcc.dg/guality/pr54519-5.c -O3 -g -DPREVENT_OPTIMIZATION line 17 y == 25
FAIL: gcc.dg/guality/pr54519-5.c -Os -DPREVENT_OPTIMIZATION line 17 y == 25
FAIL: gcc.dg/guality/pr54519-5.c -Og -DPREVENT_OPTIMIZATION line 17 x == 6
FAIL: gcc.dg/guality/pr54519-5.c -Og -DPREVENT_OPTIMIZATION line 17 y == 25
FAIL: gcc.dg/guality/pr54551.c -O1 -DPREVENT_OPTIMIZATION line 18 a == 4
FAIL: gcc.dg/guality/pr54551.c -O2 -DPREVENT_OPTIMIZATION line 18 a == 4
FAIL: gcc.dg/guality/pr54551.c -O2 -flto -fno-use-linker-plugin -flto-partition=none -DPREVENT_OPTIMIZATION line 18 a == 4
FAIL: gcc.dg/guality/pr54551.c -O3 -g -DPREVENT_OPTIMIZATION line 18 a == 4
FAIL: gcc.dg/guality/pr54551.c -Os -DPREVENT_OPTIMIZATION line 18 a == 4
FAIL: gcc.dg/guality/pr54551.c -Og -DPREVENT_OPTIMIZATION line 18 a == 4
FAIL: gcc.dg/guality/pr54693-2.c -O1 -DPREVENT_OPTIMIZATION line 21 x == 10 - i
FAIL: gcc.dg/guality/pr54693-2.c -O2 -DPREVENT_OPTIMIZATION line 21 x == 10 - i
FAIL: gcc.dg/guality/pr54693-2.c -O2 -flto -fno-use-linker-plugin -flto-partition=none -DPREVENT_OPTIMIZATION line 21 x == 10 - i
FAIL: gcc.dg/guality/pr54693-2.c -O2 -flto -fuse-linker-plugin -fno-fat-lto-objects -DPREVENT_OPTIMIZATION line 21 y == 20 - 2 * i
FAIL: gcc.dg/guality/pr54693-2.c -O2 -flto -fuse-linker-plugin -fno-fat-lto-objects -DPREVENT_OPTIMIZATION line 21 z == 30 - 3 * i
FAIL: gcc.dg/guality/pr54693-2.c -O3 -fomit-frame-pointer -funroll-loops -fpeel-loops -ftracer -finline-functions -DPREVENT_OPTIMIZATION line 21 x == 10 - i
FAIL: gcc.dg/guality/pr54693-2.c -O3 -g -DPREVENT_OPTIMIZATION line 21 x == 10 - i
FAIL: gcc.dg/guality/pr54693-2.c -Os -DPREVENT_OPTIMIZATION line 21 y == 20 - 2 * i
FAIL: gcc.dg/guality/pr54693-2.c -Os -DPREVENT_OPTIMIZATION line 21 z == 30 - 3 * i
FAIL: gcc.dg/guality/pr54693.c -Os -DPREVENT_OPTIMIZATION line 22 i == c - 48
XPASS: gcc.dg/guality/pr54970.c -O0 line 31 a[0] == 4
XPASS: gcc.dg/guality/pr54970.c -O0 line 36 a[0] == 4
XPASS: gcc.dg/guality/pr54970.c -O0 line 45 a[0] == 4
XPASS: gcc.dg/guality/pr54970.c -O0 line 45 p[-2] == 4
XPASS: gcc.dg/guality/pr54970.c -O0 line 45 q[-1] == 4
FAIL: gcc.dg/guality/pr54970.c -Og -DPREVENT_OPTIMIZATION line 15 *p == 3
FAIL: gcc.dg/guality/pr54970.c -Og -DPREVENT_OPTIMIZATION line 15 *q == 2
FAIL: gcc.dg/guality/pr54970.c -Og -DPREVENT_OPTIMIZATION line 15 a[0] == 1
FAIL: gcc.dg/guality/pr54970.c -Og -DPREVENT_OPTIMIZATION line 15 a[1] == 2
FAIL: gcc.dg/guality/pr54970.c -Og -DPREVENT_OPTIMIZATION line 15 a[2] == 3
FAIL: gcc.dg/guality/pr54970.c -Og -DPREVENT_OPTIMIZATION line 20 *p == 13
FAIL: gcc.dg/guality/pr54970.c -Og -DPREVENT_OPTIMIZATION line 20 *q == 2
FAIL: gcc.dg/guality/pr54970.c -Og -DPREVENT_OPTIMIZATION line 20 a[0] == 1
FAIL: gcc.dg/guality/pr54970.c -Og -DPREVENT_OPTIMIZATION line 20 a[1] == 2
FAIL: gcc.dg/guality/pr54970.c -Og -DPREVENT_OPTIMIZATION line 20 a[2] == 13
FAIL: gcc.dg/guality/pr54970.c -Og -DPREVENT_OPTIMIZATION line 25 *p == 13
FAIL: gcc.dg/guality/pr54970.c -Og -DPREVENT_OPTIMIZATION line 25 *q == 12
FAIL: gcc.dg/guality/pr54970.c -Og -DPREVENT_OPTIMIZATION line 25 a[0] == 1
FAIL: gcc.dg/guality/pr54970.c -Og -DPREVENT_OPTIMIZATION line 25 a[1] == 12
FAIL: gcc.dg/guality/pr54970.c -Og -DPREVENT_OPTIMIZATION line 25 a[2] == 13
FAIL: gcc.dg/guality/pr54970.c -Og -DPREVENT_OPTIMIZATION line 31 *p == 6
FAIL: gcc.dg/guality/pr54970.c -Og -DPREVENT_OPTIMIZATION line 31 *q == 5
FAIL: gcc.dg/guality/pr54970.c -Og -DPREVENT_OPTIMIZATION line 31 a[1] == 5
FAIL: gcc.dg/guality/pr54970.c -Og -DPREVENT_OPTIMIZATION line 31 a[2] == 6
FAIL: gcc.dg/guality/pr54970.c -Og -DPREVENT_OPTIMIZATION line 36 *p == 26
FAIL: gcc.dg/guality/pr54970.c -Og -DPREVENT_OPTIMIZATION line 36 *q == 5
FAIL: gcc.dg/guality/pr54970.c -Og -DPREVENT_OPTIMIZATION line 36 a[1] == 5
FAIL: gcc.dg/guality/pr54970.c -Og -DPREVENT_OPTIMIZATION line 36 a[2] == 26
FAIL: gcc.dg/guality/pr54970.c -Og -DPREVENT_OPTIMIZATION line 45 *p == 26
FAIL: gcc.dg/guality/pr54970.c -Og -DPREVENT_OPTIMIZATION line 45 *q == 25
FAIL: gcc.dg/guality/pr54970.c -Og -DPREVENT_OPTIMIZATION line 45 a[1] == 25
FAIL: gcc.dg/guality/pr54970.c -Og -DPREVENT_OPTIMIZATION line 45 a[2] == 26
FAIL: gcc.dg/guality/pr54970.c -Og -DPREVENT_OPTIMIZATION line 45 p[-1] == 25
FAIL: gcc.dg/guality/pr54970.c -Og -DPREVENT_OPTIMIZATION line 45 q[1] == 26
FAIL: gcc.dg/guality/pr56154-1.c -Og -DPREVENT_OPTIMIZATION line pr56154-1.c:20 x.a == 6
FAIL: gcc.dg/guality/pr59776.c -Og -DPREVENT_OPTIMIZATION line pr59776.c:17 s1.f == 5.0
FAIL: gcc.dg/guality/pr59776.c -Og -DPREVENT_OPTIMIZATION line pr59776.c:17 s1.g == 6.0
FAIL: gcc.dg/guality/pr59776.c -Og -DPREVENT_OPTIMIZATION line pr59776.c:17 s2.f == 0.0
FAIL: gcc.dg/guality/pr59776.c -Og -DPREVENT_OPTIMIZATION line pr59776.c:17 s2.g == 6.0
FAIL: gcc.dg/guality/pr59776.c -Og -DPREVENT_OPTIMIZATION line pr59776.c:20 s1.f == 5.0
FAIL: gcc.dg/guality/pr59776.c -Og -DPREVENT_OPTIMIZATION line pr59776.c:20 s1.g == 6.0
FAIL: gcc.dg/guality/pr59776.c -Og -DPREVENT_OPTIMIZATION line pr59776.c:20 s2.f == 5.0
FAIL: gcc.dg/guality/pr59776.c -Og -DPREVENT_OPTIMIZATION line pr59776.c:20 s2.g == 6.0
FAIL: gcc.dg/guality/pr68860-1.c -O2 -flto -fno-use-linker-plugin -flto-partition=none -DPREVENT_OPTIMIZATION line 14 arg1 == 1
FAIL: gcc.dg/guality/pr68860-1.c -O2 -flto -fno-use-linker-plugin -flto-partition=none -DPREVENT_OPTIMIZATION line 14 arg2 == 2
FAIL: gcc.dg/guality/pr68860-1.c -O2 -flto -fno-use-linker-plugin -flto-partition=none -DPREVENT_OPTIMIZATION line 14 arg3 == 3
FAIL: gcc.dg/guality/pr68860-1.c -O2 -flto -fno-use-linker-plugin -flto-partition=none -DPREVENT_OPTIMIZATION line 14 arg4 == 4
FAIL: gcc.dg/guality/pr68860-1.c -O2 -flto -fno-use-linker-plugin -flto-partition=none -DPREVENT_OPTIMIZATION line 14 arg5 == 5
FAIL: gcc.dg/guality/pr68860-1.c -O2 -flto -fno-use-linker-plugin -flto-partition=none -DPREVENT_OPTIMIZATION line 14 arg6 == 6
FAIL: gcc.dg/guality/pr68860-1.c -O2 -flto -fno-use-linker-plugin -flto-partition=none -DPREVENT_OPTIMIZATION line 16 arg1 == 1
FAIL: gcc.dg/guality/pr68860-1.c -O2 -flto -fno-use-linker-plugin -flto-partition=none -DPREVENT_OPTIMIZATION line 16 arg2 == 2
FAIL: gcc.dg/guality/pr68860-1.c -O2 -flto -fno-use-linker-plugin -flto-partition=none -DPREVENT_OPTIMIZATION line 16 arg3 == 3
FAIL: gcc.dg/guality/pr68860-1.c -O2 -flto -fno-use-linker-plugin -flto-partition=none -DPREVENT_OPTIMIZATION line 16 arg4 == 4
FAIL: gcc.dg/guality/pr68860-1.c -O2 -flto -fno-use-linker-plugin -flto-partition=none -DPREVENT_OPTIMIZATION line 16 arg5 == 5
FAIL: gcc.dg/guality/pr68860-1.c -O2 -flto -fno-use-linker-plugin -flto-partition=none -DPREVENT_OPTIMIZATION line 16 arg6 == 6
FAIL: gcc.dg/guality/pr68860-1.c -O2 -flto -fuse-linker-plugin -fno-fat-lto-objects -DPREVENT_OPTIMIZATION line 14 arg1 == 1
FAIL: gcc.dg/guality/pr68860-1.c -O2 -flto -fuse-linker-plugin -fno-fat-lto-objects -DPREVENT_OPTIMIZATION line 14 arg2 == 2
FAIL: gcc.dg/guality/pr68860-1.c -O2 -flto -fuse-linker-plugin -fno-fat-lto-objects -DPREVENT_OPTIMIZATION line 14 arg3 == 3
FAIL: gcc.dg/guality/pr68860-1.c -O2 -flto -fuse-linker-plugin -fno-fat-lto-objects -DPREVENT_OPTIMIZATION line 14 arg4 == 4
FAIL: gcc.dg/guality/pr68860-1.c -O2 -flto -fuse-linker-plugin -fno-fat-lto-objects -DPREVENT_OPTIMIZATION line 14 arg5 == 5
FAIL: gcc.dg/guality/pr68860-1.c -O2 -flto -fuse-linker-plugin -fno-fat-lto-objects -DPREVENT_OPTIMIZATION line 14 arg6 == 6
FAIL: gcc.dg/guality/pr68860-1.c -O2 -flto -fuse-linker-plugin -fno-fat-lto-objects -DPREVENT_OPTIMIZATION line 16 arg1 == 1
FAIL: gcc.dg/guality/pr68860-1.c -O2 -flto -fuse-linker-plugin -fno-fat-lto-objects -DPREVENT_OPTIMIZATION line 16 arg2 == 2
FAIL: gcc.dg/guality/pr68860-1.c -O2 -flto -fuse-linker-plugin -fno-fat-lto-objects -DPREVENT_OPTIMIZATION line 16 arg3 == 3
FAIL: gcc.dg/guality/pr68860-1.c -O2 -flto -fuse-linker-plugin -fno-fat-lto-objects -DPREVENT_OPTIMIZATION line 16 arg4 == 4
FAIL: gcc.dg/guality/pr68860-1.c -O2 -flto -fuse-linker-plugin -fno-fat-lto-objects -DPREVENT_OPTIMIZATION line 16 arg5 == 5
FAIL: gcc.dg/guality/pr68860-1.c -O2 -flto -fuse-linker-plugin -fno-fat-lto-objects -DPREVENT_OPTIMIZATION line 16 arg6 == 6
FAIL: gcc.dg/guality/sra-1.c -Og -DPREVENT_OPTIMIZATION line 21 a.i == 4
FAIL: gcc.dg/guality/sra-1.c -Og -DPREVENT_OPTIMIZATION line 21 a.j == 14
FAIL: gcc.dg/guality/sra-1.c -Og -DPREVENT_OPTIMIZATION line 32 a[0] == 4
FAIL: gcc.dg/guality/sra-1.c -Og -DPREVENT_OPTIMIZATION line 32 a[1] == 14
FAIL: gcc.dg/guality/sra-1.c -Og -DPREVENT_OPTIMIZATION line 43 a.i == 4
FAIL: gcc.dg/guality/sra-1.c -Og -DPREVENT_OPTIMIZATION line 43 a.j == 14
FAIL: gcc.dg/guality/vla-1.c -O1 -DPREVENT_OPTIMIZATION line 17 sizeof (a) == 6
FAIL: gcc.dg/guality/vla-1.c -O2 -DPREVENT_OPTIMIZATION line 17 sizeof (a) == 6
FAIL: gcc.dg/guality/vla-1.c -O2 -flto -fno-use-linker-plugin -flto-partition=none -DPREVENT_OPTIMIZATION line 17 sizeof (a) == 6
FAIL: gcc.dg/guality/vla-1.c -O2 -flto -fuse-linker-plugin -fno-fat-lto-objects -DPREVENT_OPTIMIZATION line 17 sizeof (a) == 6
FAIL: gcc.dg/guality/vla-1.c -O3 -g -DPREVENT_OPTIMIZATION line 17 sizeof (a) == 6
FAIL: gcc.dg/guality/vla-1.c -Os -DPREVENT_OPTIMIZATION line 17 sizeof (a) == 6
FAIL: gcc.dg/torture/pr52451.c -O0 execution test
FAIL: gcc.dg/torture/pr52451.c -O1 execution test
FAIL: gcc.dg/torture/pr52451.c -O2 execution test
FAIL: gcc.dg/torture/pr52451.c -O2 -flto -fno-use-linker-plugin -flto-partition=none execution test
FAIL: gcc.dg/torture/pr52451.c -O2 -flto -fuse-linker-plugin -fno-fat-lto-objects execution test
FAIL: gcc.dg/torture/pr52451.c -O3 -g execution test
FAIL: gcc.dg/torture/pr52451.c -Os execution test
FAIL: gcc.dg/vect/costmodel/ppc/costmodel-vect-33.c scan-tree-dump-times vect "loop versioned for vectorization to enhance alignment" 1
FAIL: gcc.dg/vect/costmodel/ppc/costmodel-vect-33.c scan-tree-dump-times vect "vectorized 1 loops" 1
FAIL: gcc.dg/vect/costmodel/ppc/costmodel-vect-76b.c scan-tree-dump-times vect "vectorization not profitable" 1
FAIL: gcc.dg/vect/costmodel/ppc/costmodel-vect-76b.c scan-tree-dump-times vect "vectorized 1 loops" 0
FAIL: gcc.dg/vect/bb-slp-over-widen-1.c -flto -ffat-lto-objects scan-tree-dump-times slp2 "basic block vectorized" 2
FAIL: gcc.dg/vect/bb-slp-over-widen-1.c scan-tree-dump-times slp2 "basic block vectorized" 2
FAIL: gcc.dg/vect/bb-slp-over-widen-2.c -flto -ffat-lto-objects scan-tree-dump-times slp2 "basic block vectorized" 2
FAIL: gcc.dg/vect/bb-slp-over-widen-2.c scan-tree-dump-times slp2 "basic block vectorized" 2
FAIL: gcc.dg/vect/bb-slp-pow-1.c -flto -ffat-lto-objects scan-tree-dump-times slp2 "basic block vectorized" 1
FAIL: gcc.dg/vect/bb-slp-pow-1.c scan-tree-dump-times slp2 "basic block vectorized" 1
FAIL: gcc.dg/vect/bb-slp-pr65935.c -flto -ffat-lto-objects scan-tree-dump-times slp1 "basic block vectorized" 2
FAIL: gcc.dg/vect/bb-slp-pr65935.c scan-tree-dump-times slp1 "basic block vectorized" 2
FAIL: gcc.dg/vect/no-tree-sra-bb-slp-pr50730.c scan-tree-dump-times slp2 "basic block vectorized" 1
FAIL: gcc.dg/vect/no-vfa-vect-depend-2.c scan-tree-dump-times vect "vectorized 1 loops" 1
FAIL: gcc.dg/vect/no-vfa-vect-depend-3.c scan-tree-dump-times vect "vectorized 1 loops" 4
FAIL: gcc.dg/vect/pr46032.c -flto -ffat-lto-objects scan-tree-dump-times vect "vectorized 1 loop" 1
FAIL: gcc.dg/vect/pr46032.c scan-tree-dump-times vect "vectorized 1 loop" 1
FAIL: gcc.dg/vect/pr62171.c -flto -ffat-lto-objects scan-tree-dump-not vect "versioned"
FAIL: gcc.dg/vect/pr62171.c scan-tree-dump-not vect "versioned"
FAIL: gcc.dg/vect/pr85586.c -flto -ffat-lto-objects scan-tree-dump-times vect "LOOP VECTORIZED" 1
FAIL: gcc.dg/vect/pr85586.c scan-tree-dump-times vect "LOOP VECTORIZED" 1
FAIL: gcc.dg/vect/section-anchors-vect-69.c scan-tree-dump-times vect "vectorized 4 loops" 1
FAIL: gcc.dg/vect/slp-43.c -flto -ffat-lto-objects scan-tree-dump-times vect "vectorized 1 loops" 2
FAIL: gcc.dg/vect/slp-43.c scan-tree-dump-times vect "vectorized 1 loops" 2
XPASS: gcc.dg/vect/vect-24.c -flto -ffat-lto-objects scan-tree-dump-times vect "vectorized 3 loops" 1
XPASS: gcc.dg/vect/vect-24.c scan-tree-dump-times vect "vectorized 3 loops" 1
FAIL: gcc.dg/vect/vect-31.c -flto -ffat-lto-objects scan-tree-dump-times vect "vectorized 4 loops" 1
FAIL: gcc.dg/vect/vect-31.c scan-tree-dump-times vect "vectorized 4 loops" 1
FAIL: gcc.dg/vect/vect-44.c -flto -ffat-lto-objects scan-tree-dump-times vect "Vectorizing an unaligned access" 3
FAIL: gcc.dg/vect/vect-44.c scan-tree-dump-times vect "Vectorizing an unaligned access" 3
FAIL: gcc.dg/vect/vect-50.c -flto -ffat-lto-objects scan-tree-dump-times vect "Vectorizing an unaligned access" 3
FAIL: gcc.dg/vect/vect-50.c scan-tree-dump-times vect "Vectorizing an unaligned access" 3
FAIL: gcc.dg/vect/vect-93.c -flto -ffat-lto-objects scan-tree-dump-times vect "vectorized 2 loops" 2
FAIL: gcc.dg/vect/vect-93.c scan-tree-dump-times vect "vectorized 2 loops" 2
FAIL: gcc.dg/vect/vect-over-widen-17.c -flto -ffat-lto-objects scan-tree-dump-not vect "vector[^\\\\n]*char"
FAIL: gcc.dg/vect/vect-over-widen-17.c scan-tree-dump-not vect "vector[^\\\\n]*char"
FAIL: gcc.dg/vect/vect-reduc-in-order-2.c -flto -ffat-lto-objects scan-tree-dump vect "in-order double reduction not supported"
FAIL: gcc.dg/vect/vect-reduc-in-order-2.c scan-tree-dump vect "in-order double reduction not supported"
FAIL: gcc.dg/vect/vect-strided-a-u8-i2-gap.c -flto -ffat-lto-objects scan-tree-dump-times vect "vectorized 1 loops" 1
FAIL: gcc.dg/vect/vect-strided-a-u8-i2-gap.c scan-tree-dump-times vect "vectorized 1 loops" 1
FAIL: gcc.target/powerpc/20050830-1.c scan-assembler bdn
FAIL: gcc.target/powerpc/altivec-7.c scan-assembler-times \\\\mlvx\\\\M 0
FAIL: gcc.target/powerpc/asm-es-2.c scan-assembler asm1 %?r?3,%?r?4
FAIL: gcc.target/powerpc/pr17381.c scan-assembler-times fmr 1
FAIL: gcc.target/powerpc/pr87033.c scan-assembler \\\\mlwax\\\\M
FAIL: gcc.target/powerpc/pr87033.c scan-assembler-not \\\\mlwa\\\\M
FAIL: gcc.target/powerpc/vsx-vector-6.p7.c scan-assembler-times xvcmpgtdp 8
FAIL: gcc.target/powerpc/vsx-vector-6.p7.c scan-assembler-times xvcmpgtdp. 8
FAIL: gcc.target/powerpc/vsx-vector-6.p7.c scan-assembler-times xxlnor 7
FAIL: gcc.target/powerpc/vsx-vector-6.p8.c scan-assembler-times xvcmpgedp 7
FAIL: gcc.target/powerpc/vsx-vector-6.p8.c scan-assembler-times xvcmpgedp. 7
FAIL: gcc.target/powerpc/vsx-vector-6.p8.c scan-assembler-times xxlnor 7
FAIL: gcc.target/powerpc/vsx-vector-6.p9.c scan-assembler-times xxlnor 7
=== gcc Summary ===
# of expected passes 124802
# of unexpected failures 285
# of unexpected successes 25
# of expected failures 532
# of unsupported tests 2989
/home/gccbuild/build/nightly/build-gcc-trunk/gcc/xgcc version 9.0.0 20181016 (experimental) [trunk revision 265192] (GCC)
=== gfortran tests ===
Running target unix
FAIL: gfortran.dg/elemental_subroutine_3.f90 -O1 (test for excess errors)
FAIL: gfortran.dg/elemental_subroutine_3.f90 -O2 (test for excess errors)
FAIL: gfortran.dg/elemental_subroutine_3.f90 -O3 -fomit-frame-pointer -funroll-loops -fpeel-loops -ftracer -finline-functions (test for excess errors)
FAIL: gfortran.dg/elemental_subroutine_3.f90 -O3 -g (test for excess errors)
FAIL: gfortran.dg/elemental_subroutine_3.f90 -Os (test for excess errors)
XPASS: gfortran.dg/large_real_kind_form_io_2.f90 -O0 execution test
XPASS: gfortran.dg/large_real_kind_form_io_2.f90 -O1 execution test
XPASS: gfortran.dg/large_real_kind_form_io_2.f90 -O2 execution test
XPASS: gfortran.dg/large_real_kind_form_io_2.f90 -O3 -fomit-frame-pointer -funroll-loops -fpeel-loops -ftracer -finline-functions execution test
XPASS: gfortran.dg/large_real_kind_form_io_2.f90 -O3 -g execution test
XPASS: gfortran.dg/large_real_kind_form_io_2.f90 -Os execution test
FAIL: gfortran.dg/ieee/large_2.f90 -O0 execution test
FAIL: gfortran.dg/ieee/large_2.f90 -O1 execution test
FAIL: gfortran.dg/ieee/large_2.f90 -O2 execution test
FAIL: gfortran.dg/ieee/large_2.f90 -O3 -fomit-frame-pointer -funroll-loops -fpeel-loops -ftracer -finline-functions execution test
FAIL: gfortran.dg/ieee/large_2.f90 -O3 -g execution test
FAIL: gfortran.dg/ieee/large_2.f90 -Os execution test
FAIL: gfortran.dg/vect/fast-math-mgrid-resid.f -O scan-tree-dump pcom "Executing predictive commoning without unrolling"
FAIL: gfortran.dg/vect/fast-math-mgrid-resid.f -O scan-tree-dump pcom "vectp_u.*__lsm.* = PHI <.*vectp_u.*__lsm"
FAIL: gfortran.dg/vect/fast-math-pr37021.f90 -O scan-tree-dump vect "vectorized 2 loops"
FAIL: gfortran.dg/vect/pr52580.f -O scan-tree-dump-times vect "LOOP VECTORIZED" 1
FAIL: gfortran.dg/vect/pr62283-2.f -O scan-tree-dump slp2 "basic block vectorized"
FAIL: gfortran.dg/vect/pr81303.f -O scan-tree-dump vect "vectorized 1 loops in function"
FAIL: gfortran.dg/vect/vect-8.f90 -O scan-tree-dump-times vect "vectorized 22 loops" 1
FAIL: gfortran.dg/vect/vect-gems.f90 -O scan-tree-dump-times vect "vectorized 1 loops" 1
=== gfortran Summary ===
# of expected passes 47758
# of unexpected failures 19
# of unexpected successes 6
# of expected failures 106
# of unsupported tests 100
/home/gccbuild/build/nightly/build-gcc-trunk/gcc/gfortran version 9.0.0 20181016 (experimental) [trunk revision 265192] (GCC)
=== g++ tests ===
Running target unix
FAIL: c-c++-common/asan/null-deref-1.c -O2 output pattern test
FAIL: c-c++-common/asan/null-deref-1.c -O3 -g output pattern test
UNRESOLVED: g++.dg/ext/pr82625.C -std=gnu++11 scan-tree-dump-times optimized "return 4096;" 1
UNRESOLVED: g++.dg/ext/pr82625.C -std=gnu++11 scan-tree-dump-times optimized "return 8192;" 1
FAIL: g++.dg/ext/pr82625.C -std=gnu++11 (test for excess errors)
UNRESOLVED: g++.dg/ext/pr82625.C -std=gnu++14 scan-tree-dump-times optimized "return 4096;" 1
UNRESOLVED: g++.dg/ext/pr82625.C -std=gnu++14 scan-tree-dump-times optimized "return 8192;" 1
FAIL: g++.dg/ext/pr82625.C -std=gnu++14 (test for excess errors)
UNRESOLVED: g++.dg/ext/pr82625.C -std=gnu++98 scan-tree-dump-times optimized "return 4096;" 1
UNRESOLVED: g++.dg/ext/pr82625.C -std=gnu++98 scan-tree-dump-times optimized "return 8192;" 1
FAIL: g++.dg/ext/pr82625.C -std=gnu++98 (test for excess errors)
FAIL: g++.dg/pr83239.C -std=gnu++98 (test for excess errors)
=== g++ Summary ===
# of expected passes 126535
# of unexpected failures 6
# of expected failures 537
# of unresolved testcases 6
# of unsupported tests 5442
/home/gccbuild/build/nightly/build-gcc-trunk/gcc/xg++ version 9.0.0 20181016 (experimental) [trunk revision 265192] (GCC)
=== go tests ===
Running target unix
FAIL: go.test/test/ken/cplx2.go execution, -O2 -g
=== go Summary ===
# of expected passes 7281
# of unexpected failures 1
# of expected failures 1
# of untested testcases 7
# of unsupported tests 3
/home/gccbuild/build/nightly/build-gcc-trunk/gcc/gccgo version 9.0.0 20181016 (experimental) [trunk revision 265192] (GCC)
=== obj-c++ tests ===
Running target unix
=== obj-c++ Summary ===
# of expected passes 1456
# of expected failures 10
# of unsupported tests 77
/home/gccbuild/build/nightly/build-gcc-trunk/gcc/xg++ version 9.0.0 20181016 (experimental) [trunk revision 265192] (GCC)
=== objc tests ===
Running target unix
=== objc Summary ===
# of expected passes 2803
# of unsupported tests 68
/home/gccbuild/build/nightly/build-gcc-trunk/gcc/xgcc version 9.0.0 20181016 (experimental) [trunk revision 265192] (GCC)
=== gotools tests ===
FAIL: go test cmd/go
FAIL: go test misc/cgo/testcarchive
FAIL: TestCachedInstall
FAIL: TestCompileWithoutShared
FAIL: TestEarlySignalHandler
FAIL: TestInstall
FAIL: TestOsSignal
FAIL: TestPIE
FAIL: TestSigaltstack
FAIL: TestSignalForwarding
FAIL: TestSignalForwardingExternal
FAIL: TestSIGPROF
=== gotools Summary ===
# of expected passes 330
# of unexpected failures 12
# of untested testcases 146
/home/gccbuild/build/nightly/build-gcc-trunk/./gcc/gccgo version 9.0.0 20181016 (experimental) [trunk revision 265192] (GCC)
=== libatomic tests ===
Running target unix
=== libatomic Summary ===
# of expected passes 54
=== libffi tests ===
Running target unix
=== libffi Summary ===
# of expected passes 1934
# of unsupported tests 28
=== libgo tests ===
Running target unix
FAIL: cmd/go/internal/load
FAIL: internal/cpu
FAIL: net
FAIL: os/signal
FAIL: runtime/pprof
=== libgo Summary ===
# of expected passes 178
# of unexpected failures 5
/home/gccbuild/build/nightly/build-gcc-trunk/./gcc/gccgo version 9.0.0 20181016 (experimental) [trunk revision 265192] (GCC)
=== libgomp tests ===
Running target unix
=== libgomp Summary ===
# of expected passes 5944
# of unsupported tests 394
=== libitm tests ===
Running target unix
=== libitm Summary ===
# of expected passes 42
# of expected failures 3
# of unsupported tests 1
=== libstdc++ tests ===
Running target unix
FAIL: libstdc++-prettyprinters/80276.cc whatis p4
FAIL: libstdc++-prettyprinters/80276.cc whatis p4
FAIL: libstdc++-prettyprinters/cxx17.cc print ab
FAIL: libstdc++-prettyprinters/cxx17.cc print ab
FAIL: libstdc++-prettyprinters/cxx17.cc print ai
FAIL: libstdc++-prettyprinters/cxx17.cc print ai
FAIL: libstdc++-prettyprinters/cxx17.cc print am
FAIL: libstdc++-prettyprinters/cxx17.cc print am
FAIL: libstdc++-prettyprinters/cxx17.cc print ap
FAIL: libstdc++-prettyprinters/cxx17.cc print ap
FAIL: libstdc++-prettyprinters/cxx17.cc print as
FAIL: libstdc++-prettyprinters/cxx17.cc print as
FAIL: libstdc++-prettyprinters/cxx17.cc print as2
FAIL: libstdc++-prettyprinters/cxx17.cc print as2
FAIL: libstdc++-prettyprinters/cxx17.cc print p
FAIL: libstdc++-prettyprinters/cxx17.cc print p
FAIL: libstdc++-prettyprinters/cxx17.cc print q
FAIL: libstdc++-prettyprinters/cxx17.cc print q
FAIL: libstdc++-prettyprinters/cxx17.cc print wp
FAIL: libstdc++-prettyprinters/cxx17.cc print wp
FAIL: libstdc++-prettyprinters/cxx17.cc print wq
FAIL: libstdc++-prettyprinters/cxx17.cc print wq
FAIL: libstdc++-prettyprinters/libfundts.cc print ab
FAIL: libstdc++-prettyprinters/libfundts.cc print ab
FAIL: libstdc++-prettyprinters/libfundts.cc print ai
FAIL: libstdc++-prettyprinters/libfundts.cc print ai
FAIL: libstdc++-prettyprinters/libfundts.cc print am
FAIL: libstdc++-prettyprinters/libfundts.cc print am
FAIL: libstdc++-prettyprinters/libfundts.cc print ap
FAIL: libstdc++-prettyprinters/libfundts.cc print ap
FAIL: libstdc++-prettyprinters/libfundts.cc print as
FAIL: libstdc++-prettyprinters/libfundts.cc print as
FAIL: libstdc++-prettyprinters/libfundts.cc print as2
FAIL: libstdc++-prettyprinters/libfundts.cc print as2
FAIL: libstdc++-prettyprinters/shared_ptr.cc print sp1
FAIL: libstdc++-prettyprinters/shared_ptr.cc print sp1
FAIL: libstdc++-prettyprinters/shared_ptr.cc print wp1
FAIL: libstdc++-prettyprinters/shared_ptr.cc print wp1
FAIL: libstdc++-prettyprinters/shared_ptr.cc print wp2
FAIL: libstdc++-prettyprinters/shared_ptr.cc print wp2
=== libstdc++ Summary ===
# of expected passes 13277
# of unexpected failures 40
# of expected failures 77
# of unsupported tests 285
Compiler version: 9.0.0 20181016 (experimental) [trunk revision 265192] (GCC)
Platform: powerpc64-unknown-linux-gnu
configure flags: --prefix=/opt/gcc-nightly/trunk --with-as=/usr/bin/as --with-ld=/usr/bin/ld --enable-languages=c,c++,fortran,objc,obj-c++,go --disable-multilib --disable-multilib --with-cpu=power6
fail WARNING: Could not generate test framework tests
fail WARNING: Could not generate test framework tests
fail WARNING: Could not generate test framework tests
fail WARNING: Could not generate test framework tests
fail WARNING: Could not generate test framework tests
fail WARNING: Could not generate test framework tests
fail WARNING: Could not generate test framework tests
fail WARNING: Could not generate test framework tests
fail WARNING: Could not generate test framework tests
fail WARNING: Could not generate test framework tests
fail WARNING: Could not generate test framework tests
fail XPASS: gcc.test-framework/dg-bogus-exp-XF.c (test for excess errors)
fail FAIL: gcc.test-framework/dg-do-assemble-exp-P.c (test for excess errors) (PRMS 42)
fail FAIL: gcc.test-framework/dg-do-compile-exp-P.c (test for excess errors) (PRMS 42)
fail FAIL: gcc.test-framework/dg-do-link-exp-P.c (test for excess errors) (PRMS 42)
fail FAIL: gcc.test-framework/dg-do-run-exp-P.c (test for excess errors) (PRMS 42)
fail FAIL: gcc.test-framework/dg-dot-run-exp-P.c (test for excess errors) (PRMS 42)
fail FAIL: gcc.test-framework/dg-dox-run-exp-XF.c (test for excess errors) (PRMS 42)
fail FAIL: gcc.test-framework/dg-output-exp-P.c (test for excess errors) (PRMS 42)
fail FAIL: gcc.test-framework/dg-output-exp-XF.c (test for excess errors) (PRMS 42)
fail FAIL: gcc.test-framework/dg-warning-exp-P.c warning test (test for warnings, line 9) (PRMS 42)
=== Test Framework Summary ===
# of expected passes 68
# of unexpected failures 21
| https://gcc.gnu.org/legacy-ml/gcc-testresults/2018-10/msg02062.html |
Selected Papers of Wang Yuan
Selected Papers of Wang Yuan
https://doi.org/10.1142/5774 | June 2005
Pages: 512
Edited By:
Wang Yuan ( Chinese Academy of Sciences, China )
ISBN: 978-981-256-197-8 (hardcover) SGD 297.00 Add to cart
ISBN: 978-981-4480-79-6 (ebook) SGD 119.00 Add to cart
Description
Description
Chapters
This volume presents a comprehensive collection of Wang Yuan's original important papers which are not available elsewhere, since the majority of the papers were published in China.
Covering both pure number theory and applied mathematics, this book is important for understanding Wang Yuan's academic career and also the development of Chinese mathematics in recent years, since Wang Yuan's work has a wide-ranging influence in China.
Wang Yuan is a professor and academician of the Chinese Academy of Sciences. He received his honorable Doctorship from Hong Kong Baptist University. He has published 70 papers and ten books.
Sample Chapter(s)Chapter 1: On the Representation of Large Even Integer as a Sum of a Product of at Most 3 Primes and a Product of at Most 4 Primes (308 KB)
Contents:
Number Theory:
On Sieve Methods and Some of Their Applications
On the Estimation of Character Sum and Its Applications
Diophantine Inequalities for Forms in and Algebraic Number Field
Small Solutions of Congruences
Numerical Analysis and Statistics:
A Note on Interpolation of a Certain Class of Functions
On Numerical Integration of Periodic Functions of Several Variables
A Note on Uniform Distribution and Experimental Design
Number Theoretic Method in Applied Statistics
Uniform Design of Experiments with Mixtures
and other papers
Readership:
Researchers, teachers and graduate students in number theory, numerical analysis and statistics.
FRONT MATTER
Pages: i–xxii
https://doi.org/10.1142/9789812701190_fmatter
Abstract
PDF/EPUB
The following sections are included:
PREFACE
CONTENTS
WANG YUAN: A BRIEF OUTLINE OF HIS LIFE AND WORKS
Number Theory
ON THE REPRESENTATION OF LARGE EVEN INTEGER AS A SUM OF A PRODUCT OF AT MOST 3 PRIMES AND A PRODUCT OF AT MOST 4 PRIMES
WANG YUAN
Pages: 1–15
https://doi.org/10.1142/9789812701190_0001
Abstract
PDF/EPUB
The following sections are included:
Introduction
Some Computations
Theorem A
Applications of Theorem A
Two Iteration Theorems
Proofs of Theorems
References
ON SOME PROPERTIES OP INTEGRAL VALUED POLYNOMIALS
WANG YUAN
Pages: 16–24
https://doi.org/10.1142/9789812701190_0002
Abstract
Let F(x)be an irreducible integral valued polynomial of degree kwithout any fixed prime divisor. Let π(N; F(x))be the number of primes represented by F(x)for 1 ≤ x ≤ N…
ON SIEVE METHODS AND SOME OF THE RELATED PROBLEMS
WANG YUAN
Pages: 25–28
https://doi.org/10.1142/9789812701190_0003
Abstract
First of all, let us state the grand Riemann hypothesis as follows:
(R)The real parts of all zeros of all the Dirichlet's L-functions L (s, χ)are…
ON SIEVE METHODS AND SOME OF THEIR APPLICATIONS
WANG YUAN
Pages: 29–33
https://doi.org/10.1142/9789812701190_0004
Abstract
In 1919, V. Brun [1]first proved the following result:
For sufficiently large x, there exists, between x – x ½and x, an integer of at most 11 primes factors…
ON THE REPRESENTATION OF LARGE EVEN NUMBER AS A SUM OF TWO ALMOST-PRIMES
WANG YUAN
Pages: 34–38
https://doi.org/10.1142/9789812701190_0005
For the sake of briefness, we write the following proposition by ( a, b)…
A note on some properties of the functions φ(n) , σ(n) and θ(n)
A. SCHINZEI and
Y. WANG
Pages: 39–52
https://doi.org/10.1142/9789812701190_0006
The following sections are included:
Introduction
An auxiliary theorem
Some lemmas
Estimation of R
Estimation of E
Proof of lemma 2
Theorems on the functions φ and σ
Theorems on the function θ
References
No Access
A NOTE ON SOME PROPERTIES OF THE ARITHMETICAL FUNCTIONS φ(n) , σ(n) And d(n)
WANG YUAN
Pages: 53–65
https://doi.org/10.1142/9789812701190_0007
Abstract
PDF/EPUB
Preview Abstract
The following sections are included:
Introduction
The Proof of Fundamental Lemma
Brun's Sieve Method
Several Lemmas
The Proof of Lemma 2
Applications of Fundamental Lemma
References
No Access
ON SIEVE METHODS AND SOME OF THEIR APPLICATIONS
YUAN WANG
Pages: 66–90
https://doi.org/10.1142/9789812701190_0008
Abstract
PDF/EPUB
Preview Abstract
The following sections are included:
Introduction
Computations
Theorem A
Applications of Theorem A
Theorem B
Theorem C
The Proof of the Main Results
Other Applications
References
No Access
ON SIEVE METHODS AND SOME OF THEIR APPLICATIONS
YUAN WANG
Pages: 91–108
https://doi.org/10.1142/9789812701190_0009
Abstract
PDF/EPUB
Preview Abstract
The following sections are included:
Statement of Results
Several Lemmas
Theorem A
The Estimation of the Upper Bound of P ω (x, ξ)
The Estimation of the Lower Bound of P ω (x, ξ)
Two Theorems
The Set and Some of Its Properties
The Proof of the Main Theorems
References
No Access
ON THE LEAST PRIMITIVE ROOT OF A PRIME
YUAN WANG
Pages: 109–122
https://doi.org/10.1142/9789812701190_0010
Abstract
PDF/EPUB
Preview Abstract
The following sections are included:
Introduction
Character Sum (I)
Character Sum (II)
Sieve Method of Brun
Proof of Theorem 1
Proof of Theorem 2
References
No Access
ON THE REPRESENTATION OF LARGE INTEGER AS A SUM OF A PRIME AND AN ALMOST PRIME
YUAN WANG
Pages: 123–144
https://doi.org/10.1142/9789812701190_0011
Abstract
PDF/EPUB
Preview Abstract
In this paper, we shall give the detailed proofs of certain results obtained upon assuming the truth of the grand Riemann hypothesis. (Cf. [1], [2])…
No Access
ON THE ESTIMATION OF CHARACTER SUM AND ITS APPLICATIONS
YUAN WANG
Pages: 145–152
https://doi.org/10.1142/9789812701190_0012
Abstract
PDF/EPUB
The following sections are included:
Introduction
Proof of Theorem 1
Proof of Theorem 2
Conditional Result
References
No Access
ON THE MAXIMAL NUMBER OF PAIRWISE ORTHOGONAL LATIN SQUARE OF ORDER s (APPLICATION OF SIEVE METHOD)
YUAN WANG
Pages: 153–167
https://doi.org/10.1142/9789812701190_0013
Abstract
PDF/EPUB
The following sections are included:
Introduction
N(s) and Sieve Methods
A Recurrent Formula
Estimation of P ω (x, q; ξ)
Estimation of P ω (x; ξ, η)
Proof of Main Theorem
References
ON THE REPRESENTATION OF EVERY LARGE EVEN INTEGER AS A SUM OF A PRIME AND AN ALMOST PRIME
PAN CHENG-DONG ,
XIA-XI DING , and
WANG YUÁN
Pages: 168–179
https://doi.org/10.1142/9789812701190_0014
Abstract
PDF/EPUB
In this paper, we give a modified proof of Chen's theorem “every sufficiently large even integer is a sum of a prime and a product of at most 2 primes”…
REMARKS ON A THEOREM OF DAVENPORT
YUAN WANG
Pages: 180–184
https://doi.org/10.1142/9789812701190_0015
Abstract
PDF/EPUB
We use x, a, c to denote the n-dimensional real vectors,
the modulus of x, and Λ an
n
-dimensional lattice, i.e. a set formed by the vectors
where
a 1 , …,a n
are a given linearly independent vectors in
n
-dimensional Euclidean space and
u 1 , …,u n
are any integers.
{a 1 ,…,a n }
is called a basis of Λ…
ON ЛиHHи'S METHOD CONCERNING THE GOLDBACH NUMBER
YUAN WANG
Pages: 185–199
https://doi.org/10.1142/9789812701190_0016
Abstract
PDF/EPUB
Preview Abstract
In this paper, some conditional results concerning the Goldbach number are proved. For example, assuming that the density hypothesis of ζ(s)is true, the inequalityalways has solutions; here ε is any pre-assigned positive number and p, p′are primes. It seems that there is a gap in ЛиHHи's original proof of the similar theorem.
REMARKS CONCERNING A TRANSFERENCE THEOREM OF LINEAR FORMS
YUAN WANG ,
KUN-RUI YU , and
YAO-CHENG ZHU
Pages: 200–204
https://doi.org/10.1142/9789812701190_0017
Abstract
PDF/EPUB
Let n ≥ 2and θ 1 , …, θ nbe a set of real numbers such that 1, θ 1 , …, θ nare linearly independent over rational number field ℚ. For a real number x, let
We use ε to denote a preassigned positive number and c 1, c 2the positive constants depending only on ε, n, θ 1 ,…,θ n.
A NOTE ON A TRANSFERENCE THEOREM OF LINEAR FORMS
WOLFGANG M. SCHMIDT and
YUAN WANG
Pages: 205–209
https://doi.org/10.1142/9789812701190_0018
Abstract
PDF/EPUB
In this paper, a transference theorem of linear forms in diophantine approximation is proved. The proof of the theorem depends on a theorem of Mahler.
A NOTE ON SOME METRICAL THEOREMS IN DIOPHANTINE APPROXIMATION
YUAN WANG and
KUNRUI YU
Pages: 210–221
https://doi.org/10.1142/9789812701190_0019
Abstract
The following sections are included:
Introduction
Proof of Theorem 1
Proof of Theorem 2
References
No Access
Bounds for solutions of additive equations in an algebraic number field I
YUAN WANG
Pages: 222–249
https://doi.org/10.1142/9789812701190_0020
Abstract
The following sections are included:
Introduction
Several lemmas
Reductions
Continuation
Weyl's inequality
Schmidt's lemma
The circle method
Supplementary domain
Basic domain
Continuation
The singular integral
The proof of theorem
References
No Access
Bounds for solutions of additive equations in an algebraic number field II
YUAN WANG
Pages: 250–266
https://doi.org/10.1142/9789812701190_0021
Abstract
PDF/EPUB
The following sections are included:
Introduction
Reductions
The circle method
Supplementary domain
Basic domain
Singular integral
The proof of the theorem
References
No Access
Diophantine Inequalities for Forms in an Algebraic Number Field
YUAN WANG
Pages: 267–287
https://doi.org/10.1142/9789812701190_0022
Abstract
PDF/EPUB
The following sections are included:
Introduction
Additive Forms
Analytic Method
The Proof of Proposition 2
The Proof of Theorem 1
Acknowledgment
References
No Access
ON HOMOGENEOUS ADDITIVE CONGRUENCES
YUAN WANG
Pages: 288–300
https://doi.org/10.1142/9789812701190_0023
Abstract
In this paper, the additive equations of the typeare studied,being integers of an algebraic number field Kof degree n. The main result is as follows: If s ⩾ (2k) n + 1(or s ⩾ cknlogkfor 2 + k), the equation is solved nontrivially in any-adic field, whereis a prime ideal of K.
Small Solutions of Congruences
YUAN WANG
Pages: 301–320
https://doi.org/10.1142/9789812701190_0024
Abstract
Let Q j (λ) = Q j (λ 1 , …,λ s ) (1 ⩽ j ⩽ h)be a system of quadratic forms with coefficients in integers of an algebraic number field Kof degree n, and let a be an integral ideal of K. The purpose of the paper is to prove that the system of congruences Q j (λ) ≡ 0 (mod a) (1 ⩽ j ⩽ h)has a nonzero solution λ satisfyingprovided that s ⩾ c(h,n,ɛ). This improves a result of T. Cochrane (1987, Illinois J. Math.31, 618–625) and also gives a generalisation of a result of R. C. Baker (1980, Mathematika27, 30–45). The small solutions of additive congruences are also considered.
On Small Zeros of Quadratic Forms over Finite Fields (II)
Yuan Wang
Pages: 321–328
https://doi.org/10.1142/9789812701190_0025
Abstract
Letbe a quadratic form with integer coefficients and let pdenote a prime. Cochrane [1]proved that if n ≥ 4thenhas a solutionsatisfying, where. The aim of the present paper is to generalize the above result to finite fields.
Numerical Analysis and Statistics
Remarks Concerning Numerical Integration
LOO-KENG HUA and
YUAN WANG
Pages: 329–332
https://doi.org/10.1142/9789812701190_0026
Abstract
A NOTE ON INTERPOLATION OF A CERTAIN CLASS OF FUNCTIONS
YUAN WANG
Pages: 333–337
https://doi.org/10.1142/9789812701190_0027
Abstract
On Diophantine Approximations and Numerical Integrations (I)
Pages: 338–339
https://doi.org/10.1142/9789812701190_0028
On Diophantine Approximations and Numerical Integrations (II)
Loo Keng Hua and
Yuan Wang
Pages: 340–341
https://doi.org/10.1142/9789812701190_0029
Abstract
ON NUMERICAL INTEGRATION OF PERIODIC FUNCTIONS OF SEVERAL VARIABLES
HUA LOO KENG and
YUAN WANG
Pages: 342–356
By means of the algebraic theory of numbers the authors suggest a method for evaluating multiple integrals. A numerical example of eleven dimensions shows the advantage of the present method.
ON INTERPOLATION OF A CERTAIN CLASS OF FUNCTIONS
YUAN WANG
Pages: 357–360
https://doi.org/10.1142/9789812701190_0031
ON UNIFORM DISTRIBUTION AND NUMERICAL ANALYSIS (I): NUMBER-THEORETIC METHOD
LOO-KENG HUA and
YUAN WANG
Pages: 361–383
https://doi.org/10.1142/9789812701190_0032
ON UNIFORM DISTRIBUTION AND NUMERICAL ANALYSIS (II) (NUMBER-THEORETIC METHOD)
LOO-KENG HUA and
YUAN WANG
Pages: 384–401
https://doi.org/10.1142/9789812701190_0033
Abstract
In this paper, we shall give some applications of the sequences of sets defined in a previous paper to the problems of numerical integration, interpolation, and the approximate solution of Fredholm integral equation of the second type. We have studied in addition the well-known sequences of sets introduced by Kopoób.
ON UNIFORM DISTRIBUTION AND NUMERICAL ANALYSIS (III): NUMBER-THEORETIC METHOD
LOO-KENG HUA and
YUAN WANG
Pages: 402–416
https://doi.org/10.1142/9789812701190_0034
Abstract
We present in this paper, a study of the uniformly distributed sequences of sets defined by elementary symmetric functions of roots of f(x) = 0, where f(x)is the minimal polynomial of a Pisot-Vijayaraghavan number (cf. Jacobi-Perron algorithm). We obtain the estimations of their discrepancies and then apply them to the problem of numerical integration. For practical purposes, two suggestions concerning the polynomials f(x)are given.
A NOTE ON UNIFORM DISTRIBUTION AND EXPERIMENTAL DESIGN
YUAN WANG and
Pages: 417–421
https://doi.org/10.1142/9789812701190_0035
Abstract
PDF/EPUB
The following sections are included:
Introduction
Methods
Uniform Distribution
Tables
References
On Diophantine Approximation and Approximate Analysis (I)
Yuan Wang
Pages: 422–430
https://doi.org/10.1142/9789812701190_0036
Abstract
The following sections are included:
Introduction
The Proof of Theorem 1
The Proof of Theorem 2
References
ON DIOPHANTINE APPROXIMATION AND APPROXIMATE ANALYSIS (II)
Yuan Wang
Pages: 431–440
https://doi.org/10.1142/9789812701190_0037
Abstract
PDF/EPUB
The following sections are included:
Introduction
The Proof of Theorem 1
The Case α = 2
The numerical integration over
The error term of quadrature formula
Several conjectures
References
NUMBER THEORETIC METHOD IN APPLIED STATISTICS
WANG YUAN and
KAITAI FANG
https://doi.org/10.1142/9789812701190_0038
Abstract
This paper gives some applications of number-theoretic method (or quasi Monte Carlo method) for numerical evaluation of probabilities and moments of a continuous multivariate distribution over a special domain such as cube, ball, sphere, simplex:, etc., where the uniformly distributed sets of points in such domains, which are useful in experimental design, simulation, geometry probability, etc., are suggested. Some applications of number theoretic method in optimization are discussed also.
NUMBER THEORETIC METHODS IN APPLIED STATISTICS (II)
YUAN WANG and
KAITAI FANG
Pages: 456–467
https://doi.org/10.1142/9789812701190_0039
Abstract
In this paper, the authors give some applications of F-uniformly distributed sequences, which are suggested in their previous paper under the same title, in experimental design, experiments with mixtures, geometric probability and simulation.
Uniform design of experiments with mixtures
Yuan Wang and
Kaitai Fang
Pages: 468–479
https://doi.org/10.1142/9789812701190_0040
Preview Abstract
Consider a design of experiments with mixtures: 0 ⩽ a i < x i < b i ⩽ 1, 1 ⩽ i ⩽ s, x 1 + ⋯ + x s = 1, where a i, b i, 1 ⩽ i ⩽ sare given constants. A method is proposed to treat this model by the theory of uniform distribution in number theory.
BACK MATTER
Pages: 481–486
https://doi.org/10.1142/9789812701190_bmatter
Abstract
PDF/EPUB
The following sections are included:
LIST OF PUBLICATIONS BY WANG YUAN
“This volume forms a nice tribute to one of the significant figures of Chinese number theory.”
Mathematical Reviews
Sample Chapter(s)Chapter 1: On the Representation of Large Even Integer as a Sum of a Product of at Most 3 Primes and a Product of at Most 4 Primes (308k)
| https://www.worldscientific.com/worldscibooks/10.1142/5774 |
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17/020-11:38:00.419 ON ON ON ON ON ON ON ON ON ON ON ON ON ON ON ON ON ON ON ON 0 0.0000 73 0.1781
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| https://lasp.colorado.edu/maven/sdc/public/data/sites/site-20180112T004616/anc/eng/sasm2/sci_anc_sasm217_018_021.drf |
Hypoxia-Inducible Factor-1α in Pulmonary Arterial Smooth Muscle Cells and Hypoxia-induced Pulmonary Hypertension | American Journal of Respiratory and Critical Care Medicine
Hypoxia-Inducible Factor-1α in Pulmonary Arterial Smooth Muscle Cells and Hypoxia-induced Pulmonary Hypertension
Kimberly A. Smith 1 x Kimberly A. Smith Search for articles by this author, and Jason X.-J. Yuan 1 x Jason X.-J. Yuan Search for articles by this author, + Author Affiliations 1Department of MedicineUniversity of Illinois at ChicagoChicago, Illinois
https://doi.org/10.1164/rccm.201312-2148ED PubMed: 24484328
<here is a image 18f6ba2c1b48c750-925436495f39506c Comments>
Full Text
It is imperative that organisms sense and respond to changes in oxygen concentration for their survival. Hypoxia-inducible factor-1 (HIF-1) is the highly conserved global master regulator of oxygen homeostasis, and genes regulated at the transcriptional level by HIF-1 are involved in a multitude of processes, including angiogenesis, vascular reactivity and remodeling, vasomotor control, glucose and energy metabolism, erythropoiesis, and cell proliferation and viability (1). In the lung, elevated levels of HIF-1 are associated with poor prognosis for lung cancer (2), and stabilization of HIF-1 by hypoxia-induced reactive oxygen species derived from mitochondria has been shown to contribute to pulmonary fibrosis in patients with acute lung injury (3–5).
Chronic exposure to alveolar hypoxia results in sustained pulmonary vasoconstriction and pulmonary vascular remodeling leading to the development and progression of hypoxia-induced pulmonary hypertension (HPH). Patients with a variety of chronic lung diseases, such as chronic obstructive pulmonary disease, cystic fibrosis, bronchopulmonary dysplasia, and idiopathic pulmonary fibrosis, as well as residents living at high altitude experience persistent alveolar hypoxia. This leads to pulmonary hypertension, for which there are few clinical treatments available. Patients may eventually develop right ventricular hypertrophy leading to right heart failure and death. Therefore, understanding the molecular mechanisms underlying the development of HPH is critical for the improvement of therapeutic strategies.
In this issue of the
Journal
, Ball and colleagues (pp.
314–324
) demonstrate the role of HIF-1α in the development of HPH using a smooth muscle–specific conditional HIF-1α knockout (HIF-1α-SMM-Cre) mouse (
6
). The authors identify two important concepts in this study. First, Ball and colleagues show that the right ventricular systolic pressure (RVSP) in HIF-1α-SMM-Cre mice exposed to hypoxia is significantly less than the RVSP in the hypoxic control mice. These results demonstrate that HIF-1α in the pulmonary arterial smooth muscle cells (PASMC) contributes to increased RVSP and pulmonary vascular remodeling induced by chronic hypoxia. This is consistent with previous studies using
HIF-1α
+/−
mice that demonstrate that HIF-1α deficiency significantly delays the development of pulmonary vascular remodeling, pulmonary hypertension, and right ventricular failure in
HIF-1α
+/−
mice exposed to chronic hypoxia in comparison to wild-type littermates (
7
,
8
). The authors indicate that the attenuation of pulmonary hypertension may be due to decreased pulmonary vasoconstriction in response to hypoxia in the HIF-1α-SMM-Cre mice. In PASMC, HIF-1α is required for increased cell capacitance, membrane depolarization, decreased K
+
current density, enhanced store-operated Ca
2+
entry, up-regulated canonical transient receptor potential 1 (TRPC1) and TRPC6 expression, and augmented Na
+
/H
+
exchanger expression in response to chronic hypoxia (
7
,
9
,
10
). A rise in cytosolic free Ca
2+
concentration ([Ca
2+
]
cyt
) in PASMC is a major trigger for pulmonary vasoconstriction and an important stimulus for PASMC proliferation and migration, which contribute to pulmonary vascular remodeling. One possible explanation is that in hypoxia, HIF-1α causes membrane depolarization and up-regulates Ca
2+
channel expression leading to increased pulmonary vascular remodeling (
Figure 1
). Whereas previous studies have used mouse models to demonstrate a general role for (or an association of ) HIF-1α, the current study identifies that HIF-1α is specifically required in PASMC for the development of HPH.
<here is a image 411f717c3469cb8d-01190e957e5f9020>
Figure 1.Proposed role of hypoxia-induced hypoxia-inducible factor-1α (HIF-1α) in pulmonary hypertension and right heart failure. Hypoxia causes increased expression of HIF-1α in pulmonary arterial smooth muscle cells (PASMC), which results in increased expression of canonical transient receptor potential 6 (TRPC6), increased cytoplasmic free Ca 2+concentration ([Ca 2+] cyt), and PASMC proliferation. Increased PASMC proliferation contributes to pulmonary vascular remodeling, increased pulmonary vascular resistance, and increased afterload on the right ventricle. In cardiomyocytes, the hypoxia-induced increase in HIF-1α may be a direct effect or due to coronary vascular dysfunction or reactive oxygen species. Increased expression of HIF-1α in cardiomyocytes results in increased expression of TRPC6, increased [Ca 2+] cyt, and cardiomyocyte hypertrophy. Increased afterload and cardiomyocyte hypertrophy lead to right ventricular hypertrophy and right heart failure.
The second important finding of this study is that although deletion of HIF-1α in SMC attenuates the hypoxia-induced increase in RVSP, it does not attenuate right ventricular remodeling in response to chronic hypoxia. This finding is important and suggests that something other than pressure overload contributes to right ventricular remodeling in HPH. These data are consistent with a previous report demonstrating that increased pulmonary arterial pressure is insufficient to explain right heart failure (11). It is likely that, in addition to its many known effects, HIF-1α has a direct role in the response of cardiomyocytes to hypoxia ( Figure 1). Overexpression of HIF-1α specifically in cardiomyocytes results in cardiomyopathy with contractile dysfunction resulting from reduced expression of the sarco(endo)plasmic reticulum Ca 2+-ATPase (12). Additionally, hypoxia induces increased TRPC6 expression in cardiomyocytes via HIF-1α, and increased TRPC6 expression contributes to pathogenic cardiac remodeling (13,14). There are several studies that suggest HIF-1α has cardioprotective effects in ischemic preconditioning, where exposure of the heart to short periods of ischemia and reperfusion increases HIF-1α and protects against further damage upon exposure to longer episodes of ischemic stress (15). However, studies using constitutive expression of HIF-1α in the heart suggest that the metabolic preconditioning induced by increased HIF-1α via increasing gene expression and glucose metabolism is beneficial initially; however, sustained HIF-1α expression may contribute to heart failure (16).
The current study by Ball and colleagues highlights the role of HIF-1α in PASMC in the development of HPH, and reveals that in HPH, increased pulmonary arterial pressure does not necessarily correlate with right ventricular remodeling. It would be interesting to determine if a similar concept can be applied to other forms of pulmonary hypertension, such as idiopathic pulmonary hypertension, where the initial trigger is unknown. Additionally, more studies are needed to determine the multiple molecular mechanisms by which hypoxia affects cardiomyocytes and cardiac function. The effect of hypoxia on cardiomyocytes may be direct, or it may be the result of coronary vascular dysfunction due to increased HIF-1α in the coronary arteries or the result of increased reactive oxygen species in the cardiomyocytes. This study indicates that hypoxia-induced factors other than increased afterload due to pulmonary vascular remodeling contribute to cardiac remodeling (e.g. TRPC6 and/or other HIF-1α sensitive proteins). Therefore, more studies are needed to provide a better understanding of the effects of hypoxia on cardiac remodeling in order to develop cardiac-specific therapies for the treatment of HPH.
References
Section:
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| https://www.atsjournals.org/doi/10.1164/rccm.201312-2148ED |
Continuous infusion versus intermittent administration of meropenem in critically ill patients (MERCY): A multicenter randomized double-blind trial. Rationale and design
Download Citation | Continuous infusion versus intermittent administration of meropenem in critically ill patients (MERCY): A multicenter randomized double-blind trial. Rationale and design | Objective Meropenem is a β-lactam, carbapenem antibacterial agent with antimicrobial activity against gram-negative, gram-positive and anaerobic... | Find, read and cite all the research you need on ResearchGate
Article
Continuous infusion versus intermittent administration of meropenem in critically ill patients (MERCY): A multicenter randomized double-blind trial. Rationale and design
March 2021
Contemporary Clinical Trials104(4):106346
DOI: 10.1016/j.cct.2021.106346
Authors:
<here is a image f2f62089ad6ff61c-d19572ff1996375a>
Giacomo Monti
Giacomo Monti
<here is a image f2f62089ad6ff61c-d19572ff1996375a>
Carola Galbiati
Carola Galbiati
Fabio Toffoletto
Maria Grazia Calabrò
Abstract
Objective
Meropenem is a β-lactam, carbapenem antibacterial agent with antimicrobial activity against gram-negative, gram-positive and anaerobic micro-organisms and is important in the empirical treatment of serious infections in Intensive Care Unit (ICU) patients. Multi-drug resistant gram-negative organisms, coupled with scarcity of new antibiotic classes, forced healthcare community to optimize the therapeutic potential of available antibiotics. Our aim is to investigate the effect of continuous infusion of meropenem against bolus administration, as indicated by a composite outcome of reducing death and emergence of extensive or pan drug-resistant pathogens in a population of ICU patients.
Design
Double blind, double dummy, multicenter randomized controlled trial (1:1 allocation ratio).
Setting
Tertiary and University hospitals.
Interventions
600 ICU patients with sepsis or septic shock, needing by clinical judgment antibiotic therapy with meropenem, will be randomized to receive a continuous infusion of meropenem 3 g/24 h or an equal dose divided into three daily boluses (i.e. 1g q8h).
Measurements
The primary endpoint will be a composite outcome of reducing death and emergence of extensive or pan drug-resistant pathogens. Secondary endpoints will be death from any cause at day 90, antibiotic-free days at day 28, ICU-free days at day 28, cumulative SOFA-free (Sequential Organ Failure Assessment) score from randomization to day 28 and the two, separate, components of the primary endpoint. We expect a primary outcome reduction from 52 to 40% in the continuous infusion group.
Conclusions
The trial will provide evidence for choosing intermittent or continuous infusion of meropenem for critically ill patients with multi-drug resistant gram-negative infections.
<here is a image 175d1bd4b7439d95-754927124da715c1>
... The trial protocol appears in Supplement 1 and was approved by the ethics committees of all participating centers. Details of the trial methods were published together with the statistical analysis plan
20
(appears in Supplement 2). Additional information appears in the eMethods in Supplement 3. ...
... Based on published literature, [30][31][32][33] we hypothesized the primary outcome (composite outcome of all-cause mortality and emergence of new pandrug-resistant or extensively drugresistant bacteria at day 28) would occur in 52% of patients in the intermittent administration group and that the continuous administration of meropenem would lead to an absolute risk reduction of 12% (40% of patients would have composite outcome in continuous administration group).
20
We estimated that a sample size of 300 patients per group would achieve greater than 80% power to detect such a difference at an α level of .05. An independent data and safety monitoring board oversaw and reviewed the results of 3 planned interim analyses after 150, 300, and 450 patients had completed 28-day follow-up for the primary outcome. ...
Continuous vs Intermittent Meropenem Administration in Critically Ill Patients With Sepsis The MERCY Randomized Clinical Trial
Article
Jun 2023
J Am Med Assoc
Giacomo Monti
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Nikola Bradic
Matteo Marzaroli
Alberto Zangrillo
Importance:
Meropenem is a widely prescribed β-lactam antibiotic. Meropenem exhibits maximum pharmacodynamic efficacy when given by continuous infusion to deliver constant drug levels above the minimal inhibitory concentration. Compared with intermittent administration, continuous administration of meropenem may improve clinical outcomes.
Objective:
To determine whether continuous administration of meropenem reduces a composite of mortality and emergence of pandrug-resistant or extensively drug-resistant bacteria compared with intermittent administration in critically ill patients with sepsis.
Design, setting, and participants:
A double-blind, randomized clinical trial enrolling critically ill patients with sepsis or septic shock who had been prescribed meropenem by their treating clinicians at 31 intensive care units of 26 hospitals in 4 countries (Croatia, Italy, Kazakhstan, and Russia). Patients were enrolled between June 5, 2018, and August 9, 2022, and the final 90-day follow-up was completed in November 2022.
Interventions:
Patients were randomized to receive an equal dose of the antibiotic meropenem by either continuous administration (n = 303) or intermittent administration (n = 304).
Main outcomes and measures:
The primary outcome was a composite of all-cause mortality and emergence of pandrug-resistant or extensively drug-resistant bacteria at day 28. There were 4 secondary outcomes, including days alive and free from antibiotics at day 28, days alive and free from the intensive care unit at day 28, and all-cause mortality at day 90. Seizures, allergic reactions, and mortality were recorded as adverse events.
Results:
All 607 patients (mean age, 64 [SD, 15] years; 203 were women [33%]) were included in the measurement of the 28-day primary outcome and completed the 90-day mortality follow-up. The majority (369 patients, 61%) had septic shock. The median time from hospital admission to randomization was 9 days (IQR, 3-17 days) and the median duration of meropenem therapy was 11 days (IQR, 6-17 days). Only 1 crossover event was recorded. The primary outcome occurred in 142 patients (47%) in the continuous administration group and in 149 patients (49%) in the intermittent administration group (relative risk, 0.96 [95% CI, 0.81-1.13], P = .60). Of the 4 secondary outcomes, none was statistically significant. No adverse events of seizures or allergic reactions related to the study drug were reported. At 90 days, mortality was 42% both in the continuous administration group (127 of 303 patients) and in the intermittent administration group (127 of 304 patients).
Conclusions and relevance:
In critically ill patients with sepsis, compared with intermittent administration, the continuous administration of meropenem did not improve the composite outcome of mortality and emergence of pandrug-resistant or extensively drug-resistant bacteria at day 28.
Trial registration:
ClinicalTrials.gov Identifier: NCT03452839.
... Two large multicentre randomised controlled trials (RCTs) comparing prolonged versus intermittent infusion of beta-lactam antibiotics in critically ill patients with sepsis or septic shock are due to be published in 2023: (1) the Beta-Lactam InfusioN Group (BLING) III Study, which aims to recruit 7000 ICU patients across Australia, Belgium, France, Malaysia, New Zealand, Sweden and the United Kingdom (40), and (2) the continuous infusion versus intermittent administration of MERopenem in criticallY ill patients (MERCY) Study, which aims to recruit 300 ICU patients across Croatia and Italy
(41)
. To provide context for clinicians to interpret the results of these studies in light of the larger body of evidence, we plan to perform a systematic review and meta-analysis to assess whether in critically ill patients with sepsis or septic shock, a prolonged infusion of beta-lactam antibiotic compared to standard intermittent bolus dosing is associated with reduced 90-day all-cause mortality, as well as assessing the effect on other prespecified secondary outcomes. ...
Prolonged infusion versus intermittent infusion dosing of beta-lactam antibiotics in critically ill patients with sepsis: a protocol for a systematic review and meta-analysis of randomised controlled trials
Preprint
Full-text available
May 2023
<here is a image e47d48b90c16b2a6-c5c7e8a6502cb04e> Mohd-Hafiz Abdul-Aziz
Naomi E. Hammond
Stephen J Brett
<here is a image 2ea173d4b9cd4d32-18895e1ccf22cabe> Jason Roberts
Introduction
In vitro and in vivo pharmacokinetic/pharmacodynamic data describe improved activity of beta-lactam antibiotics when administered by prolonged infusion compared with standard intermittent infusion. There remains insufficient robust clinical trial data to support a widespread practice change. Patients with sepsis and septic shock are a population in whom prolonged infusion of beta-lactam antibiotics may improve survival. Two large multicentre randomised controlled trials (RCTs) comparing prolonged versus intermittent infusion of beta-lactam antibiotics in critically ill patients with sepsis or septic shock are due for completion in 2023. With existing RCT evidence, this systematic review and meta-analysis will include these new data to measure the clinical benefits of prolonged beta-lactam infusion in critically ill patients with sepsis.
Methods and analysis
This protocol has been prepared according to the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA) statement. This systematic review and meta-analysis will include RCTs that compare prolonged infusion with intermittent infusion of beta-lactam antibiotics in critically ill adult patients with sepsis. Medline (via PubMed), CINAHL, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), and other clinical trials registries will be searched to identify eligible RCTs for review. Two reviewers will perform the study selection and extraction processes with disagreements resolved by discussion or referral to a third reviewer if needed. The Cochrane Collaborations Risk-of-Bias Tool for Randomised Trials version 2 (RoB 2) will be used to evaluate the quality of included studies. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach will be used to evaluate the overall quality of evidence for each outcome measures The a priori primary outcome is all-cause 90-day mortality. Secondary outcomes include intensive care unit (ICU) mortality, ICU length of stay, clinical cure, microbiological cure, and the development of adverse events. Bayesian random-effects meta-analyses will be conducted, with frequentist analyses planned for sensitivity analysis.
Ethics and dissemination
Human research ethics approval is not required as the study involves the use of existing collections of data that are de-identified. It is expected that findings will be presented at national and international intensive care and infectious diseases meetings, and will be submitted to a peer-reviewed journal for publication.
PROSPERO Registration Number: CRD42023399434
... Furthermore, high inter-individual variability of the pharmacokinetic (PK) pro le of beta-lactams and cipro oxacin has been reported in critically ill patients (13,14). These arguments have led to an increasing number of studies aiming at improving the e cacy of beta-lactams and cipro oxacin for ICU patients (15)(16)
(17)
. ...
Barriers And Facilitators For Therapeutic Drug Monitoring Of Beta-Lactams And Ciprofloxacin In The ICU: A Nationwide Cross-Sectional Study
Preprint
Full-text available
Dec 2021
<here is a image 0a1af89eeafb2d9c-c6c2dcf2ad9f9b0d> Tim Ewoldt
<here is a image abbdb578c9f4a720-65726f14009079c7> Alan Abdulla
Puck van den Broek
<here is a image 1bae59d0c034b199-27dcda14f80dc0cd> Birgit C P Koch
Background: Recent studies demonstrated that failure of achieving pharmacodynamic targets of commonly used antibiotics is common in critically ill patients. Therapeutic drug monitoring (TDM) can contribute to optimize the exposure of beta-lactams and ciprofloxacin. While evidence for TDM of these antibiotics is growing, translation into clinical implementation remains limited. Therefore, perceived barriers and facilitators are important for implementing TDM in this population. The primary aim of this study was to identify healthcare professionals’ barriers and facilitators for the implementation of TDM of beta-lactams and ciprofloxacin in Dutch intensive care units (ICU).
Methods: We conducted a nationwide cross-sectional online survey among healthcare professionals (HCPs) involved in antibiotic treatment of ICU patients. An adapted version of the Measurement Instrument for Determinants of Innovations was sent out. Items were considered barriers when ≥ 20% of participants responded with a negative answer. If ≥ 80% of the participants responded with a positive answer, the item was considered a facilitator.
Results: Sixty-four HCPs completed the survey, of which 14 were from academic hospitals, 25 from general hospitals, and 25 from teaching hospitals. Most participants were hospital pharmacists (59%) or medical specialists (23%). Eleven barriers and four facilitators for implementation of TDM of beta-lactams were identified; 17 barriers for TDM of ciprofloxacin and no facilitators. The most important barriers were a lack of conclusive evidence, organizational support, and low availability of assays. Additional barriers were a lack of consensus on which specific patients to apply TDM and which pharmacodynamic targets to use. Identified facilitators for beta-lactam TDM implementation are low complexity and high task perception, combined with the perception that TDM is important to prevent side effects and to adequate treat infections. Twenty-eight percent of participants reported that flucloxacillin could be analyzed in their hospital. Availability of other beta-lactams and ciprofloxacin varied (3-17%).
Conclusion: Several barriers were identified that could obstruct the implementation of TDM of beta-lactams and ciprofloxacin in the ICU. In particular, education, clear guidelines, and organizational support in particular should be considered when creating tailored implementation strategies. Finally, evidence of beneficial clinical outcomes on TDM of beta-lactams and ciprofloxacin can enhance further implementation.
... Furthermore, high inter-individual variability of the pharmacokinetic [PK) profile of beta-lactams and ciprofloxacin has been reported in critically ill patients [13,14]. These arguments have led to an increasing number of studies aiming at improving the efficacy of betalactams and ciprofloxacin for ICU patients [15][16]
| https://www.researchgate.net/publication/349877686_Continuous_infusion_versus_intermittent_administration_of_meropenem_in_critically_ill_patients_MERCY_A_multicenter_randomized_double-blind_trial_Rationale_and_design |
Series Document — BODC Document 2088223
Series Document — BODC Document 2088223
Metadata Report for BODC Series Reference Number 2088223
Metadata Summary
Data Description Data Category Water sample data Instrument Type Name Categories General Oceanics GO-FLO water sampler discrete water samplers Instrument Mounting lowered unmanned submersible Originating Country United Kingdom Originator Dr Alan Tappin Originating Organization University of Southampton Department of Oceanography (now University of Southampton School of Ocean and Earth Science) Processing Status banked Online delivery of data Download available - Ocean Data View ( ODV ) format Project(s) North Sea Project 1987-1992 Data Identifiers Originator's Identifier CH61_CTD_TMXX_29:2850 BODC Series Reference 2088223 Time Co-ordinates(UT) Start Time (yyyy-mm-dd hh:mm) 1989-10-02 02:34 End Time (yyyy-mm-dd hh:mm) - Nominal Cycle Interval - Spatial Co-ordinates Latitude 53.73378 N ( 53° 44.0' N ) Longitude 0.71634 E ( 0° 43.0' E ) Positional Uncertainty 0.05 to 0.1 n.miles Minimum Sensor or Sampling Depth 9.6 m Maximum Sensor or Sampling Depth 9.6 m Minimum Sensor or Sampling Height 21.6 m Maximum Sensor or Sampling Height 21.6 m Sea Floor Depth 31.2 m Sea Floor Depth Source PEVENT Sensor or Sampling Distribution Unspecified - Sensor or Sampling Depth Datum Unspecified - Sea Floor Depth Datum Unspecified - Parameters BODC CODE Rank Units Title ADEPZZ01 1 Metres Depth (spatial coordinate) relative to water surface in the water body BOTTFLAG 1 Not applicable Sampling process quality flag (BODC C22) CDXXFXD2 1 Nanomoles per litre Concentration of cadmium {Cd CAS 7440-43-9} per unit volume of the water body [dissolved plus reactive particulate <0.4/0.45um phase] by filtration, acidification, chelation, solvent extraction and atomic absorption spectroscopy COXXFXD2 1 Nanomoles per litre Concentration of cobalt {Co CAS 7440-48-4} per unit volume of the water body [dissolved plus reactive particulate <0.4/0.45um phase] by filtration, acidification, chelation, solvent extraction and atomic absorption spectroscopy CUXXFXD2 1 Nanomoles per litre Concentration of copper {Cu CAS 7440-50-8} per unit volume of the water body [dissolved plus reactive particulate <0.4/0.45um phase] by filtration, acidification, chelation, solvent extraction and atomic absorption spectroscopy FEXXFXD2 1 Nanomoles per litre Concentration of total iron {total_Fe CAS 7439-89-6} per unit volume of the water body [dissolved plus reactive particulate <0.4/0.45um phase] by filtration, acidification, chelation, solvent extraction and atomic absorption spectroscopy MNXXFXD2 1 Nanomoles per litre Concentration of total manganese {total_Mn CAS 7439-96-5} per unit volume of the water body [dissolved plus reactive particulate <0.4/0.45um phase] by filtration, acidification, chelation, solvent extraction and atomic absorption spectroscopy NIXXFXD2 1 Nanomoles per litre Concentration of nickel {Ni CAS 7440-02-0} per unit volume of the water body [dissolved plus reactive particulate <0.4/0.45um phase] by filtration, acidification, chelation, solvent extraction and atomic absorption spectroscopy PBXXFXD2 1 Nanomoles per litre Concentration of lead {Pb CAS 7439-92-1} per unit volume of the water body [dissolved plus reactive particulate <0.4/0.45um phase] by filtration, acidification, chelation, solvent extraction and atomic absorption spectroscopy SAMPRFNM 1 Dimensionless Sample reference number ZNXXFXD2 1 Nanomoles per litre Concentration of zinc {Zn CAS 7440-66-6} per unit volume of the water body [dissolved plus reactive particulate <0.4/0.45um phase] by filtration, acidification, chelation, solvent extraction and atomic absorption spectroscopy Definition of BOTTFLAG
Definition of Rank Rank 1 is a one-dimensional parameter Rank 2 is a two-dimensional parameter Rank 0 is a one-dimensional parameter describing the second dimension of a two-dimensional parameter (e.g. bin depths for moored ADCP data)
Problem Reports
No Problem Report Found in the Database
Data Access Policy
Open Data supplied by Natural Environment Research Council (NERC)
You must always use the following attribution statement to acknowledge the source of the information: "Contains data supplied by Natural Environment Research Council."
Narrative Documents
GO-FLO Bottle
A water sampling bottle featuring close-open-close operation. The bottle opens automatically at approximately 10 metres and flushes until closed. Sampling with these bottles avoids contamination at the surface, internal spring contamination, loss of sample on deck and exchange of water from different depths.
There are several sizes available, from 1.7 to 100 litres and are made of PVC with a depth rating of up to 500 m. These bottles can be attached to a rosette or placed on a cable at selected positions.
Dissolved Trace Metals (Cd, Co, Cu, Fe, Mn, Ni, Pb, Zn, Al, Hg) and arsenic species as part of the North Sea Project
Document History
Converted from CDROM documentation
Sampling strategy and methodology
Samples for trace metal analysis were collected, using clean techniques, in 10 litre Teflon-lined Go-Flo bottles, modified to reduce the contamination potential for trace metals, fitted to the CTD rosette sampler. Initial sample handling for trace metals was carried out on board using the facilities of the RVS clean chemistry container (Morley et al., 1988).
Each sea water sample was pressure-filtered (ca. 0.7 bar) in-line through a 0.4 µm Nuclepore membrane filter. The filtrate (samples for dissolved metal analysis) were acidified to ca. pH 2 by the addition of sub-boiled nitric acid (1 ml per litre of sea water) in order to stabilise the total-dissolved concentrations of metals. For a substantial proportion of the samples large volume filtration systems were used to obtain sufficient suspended particulate material for trace metal analysis.
The filters were stored and processed for particulate trace metals. Consequently, the particulate and dissolved trace metal data form an integrated data set from a single set of samples using compatible analytical procedures which greatly enhances their value.
Analysis of Cd, Co, Cu, Fe, Mn, Ni, Pb, Zn
This was undertaken using the specialised clean facilities in the Department of Oceanography, University of Southampton. Dissolved metals were extracted and preconcentrated following the dithiocarbamate complexation-freon extraction method of Danielsson et al. (1978), as modified by Statham (1985) and Tappin (1988), and were determined by graphite furnace atomic absorption spectrophotometry (GFAAS). Within batch analytical precision of the method is generally less than 10% (coefficient of variation) for each metal. More details of the method are given in Tappin et al. (1992).
Quality control (i.e. accuracy and between batch analytical precision) of the data was assessed by regularly analysing aliquots of the CASS-1 coastal sea water reference sample for dissolved trace metals and a bulk filtered acidified sea water sample which was used for batch-to-batch quality control. Results of these analyses were satisfactory, with very few exceptions, and ensure that the data are of high quality.
Additionally, the data set was examined to identify any values which appeared to have been affected by contamination on the basis of supporting data. Only an insignificant fraction of the total data were shown to have been contaminated and rejected.
Analysis of aluminium
An aliquot of the water sample was separately vacuum filtered through a 0.4 µm Nucleopore membrane and analysed for aluminium using the method of Hydes and Liss (1972). The complete analytical procedure was undertaken at sea, usually in the general laboratory.
It should be noted that whilst most samples were collected using the ultra-clean trace metal bottles described above, a few were collected using standard 10 litre Go-Flo bottles. As a general rule if there is aluminium data for a sample but no other trace metals then it should be assumed that a standard bottle was used to collect the sample.
Analysis of arsenic
A separate aliquot of water was filtered, in the clean laboratory, through a 0.45 µm Millipore filter for arsenic analysis. The samples were stored at 4°C to reduce biological activity and keep losses of monomethyl arsenic (MMA) and dimethyl arsenic (DMA) to a minimum. Nevertheless, some losses were inevitable as the samples had to be stored on board ship for the cruise duration (up to 2 weeks) and subjected to a 2-3 week analytical procedure. These losses have been quantified for samples from the Tamar Estuary in Kitts (1991).
The technique used for inorganic arsenic was to add 6M Analar HCl and 2 per cent Spectrosol NaBH 4solution to the water sample to generate arsines. These were purged from the apparatus by a stream of nitrogen for analysis by flame atomic absorption spectroscopy.
MMA and DMA were analysed using a similar technique using a lower acid concentration (1M) to favour the formation of organic arsines. The lower concentrations required the incorporation of an arsine trapping procedure. The nitrogen purgative, dried by NaOH traps, was passed through a glass U tube packed with glass beads cooled to -196°C by liquid nitrogen. The trap was allowed to gradually warm to room temperature giving up the trapped arsines as a series of pulses, thus achieving separation of the arsenic species. Each species was analysed by flame atomic absorption spectroscopy.
A full description and discussion of the analytical techniques is given in Kitts, 1991.
Analysis of mercury
Reactive mercury, i.e. mercury which can be determined without prior oxidation, was determined by the reduction of the mercury in the acidified sample to elemental form by the addition of tin (II) chloride. This was then removed from solution by purging with oxygen-free nitrogen and the mercury vapour trapped as an amalgam on gold chips. Once purging was complete, the gold chips were inductively heated to vaporize the mercury as a pulse which was quantified by atomic absorption spectroscopy.
Total mercury was measured by the above method on samples which had been oxidised by addition of hydrochloric acid, potassium bromide and potassium bromate. Samples were left to oxidise for at least an hour before the bromine was reduced by the addition of excess hydroxylammonium chloride solution.
Total mercury was determined on both unfiltered sea water and on sea water which had been filtered through an ashed (450°C for 24 hours) GFF filter paper. Reactive mercury was determined on filtered samples only. Full details of the methodology are given in Harper et al (1989).
References
Danielsson, L.-G., B. Magnusson and S. Westerlund (1978) An improved metal extraction procedure for the determination of trace metals in sea water by atomic absorption spectrometry with electrothermal atomization. Analytica Chimica Acta 98, 47-57.
Harper, D.J., C.F. Fileman, P.V. May and J.E. Portmann (1989). Methods of analysis for trace metals in marine and other samples. Aquatic environment protection: analytical methods number 3. MAFF Directorate of Fisheries Research, 38pp.
Hydes, D.J. and P.S. Liss (1976). A fluorometric method for the determination of low concentrations of dissolved aluminium in natural waters. The Analyst 101, 922-931.
Kitts, H. (1991). Estuaries as sources of methylated arsenic to the North Sea. Ph.D. thesis, Polytechnic South West.
Morley, N.H., P.J. Statham and C. Fay (1988) Design and use of a clean shipboard handling system for sea water samples. In: Advances in Underwater Technology, Ocean Science and Offshore Engineering, Volume 16 (Oceanology '88), Graham and Trotman, London, 283-290.
Statham, P.J. (1985) The determination of dissolved manganese and cadmium in sea water at low nmol/l concentrations by chelation and extraction followed by electrothermal atomic absorption spectrophotometry. Analytica Chimica Acta 169, 149-159.
Tappin, A.D. (1988) Trace metals in shelf seas of the British Isles, Ph.D. Thesis, University of Southampton, 279pp.
Tappin A.D., D.J. Hydes, P.J. Statham and J.D. Burton (1992) Concentrations, distributions and seasonal variability of dissolved Cd, Co, Cu, Mn, Ni, Pb and Zn in the English Channel. Continental Shelf Research (vol 12, in press).
Project Information
North Sea Project
The North Sea Project (NSP) was the first Marine Sciences Community Research project of the Natural Environment Research Council (NERC). It evolved from a NERC review of shelf sea research, which identified the need for a concerted multidisciplinary study of circulation, transport and production.
The ultimate aim of the NERC North Sea Project was the development of a suite of prognostic water quality models to aid management of the North Sea. To progress towards water quality models, three intermediate objectives were pursued in parallel:
Production of a 3-D transport model for any conservative passive constituent, incorporating improved representations of the necessary physics - hydrodynamics and dispersion;
Identifying and quantifying non-conservative processes - sources and sinks determining the cycling and fate of individual constituents;
Defining a complete seasonal cycle as a database for all the observational studies needed to formulate, drive and test models.
Proudman Oceanographic Laboratory hosted the project, which involved over 200 scientists and support staff from NERC and other Government funded laboratories, as well as seven universities and polytechnics.
The project ran from 1987 to 1992, with marine field data collection between April 1988 and October 1989. One shakedown (CH28) and fifteen survey cruises (Table 1), each lasting 12 days and following the same track, were repeated monthly. The track selected covered the summer-stratified waters of the north and the homogeneous waters in the Southern Bight in about equal lengths together with their separating frontal band from Flamborough head to Dogger Bank, the Friesian Islands and the German Bight. Mooring stations were maintained at six sites for the duration of the project.
Table 1: Details of NSP Survey Cruises on RRS Challenger Cruise No. Date CH28 29/04/88 - 15/05/88 CH33 04/08/88 - 16/08/88 CH35 03/09/88 - 15/09/88 CH37 02/10/88 - 14/10/88 CH39 01/11/88 - 13/11/88 CH41 01/12/88 - 13/12/88 CH43 30/12/88 - 12/01/89 CH45 28/01/89 - 10/02/89 CH47 27/02/89 - 12/03/89 CH49 29/03/89 - 10/04/89 CH51 27/04/89 - 09/05/89 CH53 26/05/89 - 07/06/89 CH55 24/06/89 - 07/07/89 CH57 24/07/89 - 06/08/89 CH59 23/08/89 - 04/09/89 CH61 21/09/89 - 03/10/89
Alternating with the survey cruises were process study cruises (Table 2), which investigated some particular aspect of the science of the North Sea. These included fronts (nearshore, circulation and mixing), sandwaves and sandbanks, plumes (Humber, Wash, Thames and Rhine), resuspension, air-sea exchange, primary productivity and blooms/chemistry.
Table 2: Details of NSP Process cruises on RRS Challenger Cruise No. Date Process CH34 18/08/88 - 01/09/88 Fronts - nearshore CH36 16/09/88 - 30/09/88 Fronts - mixing CH56 08/07/89 - 22/07/89 Fronts - circulation CH58 07/08/89 - 21/08/89 Fronts - mixing CH38 24/10/88 - 31/10/88 Sandwaves CH40 15/11/88 - 29/11/88 Sandbanks CH42 15/12/88 - 29/12/88 Plumes/Sandbanks CH46 12/02/89 - 26/02/89 Plumes/Sandwaves CH44 13/01/89 - 27/01/89 Resuspension CH52 11/05/89 - 24/05/89 Resuspension CH60 06/09/89 - 19/09/89 Resuspension CH48 13/03/89 - 27/03/89 Air/sea exchanges CH62 05/10/89 - 19/10/89 Air/sea exchanges CH50 12/04/89 - 25/04/89 Blooms/chemistry CH54 09/06/89 - 22/06/89 Production
In addition to the main data collection period, a series of cruises took place between October 1989 and October 1990 that followed up work done on previous cruises (Table 3). Process studies relating to blooms, plumes (Humber, Wash and Rhine), sandwaves and the flux of contaminants through the Dover Strait were carried out as well as two `survey' cruises.
Table 3: Details of NSP `Follow up' cruises on RRS Challenger Cruise No. Date Process CH62A 23/10/89 - 03/11/89 Blooms CH64 03/04/90 - 03/05/90 Blooms CH65 06/05/90 - 17/05/90 Humber plume CH66A 20/05/90 - 31/05/90 Survey CH66B 03/06/90 - 18/06/90 Contaminants through Dover Strait CH69 26/07/90 - 07/08/90 Resuspension/Plumes CH72A 20/09/90 - 02/10/90 Survey CH72B 04/10/90 - 06/10/90 Sandwaves/STABLE CH72C 06/10/90 - 19/10/90 Rhine plume
The data collected during the observational phase of the North Sea Project comprised one of the most detailed sets of observations ever undertaken in any shallow shelf sea at that time.
Data Activity or Cruise Information
Data Activity
Start Date (yyyy-mm-dd) 1989-10-02 End Date (yyyy-mm-dd) 1989-10-02 Organization Undertaking Activity Plymouth Marine Laboratory Country of Organization United Kingdom Originator's Data Activity Identifier CH61_CTD_2850 Platform Category lowered unmanned submersible
BODC Sample Metadata Report for CH61_CTD_2850
Sample reference number Nominal collection volume(l) Bottle rosette position Bottle firing sequence number Minimum pressure sampled (dbar) Maximum pressure sampled (dbar) Depth of sampling point (m) Bottle type Sample quality flag Bottle reference Comments 322832 10.00 29.10 29.70 26.20 Niskin bottle No problem reported 322846 10.00 12.50 12.80 9.60 General Oceanics GO-FLO water sampler No problem reported 322880 10.00 4.00 4.30 1.20 Niskin bottle No problem reported
Please note:the supplied parameters may not have been sampled from all the bottle firings described in the table above. Cross-match the Sample Reference Number above against the SAMPRFNM value in the data file to identify the relevant metadata.
Related Data Activity activities are detailed inAppendix 1
Cruise
Cruise Name CH61 Departure Date 1989-09-21 Arrival Date 1989-10-03 Principal Scientist(s) Ian Joint (Plymouth Marine Laboratory) Ship RRS Challenger
Complete Cruise Metadata Report is availablehere
Fixed Station Information
Fixed Station Information
Station Name NSP CTD Site EK Category Offshore location Latitude 53° 43.62' N Longitude 0° 42.75' E Water depth below MSL
North Sea Project CTD Site EK
Site EK was one of 123 North Sea Project CTD fixed stations.
Casts were performed by 11 cruises between 15/08/1988 and 02/10/1989, the measurements collected lie within a box bounded by co-ordinates 53.7095°N, 0.70738°E at the southwest corner and 53.74454°N, 0.7175°E at the northeast corner.
Related Fixed Station activities are detailed inAppendix 2
BODC Quality Control Flags
The following single character qualifying flags may be associated with one or more individual parameters with a data cycle:
Flag Description Blank Unqualified < Below detection limit > In excess of quoted value A Taxonomic flag for affinis (aff.) B Beginning of CTD Down/Up Cast C Taxonomic flag for confer (cf.) D Thermometric depth E End of CTD Down/Up Cast G Non-taxonomic biological characteristic uncertainty H Extrapolated value I Taxonomic flag for single species (sp.) K Improbable value - unknown quality control source L Improbable value - originator's quality control M Improbable value - BODC quality control N Null value O Improbable value - user quality control P Trace/calm Q Indeterminate R Replacement value S Estimated value T Interpolated value U Uncalibrated W Control value X Excessive difference
SeaDataNet Quality Control Flags
The following single character qualifying flags may be associated with one or more individual parameters with a data cycle:
Flag Description 0 no quality control 1 good value 2 probably good value 3 probably bad value 4 bad value 5 changed value 6 value below detection 7 value in excess 8 interpolated value 9 missing value A value phenomenon uncertain B nominal value Q value below limit of quantification
Appendix 1 : CH61_CTD_2850
Related series for this Data Activity are presented in the table below. Further information can be found by following the appropriate links.
If you are interested in these series, please be aware we offer amultiple file downloadservice. Should your credentials be insufficient for automatic download, the service also offers a referral to our Enquiries Officer who may be able to negotiate access.
Series Identifier Data Category Start date/time Start position Cruise 2086996 Water sample data 1989-10-02 02:34:51 53.73378 N, 0.71634 E RRS Challenger CH61 1241933 Water sample data 1989-10-02 02:35:00 53.73378 N, 0.71634 E RRS Challenger CH61 1701580 Water sample data 1989-10-02 02:35:00 53.73378 N, 0.71634 E RRS Challenger CH61 1855751 Water sample data 1989-10-02 02:35:00 53.73378 N, 0.71634 E RRS Challenger CH61
Appendix 2 : NSP CTD Site EK
Related series for this Fixed Station are presented in the table below. Further information can be found by following the appropriate links.
If you are interested in these series, please be aware we offer amultiple file downloadservice. Should your credentials be insufficient for automatic download, the service also offers a referral to our Enquiries Officer who may be able to negotiate access.
Series Identifier Data Category Start date/time Start position Cruise 770091 CTD or STD cast 1988-08-15 14:24:00 53.718 N, 0.7135 E RRS Challenger CH33 784953 CTD or STD cast 1988-10-12 23:28:00 53.72033 N, 0.713 E RRS Challenger CH37 822378 CTD or STD cast 1988-11-12 07:23:00 53.71533 N, 0.71717 E RRS Challenger CH39 785920 CTD or STD cast 1988-12-31 20:40:00 53.7095 N, 0.7175 E RRS Challenger CH43 792074 CTD or STD cast 1989-02-09 01:37:00 53.72217 N, 0.71233 E RRS Challenger CH45 793563 CTD or STD cast 1989-03-11 03:23:00 53.71783 N, 0.71433 E RRS Challenger CH47 1858275 Water sample data 1989-03-11 03:25:00 53.7179 N, 0.7144 E RRS Challenger CH47 795717 CTD or STD cast 1989-05-07 12:38:00 53.72183 N, 0.7155 E RRS Challenger CH51 1861560 Water sample data 1989-05-07 12:43:00 53.72177 N, 0.71558 E RRS Challenger CH51 2082817 Water sample data 1989-05-07 12:43:16 53.72177 N, 0.71558 E RRS Challenger CH51 2097607 Water sample data 1989-05-07 12:43:16 53.72177 N, 0.71558 E RRS Challenger CH51 797134 CTD or STD cast 1989-06-05 11:45:00 53.7445 N, 0.70783 E RRS Challenger CH53 1864164 Water sample data 1989-06-05 11:50:00 53.74454 N, 0.70785 E RRS Challenger CH53 798438 CTD or STD cast 1989-07-05 00:00:00 53.73217 N, 0.70733 E RRS Challenger CH55 1657374 Water sample data 1989-07-05 00:03:00 53.73212 N, 0.70738 E RRS Challenger CH55 1866644 Water sample data 1989-07-05 00:03:00 53.73212 N, 0.70738 E RRS Challenger CH55 802328 CTD or STD cast 1989-09-02 15:09:00 53.73283 N, 0.71667 E RRS Challenger CH59 1857014 Water sample data 1989-09-02 15:12:00 53.73289 N, 0.71673 E RRS Challenger CH59 800985 CTD or STD cast 1989-10-02 02:31:00 53.73383 N, 0.71633 E RRS Challenger CH61 2086996 Water sample data 1989-10-02 02:34:51 53.73378 N, 0.71634 E RRS Challenger CH61 1855751 Water sample data 1989-10-02 02:35:00 53.73378 N, 0.71634 E RRS Challenger CH61
British Oceanographic Data Centre National Oceanography Centre European Way Southampton SO14 3ZH United Kingdom
| https://www.bodc.ac.uk/data/documents/series/2088223/ |
Sustainability | Free Full-Text | A Win-Win Outcome between Corporate Environmental Performance and Corporate Value: From the Perspective of Stakeholders
This paper combines determinants of corporate environment performance (CEP) and the effect of CEP on corporate value together, namely how to motivate firms to conduct environmental protection from the perspective of enhancing firm value. Using a sample of 204 observations of listed corporations in Chinese pollution-intensive industries over the period of 2013–2014, we observed that: (1) compared to investment in a single stakeholder, combinations of multidimensional stakeholders are more likely to affect CEP, and the path is not unique; (2) employees have a positive role, but investors, the community, suppliers, and customers have negative roles; (3) among three patterns for high CEP, both high investment in employees and low investment in the community, suppliers and customers will not detract from firm value, i.e., a win-win outcome; (4) among three patterns for low CEP, one will enhance firm value; and (5) the investor should be seen as an important breakthrough in corporate environmental protection. Such conclusions have stronger promotional value for other emerging countries where corporate social and environmental responsibility is still in the initial stage and the traditional corporate government mode still has a leading position.
A Win-Win Outcome between Corporate Environmental Performance and Corporate Value: From the Perspective of Stakeholders
by Chun Jiang and Qiang Fu *
Economics and Management School, Wuhan University, Wuhan 430072, China
*
Author to whom correspondence should be addressed.
Sustainability 2019 , 11 (3), 921; https://doi.org/10.3390/su11030921
Received: 19 January 2019 / Revised: 2 February 2019 / Accepted: 4 February 2019 / Published: 12 February 2019
(This article belongs to the Special Issue Comparative Corporate Social Responsibility (CSR) and Sustainable Development Goals (SDGs) )
Abstract
This paper combines determinants of corporate environment performance (CEP) and the effect of CEP on corporate value together, namely how to motivate firms to conduct environmental protection from the perspective of enhancing firm value. Using a sample of 204 observations of listed corporations in Chinese pollution-intensive industries over the period of 2013–2014, we observed that: (1) compared to investment in a single stakeholder, combinations of multidimensional stakeholders are more likely to affect CEP, and the path is not unique; (2) employees have a positive role, but investors, the community, suppliers, and customers have negative roles; (3) among three patterns for high CEP, both high investment in employees and low investment in the community, suppliers and customers will not detract from firm value, i.e., a win-win outcome; (4) among three patterns for low CEP, one will enhance firm value; and (5) the investor should be seen as an important breakthrough in corporate environmental protection. Such conclusions have stronger promotional value for other emerging countries where corporate social and environmental responsibility is still in the initial stage and the traditional corporate government mode still has a leading position.
Keywords:
corporate environment performance
;
corporate value
;
fuzzy-set/qualitative comparative analysis
1. Introduction
Global environmental degradation is a side-effect of economic development, which is why achieving a balance between economic development and environmental protection has attracted significant public concern [ 1 , 2 ]. For example, based on the BP Statistical Review of World Energy 2017 , mainland China consumed 23% of global primary energy and produced 27.3% of global carbon dioxide emissions in 2016 [ 3 ]. However, according to feedback from real-world data, the policies mostly demonstrate a trade-off rather than a win-win [ 4 ]. Tang et al. [ 5 ] found that the effects of environmental regulations are constrained by economic goals, especially for local government. When we focus on corporate environment practices, only 33% of listed firms in China choose to publish social and environmental reports [ 6 ]; most firms doubt that this action will detract from firm value [ 7 ]. Herein, the corporate value mainly refers to the corporate market value [ 8 ], since it has less discretionary space, compared to the accounting-based variable [ 9 ]. Meanwhile, it can better predict firm performance in the long run, therefore testing whether a certain corporate environmental strategy is sustainable [ 10 ]. More importantly, the expectation of a win-win situation between corporate environmental performance (CEP) and corporate value is an additional incentive to make headway in the pro-environmental change process [ 11 ]. Therefore, our paper is determined to answer how to obtain a win-win outcome between CEP and corporate value.
In view of the increasing importance of corporate environmental protection, relevant theoretical research addresses the issue mainly from two perspectives, i.e., determinants of variation in CEP across firms either from legitimacy theory [ 12 ] or stakeholder theory [ 13 ] and the effect of CEP on corporate value [ 7 , 14 ]. However, as far as we know, these two representative studies are conducted separately (details discussed below). Actually, they are tightly connected, theoretically and practically speaking, because the determinants of CEP affect the formation of the corporate environmental strategy, which in turn impacts the corporate value restricted to concrete execution. Therefore, the question lies in how we select the appropriate perspective to combine two types of research together. Herein, we choose stakeholders based on two important considerations. According to the definition by Freeman [ 15 ], stakeholders can affect the enterprise’s operation while at the same time being affected by it, thus providing us a reasonable research scope with a solid theoretical foundation compared to those with a general reference, such as legitimacy theory [ 16 ]. Moreover, stakeholders’ power not only affects the corporate environmental strategy [ 17 ], but also helps internalize the concrete effect of CEP due to the stakeholders’ orientation towards CEP [ 18 ].
Though stakeholder theory is pivotal, little effort has been made to explore the interaction between stakeholders [ 19 ]. In fact, there are complementary and trade-off relations between stakeholders; recently, some scholars have attempted to address this issue from a configurational perspective [ 20 , 21 , 22 ]. That is to say, instead of employing the linear fashion method, we should turn to the configurational perspective.
As for the effect of corporate environmental protection, numerous studies have failed to reach a consistent conclusion. Evidence from the regional or industrial perspective has used an aggregate index, ignoring firm heterogeneity. Meanwhile, firm-level evidence not only neglects the conditions of CEP that have occurred, but also mainly employs the linear fashion method. Actually, the consequence of CEP should be non-linear [
2
]. Therefore, we employ the fuzzy-set/qualitative comparative analysis (fs/QCA) method, which can manage multiple interactions and non-symmetric relationships simultaneously by using firm-level data.
To test our hypothesis, we use a sample of 204 observations of listed corporations in Chinese pollution-intensive industries over the period of 2013–2014. We measured the score of each stakeholder from the Hexun Corporate Social Performance (CSP) Database [
23
], which not only provides relatively authoritative and professional scores for CSP that differ from content analyses by certain authors, but is also more suitable for CSP practices in China (seen
Section 4.2
). We choose Tobin’s Q as the related output variable. By applying an fs/QCA in view of the fact that complementarity and trade-offs exist between stakeholders [
15
], the results suggested that both high CEP and low CEP have three patterns. For high CEP, none of the three patterns were able to enhance firm value, but two patterns (~community * (~supplier and customer + employee)) did not detract from corporate value; namely, such environmental protection will be sustainable. For low CEP, high investment in the community with few employees also lowers firm value, but one pattern (investor * supplier and customer * community) will add firm value. This striking contrast in the outcome for different CEP strategies provides us with a clear explanation of why firms are more willing to choose a reactive environmental strategy. As to the effect of a single stakeholder on CEP, high investment in employees and low investment in investors, suppliers, and customers or the community are more likely to result in high CEP, while low investment in employees and high investment in investors, suppliers, and customers or the community are more likely to result in low CEP. Additionally, investment relations are more important for firm value and combinations of stakeholders rather than investment in a single stakeholder in terms of the likelihood of affecting CEP and related outcomes.
By shedding light on corporate environmental strategy selections and related outcomes, our research contributes to the prior research in several ways. First, as stated above, our study combines the effect of CEP with the formation of firms’ environmental strategy. Traditional works directly study the determinants or consequences of CEP, regardless of their combination. In this way, we focus on how to motivate firms to conduct environmental protection from the perspective of enhancing firm value, instead of passively responding to government regulations. Meanwhile, we propose a new understanding for the inconsistent effect of environmental protection. Traditional studies employ linear regression to manage such inconsistencies, but this neglects the conjunction, equifinality, and asymmetry among elements [
24
]. By using fs/QCA, we argue that the configuration rather than a single element affects CEP and the related outcome, i.e., whether CEP boosts firm value depends on the combinations of stakeholders. Besides, another contribution is that our research provides a comprehensive perspective for stakeholders’ net power with respect to CEP. Traditional research always assumes that firms passively react to stakeholders’ absolute power. Actually, firms have more space and greater chances of counteracting the absolute power of stakeholders, especially for emerging countries (discussed below). Based on this setting, the results found that the employee is in a core position to guarantee high CEP and that the investor is in a core position to guarantee a high firm value, which provides appropriate classifications of stakeholders rather than traditional elements in primary and secondary stakeholders. Such conclusions have stronger promotional value for countries where CSP is still in the initial stage and the traditional corporate government mode still has a leading position.
2. Literature Review
Although scholars have conducted fruitful studies on CEP, these studies can be mainly classified as determinants of CEP and related consequences on firm value, and they are also key research questions in this paper. Therefore, we conduct a thorough literature review from these two aspects and then present comments on the research.
2.1. Determinants of CEP
As one important component of CSP, the determinants of CEP closely resemble those of CSP [ 25 , 26 ], thereby guiding us to follow such logic to conduct a more careful literature review.
When explaining why firms are engaged in corporate environmental protection, two typical theories are used. Legitimacy theory recognizes legitimacy as an important factor that affects firm operations [ 27 ]. The firm’s legitimacy will be improved if its value system conforms to that of the social system. Conversely, the firm’s legitimacy will be threatened. Therefore, a firm may use a proactive corporate environmental strategy to improve or repair legitimacy [ 12 ]. It must be noted, however, that legitimacy theory provides firms with broader objectives whose expectations should be met. Consequently, scholars introduced stakeholder theory to better explore why firms choose different corporate protection strategies [ 13 ]. Previous studies have indicated that various CEP across firms may result from shareholders and creditors, suppliers, and customers [ 17 ], employees [ 28 ], and the general public [ 29 ]. Additionally, a few studies include broader stakeholders in exploring the formation of a corporate environmental strategy. Buysse and Verbeke [ 30 ] conducted an empirical analysis of linkages between CEP and stakeholder management, and they found that a more proactive corporate environmental strategy means broader coverage of stakeholders.
2.2. Consequences of CEP
Relevant theoretical studies have addressed the issue of the consequences of CEP from two aspects. The first representative study focused on the effect of environmental regulation from a regional or industrial perspective. Traditional views based on neoclassical economics argue for a negative relationship between environmental protection and economic development. Although environmental regulation may enhance environmentally-friendly innovations, it will crowd out other R&D investment, thus dampening economic development [ 31 ]. Evidence from Lee [ 32 ] has supported this viewpoint, and the rising cost has decreased the production rate by 12%. Meanwhile, the Porter hypothesis stresses positive outcomes through innovation offsets and learning effects [ 33 ]. Testa et al. [ 34 ] found that more stringent environmental regulations have acted as a motivation for firms to implement innovations, which in turn enhances competitive performance. Additionally, some scholars pay attention to nonlinearity, i.e., the effect of environmental regulation relies on certain context factors. For example, Zhao and Sun [ 35 ] stressed that flexible regulation can offer a stronger motivation for environmental protection. However, what is noteworthy is that evidence from the regional or industrial perspective has overlooked firm heterogeneity, and an important breakthrough point would be to identify the effect of environmental regulation from the firm perspective [ 36 ].
Another representative study focuses on the effect of CEP on firm value. Based on Friedman’s classic point that the responsibility of the firm is to increase profits, some scholars argue that CEP will crowd out resources that were originally intended for investment in core competitive business, thus leading to the lack of competitive advantage compared to its rivals. The management opportunism hypothesis also opposes CEP. In addition, some scholars agree with the reputation effect of CEP, but firms have difficulty internalizing the effects to complement the costs [ 37 ]. The alternative view argues that firms can cultivate rare, unduplicated, and irreplaceable resources in the process of increasing CEP based on instrument stakeholder theory and resource-based views [ 38 ], thus positively affecting firm value [ 8 ]. Meanwhile, Singh et al. [ 39 ] thought that getting accreditation in environmental programs such as ISO 14000 standards enables firms to achieve legitimacy by signaling to stakeholders their internal emphasis on environmental performance and pressing their supply chain partners to obtain similar accreditation. Other scholars indicated that the effect of CEP is based on certain conditions and that a non-linear relationship may be more appropriate [ 2 ].
2.3. Review Comments
With a systematic argument about the drivers and the effects of CEP, it is easy to see that numerous studies have been conducted, particularly on the effect of CEP, thus providing us a theoretical foundation for our research. However, the theoretical evidence fails to provide consistent conclusions to guide firms in balancing corporate environmental protection and firm development. We believe that there are several shortcomings that should be addressed.
Prior studies separate the two, especially studies on the consequences of CEP, which ignore the formation of corporate environmental strategy, while theoretically and intuitively speaking, various strategies result in different outputs via detailed implementation. Here, we address the issue by introducing stakeholders in view of their influence on the formation and implementation of the corporate environmental strategy.
Rooted in CSP, scholars always investigate drivers of CEP based on stakeholder theory. Nevertheless, little effort has been made to explore the interaction between stakeholders [ 19 ]. In fact, there are complementary and trade-off relations between stakeholders; recently, some scholars have attempted to address this issue from a configurational perspective [ 20 , 21 , 22 ]. Here, we still follow this view to understand the interdependence of stakeholders.
As for the effect of corporate environmental protection, numerous studies have failed to reach a consistent conclusion. Evidence from the regional or industrial perspective has used an aggregate index, ignoring firm heterogeneity. Meanwhile, firm-level evidence not only neglects the conditions of CEP that have occurred, but also mainly employs the linear fashion method. Actually, the consequence of CEP should be non-linear [ 2 ]. Therefore, we employed the fs/QCA method, which can manage multiple interactions and non-symmetric relationships simultaneously by using firm-level data.
3. Theories and Hypothesis Development
3.1. Multiple Dimensions and Classifications of Stakeholders
CSP has been explained as a corporation taking economic responsibility and having responsibilities in legislation, ethics, and charity. Although this definition from Carroll is widely used in the research, this type of classification is vague in practice, as he noted in 1991 [
40
]. The stakeholder, another component that is closely associated with CSP, specifies the dimensionality of CSP. According to Freeman, stakeholders can affect the enterprise’s operation, while simultaneously being affected by it. In general, stakeholders include investors, employees, suppliers, customers, the environment, and the community [
41
,
42
].
Among these stakeholders is the investor, who, as the funds provider, determines the funding source. If they follow the traditional corporate governance mode stating that corporate environmental protection violates firm development, corporate environmental projects cannot obtain financial support, thus determining the formation of an environmental strategy. Moreover, considering the highly risky and time-consuming traits of these projects, the investor may choose to suspend these projects, thus affecting the consequences of CEP. An employee’s environmental awareness and skills have an important effect on the success of corporate environmental projects. Environmentally-friendly materials from the supplier and the acceptance level of green products from the customer also largely impact the formation and consequences of corporate environmental strategy. Moreover, the general public can exert a certain amount of pressure on firms to force firms to obtain higher CEP.
The stakeholders’ multiple dimensions exhibit diversity, but whether they have the same weight for CEP and firm value is unclear. Kacperczyk [
43
] found that concern for the environment and the community led to higher firm value compared to other dimensions, which indicates that there are different weights for them. According to the concept of the resource-based view, the primary stakeholders are key factors in influencing the enterprise due to the irreplaceability and social complexity of the connection with enterprises when compared to secondary stakeholders that have a broader definition and connotation. Based on Clarkson [
44
], the primary stakeholders are dimensions without which an enterprise cannot exist, including the investors, employees, suppliers, and customers. However, secondary stakeholders refer to others without direct engagement in economic transactions, such as the community.
Although the above classification of stakeholders that is based on absolute power has been widely used, firms should not be recognized as passively reacting to stakeholders’ power. Actually, firms can use their power to influence absolute power from stakeholders [
45
]. Therefore, the power of stakeholders should be the difference between the firm and stakeholder [
18
]. For instance, both the supplier and customer are always considered primary stakeholders—namely, having absolute power—but certain firms may use product price or contracts to reduce the absolute power. In other words, it is the stakeholder-firm power difference rather than absolute power that determines various CEP and related results.
The stakeholder-firm power difference will be more appropriate for emerging countries. Considering the immature regulatory, industrial, and social environments in these countries, firms have more space and greater chances of counteracting the absolute power of stakeholders [ 46 ]. China, as the largest emerging market, provides us with better research materials to investigate the validity of the stakeholder-firm power difference
To sum up, we provide a joint framework for stakeholder theory with a stakeholder-firm power difference. Among them, stakeholder theory provides us with a reasonable research scope; namely, who affects the formation and consequences of the corporate environmental strategy. Meanwhile, we use stakeholder-firm power rather than absolute power to better understand the actor of each stakeholder in CEP. It is possible and helpful to link them to better understand corporate environmental practices in emerging countries.
3.2. Configurational Perspective of Stakeholders
A joint framework of stakeholder theory with the stakeholder-firm power difference only explores the single stakeholder’s role, and the next issue that should be addressed is the clarification of the interdependency among stakeholders. Actually, there are both complementary and trade-off aspects among stakeholders, i.e., a configurational perspective on the interactions of stakeholders.
Investments in two elements are complementary when the returns from an investment in Component A are an increasing function of the investments in Component B, and vice versa. Based on this logic, joint actions among elements tend to perform better than the action of a single element, and this is the key distinction of the traditional regression method. “Complementary” means that stakeholders’ multiple dimensions can have an interactive influence on the CEP, since adding an investment to a certain type of stakeholder does not mean that this must reduce the investment of other stakeholders, and companies will invest in certain types of stakeholders as a whole. They have a strong link to improve the competitive advantage of the company and their own welfare as well. As Freeman [
15
] argued, the values of each stakeholder group are diverse, but they are consistent with each other.
The trade-off between stakeholders’ multiple dimensions is the optimal input ratio among various stakeholders, which is rooted in the high cost of CSP and the scarcity of corporate slack resources [
47
]. There may be an optimal investment level in stakeholders and a centralized investment strategy with a better effect. In fact, an important view for criticizing CSP is that the lack of a clear balance among stakeholders leads to the lack of an obvious boundary level [
48
]. Meanwhile, according to Godfrey et al. [
49
], the feedback of stakeholders is based on a certain level of investment; namely focusing the resources for certain stakeholders is more likely to reach the corresponding perception level and improve corporate value more quickly.
To conclude, given the multiple dimensions of stakeholders, the analysis of the stakeholder-firm power difference on CEP is not suitable for adopting a unitary or aggregate index; the configurations should be a combination of various stakeholders in view of the complementarity. Moreover, regarding the trade-off between the multiple dimensions of stakeholders, the configurations that companies can choose possess strong heterogeneity. In light of these arguments, we propose our first hypothesis:
Hypothesis
1.
Compared to a single stakeholder, configurations are more likely to result in high or low CEP, but there is no unique optional configuration for pollution-intensive industries.
3.3. Each Stakeholder Role in the Configurations
Investors, as the funding provider, have more influence on CEP according to the empirical evidence [
50
], which demonstrates their absolute power. However, in China, where the indirect financing channel has a dominant position, it is hard for firms to exert an effective influence on this group to counter the absolute power; i.e., the investor has essentiality and exclusivity. However, this high net power does not match the willingness towards CEP. Although the green-credit policy and equator principles have been brought to China, fewer banks adopt this principle: they are more concerned with liquidity, profitability, and security than CEP. Related empirical evidence has found that both the shareholder [
13
] and creditor [
51
] have a negative effect on CEP. It is therefore hypothesized that:
Hypothesis
2.
There is a negative effect of investors on CEP for pollution-intensive industries.
According to the traditional classifications of stakeholders, the employee is among the primary stakeholders, and they have stronger absolute power with respect to corporate development. However, different from the Western background, trade unions are relatively weaker in China, especially for private firms, and it is difficult for a single employee to conduct effective negotiations with firms. Firms can use timely and accurate payroll delivery to avoid other employee responsibilities, thus allowing for the possibility of reducing this absolute power.
However, for pollution-intensive industries, environment pollution is accompanied by employee safety, so it may be best to implement an interdependent combination of environmental and occupational health and safety systems [
28
]. During the corporate practice process, firms always try to adopt an environment, health, and safety (EHS) management system following the instructions of the ISO14001 environment management system and the OHSAS18001 professional health safety control system. Additionally, being among the internal stakeholders, both the skills and participation of employees are key to implementing a proactive environmental strategy [
30
]. Following this logic, we can infer that firms will not counter the absolute power, and they are more likely to include employees in the process of implementing corporate environmental protection. Therefore, this study proposes the following hypothesis:
Hypothesis
3.
There is positive effect of employees on CEP for pollution-intensive industries.
Both the supplier and customer, as the material provider and product buyer, are essential stakeholders of firms. Related evidence found that customers are willing to buy environmentally-friendly products, and powerful suppliers also refuse to provide materials for firms producing environmentally unfriendly products [
52
]. However, in China, the extensive growth mode from decades of the economic developmental process has led to ignorance of the CEP from the supplier and customer. For example, firms can take advantage of customers’ low purchasing power and suppliers’ payment terms and conditions to reduce this absolute power. Tang and Tang [
18
] also found that high CSP cannot lead to equivalent firm performance compared to Western countries, where suppliers and customers are willing to participate in these business strategies. In conclusion, the supplier and customer have essentiality, but lack exclusivity, and it is hypothesized that:
Hypothesis
4.
There is negative effect of the supplier and the customer on CEP for pollution-intensive industries.
The community, as the secondary stakeholder, has less absolute power with respect to firms, and this weak position will be magnified by weak CSP in China. Although the community lacks essentiality and exclusivity in China, it could produce a strong reputation effect. For example, during the Sichuan earthquake in China, Wong Lo Kat became the first company to donate 100 million Yuan, thus acquiring a formidable reputation [
53
]. Additionally, firms are the main donors compared to individuals. Du et al. [
29
] found that CEP weakness is positively associated with this community feedback in conducting green-washing due to its relatively lower costs compared to other dimensions, i.e., window-dressing [
54
]. For this reason, it is hypothesized that:
Hypothesis
5.
There is negative effect of community on CEP for pollution-intensive industries.
Figure 1 summarizes how these stakeholders work together to affect CEP, which serves as a starting point of our empirical analysis. Herein, stakeholders, including investors, employees, suppliers, and customers, as well as the community, combine as a bundle, and then form configurations to affect CEP.
Figure 1. Theoretical framework. CEP, corporate environmental performance.
4. Research Design
4.1. Data and Sample
Our main data sources included the Hexun CSP Database and CSMAR Database. The Hexun CSP Database measures CSP in the dimensions of the investor, employee, supplier, customer, environment, and community, and it is the most widely-used CSP measurement in current studies (discussed below). The CSMAR Database provides other financial information, and it is generally accepted by scholars who study listed firms in China [ 6 ].
To control the lag effect of CSP, we chose CSP dimensions in 2013 and firm value in 2014 from listed A-share firms in Chinese pollution-intensive industries, which include the industries of mining, food and beverages, petroleum, chemistry and plastic, and others that are defined by the China Securities Regulatory Commission [
35
]. Considering the Chinese stock market turbulence in 2015 and 2016, the end of our sample is in 2014, since the corporate value is computed based on stock price (discussed below). In the first half of 2015, China’s Shanghai composite index increased by 60%, and reached the peak point of 5178.19 on 12 June 2015, but suddenly dropped to the point of 2850.71 in the next two months.
Beginning with the initial sample, we exclude (1) cross-listed corporations given the special regulatory system, (2) observations belonging to the IPO year due to the IPO effect, (3) ST/PT corporations due to abnormal financial conditions, and (4) observations with missing values. We ultimately obtained 204 observations for our primary tests.
4.2. Variable Definitions
The metric for the firm value is Tobin’s Q, defined as the market value divided by the book value, and it has several advantages. Compared to the accounting-based variable, it has less discretionary space [ 9 ]. Meanwhile, it can better predict firm performance in the long run, therefore testing whether a certain corporate environmental strategy is sustainable [ 10 ]. Moreover, numerous prior studies have adopted this index based on China’s setting, similar to Kong et al. [ 55 ], Singh et al. [ 39 ], etc.
We measure multiple dimensions of CSP according to the Hexun CSP Evaluation System, which measures the CSP of listed A-share firms in China from the following aspects: investors, employees, suppliers, customers, the environment, and the community. These five dimensions include 13 second indexes and 37 third indexes [ 56 ], with a potential maximum score of 100 to aggregate the extent of each firm’s overall CSP. Similar samples drawn from the Hexun CSP Database, such as Xiong et al. [ 57 ], Li et al. [ 58 ], Tang et al. [ 6 ], etc., have also been published in prestigious academic journals.
The sample distribution, definitions, and descriptive statistics of the variables are listed in Table 1 . According to Table 1 , the metal and non-metal materials industry and the petroleum, chemistry, and plastics industry account for the two largest sample proportions. Compared to the employee, supplier, and customer, the other dimensions had more fluctuations, and the mean value of Tobin’s Q for the sample firms was 1.733.
Table 1. Sample distribution and variable description statistics. CSP, Corporate Social Performance.
4.3. Research Method
Unlike the traditional linear fashion, we study this relationship from a configurational perspective. We implement fs/QCA. This method makes it possible to investigate multiple-factor interactions, while the traditional regression method fails to achieve this. Additionally, this method stresses asymmetries from the conditions to outcome, which can help explain why firms choose different environmental strategies. This method also thinks configurations are equifinal, which means that firms can implement proactive strategies in either customer relations, employee relations, or other stakeholders’ relations.
As a method of set-theory, fs/QCA uses set-subset connections rather than correlations to depict the relations between conditions. If Set A is contained in Set B, then A is the sufficient condition for B. On the contrary, B is a necessary condition for A. In the extreme case, the two variables are totally uncorrelated and still have better set-subset connections [
20
]. To compute the empirical strength of the necessary and sufficient conditions, we rely on consistency and coverage measures in the next two equations.
Consistency (X ≤ Y) = ∑min (x i , y i )/∑x i
(1)
Coverage (X ≤ Y) = ∑min (x i , y i )/∑y i
(2)
Among them, X i is the degree of membership of individual i in configuration X, and Y i is its degree of membership in outcome Y.
Although both the consistency and coverage range from 0–1, they have different meanings. Consistency indicates how closely a perfect subset relationship is approximated, and the larger the consistency is, the more perfect the relationship is. For instance, a consistency score of one demonstrates that X is completely contained in Y. We generally accept a consistency value when it is above 0.75 [
59
], and it is roughly similar to a significance score in a regression analysis, while coverage evaluates the degree to which a cause or a causal combination leads to the instance of a certain result. It is roughly akin to R-squared in a regression analysis, and it does not have this benchmark value.
To demonstrate the combination of conditions, Boolean algebra has been used. Among them, * denotes “AND”, + denotes “OR”, ~ denotes “ABSENCE”, and → denotes the logical implication operator.
To complete the transformation of a variable to a fuzzy set, we follow Garcia-Castro and Francoeur [ 20 ] and chose the 25th, 50th, and 75th percentiles as the minimum threshold, crossover point, and maximum threshold. At the same time, we used the direct method based on the fuzzy package by Longest and Vaisey [ 60 ] in Stata to complete the calibrations, and all results reported below are also based on this package. Table 2 lists the relative fuzzy sets’ calibration.
Table 2. Fuzzy sets’ calibration.
5. Empirical Analysis
According to Sharma and Vredenburg [
61
], both a proactive environmental strategy and a reactive environmental strategy can be observed as continuous variables, and their difference will be reflected in CEP scores. Thus, it is natural for us to classify high CEP as a proactive environmental strategy and low CEP as a reactive environmental strategy. On this basis, the patterns for high CEP are equivalent to a proactive environmental strategy, and the patterns for low CEP are equivalent to a reactive environmental strategy. Marquis and Qian [
62
] conducted similar actions to differentiate the symbolic CSP from substantial CSP.
5.1. Results for Proactive Environmental Strategy
Table 3 lists the sufficiency and necessity matrix. Given the benchmark value of 0.75, we found that the employee constitutes a necessary condition of superior CEP, and necessary scores of other stakeholders ranged from 0.325–0.473, below 0.75. The sufficiency scores ranged from 0.286–0.702, all of which are below 0.75, which indicates that none can be observed as a sufficient condition for CEP. Therefore, we can infer that a single stakeholder cannot lead to high CEP, and this conforms to Hypothesis 1: namely, a single stakeholder cannot result in the formation of a corporate environmental strategy.
Table 3. Sufficiency and necessity matrix for a proactive environmental strategy.
Table 4
lists patterns for high CEP and related outcomes for Tobin’s Q. Three patterns resulted in a proactive environmental strategy, and the total coverage was 0.803, which accounted for larger proportions of related samples. Although the total consistency was 0.725, the consistency of each pattern was above the benchmark value. The expression of C1 is ~investor * employee * ~ supplier and customer → high CEP, which shows low investment in the investor, supplier and customer, and high investment in employees leads to high CEP, thus supporting Hypotheses 2–4. Given the combination of these stakeholders, the consistency of C1 with a high CEP to a high Tobin’s Q was 0.374, below the benchmark value of 0.75, indicating that it cannot enhance firm value. However, its consistency with a low Tobin’s Q was 0.79, thus demonstrating the eroding of the firm value in the long run.
Table 4. Patterns for high CEP and related consequences.
Configurations of C2 and C3 not only have higher unique coverage, but also maintain the present status, namely without increasing or decreasing the firm value. The expression is ~community * (~supplier and customer + employee) → high CEP, and both patterns consider investors as being unaffected regarding the result, thus supporting Hypotheses 3–5. The employee, supplier, and customer do not possess high net power, but an employee has natural a relationship that the supplier and customer do not have in relation to the corporate environmental strategy. Moreover, firms with a high CEP decrease unnecessary green-washing to save scarce resources.
Among these three patterns, the different consequences of corporate value should draw our attention. Compared to C2 and C3, the key difference lies in low investment relations. Just as we noted that the investor had the highest net power with respect to firms in China, it is difficult to enhance corporate performance without decreasing investment in this group, and the results for a reactive environmental strategy in the following section also support this viewpoint.
5.2. Results for a Reactive Environmental Strategy
Table 5 lists the sufficiency and necessity matrix. Given the benchmark value of 0.75, we found that no single stakeholder constitutes the necessary condition, but the community, supplier, and customer constitute a sufficient condition for a reactive environmental strategy, thus supporting Hypotheses 4 and 5.
Table 5. Sufficiency and necessity matrix for a reactive environmental strategy.
Table 6
lists patterns for low CEP and related outcomes for Tobin’s Q. There are also three patterns that result in a reactive environmental strategy. The total coverage was 0.722, which accounts for larger proportions of related samples, while the total consistency is 0.860, which is far better than 0.75. The expression of C4 is investor * supplier and customer * community → low CEP, which shows significant investment in the investor, supplier, customer, and community leads to low CEP, thus supporting Hypotheses 2, 4, and 5. For C5 and C6, they had a higher unique coverage, and the expression is ~employee * (supplier and customer + community), indicating the positive effect of the employee and the negative effect of the community, supplier, and customer, i.e., Hypotheses 3–5.
Table 6. Patterns for low CEP and related consequences.
Among these three patterns, the related outcome varies greatly. The consistency of C4 for a high Tobin’s Q was 0.819, indicating enhancing firm value. Meanwhile, the consistency of C5 for a low Tobin’s Q was 0.773, demonstrating an eroding of the firm value. Moreover, the consistency of C6 with either type of Tobin’s Q was below 0.75, which means unchanged firm value. When conducting a closer analysis of these patterns’ formation, this finding still supports the argument that the investor plays a significant role in enhancing firm value. However, the new finding was that in C5, high investment in the community with weak CEP, will detract from firm value, which means that although green-washing can cover poor corporate environmental protection [
29
], this masking tactic should be controlled to a certain extent.
5.3. Robust Tests
We conducted a series of robust tests to verify that the results shown hold under different sample years, different classification methods, and different calibrations.
(1) Since the fs/QCA method could not work with the panel data, we attempted to present the results of a proactive and reactive environmental strategy in each years from 2010–2012. The beginning year of 2010 was because Hexun evaluates CSP from this year, and the calculation procedures remained unchanged.
Table 7 lists configurations for high CEP from 2010–2012. Among them, there are respectively three patterns, two patterns and three patterns for 2010, 2011, and 2012, which resemble the number from 2013. The solution consistency varied from 0.75–0.794, and the total coverage ranged from 0.574–0.697, indicating higher coverage of related samples.
Table 7. Patterns for high CEP from 2010–2012.
As for each stakeholder role in the configurations, the employee has a positive effect on CEP, while the community, supplier, and customer have a negative influence on CEP, thus supporting H Hypotheses 3–5. However, the results of C7 and C13 violated the results of C10 and C12 regarding the role of investor, which seemingly demonstrates a rejection of Hypothesis 2. Upon closer examination, these results confirm Hypothesis 1: namely, there is no unique mode. Moreover, the unique coverage of C7 and C13 accounted for a small proportion of the total coverage.
None of the related consequences can enhance firm value, but both C10 and C12 eroded firm value, which again supports the key role of the investor in affecting firm value.
Table 8 depicts patterns for low CEP from 2010–2012. A low employee effect emerged in all of these patterns, thus entirely supporting Hypothesis 3. Meanwhile, Hypotheses 2, 4, and 5 have also been supported overwhelmingly. As for the related consequences, C15, C17, C20, and C21 can enhance firm value, and none detract from firm value. The striking contrast between Table 7 and Table 8 helps explain why firms always try to meet the basic requirements of environmental regulation from the government in China.
Table 8. Patterns for low CEP from 2010–2012.
(2) Following the procedure of Fiss [ 59 ], we employed a traditional cluster method to conduct mode classification. Before the cluster analysis, we standardized all variables. In the first step, a hierarchical cluster analysis was used to find an appropriate cluster and then adopt a K-means cluster analysis.
Table 9 lists the result of the K-means cluster analysis, and it demonstrates that four clusters were better. Among them, C25 and C23 had high CEP, while C22 and C24 had low CEP. All results basically support the negative influence of employees and the positive effect of the community, supplier, and customer on CEP, i.e., Hypotheses 3–5. However, the investor serves as a mixed role in C22 and C25, seemingly rejecting Hypothesis 2. We can explain the result from the following aspects. First, unlike the community, supplier, and customer, the necessity scores and sufficiency scores in Table 3 ; Table 5 are in the middle, which indicates the possibility of introducing the investor in a proactive environmental strategy. Second, after synthesizing all results from Table 3 , Table 4 , Table 5 , Table 6 , Table 7 , Table 8 and Table 9 , we can overwhelmingly support Hypothesis 2. Third, just as Fiss [ 59 ] indicated, the results from the cluster method should be mere reference points compared to those of fs/QCA.
Table 9. Cluster analysis results.
(3) We also change the calibrations with ±10 percentile points, and the results suggested no substantial change in our main results except for the different coverage scores and consistency scores. Additionally, we used the contemporary variable for output variables and changed it into a return on assets (ROA), and the main conclusions still hold.
6. Discussion
Our study links the determinants of CEP and its corresponding effect from the perspective of stakeholders. Compared with previous studies, we drop the traditional linear regression, which neglects the conjunction, equifinality, and asymmetry among elements. Though previous studies, such as Ni et al. [
41
], Garcia-Castro, and Francoeur [
20
], have adopted the fs/QCA method to consider the conjunction, equifinality, and asymmetry among stakeholders in the corporate sustainability field, these papers mainly focus on how these stakeholders interact with each other to affect corporate value. While, in our paper, we set the corporate environment performance as the outcome and then how these stakeholders work together to affect firm value when environment performance is low or high.
Meanwhile, our study also relates to those papers mainly because it employs the linear regression method in studying determinants of CEP. Our results found that investors have a negative effect on CEP, similar to Lu and Abeysekera [
13
], while employees are positively related to a proactive environmental strategy [
30
]. Similar to Tang and Tang [
18
], our results found that suppliers and customers are also negatively related to CEP, while community donation acting as window-dressing in CEP [
29
]. However, by employing the fs/QCA method, we found that the employee is in a core position to guarantee high CEP and that the investor is in a core position to guarantee a high firm value.
Lastly, our study also denotes that whether CEP enhances firm value depends on how these stakeholders work together. However, as stated above, prior studies mainly employed the linear fashion method. Against the backdrop, we also make a beneficial supplement by employing a non-linear method.
7. Conclusions and Limitations
This paper presents how multiple dimensions of stakeholders can act as a whole to influence corporate environmental strategy and, given certain pattern, what the related performance will be. Using a sample of 204 observations of listed corporations in Chinese pollution-intensive industries over the period of 2013–2014, we found that compared to a single dimension of stakeholders, the configurations are more likely to affect CEP, but there are no uniform combinations of stakeholders. Whether stakeholders lead to higher CEP depends on combinations of stakeholders, and among these patterns, the employee has a positive role, but the investor, supplier, customer, and community have negative roles, which can be seen as an amendment for traditional stakeholder classification.
Three patterns result in proactive and reactive environmental strategies. For high CEP, all three patterns are not able to lead to high firm value, but for both C2 and C3, ~community * (~supplier and customer + employee) will not erode firm value, thus providing us appropriate modes in the long run. For low CEP, C4 can lead to high firm value, and C5 would lower firm value. These results provide new evidence for the relationship between economic development and environmental protection that the investment relationship should be an appropriate combination with CEP for a win-win outcome.
As the largest emerging country, empirical evidence from China not only provides support for relatively fewer studies from the configurational perspective of stakeholders’ net power with respect to CEP and related consequences, but also has important policy implications for other countries where CSP is still in the initial stage and the traditional corporate government mode still has a leading position.
First, firms can adopt a proactive environmental strategy that does not necessarily erode firm value. In China or other emerging countries, CEP is still in its early stage, and firms are driven by administrative laws and regulations, thus leading to a passive environmental strategy; firms hesitate to implement CEP due to it resulting in a low firm value. Our results suggest that the effect of CEP depends on configurations of stakeholders, so firms should change their attitudes toward CEP for strategic use.
Second, whether a corporate environmental strategy enhances firm value depends on the configuration, but neither a single dimension, nor all dimensions can achieve this goal. During this process, better employee relations and low investment in the community, suppliers, and customers will be the best choice. More importantly, investor relations should be intensified because for CEP, the investor has relatively higher sufficiency and necessity scores compared to the community, suppliers, and customers, thus supporting this viewpoint that the investor can be incorporated into a proactive environmental strategy to enhance firm value.
Furthermore, although these two patterns cannot enhance firm value, it does not lower firm value. In view of the conditions that CSP is still in an early stage, along with economic development, stakeholders will be more strongly orientated towards CEP. Therefore, firms can conduct a proactive environmental strategy early by following the pattern of C2 and C3. During this process, firms can accumulate enough management experience compared to their followers. Finally, the forerunners will enjoy significant rewards.
This paper also has limitations. Our results are acquired from listed firms, so we should carefully expand these explanations to non-listed firms. In the next steps, we should collect more non-listed firms’ data to conduct an analysis. In addition, fs/QCA only supplies the elements in each configuration, and we have little knowledge about the optimal level of each element, which will be important work in the next step. Finally, we hope future studies can employ the recent database after eliminating the effect of market turbulence.
Author Contributions
Conceptualization, C.J. and Q.F.; data curation, Q.F.; formal analysis, C.J. and Q.F.; funding acquisition, C.J. and Q.F.; investigation, Q.F.; methodology, C.J. and Q.F.; project administration, C.J. and Q.F.; resources, Q.F.; software, Q.F.; supervision, C.J. and Q.F.; validation, Q.F.; visualization, Q.F.; writing, original draft, Q.F.; writing, review and editing, C.J. and Q.F.
Funding
This research was funded by The National Social Science Fund of China, Grant Number 15ZDC020, The APC was funded by The National Social Science Fund of China, Grant Number 15ZDC020.
Conflicts of Interest
The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of the data; in the writing of the manuscript; nor in the decision to publish the results.
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Figure 1. Theoretical framework. CEP, corporate environmental performance.
Table 1. Sample distribution and variable description statistics. CSP, Corporate Social Performance.
Industry Type Frequency Variable Name Definitions Mean Std. Mining 21 Investor Hexun CSP Evaluation system 14.597 4.018 Food and beverages 23 Employee 9.339 2.374 Textiles, garments, and leather 17 Supplier and customer 15.289 2.887 Paper mills and printing 10 Environment 15.684 3.964 Petroleum, chemistry, and plastics 38 Community 8.007 4.487 Metal and non-metal materials 43 Tobin’s Q Market value/book value 1.733 1.425 Medicine and bio-products 27 Electricity, gas, and water, production and supply 25 Total 204
Note: The first two columns list a sample distribution based on industry, and the last three columns demonstrate the definitions and basic description statistics.
Table 2. Fuzzy sets’ calibration.
Variable Calibration Member Value Variable Calibration Member Value Investor Minimum threshold 11.835 Environment Minimum threshold 12.500 Crossover point 14.535 Crossover point 17.000 Maximum threshold 18.010 Maximum threshold 19.500 Employee Minimum threshold 7.240 Community Minimum threshold 4.545 Crossover point 9.095 Crossover point 6.500 Maximum threshold 11.255 Maximum threshold 12.040 Supplier and Customer Minimum threshold 12.000 Tobin’s Q Minimum threshold 0.782 Crossover point 15.000 Crossover point 1.322 Maximum threshold 18.000 Maximum threshold 2.269
Note: The definitions of variables can be observed in Table 1 . The minimum threshold, crossover point, and maximum threshold are the 25th, 50th, and 75th percentiles, respectively.
Table 3. Sufficiency and necessity matrix for a proactive environmental strategy.
Environment Investor Employee Supplier and Customer Community Environment 1.000 0.473 0.828 0.350 0.325 Investor 0.404 1.000 0.484 0.675 0.601 Employee 0.702 0.480 1.000 0.341 0.328 Supplier and Customer 0.288 0.649 0.330 1.000 0.768 Community 0.286 0.619 0.340 0.823 1.000
Note: The definitions of variables can be observed in Table 1 . The necessity scores are displayed in the upper right corner, and the sufficiency scores are in the lower left corner.
Table 4. Patterns for high CEP and related consequences.
Note: The first four columns list related patterns for proactive environmental strategy, and the last three columns are the related consequences corresponding to high and low Tobin’s Q. The definitions of variables can be observed in Table 1 . ● indicates the presence of a condition; ⊗ indicates the absence of a condition; while the blank space indicates “does not matter for the outcome”.
Table 5. Sufficiency and necessity matrix for a reactive environmental strategy.
Environment Investor Employee Supplier and Customer Community Environment 1.000 0.609 0.377 0.745 0.716 Investor 0.686 1.000 0.484 0.675 0.601 Employee 0.421 0.480 1.000 0.341 0.328 Supplier and Customer 0.807 0.649 0.330 1.000 0.768 Community 0.831 0.619 0.340 0.823 1.000
Note: Definitions of variables can be seen in Table 1 . The necessity scores are displayed in the upper right corner and the sufficiency scores are in the lower left corner.
Table 6. Patterns for low CEP and related consequences.
Configurations Effects on Tobin’s Q C4 C5 C6 High Tobin’s Q Low Tobin’s Q Investor ● Pattern Consistency Consistency Employee ⊗ ⊗ Supplier and Customer ● ● Community ● ● C4 0.819 0.590 Consistency 0.888 0.916 0.891 Raw Coverage 0.418 0.604 0.648 C5 0.545 0.773 Unique Coverage 0.027 0.048 0.092 Solution Consistency 0.860 C6 0.686 0.680 Total Coverage 0.722
Note: The first four columns list related patterns for a reactive environmental strategy, and the last three columns are related consequences corresponding to high and low Tobin’s Q. The definitions of variables can be seen in Table 1 . ● indicates the presence of condition; ⊗ indicates the absence of condition; while blank space indicates “does not matter for the outcome”.
Table 7. Patterns for high CEP from 2010–2012.
C7 C8 C9 C10 C11 C12 C13 C14 Investor ● ⊗ ⊗ ● Employee ● ● ● ● ● ● Supplier and Customer ⊗ ⊗ ⊗ ⊗ ⊗ Community ⊗ ⊗ ⊗ ⊗ ⊗ Consistency 0.865 0.842 0.792 0.779 0.759 0.780 0.787 0.787 Raw Coverage 0.271 0.536 0.499 0.322 0.523 0.333 0.279 0.600 Unique Coverage 0.061 0.138 0.101 0.051 0.253 0.020 0.049 0.164 Consistency_ High Tobin’s Q 0.632 0.438 0.493 0.404 0.441 0.433 0.707 0.458 Consistency_ Low Tobin’s Q 0.604 0.717 0.675 0.843 0.719 0.794 0.575 0.707 Solution Consistency 0.794 0.753 0.750 Total Coverage 0.697 0.574 0.668
Note: The patterns from C7–C9 are for 2010; the patterns of C10 and C11 are for 2011; and the last three are for 2012. Consistency_ High Tobin’s Q signifies the related value for a high Tobin’s Q, which is the same as the second to last column in both Table 4 and Table 6 , while consistency_ Low Tobin’s Q also follows this explanation. The definitions of variables can be observed in Table 1 . ● indicates the presence of a condition; ⊗ indicates the absence of a condition; while a blank space indicates “does not matter for the outcome”.
Table 8. Patterns for low CEP from 2010–2012.
C15 C16 C17 C18 C19 C20 C21 Investor ● ● ● ● Employee ⊗ ⊗ ⊗ ⊗ ⊗ ⊗ ⊗ Supplier and Customer ● ● ● ● Community ● ● ● ● Consistency 0.855 0.853 0.807 0.803 0.795 0.829 0.801 Raw Coverage 0.322 0.576 0.329 0.525 0.413 0.383 0.385 Unique Coverage 0.052 0.306 0.067 0.263 0.097 0.067 0.070 Consistency_ High Tobin’s Q 0.815 0.734 0.807 0.631 0.702 0.855 0.842 Consistency_ Low Tobin’s Q 0.528 0.582 0.543 0.667 0.525 0.456 0.452 Solution Consistency 0.844 0.784 0.766 Total Coverage 0.628 0.592 0.550
Note: The patterns of C15 and C16 are for 2010; the patterns of C17 and C18 are for 2011; and the last three are for 2012. Consistency_ High Tobin’s Q signifies the related value for a high Tobin’s Q, which is the same as the second to last column in Table 4 and Table 6 , while consistency_ Low Tobin’s Q also follows this explanation. The definitions of variables can be observed in Table 1 . ● indicates the presence of a condition; ⊗ indicates the absence of a condition; while a blank space indicates “does not matter for the outcome”.
Table 9. Cluster analysis results.
Mean of Final Cluster Centre Two-Sample t -Test C22 C23 C24 C25 C22 C23 C24 C25 Investor 0.911 0.096 0.165 0.893 C22 0.000 −0.602 a −0.020 −0.643 a Employee 0.167 0.808 0.143 0.858 C23 0.602 a 0.000 0.581 a −0.042 Supplier and Customer 0.871 0.168 0.912 0.248 C24 0.020 −0.581 a 0.000 −0.623 a Community 0.821 0.194 0.838 0.165 C25 0.643 a 0.042 0.623 a 0.000
Note: The first five columns list the mean of the final cluster center based on standardized variables, and the last five columns provide a two-sample t -test on the standardized CEP. For example, −0.602 a shows that a standardized CEP of pattern C22 minus that of C23 equals −0.602, and the superscript denotes that this value is statistically significant at the 5% level.
MDPI and ACS Style
Jiang, C.; Fu, Q. A Win-Win Outcome between Corporate Environmental Performance and Corporate Value: From the Perspective of Stakeholders. Sustainability 2019, 11, 921.
https://doi.org/10.3390/su11030921
AMA Style
Jiang C, Fu Q. A Win-Win Outcome between Corporate Environmental Performance and Corporate Value: From the Perspective of Stakeholders. Sustainability. 2019; 11(3):921.
https://doi.org/10.3390/su11030921
Chicago/Turabian Style
Jiang, Chun, and Qiang Fu. 2019. "A Win-Win Outcome between Corporate Environmental Performance and Corporate Value: From the Perspective of Stakeholders" Sustainability11, no. 3: 921.
https://doi.org/10.3390/su11030921
Jiang, C.; Fu, Q. A Win-Win Outcome between Corporate Environmental Performance and Corporate Value: From the Perspective of Stakeholders. Sustainability 2019, 11, 921.
https://doi.org/10.3390/su11030921
Jiang C, Fu Q. A Win-Win Outcome between Corporate Environmental Performance and Corporate Value: From the Perspective of Stakeholders. Sustainability. 2019; 11(3):921.
https://doi.org/10.3390/su11030921
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PRIME PubMed | In vivo formation of a stable pentameric (P2alpha/P1beta)-P0-(P1alpha/P2beta) ribosomal stalk complex in Saccharomyces cerevisiae
PubMed journal article: In vivo formation of a stable pentameric (P2alpha/P1beta)-P0-(P1alpha/P2beta) ribosomal stalk complex in Saccharomyces cerevisiae. Download Prime PubMed App to iPhone, iPad, or Android
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In vivo formation of a stable pentameric (P2alpha/P1beta)-P0-(P1alpha/P2beta) ribosomal stalk complex in Saccharomyces cerevisiae.
Yeast . 2010 Sep; 27(9):693-704. Y
Abstract
Heterodimers of acidic proteins P1alpha/P2beta and P1beta/P2alpha bind to P0 and are fundamental for the assembly of the ribosomal stalk. However, different inconsistencies are found in the literature regarding additional P protein heterodimer formations and their individual interactions with P0. Using the two-hybrid approach, we have found results that help to clarify these interactions. Thus, we have found that neither P1 nor P2 directly interact with P0 unless the endogenous heterodimer partner is being expressed in the cell. In addition, a P2-free amino end is a requisite in these heterodimers for binding to P0. With regard to the two-hybrid interactions between P1 and P2, the known canonical P1alpha-P2beta and P1beta-P2alpha interactions do not depend on either a free amino end or the presence of endogenous P0, P1 or P2 proteins. Furthermore, the non-canonical P1beta-P2beta pair also behaves similarly, although this interaction is weaker. Interestingly, P1alpha-P2alpha, P1alpha-P1beta and P2alpha-P2beta two-hybrid interactions were also detected, although in these cases the endogenous P proteins were involved. Thus, these positive interactions are the consequence of the interaction between two canonical heterodimers. As the ribosome anchorage protein P0 is also necessary, the results suggest that, in vivo, all five P proteins form a complex, independent of the ribosome, containing the two canonical heterodimers and P0. This complex has been isolated in cells expressing a P0 protein unable to bind to the ribosome.
Links
Publisher Full Text (DOI)
Authors +Show Affiliations
Francisco-Velilla R
Centro de Biología Molecular 'Severo Ochoa', CSIC, and Universidad Autónoma de Madrid, Spain.
Remacha M
No affiliation info available
MeSH
Phosphoproteins
Protein Binding
Protein Interaction Mapping
Protein Multimerization
Ribosomal Proteins
Saccharomyces cerevisiae Proteins
Two-Hybrid System Techniques
Pub Type(s)
Journal Article
Research Support, Non-U.S. Gov't
Language
eng
PubMed ID
20225338
Citation Francisco-Velilla, Rosario, and Miguel Remacha. "In Vivo Formation of a Stable Pentameric (P2alpha/P1beta)-P0-(P1alpha/P2beta) Ribosomal Stalk Complex in Saccharomyces Cerevisiae." Yeast (Chichester, England), vol. 27, no. 9, 2010, pp. 693-704. Francisco-Velilla R, Remacha M. In vivo formation of a stable pentameric (P2alpha/P1beta)-P0-(P1alpha/P2beta) ribosomal stalk complex in Saccharomyces cerevisiae. Yeast . 2010;27(9):693-704. Francisco-Velilla, R., & Remacha, M. (2010). In vivo formation of a stable pentameric (P2alpha/P1beta)-P0-(P1alpha/P2beta) ribosomal stalk complex in Saccharomyces cerevisiae. Yeast (Chichester, England) , 27 (9), 693-704. https://doi.org/10.1002/yea.1765 Francisco-Velilla R, Remacha M. In Vivo Formation of a Stable Pentameric (P2alpha/P1beta)-P0-(P1alpha/P2beta) Ribosomal Stalk Complex in Saccharomyces Cerevisiae. Yeast. 2010;27(9):693-704. PubMed PMID: 20225338. * Article titles in AMA citation format should be in sentence-case Copy Download MLA AMA APA VANCOUVER
TY - JOUR
T1 - In vivo formation of a stable pentameric (P2alpha/P1beta)-P0-(P1alpha/P2beta) ribosomal stalk complex in Saccharomyces cerevisiae.
AU - Francisco-Velilla,Rosario,
AU - Remacha,Miguel,
PY - 2010/3/13/entrez
PY - 2010/3/13/pubmed
PY - 2010/12/16/medline
SP - 693
EP - 704
JF - Yeast (Chichester, England)
JO - Yeast
VL - 27
IS - 9
N2 - Heterodimers of acidic proteins P1alpha/P2beta and P1beta/P2alpha bind to P0 and are fundamental for the assembly of the ribosomal stalk. However, different inconsistencies are found in the literature regarding additional P protein heterodimer formations and their individual interactions with P0. Using the two-hybrid approach, we have found results that help to clarify these interactions. Thus, we have found that neither P1 nor P2 directly interact with P0 unless the endogenous heterodimer partner is being expressed in the cell. In addition, a P2-free amino end is a requisite in these heterodimers for binding to P0. With regard to the two-hybrid interactions between P1 and P2, the known canonical P1alpha-P2beta and P1beta-P2alpha interactions do not depend on either a free amino end or the presence of endogenous P0, P1 or P2 proteins. Furthermore, the non-canonical P1beta-P2beta pair also behaves similarly, although this interaction is weaker. Interestingly, P1alpha-P2alpha, P1alpha-P1beta and P2alpha-P2beta two-hybrid interactions were also detected, although in these cases the endogenous P proteins were involved. Thus, these positive interactions are the consequence of the interaction between two canonical heterodimers. As the ribosome anchorage protein P0 is also necessary, the results suggest that, in vivo, all five P proteins form a complex, independent of the ribosome, containing the two canonical heterodimers and P0. This complex has been isolated in cells expressing a P0 protein unable to bind to the ribosome.
SN - 1097-0061
UR - https://www.unboundmedicine.com/medline/citation/20225338/In_vivo_formation_of_a_stable_pentameric__P2alpha/P1beta__P0__P1alpha/P2beta__ribosomal_stalk_complex_in_Saccharomyces_cerevisiae_
L2 - https://doi.org/10.1002/yea.1765
DB - PRIME
DP - Unbound Medicine
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Francisco-Velilla R
Remacha M
MESH
Phosphoproteins
Protein Binding
Protein Interaction Mapping
Protein Multimerization
Ribosomal Proteins
Saccharomyces cerevisiae Proteins
Two-Hybrid System Techniques
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An investigation of Dirofilaria immitis infection and its effects on mosquito wingbeat frequencies | Request PDF
Request PDF | An investigation of Dirofilaria immitis infection and its effects on mosquito wingbeat frequencies | Each mosquito species has a different wingbeat frequency by which they attract mates. With just a brief recording ( | Find, read and cite all the research you need on ResearchGate
An investigation of Dirofilaria immitis infection and its effects on mosquito wingbeat frequencies
DOI: 10.1016/j.vetpar.2020.109112
Abstract
Each mosquito species has a different wingbeat frequency by which they attract mates. With just a brief recording (<1/10th of a second) these acoustic signatures can be analyzed to quickly determine if mosquitoes belong to a species that is known to transmit different pathogens. A recent study has shown that mobile phones are capable of capturing acoustic data from mosquito wingbeats. We examined wingbeat signatures and flight duration patterns of D. immitis infected and non-infected Aedes aegypti to determine if mobile phone recordings of wingbeat frequencies can be used to distinguish infected mosquitoes from non-infected ones. Female mosquitoes were recorded prior to and at various time points after feeding on infected or non-infected dog blood by placing individual mosquitoes into a collection vial and recording for 60 seconds using the Voice Memo app for iPhone 7 plus and 8. To uniformly analyze audio data, recordings were processed using a previously described automated algorithm in Python 3.0 to determine wingbeat frequency. A total of 1,669 recordings were gathered, and mosquitoes were dissected to confirm the presence and number of D. immitis larvae. Our findings indicate that there was a significant effect on wingbeat frequency with an increasing number of L3 larvae. Specifically, as the number of L3, infective stage larvae increases, a decrease in wingbeat frequency is seen. However, there was no significant effect of increasing number of L1 or L2 larvae causing increasing wingbeat frequencies. The detection of a significant difference in wingbeat frequencies between mosquitoes harboring infective stage D. immitis larvae is unique and suggests the possibility of using wingbeat recordings as a tool for vector species and pathogen surveillance and monitoring.
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Aug 2021
Fernanda Rodrigues Pinheiro
Aline Christine Bernegossi
Mayara Caroline Felipe
Juliano J. Corbi
ELABORAÇÃO E APLICAÇÃO DE ENSAIOS DE TOXICIDADE UTILIZANDO ESPÉCIES DE INVERTEBRADOS AQUÁTICOS NATIVOS DO BRASIL
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Aline Christine Bernegossi
Mayara Caroline Felipe
Fernanda Rodrigues Pinheiro
Juliano J. Corbi
INDICADORES BIOLÓGICOS DE QUALIDADE EM AMBIENTES AQUÁTICOS CONTINENTAIS: MÉTRICAS E RECORTES PARA ANÁLISES
Book
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Aug 2021
Juliano J. Corbi
FERRAMENTAS ECOTOXICOLÓGICAS APLICADAS AO BIOMONITORAMENTO DE EFLUENTE DE REFINARIA SUCROALCOOLEIRA
Chapter
Aug 2021
Mayara Caroline Felipe
Aline Christine Bernegossi
Fernanda Rodrigues Pinheiro
Marcelo Zaiat
A vinhaça é o principal efluente líquido gerado no processo produtivo do etanol em usinas sucroalcooleiras, sendo caracterizada como um subproduto rico em matéria orgânica e de pH ácido. Atualmente, o principal destino dado à vinhaça é a sua aplicação no setor agrícola como um agente fertilizante. Devido ao grande volume gerado desse efluente - 13 litros (em média) de vinhaça para cada litro de etanol, a fertirrigação em excesso e por longos períodos pode causar problemas ambientais como: acidificação do solo, contaminação da água subterrânea e dos corpos d’água vizinhos, entre outros. Assim, a ecotoxicologia como metodologia para análises de toxicidade de contaminação ambiental tem sido um dos principais focos de pesquisas, visando monitorar o impacto ambiental de contaminantes. O objetivo deste capítulo é discorrer sobre o impacto ambiental da vinhaça da cana- -de-açúcar in natura em duas espécies de invertebrados aquáticos: Allonais inaequalis e Daphnia magna. Também abordaremos o conceito de fitotoxicidade e mostraremos sua aplicação em duas espécies de plantas: Lactuca sativa e Eruca sativa. A partir dos resultados foi possível observar a relevância de testes de ecotoxicidade e fitotoxici- dade como importantes ferramentas para ao biomonitoramento de efluentes. Nota- -se que a vinhaça pode apresentar efeitos tóxicos para a germinação das sementes de L. sativa e E. sativa. Além disso, o escoamento sub/superficial pode carrear esse subproduto fertirrigado para dentro dos cursos d ́água, possibilitando mais um efeito tóxico, agora na matriz aquática, já que 50% de mortalidade/ imobilidade para os organismos A. inaequalis e D. magna em exposição à vinhaça foi evidenciado a partir de diluições de 0,7%. Tais resultados ressaltam a importância dos cuidados com a utilização da vinhaça em fertirrigação, a necessidade de tratamento desse efluente e demonstraram como análises ecotoxicológicas podem ser aplicadas como ferramenta para diferentes impactos ambientais.
GUIA PRÁTICO PARA IDENTIFICAÇÃO DE GÊNEROS OLIGOCHAETA (ANNELIDA: CLITELLATA) EM ECOSSISTEMAS AQUÁTICOS
Chapter
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Guilherme Rossi Gorni
Douglas Aparecido Girolli
Mariana Futenma de Lima
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| https://www.researchgate.net/publication/341667146_An_investigation_of_Dirofilaria_immitis_infection_and_its_effects_on_mosquito_wingbeat_frequencies |
NPG x156294; Hersey Cecilia Hester (née Butler), Countess Saye and Sele - Portrait - National Portrait Gallery
Hersey Cecilia Hester (née Butler), Countess Saye and Sele
1 portrait of Hersey Cecilia Hester (née Butler), Countess Saye and Sele
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Hersey Cecilia Hester (née Butler), Countess Saye and Sele
by Bassano Ltd
half-plate film negative, 11 May 1939
Given by Bassano & Vandyk Studios, 1974
Photographs Collection
NPG x156294
Sitter
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Hersey Cecilia Hester (née Butler), Countess Saye and Sele
(1889-1968), Wife of 20th Baron Saye and Sele; daughter of Sir Thomas Dacres Butler. Sitter in 5 portraits.
Artist
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Bassano Ltd (active 1901-1962), Photographers. Artist or producer associated with 42746 portraits.
Places
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Place made: United Kingdom: England, London
(photographer's studio, 38 Dover Street, London)
Portrait set
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Bassano 1939
Events of 1939
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Current affairs
Britain goes to war. The German invasion of Poland demonstrated that the policy of appeasement had failed. After refusing to meet Britain's ultimatum to withdraw troops, Britain and France declared war on Germany. The Second World War had begun.
Art and science
The Sutton Hoo burial ship is discovered. Apparently following a dream, Mrs Pretty invited the archaeologist Basil Brown to investigate a series of burial mounds on her estate on the banks of the river Deben in Suffolk. The excavation revealed an Anglo-Saxon burial, uncovering the most significant horde of early medieval artefacts found in Britain (now housed at the British Museum).
International
The Second World War begins. Germany's invasion of Poland prompted Britain and France to declare war forming the core of the Allied powers. As part of the Soviet-Nazi Pact, the Soviet Union joined the war on the German side, helping, with Italy, to form the Axis Powers. Poland was soon overpowered and the Baltic Republics and Finland were invaded by the Soviet Union.
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(PDF) Studies Regarding Primary Succession in a Mine Tailing Pond from Bozanta, Maramureș County
PDF | The objective of this study is to carry out a vegetation study at the Bozanta’s tailing pond, located 5 km away from Baia-Mare.Between 2016 and... | Find, read and cite all the research you need on ResearchGate
Article
PDF Available
Studies Regarding Primary Succession in a Mine Tailing Pond from Bozanta, Maramureș County
May 2020
Bulletin of University of Agricultural Sciences and Veterinary Medicine Cluj-Napoca Agriculture 77(1):27
DOI: 10.15835/buasvmcn-agr:2020.0011
License
CC BY-NC-ND
Authors:
University of Agricultural Sciences and Veterinary Medicine
University of Agricultural Sciences and Veterinary Medicine
Download full-text PDF Download full-text PDF Read full-text
Abstract
The objective of this study is to carry out a vegetation study at the Bozanta’s tailing pond, located 5 km away from Baia-Mare.Between 2016 and 2017, using the metric frame, the existing species were identified and the following phytocenothic and population indices were determined: presence, frequency, presence classes, and the average abundance-dominance. Soil samples were taken to perform the following physico-chemical analyses: pH, P, K, N, humus and heavy metals.The floral inventory shows the presence of six tree species, four species of and 30 herbaceous species. Eleven years after the pond closure, the surface is covered with: 30% vegetation coverage, 35% water gloss and the 35% difference is occupied by arid. The average abundance-dominant synthetic indicator showed that the highest coverage is found in Betula pendula, Salix caprea, and in the grass species, Phragmites australis.The results of physicochemical analyses of the substrate showed very wide ranges of pH and different amounts of phosphorus, potassium and humus, and low amounts of nitrogen. The presence and concentration of the following heavy metals were determined from three samples: Cd, Pb, Ni, Cr. In regards to lead and chromium level, the alert threshold has not been reached.
13710-53986-1- PB.pdf
All content in this area was uploaded by Aurel Maxim on Jun 29, 2020
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Technogenic Ecological Sequences in Tailing Pond from Căpușu Mare, Built between 1975-1981
Article
Full-text available
Nov 2017
Aurel Maxim
Mignon Sandor
Opincariu Adriana
Larisa BILC
In Romania, all actions related to mining management are found in “Strategy of the mining industry for 2012-2035”. Today, numerous tailing ponds have remained outside rehabilitation operations, and they are becoming more natural, as is the case of the tailing pond in Capusu Mare. The vegetation study was conducted in 2015, at the tailing pond III in Căpușu Mare that was operational between 1975-1981. The following phytopopulation and phytocenotic indices were calculated: presence, frequency, class of presence, abundance-dominance and average abundance-dominance (ADm) of species. Floral studies show the presence of 40 plant species. The wood species with the highest mean dominant abundance are Hippophäe rhamnoides (14.78%) and Salix alba (10.55%), and of herbaceous species stands Phragmites communis with 7.49%. After 34 years from the heap closure, the degree of vegetation coverage is 77%. Wood species occupy about 32% of the heap surface.
Evaluation of Seed Germination Ability of Native Calamine Plant Species on Different Substrata
Full-text available
Jan 2013
POL J ENVIRON STUD
Ewa Muszyńska
Ewa Hanus-Fajerska
Krystyna Ciarkowska
The purpose of our work was to evaluate the seed germination ability of native species representing calamine populations of Alyssum montanum, Biscutella laevigata (Brassicaceae), and Dianthus carthusianorum (Caryophyllaceae). As substrata for germination, calamine substrate on which populations of examined plant species were grown in natural conditions, and horticultural substrate constituting a mixture of sand and garden soil were used. A. montanum and B. laevigata seeds demonstrated a high ability to germinate on calamine substrate, which was characterized by large contents of soluble forms of zinc (115.1 mg•kg-1), lead (0.91 mg•kg-1), and cadmium (3.12 mg•kg-1), and low water capacity (18.95% g/g). The seed germination ability of calamine Dianthus carthusianorum ecotype was comparable on both studied substrata types.
The Natural Rehabilitation of Tailing Ponds from Căpuș, Cluj
Article
Full-text available
May 2015
Aurel Maxim
Andrei Stoie
Mignon Sandor
Lucia MIHALESCU
Mining industry is one of the most polluting, in particular through the mine tailings and tailing ponds. In Romania, most of these were rehabilitated natural, as is the case at Căpuș.Our studies and research were conducted in 2013 and had two main objectives: to establish natural recovery capacity of the four tailings ponds from the exploitation and processing of iron from from Căpușu Mare (1962-1985), after 28 years from closure, achieving phytocenologic investigations to study the evolution of ecological succession on a lifeless biotope. Genuine identification species installed on the tailings ponds was made by using the dichotomy keys. Quantitative study of characteristics was made by the following indices: coverage using abundance-dominance scale (Braun-Blanquet), calculating the frequency and classification in class presence. For this ecological study of vegetation we used stationary research, with the planimetric method using metric frame 1 square (1 x 1 m). The coverage of vegetation varies from 87% (tailing pond I) to 69% (tailing pond IV). The wood species occupying from 56% (tailing pond I) of the surface of the tailing pond, to 14% (tailing pond IV).Floristic inventory conducted shows that the floristic diversity is at the tailing pond III where were identified, 8 species of trees, 3 species of shrubs and 30 herbaceous species. The lower diversity at the tailings pond I can be explained by the high percentage of land cover by wooden species at the expense of herbaceous. Phytocenologic results of our investigations show that the tailings ponds from Căpuşu Mare are naturally rehabilitated after 28 years, which is the age of the latest pond. Unfortunately there is no description of the dynamics of these phytocenosis. Although species don't have a great economic value, spontaneous vegetation installed here has the advantage of a positive visual impact, setting ponds, preventing air pollution by drifting the tailings by wind and its transport by rain.
Phytostabilization of Zn-Pb ore flotation tailings with Dianthus carthusianorum and Biscutella laevigata after amending with mineral fertilizers or sewage sludge
| https://www.researchgate.net/publication/342072657_Studies_Regarding_Primary_Succession_in_a_Mine_Tailing_Pond_from_Bozanta_Maramures_County |
Tammy Abraham 2019/20 - scout report
Tactical analysis scout report of Tammy Abraham's role in Chelsea's tactics. This tactical analysis scout report profiles Tammy Abraham in Chelsea's tactics. Our tactical analysis scout report details Tammy Abraham's role in Chelsea's tactics.
Tammy Abraham 2019/20 – scout report
After scoring 15 goals in 34 appearances (2,490 minutes), with a further six assists, one can say thatTammy Abrahamhas had a decent debut season atChelsea. Previously, the 22-year-old had a few loan spells at other clubs, including Aston Villa and Bristol City, where he scored more than 20 goals in a single season. Despite missing a penalty againstLiverpoolin the UEFA Super Cup, Abraham still won a place in the team with his performances, keeping Olivier Giroud and Mitchy Batshuayi on the bench.
In thistactical analysisscout report, we will show you the strengths of Abraham. It is also ananalysisthat explains the role of the Englishman in Frank Lampard’stactics.
Statistical analysis & role at Chelsea
The below graph summarizes the strengths of Abraham by numbers. The former Villa man is sharp in some areas. Abraham had113touches in the box,4.99per 90 minutes, ranked 13th in the Premier League. With an average of2.87shots per game, his goal conversion ratio and shot on target percentage were20%and44.62%respectively. The goal/90 minutes ratio was0.57. These statistics hint that Abraham was doing quite fine in terms of finishing.
Cr. Wyscout
Below is the heat map of Abraham. You could see his active involvements in the central areas, especially within the penalty box. Despite Chelsea attacking the flanks, the 22-year-old tended seldom move to the wide areas, and we will explain his role under Lampard in the coming section.
Heat map of Abraham (Cr. Wyscout).
At Chelsea, Abraham mainly had two sources to receive a pass in the build-up phase. Since it was unnecessary for the Blues to play out from the back via the sole pivot, their full-backs were tasked to provide the out balls. Abraham is a 191 cm tall striker, and so he served as the target man as well.
The movements are twofold as shown in the following image. For the first case, Abraham stayed beside a centre-back, and his movement would depend on the situation. If it was a long ball, then, he attempted an aerial duel. If the pass was not deep enough, he dropped slightly and took a defender with him. On some occasions, when the central areas had another Blue, he freed himself to receive the pass in the wide areas. However, this movement was less likely to happen as Willian or Mount would cover the wide areas for him.
In such a case, as demonstrated in the following image, these two strikers could occupy both centre-backs, creating two 1 v 1 situations. With this approach, Abraham would be the striker lurking at the far post and as a target of the crosses. This maximized the strength of Abraham, as he was isolated against a defender. Please notice the gap between the defenders, Abraham was clever to read these spaces and attack them.
Abraham has the compatibility to play in a 4-4-2.
Aerial abilities
As mentioned, Abraham has physical superiority. Therefore, Lampard has tried to utilize his height in different phases of the game. Abraham served as a target man to receive the chip passes or long passes.
The 22-year-old is not a muscular striker, but his height helped him to win aerial duels easily. The stark contrast when jumping was illustrated in this image. Fikayo Tomori headed the ball in the air, with this aerial duel involving Abraham and Jesús Vallejo. When Abraham jumped, the Spaniard was nowhere near the ball. The attack was progressed as the guided pass reached Mason Mount easily, without any pressure.
Also, the Chelsea no.9 could also use his body to shield the ball. In this case, Wolves’ Romain Saïss challenged Abraham from behind. Abraham used his body to separate the ball and the defender. Furthermore, Saïss could not see the ball clearly as Abraham was too big to deal with, and hence was unable to anticipate the next move of the target.
In this scenario, Abraham also demonstrated his recognition of space, as his second touch took the ball to the space between the Wolves players. Then, it was quickly released to the wide player, César Azpilicueta.
However, in some other cases, when Abraham was dealing with the pressure from behind, the pass was suboptimal as he could not resist the tight marking by using only his body. This might be the area for the Englishman to work on if he wants to further develop as a target man.
An example combined space recognition and use of the body.
Positioning
Capitalizing on Chelsea’s tactics, Abraham often chose his positions wisely. When playing teams with a back four, Abraham liked to position himself around the far side centre-back. When Chelsea attacked the flanks, they could commit the full-backs and the advanced midfielders to the wide areas. Also, wingers like Willian, Callum Hudson-Odoi and Christian Pulisic had the ability to take on the defenders to cross. Therefore, the task of Abraham was to stay at the centre for the cross.
In such a case, when Chelsea attacked the flanks, the opposition defenders inevitably moved to the wide areas. Usually, the gap appeared between the centre-backs. Abraham liked to attack those spaces to meet the cross. The 22-year-old only showed up at the last moment to meet the cross, as he stayed at the blindside of the far side centre-back initially. If he positioned himself between the defenders too early, his presence would be visible and easy to mark.
The below situation is an example. In this case, Chelsea tried to penetrate through the centre with Tariq Lamptey’s progressive run. Abraham stayed around Callum Chambers initially, reading the spaces behind David Luiz. He quickly made a diagonal run to exploit those spaces and receive the pass from the right-back. BothArsenalcentre-backs were unaware of his run, hence, he was free to receive the ball in the box.
The first step, pick one centre-back to stay. Second, beat him with pace and run through the gaps.
Movement
Apart from the above examples which demonstrate how Abraham attacked spaces between centre-backs, his movements also helped his team in open plays. As explained, Abraham kept himself centrally, so he was ready to attack spaces behind a high defensive line always.
In this scenario, Abraham used his pace to beat Ajax’s centre-back, Daley Blind with a run outlined by the blue arrow. Since the 22-year-old is young and quick, he was faster than the Dutchman. In this case, he had a 1 v 1 opportunity against the keeper thanks for his pace.
Abraham was quick enough to generate an opportunity for himself.
Abraham is also a forward player who is willing to provide unselfish runs for his teammates. Some of the Blues (e.g. Willian, Pulisic or Mateo Kovačić) like to carry the ball forward; in those situations, Abraham would try to run laterally or diagonally to bring away the defenders.
In this image, you can see Hudson-Odoi was carrying the ball forward. Abraham understood the 1 v 1 ability of the youngster, therefore, he ran inward to the centre. This run forced the centre-back, Jamaal Lascelles, to follow him. As a result, Hudson-Odoi can take on the wide defender alone.
An unselfish run of Abraham.
Abraham also had his preferred movements in the box. As mentioned, he liked to stay at the far side centre-back’s far side, then exploit spaces between the defenders. In this scenario, Alonso attempted a cross. The 22-year-old stays behind Conor Coady initially, then, steps ahead to attack the ball before the Irishman.
This movement originated from the clever positioning as explained, and resulted in a goal.
Shooting
When analyzing a striker, we have to mention his shooting. Abraham is gifted in this aspect. On some occasions, even if his body orientations are suboptimal, he has still managed to put the ball into the net. The number nine of Chelsea has a good sense of finishing when shooting a bouncing ball or a dropping ball.
This example was his first goal at Chelsea. In the game against Norwich City, Abraham scored within three minutes. As you can see below, despite the ball dropping, Abraham still managed to score with a first-time shot.
In these situations, Abraham contacts the ball very well.
A minor flaw of Abraham’s shooting is his preparation before the ball arrives. When he is fit, he can score goals with suboptimal body orientations. However, sometimes this flaw still adversely affects the execution of Abraham’s ideas.
In this scenario, Abraham noticed Ederson’s positioning. The Brazilian was out of position. In this fast break, if the 22-year-old could loft the ball over Ederson, then it was likely to reach the top corner. The idea was right, however, when N’Golo Kanté passed him the ball, Abraham was still facing the touchline. Better body orientation would be to face the goal, which would give him a wider angle to generate the shot as he wished. Therefore, the idea was not executed perfectly, with the ball not even on target.
Some similar issues also exist in Abraham’s headers. He is too focused on the ball – if the ball is aimed right above his head, it is an easy header for him. However, if Abraham has to adjust his position to meet the cross, for example, with a dash to the front post, he is less likely to generate an optimal body shape for a shot.
Defensive duties
In the last section of the analysis, we are going to explain the defensive duties of Abraham. The former Swansea striker had2.58recoveries,1.99interceptions and1.1clearances. Of course, Abraham is not a defensive forward, but he still had his job to do in these phases.
When Chelsea are pressing, winning the ball high up on the pitch was not their top priority. Forcing the attacking team to play long and letting the centre-backs take part in the duels are their primary aim. Therefore, Abraham does not need to win the ball high. Instead of pressing the ball, only shutting the passing lanes is enough. When covering a player, the priority is to prevent a switch of play.
The circumstances were a bit similar in the defensive transitions. In this image, Wolves just regained possession, Rúben Neves was surrounded by the Chelsea players. Instead of approaching the Portuguese, Abraham only covered the deep options, Coady and Saïss. This forced Neves to play long and Chelsea won the ball back.
Lampard also tried to utilize the height of the 22-year-old when defending set-pieces, including the indirect freekicks and corners. Abraham was tasked to position himself at the front post to protect the zone, instead of marking an individual. Of course, the instruction was simple – clear any deliveries if possible.
In the following image, you can see Chelsea were defending a freekick and the position of Abraham. The English forward was not tasked to mark a target.
Conclusions
“He is a very good forward, with strong finishing skills, and good movement for his age.” – Luis Suárez
Abraham had a very strong start early this season. He was already one of the best young strikers in the world. As praised by Suárez, the 22-year-old was doing well in terms of movements and finishing at his age. His xG was18.89, almost four more than his current goals (15). As mentioned, the details and executions of the ideas still has room for improvement, and he has the time to improve himself.
| https://totalfootballanalysis.com/competitions/premier-league/tammy-abraham-2019-20-scout-report-tactical-analysis-tactics |
Answer to: The possible risk of cancer in multiple sclerosis patients: A controversial issue | Request PDF
Request PDF | On Dec 1, 2010, P Ragonese and others published Answer to: The possible risk of cancer in multiple sclerosis patients: A controversial issue | Find, read and cite all the research you need on ResearchGate
Answer to: The possible risk of cancer in multiple sclerosis patients: A controversial issue
December 2010
European Journal of Neurology 18(5)
DOI: 10.1111/j.1468-1331.2010.03304.x
[12]
[13][14]. These inconsistencies are due to methodological differences in study design, by the difficulty in selecting an appropriate reference group for comparisons, and length of follow-up, which is of particular relevance in clinical trials exploring the safety of drugs. ...
Association between multiple sclerosis, cancer risk, and immunosuppressant treatment: A cohort study
Paolo Ragonese
Paolo Aridon
Giulia Vazzoler
Giuseppe Salemi
Background
The association between multiple sclerosis (MS) and cancer has long been investigated with conflicting results. Several reports suggest an increased cancer risk among MS patients treated with immunosuppressant (IS) drugs.
Methods
We performed a cohort study including MS patients recruited at the Neurological Department of the University of Palermo. Mean follow-up period was ten years for the whole cohort. We calculated cancer incidence among patients treated with IS. Incidence rates were compared in the cohort by calculating the relative risk according to length and dose of exposure to IS. Cancer incidence among MS patients was compared to cancer incidence in the general population of Sicily in similar age groups.
Results
On an overall cohort of 531 MS patients (346 women and 185 men) exposed to IS, we estimated a crude incidence rate for cancer of 2.26% (2.02% in women, 2.7% in men). Cancer risk was higher compared to rates observed among an equal number of patients not exposed to IS, and to the risk in the general population in Sicily at similar age groups (adjusted HR: 11.05; CI 1.67–73.3; p = 0.013).
Conclusion
The present study showed a higher cancer risk in MS patients associated only to previous IS exposure. Studies on long-term outcomes are essential to evaluate the possibility that treatment options that need to be considered for a long time-period may modify risk for life threatening diseases.
Cancers and multiple sclerosis: Risk of comorbidity and influence of disease modifying therapy
Data of clinical-epidemiological studies on the risk of cancer in patients with multiple sclerosis (MS) are discussed. A trend towards increased risks of brain tumors and urological cancers has been shown. The author considers risk factors, including disease modifying therapies (DMT), for different cancers. It has been concluded that longitudinal observational and large cohort studies along with MS registers are needed to clarify a role of DMD in the development of malignant neoplasms.
To determine the risk of cancer before and after the diagnosis of motor neuron disease (MND), multiple sclerosis (MS) and Parkinson's disease (PD).
Analysis of statistical database of linked statistical abstracts of hospital and mortality data in an area in southern England.
Only people with PD showed a significant difference in the overall incidence of cancer compared with controls (rate ratio (RR) 0.76, 95% CIs 0.70 to 0.82 before PD; RR 0.61, 0.53 to 0.70, after PD). RRs were close to 1 for cancer in patients after MND (0.98, 0.75 to 1.26) and after MS (0.96, 0.83 to 1.09). There were high rate ratios for malignant brain cancer (7.4, 2.4 to 17.5) and Hodgkin's lymphoma (5.3, 1.1 to 15.6) in patients diagnosed with MND after cancer. In people with MS, malignant brain cancer also showed an increased RR both before hospital admission with a diagnosis of MS (3.2, 1.1 to 7.6) and after (2.4, 1.2 to 4.5). In people with PD, several specific cancers showed significantly and substantially reduced RRs for cancer, notably smoking related cancers, including lung cancer (0.5, 0.4 to 0.7, before PD; 0.5, 0.4 to 0.8, after PD) but also cancers that are not strongly smoking related, including colon cancer (0.7, 0.6 to 0.9, before PD; 0.5, 0.4 to 0.8, after PD).
People with MND, or MS, do not have an altered risk of cancer overall. There may sometimes be misdiagnosis between MND or MS and brain tumours. PD carries a reduced risk of cancer overall, of some smoking related cancers and of some cancers that are not smoking related.
Cancer risk and impact of disease-modifying treatments in patients with multiple sclerosis
Prior to the era of immunomodulating or immunosuppressive (IS) treatments Multiple Sclerosis (MS) was linked to reduced rates of cancer. Method A descriptive study of MS patients with a documented oncological event was performed. From 1 January 1995 to 30 June 2006, we collected and studied the profile of 7,418 MS patients gathered from nine French MS centers. We evaluated the incidence of cancer in a Cancer Risk In MS Cohort.
Thirty one patients (1.75%) with confirmed MS had a history of cancer: mean age at MS diagnosis of 37.9 years and a mean age at cancer diagnosis of 46.4 years. The most frequent cancers were breast (34.5%), gynecological (12.5%), skin (10.2%), acute leukemia and lymphoma (5.9%), digestive (8.8%), kidney and bladder (5.1%), lung (3.4%) and central nervous system (3%). Calculated standardized incidence rates were 0.29 (0.17-0.45) for men and 0.53 (0.42-0.66) for women. The incidence of cancer in this MS population was lower than that expected for the general population. Matched to age, gender and histology, cancers in MS were associated with a young age and exposure to IS treatments. When considering all patients, treated patients had a 3-fold higher risk of developing cancer, if they had a history of IS (P = 0.0035). For treated patients, the cancer sites were more likely the breast, the urinary tract, the digestive system and the skin.
Our data suggest that MS patients do not have an increased risk of cancer. Rather for several types of cancer a significantly reduced risk was observed, except for breast cancer in women treated with IS. The relative increased risk of breast cancer in MS women under IS treatment warrants further attention.
| https://www.researchgate.net/publication/49722059_Answer_to_The_possible_risk_of_cancer_in_multiple_sclerosis_patients_A_controversial_issue |
UK - Election: Vote Corbyn | libcom.org
UK - Election: Vote Corbyn
Submitted bywishfaceon October 25, 2016
As I write this, I'm deluged with facebook/social media reports of more ordinary, working class, people, here in the UK, suffering the effects of austerity (ie capitalism). Every day this is the case: people forced into starvation, sick people denied the means to live, mentally ill people bullied and spat on, scrounger rhetoric and division. This country is a time bomb right now. Something, soon, is going to happen.
There isn't going to be a revolution. As much as I would like there to be one - need there to be one - it isn't on the cards. Not remotely close. This country is a class addled divided shithole. The media is against us, vehemently so, the authorities don't care and aren't going to let up. The Tories have al the power, irrespective of the size of their majority.
So in 2020, the only chance there is for anything closely resembling change, the only sane choice, whatever your position, if you care about social justice, is to vote for Jeremy Corbyn. Even then, there's no guarantee he'll be on the ballot (and I wouldn't advocate voting for someone like Owen Smith or Angela Eagle, fwiw). But for the sake of argument, I assume he will be.
Why do I say this? The following reasons:
1. As I have said, there will not be a revolution. This isn't going to happen. I wish it weren't so, desperately. It's what this country needs. But what it needs it's not going to get. So we have to make do with what we have right now. That said, I fully endorse and support revolutionary activity and grassroots activism such as we have seen from groups like DPAC for example, or those resisting bailiffs and evictions - including those instigated by Labour councils. I'm not naive.
2. Since an election is inevitable, the left has a responsibility. If it doesn't vote that then translates into a vote for the Tories. Why: because Tory supporters always vote. They love this system, it's given them tangible results. This is not ideal of course, but there is no reason not to hold your nose and vote when doing so will at the very least send a message to the Tories they are not liked. This is important because, even though Labour are far from socialist (even under Corbyn), the Tories think they are.
It is a necessary evil and a simple brutal truth in the real world: if you don't' vote, you make it 1 vote easier for those that do to retain power and continue their evisceration of our society. Caveat: safe seats are an exception. I recognise all the faults with our electoral system. I accept all the criticisms against this argument, but it does not address the reality: if Corbyn only does one good thing, for instance repealing the Bedroom Tax, that alone is worth holding your nose and helping him win.
You can point to all the shit Labour councils do, such as as I have already hinted at, but that will happen anyway - and if they weren't in power locally do you think their opponents will do better? At least under Corbyn there is a chance, slim or otherwise, this may change.
The bottom line is this: you can still fight for revolutionary change, you can still campaign grassroots direct action, but if you enable the Tories to remain in power, knowing what they have done over the last 6 years already (never mind the next 4), you are complicit in that (aforementioned caveat aside, and any others I have not considered).
NB: I am not stupid, I am not anti working class, I am fully aware how this sounds. But the reality remains. What is your alternative? Thank you for reading.
jondwhite
6 years 8 months ago
In reply toWelcomebylibcom.org
Submitted byjondwhiteon October 25, 2016
Not sure if you are trolling
Not sure if you are trolling or flamebaiting or whatever but assuming you are serious.
We are not 'the left'.
Voting Corbyn is not 'the only chance', 'the sane choice'.
This is the reheated lesser-evil argument which even would have been made against forming a Labour party when the workers chose between Tories and Liberals.
Supporting the lesser of two evils always returns evil and hampers long-term organising. It is not a stepping stone, a halfway house and delays and postpones real revolution. It runs contrary to working class interest.
There is an alternative and it doesn't involve voting for Hillary or Corbyn so not every election is crucial to keep the more reactionary candidate out..
wishface
6 years 8 months ago
In reply toWelcomebylibcom.org
Submitted bywishfaceon October 25, 2016
jondwhite wrote: Not sure if
jondwhite
Not sure if you are trolling or flamebaiting or whatever but assuming you are serious.
We are not 'the left'.
Voting Corbyn is not 'the only chance', 'the sane choice'.
This is the reheated lesser-evil argument which even would have been made against forming a Labour party when the workers chose between Tories and Liberals.
Supporting the lesser of two evils always returns evil and hampers long-term organising. It is not a stepping stone, a halfway house and delays and postpones real revolution. It runs contrary to working class interest.
There is an alternative and it doesn't involve voting for Hillary or Corbyn so not every election is crucial to keep the more reactionary candidate out..
"not sure if you are trolling"...sigh.
If that's what you want to think then by all means show me your alternative,
I don't care what side you identify with, what your ideology is, or anything. I care about social justice. I think I made my point clear enough, if there is something you didn't understand then I welcome the opportunity to try and clarify. If you just want to call me a troll, then you can enjoy doing so under another 5 years of austerity and misery. Your choice.
All the class theory in the world isn't going to bring about change without activity. There isn't enough interest in our society to bring about a revolution so now you have the choice:
1. Hold your nose and vote Corbyn on the likelihood he will offer some form of respite for those dying (no joke) under austerity.
2. Hide inside your ideological bubble and, by refusing to vote, support the status quo.
That's it. I'm sorry if this sounds unpleasant, but in my view this is the only reality.
But, as I say: give me an alternative. I'm not interested in theory. There is no long term organisation. Where we are right now is a situation unprecedented in modern era; Even Thatcher was nowhere near as vicious as this lot. We are losing everything. The NHS is gone, the welfare state is killing people, racism and bigotry are spiralling out of control, we are about the leave the EU, the economy is fucked.
yet in spite of this, there is no hunger for class revolution. Even using this kind of language shuts down the discussion: people don't want to hear about communism, marxism, class this or that. They have been conditioned to reject this stuff. So where does that leave us?
wishface
6 years 8 months ago
In reply toWelcomebylibcom.org
Submitted bywishfaceon October 25, 2016
jondwhite wrote: Supporting
jondwhite
Supporting the lesser of two evils always returns evil and hampers long-term organising. It is not a stepping stone, a halfway house and delays and postpones real revolution. It runs contrary to working class interest.
There is an alternative and it doesn't involve voting for Hillary or Corbyn so not every election is crucial to keep the more reactionary candidate out..
Prove your claim please, and tell me what the alternative is.
Ed
6 years 8 months ago
In reply toWelcomebylibcom.org
Submitted byEdon October 25, 2016
Firstly, where I live, Labour
Firstly, where I live, Labour will win regardless of whether I vote or not. It's a safe Labour seat. We don't have proportional representation so it's not 'every vote matters'.
Secondly, other safe Labour seats are those in Southwark and Lambeth, where Labour have been decimating social housing. Are you calling on Southwark and Lambeth social housing tenants to vote for the people who're trying (and largely succeeding) to kick them out of their homes?
Lastly, not voting Corbyn isn't about fighting the revolution that isn't here instead. It's about spending our campaigning time building organisations that can fight to improve our conditions in the here and now: whether that means unions or extra-union workers' networks, tenants' groups, or local groups to stop closure/cuts to services. And fighting means fighting whoever it is that's attacking us, including Labour councils.
What you're proposing is all of that is subordinated to getting Labour elected in four years' time: what do we do until then? Let Southwark and Lambeth councils sell off all the social housing stock? And what if Corbyn then doesn't come good on his promises? Four years of energy and activism sunk while conditions deteriorate.
Oh well, there's always 2025..
wishface
6 years 8 months ago
In reply toWelcomebylibcom.org
Submitted bywishfaceon October 25, 2016
I covered the exception of
I covered the exception of safe seats, so we don't need to go into that again.
I also highlighted the example of Labour councils decimating social housing and mentioned that it doesn't matter who runs those councils, they will be making the same decision.
You can spend your time building organisations and doing all those things. Voting takes ten minutes of your time so really there is no logistical problem.
However fighting those councils isn't really working. There have been a few victories - the Focus E15 mums for instance, and I commend and support those entirely.
But, for example, Bristol faces almost a total of 100 million worth of cuts udner a labour mayor over the next 4 years. These cuts are horrific and will decimate the city. The counter argument is the Tories will, if those cuts are rejected, simply step in and run the city instead. What is your alternative there, given there is no revolution? There will not be the direct action required to prevent or disrupt that successfully because again there is no revolution. And again I wish it weren't so - in fact having to repeatedly point that out to people that claim to be anarchists is depressing, but there we go.
There will be 2025, there will be 2030 as well, and so on, because there won't be a revolutionary society anytime soon. If you don't like that reality, too bad because we are where we are.
I don't believe Corbyn will come good on everything, I believe that was part of my point made explicit.
My point was that he will ameliorate some conditions, he will offer some respite to people in situations so desperate as to be unprecedented.
What alternative do you offer to the pregnant single mother sanctioned off benefits? Ideology? A few books by Marx or Bakunin? Can she cook them?
jondwhite
6 years 8 months ago
In reply toWelcomebylibcom.org
Submitted byjondwhiteon October 25, 2016
Nobody is proposing
Nobody is proposing inactivity. Nobody has to support or vote for Corbyn to defend the working class. The 'alternatives' have been organising for a very very long time. For at least a hundred and fifty years. Are you proposing what has gone before should be jettisoned?
Where we are now is not unprecedented in the modern era!!!
At the start of the twentieth century, supporters of the Liberals might have called for support on the basis they were the lesser evil compared to the Tory party rather than supporting the new Labour party. In case this isn't clear, lesser-evilism was an argument against the Labour party back then and had it been followed would have kept Labour out of power for longer.
There was no welfare state, there were economic recessions, wars and people dying throughout the modern era (including PMs worse than Thatcher) and people still rejected the lesser-evilism argument so they could build the alternatives they wanted and needed today. There was racism, bigotry and low levels of class consciousness.
The Labour party is anti-working class. They only keep getting elected because people vote for them. If you stop voting for them at the next election they will be less effective at the following one. You have the next generation in 2025 and the generation after that in 2030 to answer to if you keep returning Labour oppositions or Labour governments whether with slim majorities or by landslide. Part of the revolution is and will be keeping Labour out of power. You don't do that in the future by electing them now.
If alternatives aren't on the agenda, you should be putting them on, not somebody else, you!
If you are willing to trade ameliorated conditions under austerity to install the Labour party as the ruling class, then the working class will be accustomed to being ruled, and the Labour party will always be prepared to make (or promise) trade-offs or buyouts with some sections in order to rule over you and your class. Alternatives will never be built by those arguing for the lesser-evil.
If you vote for evil and get evil then you are responsible.
wishface
6 years 8 months ago
In reply toWelcomebylibcom.org
Submitted bywishfaceon October 25, 2016
Inactivity is what we have.
Inactivity is what we have. Revolutionary activity is marginal, support is marginal. That's the reality and that's what I'm talking about. Idealism isn't feeding people, foodbanks are and they are overwhelmed. Homeleness has skyrocketed - I've never seen it so bad. This country is fucked, absolutely and totally IMO - and we have three more years to the next election.
The modern era I'm talking about is the one we are living through right now. This is a post industrial advanced society with access to cutting edge technology and yet we are throwing people off the dole to die in poverty. There might not have been a welfare state back then, but there is one now and we are losing it inexorably. I fully expect it to disappear by 2020, privatised likt the NHS. Only today I read an article about tory cuts that will decimate the nation's provision of pharmacies. What will stop this?
I am not disagreeing with the broader points being made. I am speaking in practical terms. You have yet to evidence your claim about stifling revolutionary activity and you have yet to provide an alternative. I do not have the power to put anything on the agenda, but Jeremy Corbyn has the potential to effect at least some, small measure, of change. I believe him to be a relatively decent man (for a politician). That's why I mention him and that's why I said I wouldn't advocate supporting the others, like Eage or Smith. There is a perceptible difference here and dismissing him as the same as the likes of Blair Brown or whoever is just ignorance.
Certainly I could be wrong, but what do I lose by advocating this? The point you are missing is that there is going to inevitably be an election in 2020. That's a given, and someone is going to win it. If that someone can be a person or party that can, at least, ameliorate the suffering currently experience by so many in the working class (and indeed the precariat) then why would you throw that away when you haven't even proven that voting Corbyn would be a worse alternative? To call him evil is just childish, please do better. This isn't a joke, people are fucking dying.
jondwhite
If you are willing to trade ameliorated conditions under austerity to install the Labour party as the ruling class, then the working class will be accustomed to being ruled, and the Labour party will always be prepared to make (or promise) trade-offs or buyouts with some sections in order to rule over you and your class. Alternatives will never be built by those arguing for the lesser-evil.
As opposed to...?
I have no power to put anything on the agenda. I live in a Tory safe seat. It's a shithole, like the rest of this cunt-ry.
jondwhite
6 years 8 months ago
In reply toWelcomebylibcom.org
Submitted byjondwhiteon October 25, 2016
No, people were unnecessarily
No, people were unnecessarily dying from poverty at worse rates throughout the twentieth century which was a post-industrial advanced society in the modern era. Inactivity is not what we have, revolutionaries have been organising for over a hundred and fifty years.
What will stop Tory cuts will be getting rid of the Tories and their cuts, but ruling classes have always cut living conditions of the working-class as they see fit. You won't change this by installing a new ruling class.
Please don't claim to be speaking in practical terms as if it is an argument for Corbyn, I am speaking in practical terms, so was Marx, Engels and William Morris.
We have had over eleven Labour governments who have done nothing for revolution. Revolution is what will liberate the working class not amelioration. Don't delay it by helping another Labour government govern no matter how decent the leader happens to be (and yes Corbyn seems more decent than most). You will lose fellow workers trust and credibility as a revolutionary worker.
If you want a revolution and including Labour out of power, when are you going to start and stay true to keeping Labour out?
wishface
6 years 8 months ago
In reply toWelcomebylibcom.org
Submitted bywishfaceon October 25, 2016
jondwhite wrote: No, people
jondwhite
No, people were unnecessarily dying from poverty at worse rates throughout the twentieth century which was a post-industrial advanced society in the modern era. Inactivity is not what we have, revolutionaries have been organising for over a hundred and fifty years.
What will stop Tory cuts will be getting rid of the Tories and their cuts, but ruling classes have always cut living conditions of the working-class as they see fit. You won't change this by installing a new ruling class.
Please don't claim to be speaking in practical terms as if it is an argument for Corbyn, I am speaking in practical terms, so was Marx, Engels and William Morris.
We have had over eleven Labour governments who have done nothing for revolution. Revolution is what will liberate the working class not amelioration. Don't delay it by helping another Labour government govern no matter how decent the leader happens to be (and yes Corbyn seems more decent than most). You will lose fellow workers trust and credibility as a revolutionary worker.
If you want a revolution and including Labour out of power, when are you going to start and stay true to keeping Labour out?
The comparison to life around 100 years ago wasn't the comparison I was making, and I have explained this.
Yes, to stop the cuts we need to get rid of the people making them. So again what is your solution for this?
You have not spoken in practical terms, you have made numerous appeals to ideology.
You misrepresent my argument once more: i did not say that Labour had or will ever do anything for the revolution. That is not my argument. However reolutionary or not, it was Bevan and a Labour government that brought in the NHS. While it might not be the most egalitarian system ever, it remains a consistently better healthcare service than the american model advocated and being brought into place by the current government. If you wish to argue that was a capitalist sop you will have to provide evidence for this also, as I do not believe Bevan thought that was what he was doing.
When am I going to start? When the bleeding has stopped. Currently our society is an open wound. You don't heal it before stopping the flow of blood.
ajjohnstone
6 years 8 months ago
In reply toWelcomebylibcom.org
Submitted byajjohnstoneon October 25, 2016
Which party do you recommend
Which party do you recommend workers vote for in Northern Ireland and Scotland?
Is it still Corbyn and the Labour Party?
Northern Ireland if i recollect, doesn't have a UK Labour Party so that is out.
Scotland - Labour has not got a snowball in hells chance of beating the SNP who have adopted most of the Labour Party's positions so a Labour vote is a wasted vote.
So your proposal for the Labour vote is much the same as for the EU referendum...only England and Wales count politically.
wishface
6 years 8 months ago
In reply toWelcomebylibcom.org
Submitted bywishfaceon October 25, 2016
ajjohnstone wrote: Which
ajjohnstone
Which party do you recommend workers vote for in Northern Ireland and Scotland?
Is it still Corbyn and the Labour Party?
Northern Ireland if i recollect, doesn't have a UK Labour Party so that is out.
Scotland - Labour has not got a snowball in hells chance of beating the SNP who have adopted most of the Labour Party's positions so a Labour vote is a wasted vote.
So your proposal for the Labour vote is much the same as for the EU referendum...only England and Wales count politically.
I don't live in those areas so there may be circumstances that are different due to the vagaries of devolved politics. But tentatively I would still advocate Corbyn or perhaps the SNP who seem to have similar ideas.
This isn't a permanent deal. I'm not advocating voting for labour under all conditions all the time. I am saying that, right now, this is what needs to happen because if you genuinely care about the working class you will do what you can to effect whatever positive change can be wrought given how dire the situation is now.
It seems peculiar to me that it's impossible to both hold to a revolutionary ideal while supporting using the system to effect change where possible. That doesn't mean you have to support the parliamentary system per se, just that, given the situation, you use it to make things better where possible while working toward a long term revolutionary goal. But that long term is decades if not centuries away.
I'm still waiting on a workable alternative. Just saying we need revolution will not make it so and, in my experience, the anarchists i've come across have been all talk. Just look at the idiots that call themselves 'Class War'; all they do is resort to abuse and cuss words; they have a photo on their facebook calling Corbyn a reformist wanker, meanwhile they put Lisa McKenzie up to stand against IDS! Utter hypocrisy. Meanwhile in bristol they are petrol mombing cars in suburbs. Great!
Spikymike
6 years 8 months ago
In reply toWelcomebylibcom.org
Submitted bySpikymikeon October 25, 2016
Those who wait for others die
Those who wait for others die waiting. A Corbyn led government is unlikely, but if it were to come about, then bar a few scraps thrown to the fools who voted for it, nothing of substance will have changed. The problem is capitalism, whichever government tries to run it - because it runs them!
Chilli Sauce
6 years 8 months ago
In reply toWelcomebylibcom.org
Submitted byChilli Sauceon October 25, 2016
Quote: As I have said, there
As I have said, there will not be a revolution. This isn't going to happen.
So, this has already been covered, but we can accomplish a lot short of revolution and the ways we accomplish that (direct action, self-organization, industrial action, campaigning) don't change regardless of who's in power.
I sort of see why the extremely low level of class power and class confidence leads to a sense of defeatism that makes voting look attractive. But a belief in electoralism (either proactive or lesser of two evils) reinforces that passivity.
Anyway, go ahead and vote, I don't really care and I don't even usually bother to have the argument, but please spare us the lecturing.
Red Marriott
6 years 8 months ago
In reply toWelcomebylibcom.org
Submitted byRed Marriotton October 25, 2016
Just join The Pirate Party
Just join The Pirate Party and all your dreams will come true and capitalism will magically become something really nice;
The party that could be on the cusp of winning Iceland’s national elections on Saturday didn’t exist four years ago.
Its members are a collection of anarchists, hackers, libertarians and web geeks. It sets policy through online polls – and thinks the government should do the same. http://www.independent.co.uk/news/world/europe/iceland-braces-for-a-digital-revolution-as-pirate-party-prepares-power-election-2016-a7377456.html
Fleur
6 years 8 months ago
In reply toWelcomebylibcom.org
Submitted byFleuron October 25, 2016
wishface: You're really not
wishface:
You're really not going to get a lot of support for voting Labour here, although to be quite honest I don't really care if you do or don't vote. I think people who fetishize not voting to be as dreary and preachy and irrelevant to my life as those bang on about how important voting is.
However, I think you might be investing a wee bit too much hope in this one man. Even if Labour wins the next election (unlikely) Corbyn doesn't have the support of the PLP, it's highly unlikely that all the MPs involved in the coup will be de-selected, so they'll all be sitting behind him, not co-operating. That's not much of a recipe for Corbyn ushering any serious changes.
If I was really, really cynical* I would suspect that the Labour right might be playing the long game and actually hoping not to win the next election, so they can get rid of Corbyn et al return to the status quo.
I understand the desperation of UK folks, from what I see things have deteriorated to something abysmal and the Tory party are a very special kind of pond scum, but investing so much hope in one man is destined to lead only to disappointment, not to mention a huge waste of time. How much energy was spent on Momentum this summer, energy which could have been spent more productively elsewhere?
*Actually, I'm really, really, really, really cynical.
Fleur
6 years 8 months ago
In reply toWelcomebylibcom.org
Submitted byFleuron October 25, 2016
Also, I'm pretty sure you're
Also, I'm pretty sure you're wasting your time trying to talk us into voting for Labour. The potential anarchist voting power is probably not even large enough to swing a parish council vote, let alone a general election :P
wishface
6 years 8 months ago
In reply toWelcomebylibcom.org
Submitted bywishfaceon October 25, 2016
Spikymike wrote: Those who
Spikymike
Those who wait for others die waiting. A Corbyn led government is unlikely, but if it were to come about, then bar a few scraps thrown to the fools who voted for it, nothing of substance will have changed. The problem is capitalism, whichever government tries to run it - because it runs them!
How does that alter anything I've said?
A few scraps is better than no scraps for those 'fools' (nice attitude) who need them.
So by all means continue fighting against capitalism. I support that entirely, but the two positions aren't mutually exclusive.
And again, no alternative is offered, only platitudes.
wishface
6 years 8 months ago
In reply toWelcomebylibcom.org
Submitted bywishfaceon October 25, 2016
Chilli Sauce
Chilli Sauce
As I have said, there will not be a revolution. This isn't going to happen.
So, this has already been covered, but we can accomplish a lot short of revolution and the ways we accomplish that (direct action, self-organization, industrial action, campaigning) don't change regardless of who's in power.
I sort of see why the extremely low level of class power and class confidence leads to a sense of defeatism that makes voting look attractive. But a belief in electoralism (either proactive or lesser of two evils) reinforces that passivity.
Anyway, go ahead and vote, I don't really care and I don't even usually bother to have the argument, but please spare us the lecturing.
What is being accomplished right now?
Has it succeeded in getting justice for those sanctioned to death? Has it removed the bedroom tax? Has it stopped fracking, and so on?
I fully support the efforts of those undertaking such actions. DPAC for example are nothing short of heroes. But they are alone and not enough. That's the tragedy and the reality of it all.
I will not spare you the 'lecturing'. Is this an authoritarian posture? I have every right to proffer my opinion.
wishface
6 years 8 months ago
In reply toWelcomebylibcom.org
Submitted bywishfaceon October 25, 2016
Red Marriott wrote: Just join
Red Marriott
Just join The Pirate Party and all your dreams will come true and capitalism will magically become something really nice;
The party that could be on the cusp of winning Iceland’s national elections on Saturday didn’t exist four years ago.
Its members are a collection of anarchists, hackers, libertarians and web geeks. It sets policy through online polls – and thinks the government should do the same. http://www.independent.co.uk/news/world/europe/iceland-braces-for-a-digital-revolution-as-pirate-party-prepares-power-election-2016-a7377456.html
Or you could actually respond to what i've said and not what you think I've said.
wishface
6 years 8 months ago
In reply toWelcomebylibcom.org
Submitted bywishfaceon October 25, 2016
Fleur wrote: Also, I'm pretty
Fleur
Also, I'm pretty sure you're wasting your time trying to talk us into voting for Labour. The potential anarchist voting power is probably not even large enough to swing a parish council vote, let alone a general election :P
It's my time to waste.
And I'm not talking you into voting labour. I'm trying to talk you into recognising that, in 2020, the just thing to do is to put Corbyn into power. He may not even be leader by then and if someone like Owen Smith is on the ballot, then, as I've already said, I wouldn't support that.
That the anarchist bloc in the uk is tiny is exactly my point.
So, for the fourth time of asking, what is the alternative, other than putting the Tories back into power for five more years of misery. People are suffering and I don't see much compassion here at all.
radicalgraffiti
6 years 8 months ago
In reply toWelcomebylibcom.org
Submitted byradicalgraffition October 25, 2016
replace syriza with corbyn
replace syriza with corbyn
wishface
6 years 8 months ago
In reply toWelcomebylibcom.org
Submitted bywishfaceon October 25, 2016
Fleur
Fleur
wishface:
However, I think you might be investing a wee bit too much hope in this one man. Even if Labour wins the next election (unlikely) Corbyn doesn't have the support of the PLP, it's highly unlikely that all the MPs involved in the coup will be de-selected, so they'll all be sitting behind him, not co-operating. That's not much of a recipe for Corbyn ushering any serious changes.
That may be true, but you're still not getting it.
Even if that's your reason not to vote Corbyn in, the alternative is that, since there will be an election in 2020 and there won't be a revolution, the Tories will retain power. Which is worse?
wishface
6 years 8 months ago
In reply toWelcomebylibcom.org
Submitted bywishfaceon October 25, 2016
radicalgraffiti
radicalgraffiti
replace syriza with corbyn
Our situation is different so there isn't the likelihood of Corbyn being humbled by the troika as Sypras (sp?) was. We are a sovereign currency.
So, for the fifth time of asking, what is the alternative?
radicalgraffiti
6 years 8 months ago
In reply toWelcomebylibcom.org
Submitted byradicalgraffition October 25, 2016
wishface wrote: So, for the
wishface
So, for the fourth time of asking, what is the alternative, other than putting the Tories back into power for five more years of misery. People are suffering and I don't see much compassion here at all.
ajjohnstone
6 years 8 months ago
In reply toWelcomebylibcom.org
Submitted byajjohnstoneon October 25, 2016
http://www.parliament.uk/edm/
http://www.parliament.uk/edm/2006-07/1240
Never mind, the cost of running the NHS under Corbyn is guaranteed to come down if elected
The homeopathy-believing/trusting Labour Party leader just needs to change all the Big Pharma pills and potions to water, as long as they don't buy them from Boots the Chemist
http://www.boots.com/en/Pharmacy-Health/Health-shop/Alternative-therapy/Homeopathy/
The alternative is simple...keep telling your family, your friends, your fellow workers, they are f##ing delusional to think there will be a permanent amelioration of their circumstances from a Labour Govt. eventually the message might sink in when they witness the actions of Labour.
Introduces the national health service, as you say - and then the first to introduce charges to this free health service ...
Rob Ray
6 years 8 months ago
In reply toWelcomebylibcom.org
Submitted byRob Rayon October 25, 2016
Quote: Our situation is
Our situation is different so there isn't the likelihood of Corbyn being humbled
Lol "wishface" really is a wonderfully accurate moniker.
jondwhite
6 years 8 months ago
In reply toWelcomebylibcom.org
Submitted byjondwhiteon October 25, 2016
wishface wrote: The
wishface
The comparison to life around 100 years ago wasn't the comparison I was making, and I have explained this.
Yes, to stop the cuts we need to get rid of the people making them. So again what is your solution for this?
You have not spoken in practical terms, you have made numerous appeals to ideology.
You misrepresent my argument once more: i did not say that Labour had or will ever do anything for the revolution. That is not my argument. However reolutionary or not, it was Bevan and a Labour government that brought in the NHS. While it might not be the most egalitarian system ever, it remains a consistently better healthcare service than the american model advocated and being brought into place by the current government. If you wish to argue that was a capitalist sop you will have to provide evidence for this also, as I do not believe Bevan thought that was what he was doing.
When am I going to start? When the bleeding has stopped. Currently our society is an open wound. You don't heal it before stopping the flow of blood.
You can start by explaining why political and especially class consciousness, and membership of organised labour unions has probably gone down over the last hundred years. Maybe something to do with, among other reactionary arguments, what is commonly known as the lesser of two evils argument. Sure you are happy to subjugate history and the future to the now, where you are urging us vote for Corbyn. Forget about elections gone by and elections to come after the next one. Living standards can be better under lesser evils but we want the best and the way to get that is refusing to accept anyone to rule over us.
wishface
6 years 8 months ago
In reply toWelcomebylibcom.org
Submitted bywishfaceon October 25, 2016
ajjohnstone
ajjohnstone
http://www.parliament.uk/edm/2006-07/1240
Never mind, the cost of running the NHS under Corbyn is guaranteed to come down if elected
The homeopathy-believing/trusting Labour Party leader just needs to change all the Big Pharma pills and potions to water, as long as they don't buy them from Boots the Chemist
http://www.boots.com/en/Pharmacy-Health/Health-shop/Alternative-therapy/Homeopathy/
The alternative is simple...keep telling your family, your friends, your fellow workers, they are f##ing delusional to think there will be a permanent amelioration of their circumstances from a Labour Govt. eventually the message might sink in when they witness the actions of Labour.
Introduces the national health service, as you say - and then the first to introduce charges to this free health service ...
Firstly, his comment about homeopathy is as follows:
"4. The NHS currently spends hundreds of millions of pounds funding alternative and homeopathic medicine. Would this policy continue under your Labour government?
I don't support the NHS spending taxpayers’ money on medicine where it is not backed up by clear, scientific evidence as to its effectiveness."
(source:
http://www.scientistsforlabour.org.uk/en/index.php?option=com_content& view=article& id=156:jeremy-corbyn-statement-on-science& catid=41:articles& Itemid=140)
So we can ignore the nonsense about homeopathy on good grounds. However it's not really relevant is it: plenty of anarchists engage in alternative medicines and other 'unscientific' practices. Should they be ignored within our community? What about those community members who believe vaccinating kids is dangerous? This is not really a rabbit hole you want to go down I think.
I presume your comment about the cost of the NHS is intended as sarcasm. It's hard to tell quite honestly and I wish people wouldn't engage in that kind of puerile banter tbh.
So to you real point, that doesn't address what I have said either. I didn't say Corbyn would make a permanent change. I am talking about the election in 2020 and, as I've made repeatedly clear, I am not selling the notion the Labour party will permanently change things. At this point I dont know how to make that clearer. I have repeatedly stated that revolutionary activity should occur simultaneously so that we don't have to rely on Labour. My only argument is based on ameliorating the conditions that exist right now. If you are not prepared to offer anything to support that end, and it seems people on here aren't, then I can only conclude that youre anarchists in theory, not in practice.
wishface
6 years 8 months ago
In reply toWelcomebylibcom.org
Submitted bywishfaceon October 25, 2016
Rob Ray wrote: Quote: Our
Rob Ray
Our situation is different so there isn't the likelihood of Corbyn being humbled
Lol "wishface" really is a wonderfully accurate moniker.
unlike wishing for a revolution?
wishface
6 years 8 months ago
In reply toWelcomebylibcom.org
Submitted bywishfaceon October 25, 2016
jondwhite wrote: You can
jondwhite
You can start by explaining why political and especially class consciousness, and membership of organised labour unions has probably gone down over the last hundred years. Maybe something to do with, among other reactionary arguments, what is commonly known as the lesser of two evils argument. Sure you are happy to subjugate history and the future to the now, where you are urging us vote for Corbyn. Forget about elections gone by and elections to come after the next one. Living standards can be better under lesser evils but we want the best and the way to get that is refusing to accept anyone to rule over us.
I don't know how any of this relates to anything I have said. What does 'subjugate history' even mean? How many times have I asked for an alternative? You have yet to provide anything remotely credible that will effect real change, no matter how small.
We want the best, but that isn't going to happen anytime close to soon. There is more chance of being struck by lightning than there being a revolution in the UK. Again I wish it were different, but wishful thinking seems to be all that you have. I am dealing with practicalities and yet noone here seems to be able to grasp the idea of using existing structures to benefit the working class on a temporary basis while working toward something better.
Tell me your alternative. I've yet to hear it. I asked afed in Bristol how big they were. The number was about 20 (iirc). It was a dismally small number. All of these people (arsonists aside) I'm sure are decent honourable people, that's not my contention, but 20 people aren't going to change anything, so what do you propose?
Serge Forward
6 years 8 months ago
In reply toWelcomebylibcom.org
Submitted bySerge Forwardon October 25, 2016
Well, that's us told. Maybe
Well, that's us told. Maybe I'll go and find a Momentum forum and tell them they're all wrong. Or maybe I'll just see what's on telly instead.
Rob Ray
6 years 8 months ago
In reply toWelcomebylibcom.org
Submitted byRob Rayon October 25, 2016
You seem to be under a
You seem to be under a misapprehension that anyone on these boards thinks a "revolution" in the teenage rebel sense is likely and/or desirable?
I realise it must be quite hard, coming at it from fantasy Corbyn-island where most of your critics are to your right, to imagine that people on your left might not see your sub-Bevanite schtick as particularly impressive whilealsonot being a Daily Mail pastiche of the screeching ideologue, but you do yourself no favours by coming on boards with (clearly) fuck all understanding of the creed you're trying to debate against with the big patronising I Am.
Ed
6 years 8 months ago
In reply toWelcomebylibcom.org
Submitted byEdon October 25, 2016
Ok, so before I carry on I'm
Ok, so before I carry on I'm going to ask that you stop replying with 'what's your alternative? revolution?' and 'can single mothers eat Bakunin?'. I haven't once mentioned revolution or Bakunin (and I don't think anyone else has either) and it's just plain disrespectful to expect me to write lengthy replies only for you to discount them out of hand based on your own prejudices about things I haven't said. I write this now assuming you'll knock that on the head and engage with what is actually said rather than what's easier to answer..
wishface
You can spend your time building organisations and doing all those things. Voting takes ten minutes of your time so really there is no logistical problem.
Ok but as we already covered, I live in a Labour safe seat and, I'd hazard to guess, so do most far-left revolutionary types.. just look at the local groups of most anarchist/socialist organisations: they're mostly based around big urban centres i.e. where the Labour vote is strong.
If you want to make a difference to Corbyn's electoral chances, it's not enough that the relatively few revolutionaries living in Labour strongholds vote Labour; it means campaigning where Labour are weak. That's more than just ten minutes: that's hundreds, maybe thousands, of activist hours being bussed out to fucking Wealden or wherever, knocking on doors, talking to people. Hours which could be spent campaigning to defend social housing, against pay cuts etc rather than trying to get politicians elected in four years time (hoping not just that they'll stick to their promises but reverse all the shit we've put up with in the meantime)..
wishface
However fighting those councils isn't really working. There have been a few victories - the Focus E15 mums for instance, and I commend and support those entirely.
wishface
I fully support the efforts of those undertaking such actions. DPAC for example are nothing short of heroes. But they are alone and not enough. That's the tragedy and the reality of it all.
So, yeah, I know we're mostly losing. But that's precisely because people aren't active. You can't look at general inactivity and conclude that taking action doesn't work. And while Corbyn may have rejuvenated some CLPs you'll have to admit that many thought they could change the direction of UK politics by paying £3 and voting him as Labour leader.
Compare that to the situation in the 1970s where one in six workers was a union rep; criticisms of unions aside, that's an entirely different form of politics (and one we've largely lost, some industries don't even have one in six in a union!). It involves active participation, a willingness to disrupt institutions (their workplace, letting agents or whatever) and an ability to take the shit that comes with it from bosses, landlords, the law etc.
So the decision really is between trying to build a movement that fights now or one that tries to get someone elected in four years in the hope they really do improve our lives. It very much isn't about some distant revolution.
wishface
Our situation is different so there isn't the likelihood of Corbyn being humbled by the troika as Sypras (sp?) was. We are a sovereign currency.
So, people like to say this but I honestly don't get why this is true for the following reasons:
1) Pressures within the Labour Party: fact is, Corbyn could literally stop cuts in loads of Labour councils and really take the fight to the Tories tomorrow just by telling his MPs, councilors etc to break cuts budgets.But he's done the opposite. Now he's obv trying to hold his party together (same way we're bombing Syrians coz he wanted to keep his party together). That will still be the case even if he's elected PM; there'll still be a Labour right, unless there are mass deselections they'll still be a majority of the PLP and they'll still be politicking and undermining him/the Labour left. For Jeremy to win, at a minimum, voters in Southwark will have to vote for the arseholes destroying the borough's social housing, which means they'll still be in the PLP of a Corbyn govt, threatening to ignore the whip, leaving Cabinet, publicly criticising etc. That pressure to hold the party together will always be there.
2) Pressures on the UK economy: Brexit has sent the pound ('our sovereign currency') crashing, we're expecting price rises on imports and banks are threatening to leave, all because the government has moved against the wishes of international (specifically European) capital. The government wanted businesses to provide lists of foreign workers; the CBI kicked up a fuss and got it scrapped. Now imagine instead of a right-wing racist capitalist govt, it was Corbyn's lefty govt. The non-cooperation and active sabotage from capital would be even stronger (with added pressure of having the entire media against him). Seriously, there's nothing about the UK that means our government can boss capital around..
The idea that Corbyn wouldn't end up like Tsipras (or Hollande, or the German and Irish Greens, or the Italian Communist Party of the 1970s etc etc) is a false hope. In all likelihood, that's exactly what would happen.
So you might say that building a militant social movement is a long way off and tbh you're completely right. But just coz we're nowhere near such a movement and staring disaster in the face, doesn't make your proposal any more likely..
ajjohnstone
6 years 8 months ago
In reply toWelcomebylibcom.org
Submitted byajjohnstoneon October 26, 2016
New Scientist quotes him on
New Scientist quotes him on Twitter saying
" I believe that homeo-meds works for some ppl and that it compliments 'convential' meds. they both come from organic matter..."
https://www.newscientist.com/article/dn28169-jeremy-corbyn-where-he-stands-on-science-and-medicine/
So does bear bile and tiger gonads "work" for some people.
I am a member of a small party with the only saving grace is that it has survived and stuck to its principles. However, it has survived for over a century, listening to all manner of well-intentioned folk defend the Labour Party and all the pressure and ginger groups which sprung up over all these decades, many now deceased and buried .. the ILP, the Socialist League ...
I have no wish to complain but if less people like your good self stopped offering apologies for the failure of decades of Labour Party and began the laborious task of education and persuasion rather than engaging in dead-end cul de sac lesser evil arguments we might actually be a bit closer to socialism that we were when my party actually was founded.
For anyone genuine and sincere in wishing to bring about a new and better world, supporting the Labour Party requires a pact with the devil. Where the forming of a government means being sucked into running the system. Over decades, millions of workers have invested their hopes in so-called ‘practical’, ‘possibilist’ organisations like the Labour Party, hoping against hope that they would be able to neuter the market economy when, in reality, the market economy has successfully neutered them. they turned out to be the real ‘impossibilists’ – demanding an unattainable humanised capitalism – is one of the greatest tragedies of the last century, made all the greater because it was so predictable.They held the idea that capitalism could be reformed into something kindly and user-friendly. It couldn't and it can't. Socialists make a choice. We choose to use our time and limited funds to work to eliminate the cause of the problems. One can pick any number of single problems and find that improvements have taken place, usually only after a very long period of agitation. But rarely, if ever, has the problem actually disappeared, and usually, other related problems have arisen to fill the vacuum left by the "solution".
If you insist upon the view that the struggle for reforms remains worthwhile then imagine just how many more palliatives and ameliorations will be offered and conceded by a besieged capitalist class in a desperate attempt to retain ownership rights if the working class were demanding the maximum programme of full dispossession and complete appropriation and nothing less. To stem the socialist tide the capitalist parties will sink their differences and draw closer together, much as religions do today in the face of the world avalanche of secularism. Reforms now derided as utopian will be two a penny - in an attempt to fob off the workers. Perhaps, for example, capitalism will provide a batch of free services, on the understanding that this is "the beginning" of a free society, but socialists will not be taken in. Perhaps the "libertarian right" and the "liberal left" will coalesce around a citizen's income
jesuithitsquad
6 years 8 months ago
In reply toWelcomebylibcom.org
Submitted byjesuithitsquadon October 26, 2016
wishface-- So here's what you
wishface--
So here's what you don't get about electoral politics--reforms that matter to our day to day lives don't just happen. Any and all meaningful reforms that actually do impact our lives positively were won in reaction to a strong working class movement. Without such a movement in play, believing that anything meaningful will happen through electoral politics is a particular kind magical thinking.
But here's the thing Very, very few things from the macro-political world have any impact on our daily lives. Most of the things that matter happen at our workplaces, where we live, in our neighborhoods, etc. Those things simply cannot/will not be solved through electoral politics.
It's like this--What Capital wants, capital will get without a militant working class fighting back. It doesn't matter who is in office. If a particularly principled politician were in office and had both the will and the political muscle to follow-through, and this politician refused to do what the ruling class wanted, they would find a way to remove them from office. The only way you'd be able to stop it would be through having people in the streets. So, even if what you think we really should be doing is supporting a particular politician, the best way to do that would be through working to build a radical movement.
But then the question is, if you have such a movement, why the hell would we settle for reforms? Why not just make the new world we want?
Tell me your alternative. I've yet to hear it. I asked afed in Bristol how big they were. The number was about 20 (iirc). It was a dismally small number. All of these people (arsonists aside) I'm sure are decent honourable people, that's not my contention, but 20 people aren't going to change anything, so what do you propose?
So, if 20 communists are too small to 'change anything' exactly how do you think their votes are going to matter? You've completely undermined your own point.
Furthermore your aggressive posting style, making demands of other posters is unhelpful. Yesterday in the other thread, you made similar demands asking about Trotsky. When I took the time to explain it to you, you disappeared and started a new thread where you're making demands about something else. People have patiently answered your question, but you dismiss and ignore their answers.
For future reference, the search function is your friend. I guarantee any question you want to ask has already been asked and answered, probably a dozen times at least--The 'pragmatic electoral politics' vs the 'utopian communist' routine even more so, and every time this dichotomy is shown to be reversed.
jef costello
6 years 8 months ago
In reply toWelcomebylibcom.org
Submitted byjef costelloon October 26, 2016
wishface, I'm guessing that
wishface, I'm guessing that you're relatively young.
I'm going to sound patronising but try and stick with me. I can remember feeling like that, that horrible feeling that everything is going to shit and we have to do something. Still get it sometimes. The problem is that you end up pushed into dojng something pointless. You've already said as much, with regard to councils. If councils will do largely the same thing then why would governments be any different, remember that the ruling class doesn't change when the government does.
Everyone on here has heard these arguments before and has disagreed with them at length. Holding your nose and voting Labour has almost become a running joke.
You've come on here to argue in favour of it but you're not responding to people's arguments, you're just repeating your own. You are unlikely to persuade anyone of anything but if you want to do so then you need to debate rather than earnestly repeating the same things. We'e aware of what is hapening. I come from an area that is gentrifying out long-term residents, where aggressive and racist police act with impunity, where we have a Labour MP that tells us he can change things while angling for the next big chance for personal power and wealth. I don't think anyone is under any illusions about how severe the problems are, nor about the horrible effects that they are having on people. IT's emotive rhetoric, and the politicians use the same to try to get us care about whichever one of them wants our vote this time. The difference is that as communists, anarchists etc. we actually care, it's not just a selling tactic. People in general are sick of lying, interchangeable politicians so they try to whip up these existential battles to make us care. Abortion, Trump etc.
I care. A politician doesn't and won't. On the off chance that he she does then they won't be able to do anything about it.
A part of me wondered if I shouldn't have voted "against the Tories" because I was disgusted with the mixture of glee and arrogance they showed while destroying people and their lives. But Labour introduced internal markets to the NHS (preparing for privatisaton and swallowing up huge chunks of the 'extra' funding) Labour made academies, forced schools to become businesses, saddled them with expensive PFI contracts (much like the NHS) to profit private companies, shut down benefits offices, hired private contractors to take away invalidity benefits and so on and so on.
Now you might say that the Tories would have done that anyway, which is probably correct (some people think that Labour helped keep working class resistance down, I'm not so sure) but you can't argue that one side would be better while explaining away every example of them being equally bad on the grounds that whoever is in charge would have done it. Either governments make a difference or they don't.
rat
6 years 8 months ago
In reply toWelcomebylibcom.org
Submitted byraton October 26, 2016
Good posts Ed and
Good posts Ed and jesuithitsquad.
Basically speaking, wishface is just trotting out that moth-eaten SWP slogan:
“Vote Labour – with no illusions”
fingers malone
6 years 8 months ago
In reply toWelcomebylibcom.org
Submitted byfingers maloneon October 26, 2016
I agree with Ed and jeff
I agree with Ed and jeff costello.
Where I live has been Labour since the borough boundaries were first drawn. Nothing I do in electoral terms will mean anything in the general election. Ed put it very well, the election gets decided in the marginal constituencies, which are not anarchist strongholds usually. If every single poster on Libcom voted Labour I seriously don't think it would swing a single seat. You're assuming that anarchists are all going to refuse to vote, but I did actually vote in the referendum, I got properly shouted at for it by some people but would go and do it again.
Your average anarchist has probably had the 'if you don't vote you're letting the tories win' argument before every election since the age of about seventeen from their neighbours, workmates, parents, aunts, and all the other Labour voters around you over and over and over again, it's one of the most common arguments you have. People will have made their minds up one way or another and don't need to have the argument again, there's more interesting things to argue about. If you want to influence the results of the general election, which I think is perfectly understandable given the terrible circumstances we are in, go out and argue with people who are thinking of voting conservative, seriously we are not the crucial constituency you should be spending time convincing.
fingers malone
6 years 8 months ago
In reply toWelcomebylibcom.org
Submitted byfingers maloneon October 26, 2016
I'd also like to say, don't
I'd also like to say, don't accuse posters of not caring about what people are going through, a lot of posters do loads in the campaigns you mentioned like E15 and are fully aware of how bad things are, don't assume people are coming from an aloof position of not caring, whether they vote or not.
wishface
6 years 8 months ago
In reply toWelcomebylibcom.org
Submitted bywishfaceon October 26, 2016
Serge Forward wrote: Well,
Serge Forward
Well, that's us told. Maybe I'll go and find a Momentum forum and tell them they're all wrong. Or maybe I'll just see what's on telly instead.
Really? That's the best you can manage?
I have repeatedly invited you or anyone else interested to provide an alternative, but instead you think a petulant snide jab is the answer?
Is that your idea of anarchism or left libertarian politics? To sneer at people trying to address real issues? If so you ought to consider a career in government or print media. They'd love you.
fingers malone
6 years 8 months ago
In reply toWelcomebylibcom.org
Submitted byfingers maloneon October 26, 2016
You don't know serge forward
You don't know serge forward and you don't know what 'real issues' he might be involved with.
wishface
6 years 8 months ago
In reply toWelcomebylibcom.org
Submitted bywishfaceon October 26, 2016
Rob Ray wrote: You seem to be
Rob Ray
You seem to be under a misapprehension that anyone on these boards thinks a "revolution" in the teenage rebel sense is likely and/or desirable?
I realise it must be quite hard, coming at it from fantasy Corbyn-island where most of your critics are to your right, to imagine that people on your left might not see your sub-Bevanite schtick as particularly impressive whilealsonot being a Daily Mail pastiche of the screeching ideologue, but you do yourself no favours by coming on boards with (clearly) fuck all understanding of the creed you're trying to debate against with the big patronising I Am.
I don't know what the 'teenage rebel sense' means, perhaps you could define that before accusing me of a misapprehension. You won't, of course. All I see here is people hiding behind cheap remarks, too afraid to actually engage with the issues. That's a nice luxury, but it's one our society can't afford; people are dying because of the Tories. Instead of addressing that reality you just want to play at being anarchist because it sounds cool. Tell me who's the teenage rebel again?
If you feel patronised by what I've said then perhaps you should look in the mirror instead of blame me. I've repeatedly conceded that I don't like the reality I'm putting forward and have, for the umpteenth time, invited alternatives in the discussion. But it seems you don't want to have a discussion you just want to engage in facile superficial politics while bandying about nonsense regarding a particular notion of rebellion I haven't put forward.
The reality is what we have to deal with. If you can't see how bad life is for millions under this government then frankly you have no business calling yourself an anarchist or a left libertarian. You're just an apologist and enabler for the likes of this government.
We've had six years of Tory misery with the very real possibility of another 5. During that time there hasn't been any uptake in revolutionary activity. There is no possibility of any alternative coming into play. AGAIN: I wish that were different, but wishes don't pay the bills. What has happened has been a hardening and a polarisation of attitudes. Our society is divided as never before. People don't care, they have become callous. This is exceptionally dangerous, but you don't' seem to grasp this point. It doesn't breed revolutionary activity or a desire to change things in any way you deem acceptable (whatever that is, since you don't articulate it). Instead it breeds indifference and malaise: people just sit in front of the TV where they are spoonfed hateful propaganda that reinforces that callousness and encourages the division we see.
This is one of the reasons why it is important to get the Tories out and the only realistic option to do so is in 2020. If that callousness persists then the suffering will increase and the will to effect real lasting change will diminish. It hasn't happened so far, it's not going to happen in 2020. By 2025 this society will be unrecognisable, we are already about to lose the NHS - the groundwork is there as the secretary of state is no longer duty bound to provide healthcare for all citizens (thanks to the health and social care act of 22012), and the welfare state will have gone completely.
Play your revolutionary politics at our peril, that's the game you are playing. The pieces are people's lives.
wishface
6 years 8 months ago
In reply toWelcomebylibcom.org
Submitted bywishfaceon October 26, 2016
fingers malone wrote: You
fingers malone
You don't know serge forward and you don't know what 'real issues' he might be involved with.
But we do know the issues that people in society are dealing with. These are people screaming for help, dying for help. Why don't you support the only thing, right now, that can ameliorate their suffering? Why do you persist with the false narrative that supporting a Corbyn vitory in 2020 (all things being equal) prevents long term revolutionary activity. I have repeatedly and explicitly made it clear that I am not proposing long term support for labour or the westminster system. But in lieu of an alternative none of you are providing this is the only chance to help people who are dying?
Are his circumstances any worse than the people faced with tory penury and destitution? People that have already died?
wishface
6 years 8 months ago
In reply toWelcomebylibcom.org | https://libcom.org/comment/586956 |
Early application of negative pressure wound therapy to acute wounds contaminated with Staphylococcus aureus: An effective approach to preventing biofilm formation
Early application of negative pressure wound therapy to acute wounds contaminated with Staphylococcus aureus: An effective approach to preventing biofilm formation
Authors:
Tongtong Li
Guoqi Wang
Peng Yin
Zhirui Li
Licheng Zhang
Qi Guo
Daohong Liu
Peifu Tang
Published online on: January 20, 2016 https://doi.org/10.3892/etm.2016.3008
Pages: 769-776
Abstract
Introduction
Bacterial biofilms have long been considered to be
one of the most difficult problems in the field of wound care
(
1
–
8
). Defined as complex microbial communities
irreversibly attached to the wound surface and embedded in
self-secreted extracellular polymeric substances (EPS), biofilms
provide bacteria with an effective barrier against host immune
cells and antimicrobial agents (
6
,
9
). As the
most common pathogen of wound infection,
Staphylococcus
aureus
(
S. aureus
) has been widely studied by
researchers (
10
–
12
). The EPS of staphylococcal biofilms are
primarily composed of polysaccharide intercellular adhesin (PIA),
extracellular DNA (eDNA), protein and cellular debris (
13
,
14
). In
particular, PIA and eDNA are the main components of the
extracellular matrix of biofilms, and their roles in intercellular
adhesion and biofilm formation have been investigated by numerous
studies (
14
–
20
). Furthermore, the compromised open
wounds create an ideal microenvironment for bacterial colonization
and biofilm development (
6
). A
series of
in vitro
and
in vivo
studies have revealed
that wound-associated biofilms grow rapidly and mature within 24 h
post-infection (
12
,
21
–
23
).
Once bacteria form a mature biofilm they are difficult to eradicate
(
8
). Despite traditional therapies
such as serial debridement and lavage that can remove the majority
of mature biofilms and necrotic tissue, residual bacteria may
rapidly reestablish a robust biofilm architecture, causing pain to
the patients during the process (
24
,
25
). The
ultimate consequence is a delay in wound healing and
reepithelialization (
8
,
26
–
28
).
The durability of a mature biofilm highlights the
importance of preventing biofilm formation at the early stages of
wound infection. Although specialized dressings for wound care do
have an inhibitory effect on biofilms, the efficacy varies greatly
with the type, concentration and release of active compound
(
29
). Antibiofilm agents, such as
dispersin B and DNase I, have been demonstrated to be effective in
the degradation of biofilm matrix both
in vitro
and
in
vivo
, although these are lacking in clinical application and
standard treatment regimens (
9
,
30
). In
addition, numerous small molecules targeting bacterial signaling
pathways, such as autoinducing peptide, have demonstrated
antibiofilm biological activities, although the clinical efficacy
and safety of these compounds has not been sufficiently evaluated
(
9
,
26
,
31
).
Despite considerable research, a significant improvement in biofilm
prevention in the clinical setting remains lacking.
Physical therapies have emerged in biofilm
management due to their satisfactory efficacy and low risk for
microbial resistance (
32
). In
particular, negative pressure wound therapy (NPWT) has been shown
to improve the healing process of infected wounds and to avoid
biofilm-associated infections when applied as early as possible
(
33
–
38
). Previous studies have attributed these
benefits to the secondary effects of NPWT, including fluid removal,
modulation of inflammation, and the stimulation of wound healing
signaling pathways (
38
–
41
). However, investigations into the role
of NPWT in biofilm formation remain limited. Despite individual
studies suggesting its compression effect on established mature
biofilms
in vitro
(
42
–
44
), the
efficacy of NPWT on biofilm prevention remains unclear,
particularly
in vivo
.
The aim of the present study was to evaluate and
validate the potential effect of NPWT on biofilm prevention when
initiated rapidly following wound contamination. Subsequent changes
in bacterial burden and wound healing secondary to NPWT were also
investigated. The results may provide a better understanding of the
therapeutic regimen required for wound care.
Materials and methods
Ethical statement
All animal experiments in the present study were
approved by the Medical Ethics Committee of the Chinese PLA General
Hospital (Beijing, China) in compliance with the Guidelines for
Care and Use of Animals in Research (
45
).
Animals
A total of 18 adult female Japanese large-ear white
rabbits (age, 3–6 months; weight, ~3 kg; purchased from the
Laboratory Animal Center of the Academy of Military Medical
Sciences, Beijing, China) were used for this study. The rabbits
were acclimated to standard housing and fed
ad libitum
under
constant temperature (22°C) and humidity (45%) with a 12-h
light/dark cycle.
Bacterial strains and culture
S. aureus
strain RN6390 constitutively
expressing green fluorescent protein (obtained the from Chinese PLA
Institute for Disease Control and Prevention, Beijing, China) was
utilized for wound inoculation.
S. aureus
was grown
overnight and subcultured in Luria-Bertani broth (AOBOX
Biotechnology Co. Ltd., Beijing, China) at 37°C until log phase.
Cells were harvested by centrifugation at 4°C (5,000 × g), and
washed three times with phosphate-buffered saline (PBS). The final
bacterial resuspension was diluted with PBS to an optical density
of 1.0 at 600 nm equivalent to 10
5
colony-forming units
(CFUs)/µl empirically (
11
).
Wound protocol and bacterial
inoculation
The wounding and bacterial inoculation protocol was
based on the previously published wound model with minor
modifications (
12
). Briefly,
rabbits were anesthetized by intramuscular injection of a ketamine
(45 mg/kg; Gutian Pharma Co., Ltd., Fujian, China) and xylazine (5
mg/kg; Huamu Animal Health Product Co., Ltd., Jilin, China)
mixture. Ears were shaved and sterilized twice with 70% ethanol.
Following local anesthesia with 1% lidocaine (Yimin Pharmaceutical
Co., Ltd, Beijing, China), six standardized 8 mm diameter
full-thickness dermal wounds were created by an experienced surgeon
on each ventral ear down to the perichondrium using a scalpel.
Following hemostasis, the wounds were dressed with semiocclusive
IV3000 Transparent Adhesive Film Dressing (Smith & Nephew
Healthcare Ltd., Hull, UK). On postoperative day (POD) 3, each
wound was inoculated with 1×10
6
CFUs of
S. aureus
at a volume of 10 µl. Planktonic bacteria were allowed to
proliferate
in vivo
under the semiocclusive transparent film
for a minimum of 6 h to ensure bacterial adhesion and colonization
(
12
,
41
,
46
,
47
).
Study design and treatment
protocol
All rabbit ears were used to create acute
S.
aureus
-contaminated wounds (6 wounds/ear; 36 ears). For each
animal, the two ears were respectively and randomly assigned to the
‘untreated control group’ and the ‘NPWT group’ (18 ears/group),
with the 6 wounds on each ear following the same protocol (
32
).
The wounds were treated under the previously
published protocol with minor modifications (
48
). Briefly, 6 h postinoculation on POD 3,
the wounds were dressed with a standard NPWT dressing (consisting
of polyvinyl alcohol foam, semiocclusive transparent dressing and
suction tube; Wuhan VSD Medical Science & Technology Co., Ltd.,
Wuhan, China) trimmed in advance to the appropriate size. The
suction tube was then connected to a vacuum pump device (provided
by Professor Lei Hu, Beihang University, Beijing, China). Wounds
treated with NPWT were subjected to continuous negative pressure at
−125 mmHg throughout the study (
41
,
47
).
Dressings were checked daily and changed on PODs 4, 6, 8 and 10, as
recommended for infected wounds by the manufacturer. Animals were
sacrificed via an overdose of intravenous pentobarbital sodium
(100–240 mg/kg; Sigma-Aldrich, St. Louis, MI, USA) on PODs 4 (n=8),
6 (n=2), 8 (n=2), 10 (n=2) and 13 (n=4). Wounds were harvested
using an 8-mm dermal biopsy punch (Miltex, Inc., York, PA, USA) for
PIA, eDNA, viable bacterial count and scanning electron microscopy
(SEM) analyses, or a scalpel for epifluorescence and histological
analyses.
Detection of PIA and eDNA in wound
biofilms
The dorsal side of the wound was removed to
eliminate the interference of non-specific bacteria outside of the
wound surface (
32
). The tissue
samples were placed in centrifuge tubes with 1 ml PBS, and
sonicated for 2 min to remove bacterial biofilms from the tissue
(
32
,
49
). The insoluble material was discarded
by centrifugation at 4°C (13,400 × g). In total, 0.5 ml supernatant
was used for the measurement of PIA, and the remainder was used for
eDNA extraction. An improved Elson-Morgan assay was performed
subsequently to measure the levels of PIA (
13
,
19
,
20
,
50
).
Briefly, 0.5 ml supernatant was supplemented with 0.1 ml potassium
tetraborate (0.8 mol/l; Vetec; Sigma-Aldrich) in a test tube. Tubes
were heated in a boiling water bath for 3 min and were subsequently
cooled using tap water. A total of 3 ml Ehrlich's reagent (Vetec;
Sigma-Aldrich) was added and, immediately after mixing, the tubes
were placed in a water bath at 37°C for 20 min. The reaction was
terminated by cooling the tubes with tap water. The results were
expressed as the absorbance of the final reaction solution at 585
nm as determined using a spectrophotometer (GeneQuant 1300; GE
Healthcare Life Sciences, Logan, UT, USA) (
50
).
The remaining supernatant was used for the
extraction of eDNA using the TIANamp Micro DNA kit (Tiangen Biotech
Co., Ltd., Beijing, China) according to the manufacturer's
protocol. The eDNA levels/wound were expressed as the DNA
concentration, quantified using a Qubit® 2.0 fluorometer with a
Qubit® dsDNA BR Assay kit (both Invitrogen; Thermo Fisher
Scientific, Inc., Waltham, MA, USA) according to the manufacturer's
protocol (
30
).
SEM
Following 2.5% glutaraldehyde and 1% osmium
tetroxide fixation, the tissue samples were dehydrated through a
series of graded ethanol (30, 50, 70, 80, 90 and 100%) and dried
with a critical point dryer (HCP-2; Hitachi, Ltd., Tokyo, Japan) by
flooding with liquid carbon dioxide at 5°C for 20 min and raising
the temperature to the critical point (~35°C). Subsequently,
samples were mounted using double-sided tape and coated with gold
in an auto sputter coater (E-1010; Hitachi, Ltd., Tokyo, Japan).
Imaging of the tissue samples was performed by SEM (S-3400N;
Hitachi, Ltd., Tokyo, Japan) operated at the scanning voltage of 15
kV.
Fluorescent staining and fluorescence
light microscopy
The wounds were bisected at the largest diameter and
embedded in optimal cutting temperature (O.C.T.) Compound (Sakura
Finetek USA, Inc., Torrance, CA, USA), snap-frozen, and stored in
liquid nitrogen until cryosectioning. Tissue sections (6 µm) were
obtained with a Leica CM1950 freezing microtome (Leica Microsystems
GmbH, Wetzlar, Germany). Visualization of biofilm matrix was
accomplished by staining with Concanavalin A Texas Red® Conjugate
(Invitrogen; Thermo Fisher Scientific, Inc.), specific for
S.
aureus
exopolysaccharides, for 15 min in the dark at room
temperature (
12
). The tissue
sections were then rinsed three times in PBS and incubated with
4′,6-diamidino-2-phenylindole dilactate (Invitrogen; Thermo Fisher
Scientific, Inc.) for 5 min to visualize the host cells.
Fluorescence microscopy was performed with an Olympus BX51
microscope (Olympus Corporation, Tokyo, Japan).
Viable bacterial count
measurements
Wounds were pretreated as described in the protocol
of PIA measurement. Tissue specimens were homogenized into 1 ml
suspension with sterile PBS, followed by sonication for 2 min to
disrupt bacterial aggregates in the biofilm. Subsequently, the
homogenates were serially diluted with sterile PBS (ranging from
10
−1
, 10
−2
, 10
−3
to
10
−6
times the concentration of the homogenates), plated
on
Staphylococcus
Isolation Agar (Hardy Diagnostics, Santa
Maria, CA, USA) and incubated at 37°C for 24 h. A standard
colony-counting method was conducted and the results were expressed
as the logarithm of CFUs/wound (
12
,
41
).
Measurement of wound closure
From POD 0 (the day of wounding), images of the
wounds were captured with a digital camera (IXUSi; Canon, Inc.,
Tokyo, Japan) on each day of dressing change. Wound size was then
determined by quantifying the wound area using Image-Pro Plus
version 6.0 software (Media Cybernetics, Inc., Rockville, MD, USA).
The rate of wound closure was expressed as a percentage of the
initial wound area (
51
).
Histological analysis
Wounds were bisected at the maximum diameter and
fixed in 10% neutral formalin (Yili Fine Chemicals Co., Ltd.,
Beijing, China). The tissue samples were then embedded in paraffin,
sectioned into 5-µm sections and stained with hematoxylin and
eosin. The observation of the tissue sections was performed with an
Olympus MVX10 macro-microscope (Olympus Corporation). Images of the
stained wounds were captured and analyzed using Image-Pro Plus
software, version 6.0. The morphometric parameters included the
epithelial and granulation gaps (the distance between the leading
edges of newly formed epithelial or granulation tissue) and the
epithelial or granulation area (the sum of the area of newly formed
epithelial or granulation tissue on the two sides of the wound bed)
(
28
). The measurements were carried
out by two independent observers who were blinded to the treatment,
and an average result was calculated.
Statistical analysis
Data are reported in graphical form as mean ±
standard deviation. Student's t-test (two-tailed and paired) was
used to compare the PIA/eDNA content, viable bacterial counts and
histological parameters between NPWT-treated wounds and their
untreated control. Wound closure was analyzed using
repeated-measures analysis of variance, followed by the least
significant difference post-hoc test to evaluate the statistical
difference between groups at each time point. All analyses were
performed using SPSS software, version 17.0 (SPSS Inc., Chicago,
IL, USA) at a significance level of α=0.05.
Results
NPWT reduces PIA and eDNA levels and
inhibits the production of extracellular matrix
With the previously established rabbit ear wound
model,
S. aureus
-contaminated wounds were treated with or
without NPWT from 6 h postinoculation. For the main components of
S. aureus
biofilm, namely PIA and eDNA, NPWT resulted in a
significant reduction in their levels in the wound beds (PIA,
P<0.05; eDNA, P<0.01) (
Fig.
1
). This reduction could be visualized through SEM (
Fig. 2
). The untreated wounds manifested a
relatively intact biofilm structure (
Fig. 2A
) with large amounts of cocci-shaped
S. aureus
embedded within the lattice-like extracellular
matrix (arrows,
Fig. 2B
).
Conversely, wounds treaded with NPWT showed comparable amounts of
bacteria but a lack of extracellular matrix (
Fig. 2C
), which was more visible at a higher
magnification (
Fig. 2D
). To verify
the results, epifluorescence microscopy was performed, showing a
mature biofilm with large amounts of exopolysaccharide matrix
surrounding the bacteria in untreated wounds (
Fig. 3A
). By comparison, bacteria in the
NPWT group spread over the wound beds with sparse exopolysaccharide
matrix (
Fig. 3B
). An uncolonized
area of the wound tissue showed background staining of Concanavalin
A, and served as a negative control (
Fig. 3C
).
Figure 1.Detection of components of the
biofilm matrix from Staphylococcus aureus-infected wounds
with and without NPWT treatment. NPWT resulted in significant
reductions in (A) PIA and (B) eDNA content relative to untreated
wounds. *P<0.05 and **P<0.01 vs. untreated control. Data are
presented as mean ± standard deviation (n=10–12 wounds/group).
NPWT, negative pressure wound therapy; PIA, polysaccharide
intercellular adhesin; eDNA, extracellular DNA; A585,
absorbance at 585 nm.
Figure 2.Scanning electron microscopy of
Staphylococcus aureus-infected wounds with and without NPWT
treatment. (A) The untreated wounds exhibited a mature biofilm
structure. (B) Higher magnification of the same visual field showed
large amounts of cocci-shaped Staphylococcus aureus embedded
within the lattice-like extracellular matrix (arrows). (C)
Conversely, wounds treated with NPWT presented approximately equal
amounts of bacteria but lack of extracellular matrix, (D) which was
more explicit at higher magnification. NPWT, negative pressure
wound therapy.
Figure 3.Fluorescence light microscopy of NPWT
untreated and treated Staphylococcus aureus-infected wounds
counterstained with ConA and DAPI. (A) GFP-labeled
Staphylococcus aureus (green) formed a mature biofilm on the
untreated wound surface (blue), showing a complex structure with
large amounts of exopolysaccharide (red) around the bacteria. (B)
Staphylococcus aureus in the NPWT group spread over the
wound bed with sparse exopolysaccharide matrix. (C) As a negative
control, an area of wound tissue with no bacterial aggregates was
shown to exhibit background staining of ConA. Scale bar = 100 µm.
NPWT, negative pressure wound therapy; ConA, Concanavalin A; DAPI,
4′,6-diamidino-2-phenylindole; GFP, green fluorescent protein.
Prolonged NPWT reduces bacterial
load
Viable bacterial counts were measured over time to
investigate the effect of early application of NPWT on bacterial
burden (
Fig. 4
). On POD 4 and 6, the
bacterial load in the wounds treated with NPWT was not
significantly different from that in the untreated controls with
~10
7
CFUs/wound. However, from POD 8 there was a
significant decline of the bacterial load in the NPWT group (POD 8,
P<0.05; POD 10, P<0.01). At the end of the study (POD 13),
NPWT resulted in a significant reduction in the bacterial count by
two-log fold compared with the untreated wounds (P<0.001).
Figure 4.Viable bacterial counts from
Staphylococcus aureus-infected wounds with and without NPWT
treatment. Serial bacterial counts from untreated wounds revealed a
persistent bacterial burden averaging between
105−107 CFUs/wound. However, wounds treated
with NPWT showed a gradual but significant reduction in viable
bacteria compared with untreated controls, with ~103
CFUs/wound on POD 13. *P<0.05, **P<0.01 and ***P<0.001 vs.
the untreated control. Data are presented as mean ± standard
deviation (n=10–12 wounds/group/time-point). NPWT, negative
pressure wound therapy; CFUs, colony-forming units; POD,
postoperative day.
NPWT enhances wound healing
The reduction in bacterial burden secondary to NPWT
correlated with a synchronous enhancement in wound healing. Gross
appearance on POD 13 manifested a marked difference between the two
groups. Compared with the film-like exudates overlying the
untreated wounds (
Fig. 5A
), NPWT
accelerated wound closure and epithelialization, with clean
granulation tissue beds (
Fig. 5B
).
The rate of wound closure in the NPWT group was significantly
higher compared with that of the untreated group (
Fig. 5C
). Images of histological tissue
sections showed increased amounts of new epithelial and granulation
tissue in NPWT-treated wounds (
Fig.
6B
) compared with untreated controls (
Fig. 6A
). Trends in wound healing were
quantified by measuring the epithelial and granulation gaps and
areas. NPWT led to a significant reduction in epithelial and
granulation gaps (P<0.001) and increase in new epithelial
(P<0.01) and granulation (P<0.001) areas compared with the
untreated wounds (
Fig. 6C and
D
).
Figure 5.Appearance of wounds and wound
closure rates. (A) The untreated wounds on POD 13 manifested a
delay in healing and film-like exudates overlying the wound
surfaces. (B) Conversely, NPWT accelerated wound closure and
epithelialization, with clean granulation tissue beds. (C) The
wound closure rate, shown as the percentage of initial wound area,
was significantly increased in the NPWT group compared with the
untreated control group from POD 6. (A and B) Scale bar = 5 mm.
*P<0.05, **P<0.01 and ***P<0.001 vs. the untreated
control. Data are presented as mean ± standard deviation (n=12
wounds/group). NPWT, negative pressure wound therapy; POD,
postoperative day.
Figure 6.Comparison of histological sections
and healing parameters between NPWT untreated and treated
Staphylococcus aureus-infected wounds. Histological tissue
sections, stained with hematoxylin and eosin on POD 13, showed that
compared with (A) the untreated control, the amounts of new
epithelial and granulation tissue in (B) the NPWT-treated wounds
were increased. As determined by quantitative analysis, NPWT was
shown to result in improvements in all healing parameters, (C) with
a significant reduction in epithelial and granulation gaps and (D)
increase in new epithelial and granulation areas. Scale bar =1 mm.
**P<0.01 and ***P<0.001 vs. the untreated control. Data are
presented as mean ± standard deviation (n=10–12 wounds/group). EG,
epithelial gap; NPWT, negative pressure wound therapy; POD,
postoperative day.
Discussion
Bacterial biofilm remains a challenging issue in the
field of wound care (
1
–
8
). Although there is a greater
understanding of the necessity of biofilm prevention, the
therapeutic strategies to prevent biofilm formation are limited in
clinical practice (
8
,
9
,
24
–
31
). In
an effort to seek safe and effective wound care modalities, early
application of NPWT has been widely acknowledged for its
considerable efficacy and low incidence of biofilm-associated
infections (
32
–
38
). However, despite an increasing number
of studies investigating this type of therapy, the potential role
of NPWT in biofilm prevention has yet to be elucidated (
37
–
44
). The
present study examined and evaluated the effect of NPWT on biofilm
prevention when initiated rapidly following wound
contamination.
The results indicated that the early application of
NPWT may be an effective approach for the prevention of biofilm
formation in
S. aureus
-contaminated wounds. Although the
exact mechanism underlying the effects of NPWT has yet to be
established, a possible explanation for the benefits observed
following treatment with NPWT may be the lack of biofilm matrix. As
the structural components of staphylococcal biofilms, PIA and
extracellular DNA have an important role in bacterial aggregation
and biofilm formation (
15
–
18
). Scavenging these matrix components or
inhibiting their biosynthesis can effectively prevent biofilm
formation and development (
9
).
Previous studies have demonstrated the effectiveness of NPWT in
fluid removal and wound cleaning due to the continuous suction
(
39
). The continuous suction may
also clear PIA and eDNA from the contaminated wounds before these
components are able to form extensive intermolecular crosslinks
around the bacteria. In addition, due to the physical effect of
negative pressure, NPWT leads to an essentially different
microenvironment for wound healing, characterized by hypoxia and
microstress (
38
). These
environmental factors, which may stimulate host gene expression and
cell proliferation through a variety of signaling pathways
(
38
,
40
), may also have an effect on the
bacteria. Therefore, another possible mechanism is that the
environmental factors secondary to NPWT inhibit the biosynthesis of
bacterial biofilm components, such as PIA and eDNA. Therefore, the
early application of NPWT may prevent biofilm formation in
S.
aureus
-contaminated wound beds.
Without the protection of the biofilm matrix, the
bacteria may be eliminated by host immune cells more effectively
(
9
), as shown by viable bacterial
counts. Notably, the reduction of the bacterial burden should not
be attributed to physical suction, as the bacterial counts did not
significantly decrease at the early stages of NPWT. The immune
response is more likely to have a leading role in bacterial
clearance, as previously demonstrated (
41
,
46
).
Subsequently, a reduction in biofilm matrix and bacterial burden
secondary to NPWT may be beneficial to wound healing, since both of
these factors are thought to inhibit the healing process (
26
–
28
). In
addition, NPWT may also improve wound healing through its ability
to stimulate host gene expression and cell proliferation (
38
).
Previous studies have investigated the effect of
topical negative pressure used with or without bactericide on
established mature biofilms
in vitro
, and demonstrated the
presence of several changes in biofilm morphometric parameters and
a reduction in bacterial counts (
42
–
44
).
However, a compression (perhaps fragmentation) effect on biofilm
architecture alone was inferred from the results (
42
,
44
).
There was no evidence that NPWT was able to remove an established
mature biofilm. Unlike these previous studies, the present
investigation predominantly focused on the initial stages of wound
infection, and examined the efficacy of NPWT on biofilm formation
and development. For clinicians and researchers, processes that
impede biofilm formation at the initial stage have long been
regarded as a promising approach to prevent biofilm-associated
infections and chronic infections (
25
,
37
).
Bacteria without the protection of a biofilm matrix are more
susceptible to immune cells and antimicrobial treatment (
9
,
25
). The
results of the present study suggested that the early use of NPWT
rapidly following wound contamination may be more effective than
delayed application in impeding biofilm formation. These results
are concordant with those of previous studies that have
demonstrated a satisfactory efficacy of NPWT on managing acute
wounds with contamination when initiated early (
33
).
Although further investigations are required in order to clarify
the role of biofilm matrix reduction in wound care, the present
study provides a possible mechanism of action for this therapy.
Despite rigorous methods and significant results,
there were limitations to the study. In particular, the effect of
NPWT on
S. aureus
alone was investigated. As the majority of
clinical cases are mixed infections, the investigation of other
bacterial species is required during further studies to validate
the results discussed herein. In addition, compared with previous
studies, NPWT was not combined with traditional therapies, such as
bactericide or irrigation. Although biofilm formation and
development were inhibited by NPWT alone, viable bacterial counts
did not decrease until immune cells infiltrated the wounds.
Combined treatment is may have the potential to enhance the
elimination of bacteria.
In view of the fact that mature biofilms are
difficult to eradicate, the demand for effective and practical
measures to avoid biofilm-associated infections is rising in
clinical settings. Early application of NPWT to wounds contaminated
with
S. aureus
has shown a significant efficacy on biofilm
prevention in the present study. With an increasing number of
clinical trials to validate its role in wound infection management,
NPWT appears to reduce the accumulation of biofilm matrix,
providing more opportunities for host cells or antimicrobial
treatments to eliminate the unprotected bacteria. A better
understanding of the potential role of NPWT in wound management and
biofilm prevention should contribute to innovations in the field of
wound care.
Acknowledgements
The present study was supported by a grant from the
National Natural Science Foundation of China (grant no.
81472112).
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Refworld | Country Reports on Terrorism 2007 - The Netherlands
Refworld is the leading source of information necessary for taking quality decisions on refugee status. Refworld contains a vast collection of reports relating to situations in countries of origin, policy documents and positions, and documents relating to international and national legal frameworks. The information has been carefully selected and compiled from UNHCR's global network of field offices, Governments, international, regional and non-governmental organizations, academic institutions and judicial bodies.
Country Reports on Terrorism 2007 - The Netherlands
Publisher United States Department of State
Author Office of the Coordinator for Counterterrorism
Publication Date 30 April 2008
Cite as United States Department of State, Country Reports on Terrorism 2007 - The Netherlands , 30 April 2008, available at: https://www.refworld.org/docid/48196cb428.html [accessed 18 June 2023]
The Dutch responded to the global terrorist threat with leadership and energy in the areas of border and transportation security, terrorist financing, bilateral counterterrorism cooperation, and Coalition efforts in Afghanistan. The Netherlands deployed over 1700 troops to Afghanistan as part of the International Security Assistance Force (ISAF). The Dutch led a Provincial Reconstruction Team (PRT) in Uruzgan province, headed the rotational command in Kandahar of NATO's efforts in southern Afghanistan for six months (ending in May), and provided in extremis support for Iraq. The Netherlands deployed as many as 14 trainers and security guards in support of the NATO Training Mission in Iraq, and pledged approximately 40 million USD for Iraqi reconstruction.
In an April quarterly terrorism threat analysis, the Dutch National Counterterrorism Coordinator (NCTb) lowered the threat level from "substantial," where it had been since the government began producing the quarterly assessments in 2005, to "limited." The second lowest of the four levels, "limited" means that the identified threat from individuals or networks is relatively slight, but cannot be ruled out entirely. In the October threat assessment, the NCTb cited events in Denmark and Germany, and concern about continuing internationalization of the violent jihad in Afghanistan as the rationale for maintaining the level at "limited." It also noted a significant drop in the number of reports about possible Islamic radicalization among the Dutch population, citing growing resistance among the Muslim population to terrorist actions.
Nevertheless, the assessment warned about growing support for Salafism. According to an October report by the AIVD intelligence service, the Netherlands had approximately 20,000 to 30,000 Muslims who are susceptible to extremist ideology. As concern over possible radicalization mounted, the government launched efforts meant to foster integration and to combat the appeal of violent extremists, including teaching imams the Dutch language and culture. In 2007, the Dutch government devoted millions of euros and reorganized some offices in order to take on these issues in a more concerted way.
In November, the Justice Ministry launched a new phase in the "Netherlands against Terrorism" campaign that began in 2006, with a particular focus on the prevention of radicalization. In November, the Interior Ministry's National Advisory Center for Vital Infrastructure Protection (NAVI) was opened. The government's terror alert system, initiated in June 2005, now includes 14 economic sectors: the financial sector, seaports, airports, drinking water, railway, natural gas, oil, electricity, nuclear, chemical, municipal and regional transport, hotels, public events, and tunnels and flood defense systems. This early-warning system was designed to trigger a clear and rapid response to terrorist threats by both the public and private sectors. It linked sector-specific measures to be taken in response to the latest threat information from the National Counterterrorism Coordinator. In June, the Port Security Act came into force, expanding the definition of a "port" to include all works and facilities in the port area, including both seagoing and inland commercial maritime transportation-related facilities. In October, a biannual national disaster exercise, known as "Voyager," was held in and around the port of Rotterdam.
There were three major terrorism-related cases this year. In the Hofstad group appeal case, the public prosecutor's office sought 18-year prison sentences for both Jason Walters (a dual U.S.-Dutch national) and Ismael Aknikh, who were sentenced to 15 and 13 years imprisonment, respectively, for attempted murder and weapons violations in the trial court's March 2006 verdict. The prosecution argued that the two had acted with terrorist intent when they threw a hand grenade at police officers in The Hague in November 2004. The prosecution further argued that all Hofstad Group members acted with terrorist intent in sowing hatred and threatening politicians. The trial court ruled, in March 2006, that the Hofstad Group was a criminal organization "with terrorist intent," and found nine of the 14 defendants guilty of membership in a criminal and terrorist organization, but that there was insufficient evidence to convict the individual defendants of acting with "terrorist intent" in committing the criminal offences with which they were charged.
After two previous acquittals, the Amsterdam appeals court sentenced Samir Azzouz to four years imprisonment for having prepared terrorist attacks on government buildings in 2004. Azzouz was currently serving an eight-year sentence in the separate "Piranha" terrorism case.
In October, the Rotterdam district court acquitted five of the six suspects arrested in November 2006 on suspicion of terrorist recruitment, participating in a terrorist organization, and obtaining false travel documents. The court ruled that there was insufficient evidence that the defendants had "ideologically prepared" each other or other persons to fight in Afghanistan or Iraq to convict them on terrorist recruitment charges. One female defendant in the case was sentenced to one month imprisonment for distributing subversive documents.
Dutch officials remained committed to active cooperation with the United States in designating known terrorist organizations, and interdicting and freezing their assets, and supported the continued exchange of information on financial transactions. The Dutch government worked with the United States to emphasize the importance of balancing security, the effectiveness of the financial system, and data protection concerns in the debate over SWIFT, an international messaging service for cross-border money transfers that provided information to track terrorist financing.
In October, the Cabinet approved a bill to make participation and cooperation in a terrorist training camp a serious punishable offence, even if the training takes place outside the Netherlands; the offense would carry a maximum prison sentence of eight years. The bill, currently before the Council of State for review prior to submission to Parliament, would implement Article 7 of the Council of Europe Convention on the Prevention of Terrorism. In March, the lower house of Parliament approved the Bill on Administrative National Security Measures, which would allow the Interior Minister to issue restraining orders to prohibit a terrorist suspect's physical proximity to specific locations or persons. At year's end the bill was awaiting action by the upper house of Parliament.
The port of Rotterdam completed the installation of 31 radiological portal monitors at container facilities. The radiological monitoring program was initiated in 2004 as a pilot project under the U.S. Department of Energy's Megaport/Second Line of Defense Initiative. In October, a new mobile container scanner became operational in the port of Rotterdam. The scanner has a processing capacity of 20 containers per hour, or 175,000 per year.
During bilateral law enforcement consultations in October, the United States and the Netherlands agreed to continue operational cooperation on counterterrorism, including the exchange of information on terrorism-related investigations. In October, three Dutch government officials observed the U.S. Top Officials (TOPOFF 4) national crisis management exercises.
In January, Wasem al Delaema, an Iraqi-born Dutch citizen was extradited to the United States for trial on charges of conspiring to attack U.S. troops in Iraq in 2003. Al Dalaema was the first Dutch citizen extradited on charges of terrorism, and the first person to be indicted in the United States for terrorist activities in Iraq.
| https://www.refworld.org/cgi-bin/texis/vtx/rwmain?docid=48196cb428&page=printdoc |
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Anderhub, H Andersen, G. L. Andersen, Dale T Andersen, Julie K Andersen, Gary L Anderson, Eric R Anderson, Thomas H Anderson, Paul Anderson, Gretchen L Anderson, M W Anderson, J Anderson, Karl E Anderton, Brian H Andexer, Jennifer N Andino, Myrna Ando, David Andrade, L. E. Andreeff, Michael Andrés, M C Barrio Andres, A Andresen, BF Andrews, Elizabeth B Andrews, E B Ang, Yen-Sin Ángel, M. Angeli, Nicole Angelidou, Georgia Anglada-Figueroa, David Angleró, Yesseinia I Angulo, J A Angulo-Barturen, Iñigo Anis, M Ansari, A A Ansari, Aseem Z Ansari, AZ Ansari, A. Z. Ansari, Z. A. Anthony, Kenneth R. N. Anthony, J Anthony, Karen Antin, Joseph H Antoine, Michelle W Antoine, Pierre-Olivier Anton, G Anton, A H Antonelli, L A Antonio Orden, José Antoranz, P Antos, Laura K Anur, Praveen Anwar, Azlinda Aponte, N. A. Aponte, N. 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Armaiz-Pena, Guillermo Armony, J L Armstrong, Andrew J Armstrong, Tom Armstrong, R Armstrong, Roy Arnold, Steven Arnold, Steven E Arnold, Eddy Arnold, Kathryn B Arocha, MA Arocho, Luz C Arold, Stefan T Aronow, Bruce Arora, Mukta Arreaga, Patricia Arredondo, M Arredondo-Arechavala, Miryam Arribas, Paz Arriola, CS Arriola, Leon Arroyo, LE Arroyo, Luz Arroyo, L.E. Arroyo-Ramírez, L ; Arstikaitis, Pamela Arteaga, Carlos L Arthur, Simon C Artiguenave, François Arulpragasam, Amanda R Arumi, D Arumugam, Thiruvengadam Arumugam, T. Arumugaswami, Vaithilingaraja Arun, Alok Arvai, Andrew S Arvidson, Raymond Arvidson, RE Arya, S. K. Aryal, S. Arzuaga, Emmanuel Arzuaga-Cruz, E Arzuaga-Cruz, Emmanuel Asensio, A Ash, John D Ashbrook, Alison W Ashe, Taylor Ashmore, Lillian Aslan, B. Aster, J C Astolfi, Annalisa Astrid, M Astruc-Diaz, F Atalay, R Atkinson, Rachel Atkinson, M. Atmar, Robert L Atrash, Hani K Attardi, Laura D Attia, Erik Aubrecht, Taryn G Aucejo-Romero, S Aue, G. August, Euna M Auluck, Kshitij Aury, Jean-Marc Australian Ovarian Cancer Study Group Ausubel, Frederick M Avalos, Arian AVANTEL, SA Aveiro, H. C. Avellanet, Yaniris Avena, Sergio Aviles, Misael O Avilés-Reyes, Alejandro Avilés-Rodríguez, Kevin J. Aviles-Santa, L. Avilés-Santa, L.M. Ayala, Miguel A Ayala, Dara L. Rodrigu Ayala-Marín, Yoshira M Ayala-Peña, S Ayala-Santiago, Christian Ayala-Torres, Sylvette Ayas, Mouhab Aydin, Atakan Ayendez, Melba Sánchez Aylward, S Aymat, Efrain Aymat, Efrain Y. Ayres, M P Ayyad, O. Ayyavoo, Velpandi Ayyavoo, V Azadi, Parastoo Azadi, J ; Azam, Mahrukh Azimi, Roxana Aziz-Zaman, Sonya Aznar, L Aznar, M. Azzoni, Livio Azzoni, L B, Santiago-Berrios Mitk'El B, Santiago-Berríos Mitk’El B, Santiago Berríos M B., Hanisch Babensee, Julia E Babinchak, Timothy Babu, Challa Ram Baby, Patrice Babyak, A. Bacelli, G Bacelo, Daniel E Bach, Daniel Bach, J. F. Bacheller, Darlene Bachtell, Ryan K Backes, M Bacon, J. P. 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Cruz, Iadelisse Cruz, Juan González Cruz, Daryana Cruz, Beatriz Cruz, Gustavo D Cruz, Irelys A Cruz, Juan Cruz-Acuna, Ricardo Cruz-Aponte, Maytee Cruz-Collazo, Ailed Cruz-Cruz, Luis Cruz-Gonzalez, Iadelisse Cruz-Martín, A. Cruz-Martínez, Gibrán Cruz-Monserrate, Z. Cruz-Nieves, Omar A Cruz-Orengo, Lillian Cruz-Orengo, L. Cruz-Reyes, Nicole Cruz-Ruiz, E Cruz-Sánchez, A Cruz-Torres, A Cuadrado, Lumarie Cuadrado, Brenda Cuamba, P. Cubano, L. A. Cubano, Luis A Cudic, Mare Cuenda, Ana Cuevas, Marielly Cuevas, Wilfredo Cuevas, Ana A Cuevas, N Cuevas, E. Cui, Huxing Cui, W Cuitino, Alberto Culebras, E Cullen, Sean Cullen, Kacy Cullen, P.J. Cullen, P.J. Culley, Kirsty L Culley, Kirsty Culligan, Melissa Culnan, Derek M Cumba, Luz Cummings, C. A. Cummings, Kevin J Cummings, K J Cummings, KJ Cummings, Craig A Cummings, K. J. Cundari, T.R. Cunningham, RM Curb, J.D. Curiel, Tyler J Curley, Steven A Curran, Seamus Currier, Jenna Curtef, V Curtis, Michelle L Curtis, Jennifer E Curtis, Michele G Cusicanqui, E Cusick, Michael E Cutler, Sarah M Cutler, Corey S Czaja, Wojtek Czako, Rita Czjzek, Mirjam D'Agostino, Ralph B D'Agostino, Darrin D'Alessandro, Lara D'Andrea, Alan D d'Enfert, C D'Souza, Sunita L Da Costa, Victor DA SANCHEZ, QUINTERO da Silva, R P da Silva, ANR da Silva, Marco A. Coutinh Da Silva, Corinne Dabestani, R Daehler, Curtis C. Daehler, Curtis C. Daehler, Curtis C Daffin, Lee W Dagenais, Christian Dahl, Rolf H Dahl, Gary V Dai, Anlan Daiz, Agustin Dalal, Jignesh Dalcanton, J. Dalcanton, J. J. Dallas, N A Dalmas, Guillaume Dalmau, R Dalmau, RF Dalonneau, Fabien Dalton, Heather J Dalton, H. J. Dalton, M Damoiseaux, Robert Danahay, Henry Dandamudi, Rajasekhar Danes, Christopher G Danes, C. G. Daneshian, Mardas Dang, Vuong Q. Daniel, M D Daniel, M K Daniel, G.A. Daniel, Gabriel A Daniell, Henry Daniels, D Daniels, Brian P Danilova, A. P. 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Daxon, Eric G Day, Elizabeth Day, Ellen Dayes, Nathanael S Dayton, Talya L DAZA, JUAN D Daza-Vaca, Juan D Daza-Vaca, J D Dazzi, F de Almeida, Barres de Andrés, María C De Angelis, A de Burgos, Fernando G DE CARVALHO, A P De Clerck, Olivier de Crombrugghe, Benoit de Díaz, I De Geest, K. De Geest, Koen De Gracia, B P De Gracia, Carlos De Groot, Anne S de Haseth, James A. de Jager, O C De Jesus, M. De Jesús, Ricardo García- de Jesús, Carlos Miranda De Jesus, Kassandra De Jesús, Inés Sastre- De Jesús, Walleska De Jesús-Bonilla, Walleska De Jesús-Cortés, Mayralis De Jesus-Cortes, H De Jesús-Cortés, Héctor De Jesús-Cortés, Héctor De Jesús-Cortés, Héctor J De Jesús-Escobar, J M De Jesús-Laboy, K.M. De Jesús-Laboy, Kassandra M de la Campa, Melanie Ortiz-Alva de la Cruz, Angel De la Cruz-Sanchez, Francisco De La Harpe, K ; De La Mota-Peynado, A. 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Lee, Gui Han Lee, B Lee, Maurice duPont Lee, Jeong-Won Lee, M. C. Lee, J.-K. Lee, R Lee, J. W. Lee, Stephanie J Lee, Benhur LEE, L.J. Lee, A Lee, Andrew Lee, J. Lee, David Y-W Lee, S. J. Lee, A S Lee, Yean Lee, Young-Ju Lee, Jin-Kyun Lee, Sun-Joo Lee, Eunkyung Lee, Jason E Lee, Cheng-Sheng Lee, Ju-Seog Lee, Jane Leelapornpisid, Pimporn Leemis, Ruth W Leen, Ann Lees, Jacqueline LeFurgey, A Legatzki, Antje Legesse-Miller, Aster LEGLER, DM Lehman, CU Lehman, Susan M Lehmann, Christoph U Lehmann, Leslie Lehtonen, Samuli Leibiger, Barbara Leibiger, Ingo B Leibold, Josef Leinisch, Fabian Leite, Domingos da Silva Leko, Vid Lemischka, Ihor R Lemoine, Raymond Lemos, José A LeMotte, Peter Lenain, J-P Lenkeit, Evan Leon, Ruth León, Joshua Leon, Ruth G León, Alfredo J León, Ruth Gretchen Leon, R León-Cardona, Abimael León-Félix, J. Leonard, Mary K Leonardo, E Leong, K M Leong, Kok Mun Leonoudakis, Dmitri Leppla, C A Ler, Siok Ghee Lerma, Lader Lerma-Caicedo, Láder Lerner, Norma B Leshane, E. S. 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Lombard, Mark Lombardi, S Lombardi, ME London, Anne Long, Suzanna K Long, Suzanna Longo, Ana V Longo, AV Longo, F Longo, N Loo, Rachel Loo, Joseph Loots, Eli Lopac, Senja K Lopatto, David Loperena-Alvarez, Y. Lopez, Gustavo E López, Marcos López, Lizbeth López, Gustavo E López, Xaira López, R.G. Lopez, Ivette D López, R J García López, G E López, R J García López, Mercedes N López, Carlos Lopez, Pascal J Lopez, A. Lopez, G. E. López, Armando López, M Lopez-Berestein, G Lopez-Berestein, Gabriel Lopez-Berestein, G. López-Brea, M Lopez-Castroman, Jorge Lopez-Cruz, L. M. López-Garriga, Juan López-Gejo, J. López-Gejo, Juan López-Hernández, Javier E. López-Lara, I. M. López-López, L López-Malpica, F. 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Martinez, Melween I Martinez, M Martinez, Karen G Martínez-Cartagena, Pedro A. Martínez-Cartagena, Pedro A. Martínez-Cartagena, Pedro Martinez-Cruzado, J. C. Martinez-Cruzado, Juan Carlos Martínez-Dolz, Luís Martínez-Fernández, Lara Martínez-Ferrer, Angeles Martínez-Ferrer, M T Martínez-Ferrer, María Teresa Martinez-Ferrer, M J Martínez-Ferrer, Teresa Martinez-Ferrer, M Martinez-Ferrer, M. Martinez-Ferrer, Magaly Martínez-Frías, M L Martinez-Frias, Jesus Martinez-Maldonado, M Martinez-Marin, D. Martinez-Montemayor, MM Martínez-Montemayor, Michelle M Martinez-Montemayor, M. M. Martinez-Montemayor, Michelle Martínez-Ortiz, Yaiza Martínez-Pulgarín, Susana Martinez-Ramirez, Rachell Martínez-Rivera, Arlene Martínez-Rubio, Clarissa Martínez-Torres, D.D. Martínez-Torres, Dinorah D Martínez-Torres, Dinorah Martínez-Velázquez, Luis A Martins, Antonio Henrique Martí, Angel A Marvin, Marian Marx, Preston A Marxuach-Cuétara, Acisclo M Marzal, C Masalmah, Yahya M. 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Rodriguez-Rivera, Lorraine D Rodriguez-Rivera, Lorraine Rodriguez-Rivera, Jennifer Rodriguez-Rivera, L D Rodriguez-Rodriguez, Weyshla Rodríguez-Rodríguez, Weyshla A. Rodríguez-Rodríguez, Weyshla A Rodríguez-Rodríguez, W.A. Rodriguez-Romaguera, Jose Rodriguez-Sanchez, M. Rodríguez-Sargent, C Rodríguez-Sierra, C J Rodríguez-Torres, Maribel Rodriguez-Valentin, M. Rodríguez-Vallés, Harry Rodr{\'ıguez, G.J.M. Rodr{\'ıguez-Padilla, C. Roe, L. A. Roe, H. Roehrs, Philip A Roemer, Sarah Roeper, P Roghanian, Ali Roh, J. W. Rojas, Legier Rojas, Legier V Rojas-Sanchez, Fátima Roland, Joseph T Rollason, R.J. Rollason, R. J. Romaguera, Josefina Roman, Laura Roman, M Roman, FR Román, Félix Román, Félix R Roman, F Roman, Elddie Román, Enid Román-Montalvo, Natalia I Roman-Montalvo, Natalia Román-Montalvo, Natalia I Singhal Román-Montalvo, N.I. Roman-Ortiz, Ciorana Román-Ospino, Andrés D. Román-Ospino, Andrés D. 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Rosario, Samuel Rosario, M Rosario, S Rosario, O Rosario, O Rosario, M. Rosario, N Rosario, Osvaldo Rosario, Nydia Rosario-Acevedo, Raysa Rosario-Ortiz, Fernando Rosario-Ortiz, Fernando L Rosario-Torres, Samuel Rosario-Torres, S Rosas, Guillermo Rosas, Odrick R Rosas, Juan G. Rosas-Vidal, Luis E Rosati, Margherita Rosbash, M Rose, M Rose, K J Rose, H J Roselló-Lletí, Esther Rosemond, Zemoria Rosenberg, M G Rosenberg, Mara Rosenfeld, Robin J Rosengren, Johan Rosenshien, N. B. Rosenthal, Joshua J C Rosenthal, Joshua Rosenthal, J L Rosier-Lees, S Roska, Botond Roskowski, A Ross, Brian N Ross, M. D. Ross, Leila Ross, Timothy J. Ross, Elizabeth Ross, L. M. Ross, Christina K Cajigas- Rossi, Vincent Rossi, Rolando C Rossi, R C Rossmiller, Brian Rossow, Charles F Rosti, Ozgur Rotés, Delfín Roth, Matt E Roth, Matthew E Roth, Monica J Roth, L. A. Rotter, J. I. Rouault, M Rouault, Mathieu Rouse, D. Roussel, C. Roussos, Katerina Rousvoal, Sylvie Routaboul, L Routaboul, Pierre Braunstein Routaboul, Lucie Routtenberg, A Roux, Benoit Rowell, G Rowlands, Amanda L Rowlette, Laura-Leigh Rowley, Ann Rowley, J Roy, Sudipa Saha Roy, Sourav Roy, S Roy, Danielle M Roybal, Kole Roychoudhury, Jayeeta Roysam, Badrinath Rozek, Wojciech Rozo, Jackeline I. Jérez Rozov, Roye Rozowsky, Joel Ruan, Gedeng Ruaño, Gualberto Rubiano, J. C. Ulloa Rubin, D. A. Rubin, DM Rubin, David M Rubinstein, Jill Rubio, C E Rubio, Doris McGartland Rubio-Dávila, M Rubuluza, P. Rudak, B Ruddell, Benjamin L Rudin, Charles M Rudlaff, R. Rudra, Soumon Rudy, J. Rueda-Garcia, D. Ruff, SW Ruff, Steven W Rügamer, S Ruhe, Alison L Ruiz, Abigail Ruiz, Oscar N Ruiz, A Ruiz, Lynnette A Ruiz, Francesc X. Ruiz, M Ruiz, A. Ruiz-Arocho, Jorge Ruiz-Diaz, Claudia P Ruiz-Fullana, Francisco J. Ruiz-Jiménez, Caleb Ruiz-Jimenez, C. Ruiz-Linares, Andres Ruiz-Rodríguez, Eduardo A Rule, A.M. Rullán, Johnny Rullan-Cardec, J. M. Rullán-Lind, Carlos Rullan-Matheu, Yarely Rulten, C B Rump, Andreas Ruohoniemi, J.M. Rupaimoole, Rajesha Rupaimoole, R. Rupairmoole, R. Rupert, Allison Ruppel, J Rupprecht, Charles E Rusbjerg, Matilde Ruscetti, Marcus Rusch, Michael Rushe, M Rusniok, C Russell, JE Russell, John H Russo, G K Russo, James J. Russo, Angela Russo, James J Rustgi, Anil Rutstein, Richard Rutstein, R M Ruvkun, Gary Ruvkun, G. Ruzzi, M. Ruzzi, Marco Ryan, Michael J Ryan, J. Ryan, Peter G. Rymond, B C Ryu, Jubin Ryu, Hodon R{\'ıos, M.C. R{\'ıos, Cabrera R{\'ıos-Mercado, R.Z. Saadeddin, Anas Saag, Michael Saavedra, Priscilla M Sabat, A.M. Sabatini, Bernardo L Sabirianov, Renat F Sabirianov, RF Saboe, Patrick O Sabree, Z. L. Sacher, Joshua R Sadaoui, N. C. Saddler, Gerry Sadir, Rabia Sadler, Kirsten C Saez, Liz-Marie Albertorio Saez, Liz-Marie Albertorio Saez, AE Saez, Eduardo Sáez, M Sagaro, E Sage, Julien Saggion, A Saha, Avishek Saha, A. Saha, S. Sahadeva-Reddy, D Sahakian, V Sahara, N. 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Sánchez-Rivera, Francisco Sánchez-Rivera, D Sanchez-Rivera, FJ Sánchez-Rivera, Francisco Javier Sanchez-Rivera, Francisco J Sánchez-Vazquez, María M Sánchez-Zalduondo, Alejandra Sandberg, Jesse Sandberg, J K Sandberg, Bengt Sandberg, Johan K Sanders, Jean E Sanders, Mark A Sanders, J E Sanderson, J. D. Jeremy Sandmaier, Brenda M Sandoval, Karla Sandoval, J.M Sanguino, Angela Sanguino, A M Sanguino, A. M. Sankaran, Banumathi Sanne, Ian Sanne, I Santacana, G E Santacana, Guido E Santaella, M Santamaria, X Santana, Luis F Santana, Jorge L Santana, Alberto Santana, J Santana, Fernando Santana, JA Colón Santana, Jorge Santana, Jose Santangelo, A Sante, Joshua M Santé, Maria Santella, Regina M Santella, Anthony Santiago, Luis E. Santiago, G Santiago, Cesar Santiago, T Santiago, M.B. Santiago, Mitk’El B Santiago, N Santiago, Mitk'El B Santiago, Mitk'El B Santiago, Gladys S Santiago, M Santiago, Myrna J. Santiago, Nayda G. Santiago, MB Santiago, José M Santiago, Luis Santiago, Luis Enrique Ra Santiago, Olga I Santiago, Mitk'El B Santiago, Mitk’El B Santiago, Kiara M Santiago-Acevedo, Luis E. Santiago-Bartolomei, Raúl Santiago-Berrios, M.B. Santiago-Berrios, Mitk’El B Santiago-Berrios, Mitk'El Santiago-Berrios, MEB Santiago-Berrios, M. Santiago-Berrios, Mitk’el Santiago-Berríos, Mitk’El B Santiago-Borrero, Pedro Santiago-Borrero, Pedro J Santiago-Cartagena, Ednalise Santiago-Casas, Yesenia Santiago-Martínez, Edgardo Santiago-Morales, K. Santiago-Quinonez, Darlene Santiago-Rodriguez, Lenibel Santiago-Rodriguez, Tasha Santiago-Rodriguez, Tasha M Santiago-Santiago, Nayda G. Santiago-Tirado, Felipe Santiago-Tirado, Felipe H Santini, E Santini, Edwin Santini, Emanuela Santini, Emmanuela Santos, P.T. Santos, Ricardo Santos, María A. Santos, Hernán Santos, P.T. Dos Santos, Gabriel-Philip Santos, Gabriel-Phillip Santos, M.A. Santos, H Santos-Campis, Laura E Santos-Figueroa, Gilmarie Santos-Garcia, Andrea Santos-Pérez, J ; Santos-Vera, Bermary Santos-Vera, Bermary Sapiro, Guillermo Sapiro, Guillermio Sapparapu, Gopal Sarangi, Anindita Sarantopoulos, Stefanie Sariol, Carlos A Sariol, C A Sarkar, Ajoy K Sarkhel, S. Sarma, Vidur Sarriera, J E Sarto, Gloria E. Sartori, P Sartori, E. Sartori, Elena Sasaki, Clarence Sass, Steffen Satalecka, K Sater, Amy K Sather, G E Sattelle, D B Saturday, G. Saulino, Vera Saunders, Timothy P Saunders, Kevin O Saunders, Michael Savani, Bipin N Savary, C. A. Savasan, Sureyya Sawcer, Stephen J Sawin, Robert W Sawyer, Travis W. Sawyer, Travis Sawyer, T. Saxena, Vipin Sayin, Volkan I Sayles, Leanne C Sánchez-Rivera, Francisco J SC, Dexter Scalzotto, V Scapin, V Scaringi, Vincent J Sceusi, Eric L Schäfer, K. Schaff, James Schaffer, Paul J Schaid, D. Schall, Hayley E Schall, H. E. Schaller, Michael D Schaller, M. D. 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Schoonmaker-Bopp, Dianna Schoonmaker-Bopp, Diana J Schoonmaker-Bopp, D J Schore, Reuven J Schormann, M Schotanus, Mark Schott, Kelly Schott, Daniel Schowengerdt, RA Schrader, T E ; Schrander-Stumpel, C Schreiber, Stuart L Schreier, W J ; Schreiter, Eric R Schröder, E C Schröder, R Schroeder, F. A. Schroeder, Frederick A Schroeder, Jörg Schroedter, M Schteingart, David E Schuler, Linda A Schullery, Daniel Schultz, Kirk R Schulz, DL Schulze, J H Schulze, Doreen SCHUMANN, EH Schumm, Michael A Schunk, R.W. Schunk, Robert W. Schutt, Carolyn Schwanke, U Schwartz, B Schwartz, A Schwartz, Abe Schwartz, Zvi Schwartz, Michael Schwarz, David Schwarzbauer, Jean E Schwarzburg, S Schwarzer, Dirk Schwed, Daniel Schweitzer, C E Schweitzer, Carrie E Schweitzer, Anabel Y Schweitzer, Julie B Schweizer, F.E. Schweizer, T Schwemmer, S Schwer, Bjoern Scicolone, James V. 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Sela, Yogev Select Panel on Preconception Care Self, David W Selimović, Šeila Selleri, Licia Selma, J L Selmic, S Selmic, Sandra Selnes, Ola Selnes, O Selvam, Shivaram Sembroski, G H Semon, J Sen, Kapildeb Sen, Ayusman Senerchia, S Senevirathna, MKI Senevirathna, I Senftle, Thomas P Sengupta, Partho P Sengupta, Samudra Senseney, Justin Seo, Soo Jung Sepulveda, Gladys Sepulveda, Manuel A. Sepúlveda-Torres, Lycely Del C Serena, Thomas E Serena, Thomas Serpico, SB Serra, Viviana Serrano, Geidy E Serrano, Melissa Serrano, Antonio E Serrano, A E Serrano, Adelfa E Serrano, A Serrano, Juan Serrano-Rios, M. Serrano-Rodriguez, R Serrano-Vargas, Alberto Servat, E Seshacharyulu, Parthasarathy Sessions, October M Seth, Pankaj Seth, Puneet Severson, Nicolette Sevilla, Ana Seward, J Sgagias, Magda Shabanova, Veronika S Shacklett, B L Shah, Pavak Shah, Amil Shaheen, Farida Shahinpoor, M Shahzad, Mian M K Shahzad, M. M. Shakes, Diane C Shalchi, A Shalhoub, R. Shames, Jason P Shamloo, M Shan, Siqing Shang, Y Shang, Junjun Shankar, Sucharita P Shankar, A H Shanker, Sreejesh Shanker, Virendra Shanker, V. Shanker, V Shao, Zhiyong Shao, Jianqiang Shapiro, Michael Shapiro, L Sharif-Afshar, Ali-Reza Sharma, P Sharma, Renu Sharma, Kapil Sharma, Pankaj Sharpe, Paul Sharrar, R G Sharron, M Shaw, Bronwen E Shaw, Bryan F Shawver, Linda Shayduk, M Shazhad, Mian M K She, J. X. She, C. Y. Shea, E. M. Shekaran, Asha Shelton, Robert J Shelton, Stephen P Shelton, TC Shen, Qiang Shen, Yu Shen, SS Shen, Kang Shen, Zhuofan Shen, Shi-Hsiang Shen, Q. Shen, Chen Shen, Kuo-Fang Shen, Y. Sheng, Jipo Sheng, Morgan Shenoy, Shailesh M Shenoy, Shalini Shenvi, Christina L Shepard, T H Shereck, Evan B Shetrone, MD Shetrone, Matthew Shevde, Lalita A Shevenell, Lisa Shi, Linda Shi, Yunhua Shi, H Shi, Zhenqi Shi, Guixin Shibayama, Mineko Shields, J. Shields, K E Shields, Jessica Shiels, Aaron B. Shikani, B. T. Shillington, Frank A. SHILLINGTON, FA Shimamura, Akiko Shimizu, Tomohiro Shin, Heungsoo Shinozaki, K Shiramizu, Bruce Shklyaev, S Shklyaev, Sergey Shklyaev, S. Shlobin, O. Shoemaker, James T Shore, S N Showe, Louise Showe, Louise C Shrestha, S. Shroff, Hari Shu-Hu, Wei Shub, Mitchell D Shukla, M K Shulga, Nataliya Shull, Sheila M Shull, J Shull, Jane Shum, W.W. Shum, William W Shurtleff, Sheila Siantz, Elizabeth Sicard, Kenneth M Sicard, K. M. Sicinska, Ewa T Sickle, Eileen J Siddik, Z. H. Siddik, Zahid H Siddiqui, Almas Sidhu, M Sidhu, Amar Bir Sidor, Michelle M Sidro, N Siebert, S. J. Siegel, Micah S Sierant, M. Sierpowska-Bartosik, A Sierra, Ali J Altamira Sierra-Mercado, Demetrio Sierra-Vega, Nobel O. Sierra-Vega, Nobel O. Sievens-Figueroa, L. Sievens-Figueroa, Lucas Sievert, C F Sigman, M E Signore, Anthony V Sikora, M Silander, Susan Silbernagel, Rita Silén-Rivera, Pamela Siler, J D Siler, JD Siler, J. D. 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Skatchkov, Serguei Skerlj, Renato Skilton, J L Skoda, Erin M Skoda-Smith, Suzanne Skolasky, R L Skolasky, Richard L Skolasky, Richard Skolasky, R Slater, Brian K. Slater, E Slavotinek, A M Slazyk, W E Slepushkin, Vladimir Smerkers, Brain Smerkers, B. Smeyne, Richard Smirnov, Denis Smit, Ellen Smith, Barbara A Smith, Ewan St John Smith, Ronald A Smith, P Smith, JM Smith, Adrian Smith, J. A. Smith, M. W. Smith, Gary K Smith, Steve Smith, A W Smith, Joseph A Smith, S. Smith, Rosamund Smith, G Smith, C Smith, Lynette M Smith, Cody J Smith, L. C. Smith, Angela Smith, H. H. Smith, S. M. Smith, James Smith, Cynthia Smith, HA Smith, Collette Smith, Graeme Smith, D L Smith, Christopher W J Smith, David L Smith, M. H. Smith-Parker, Heidi K Smotkin, E. S. Smotkin, Eugene S Snyder, S. Snyder, Stephen Snyder, Shane Snyder, Shane A Snyder, Bruce A Snyder, Stacey A Sobczynska, D Sobsey, M. Sobsey, M. D. 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Stabenfeldt, Sarah E Stabler, Sally Stack, Kathryn M Stack, Kathryn Stack, KM Stack, K Stack‐Morgan, Kathryn M Stagg, Loren J Staggers, Sophia Stål, Olle Stamerra, A Stamler, Jonathan S Stankovic, AM Stanley, Brandon T Stanley, C Stany, Michael P Staprans, Silvija Stark, L S Starkman, Jonathan S Starkman, Jonathan Starwalt, Ruth Staub, Julie Staunton, James Stavoe, Andrea K H Stawarz, Ł Steenkamp, R Stefanov, William L Stefanski, Heather E Steffensmeier, Eric Steffenson, D M Stegmaier, Kimberly Stegmann, C Stein, Nathan Stein, E. A. Stein, Viktor Stein, Jamie Stein, Elliot A Stein, TI Stein, S. Stein, S. R. Stein, David Stein, N Steinbach, Gideon Steinbusch, Harry W M Stellar, J. R. Stellar, J R Stelzer, T. Stephan, A. Stephens, Edward B Stephens, R. M. Stephenson, Stacy I Sterman, Daniel H Stern, John Stern, Mariana C Stern, P Stern, David F Stern, Estee Stern, M Stern, L J Sternberg, L. D. S. 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Zuzga, David Zwiller, Jean Zybarth, G Zyla, T R Type any Journal Article Miscellaneous Conference Paper Book Book Chapter Presentation Thesis Manuscript Conference Proceedings Patent Unpublished Web Article Report Government Report Journal Website Magazine Article Term any Biblio Keywords - Biblio Keywords - *Anoikis Biblio Keywords - *Antigens, Bacterial/chemistry/genetics/metabolism Biblio Keywords - *Bacillus anthracis/chemistry/metabolism Biblio Keywords - *Bacterial Toxins/chemistry/genetics/metabolism Biblio Keywords - *Bacteriophage T7 Biblio Keywords - *cd38 Biblio Keywords - *Cell Proliferation Biblio Keywords - *covid-19 Biblio Keywords - *COVID-19/genetics/immunology Biblio Keywords - *cytokines Biblio Keywords - *Dietary Supplements Biblio Keywords - *Disease Models, Animal Biblio Keywords - *Ecology Biblio Keywords - *Efficiency Biblio Keywords - *Environmental Microbiology Biblio Keywords - *Epitopes/genetics/immunology Biblio Keywords - *Fasciola hepatica Biblio Keywords - *fatty acid binding protein Biblio Keywords - *fostamatinib Biblio Keywords - *Gastric Mucosa/metabolism Biblio Keywords - *Gene Expression Regulation, Neoplastic Biblio Keywords - *Gene Silencing Biblio Keywords - *Health Status Disparities Biblio Keywords - *Healthcare Disparities Biblio Keywords - *Immunity, Humoral Biblio Keywords - *immunothrombosis Biblio Keywords - *Infectious Disease Transmission, Vertical Biblio Keywords - *macrophages Biblio Keywords - *Mutation Biblio Keywords - *Neovascularization, Pathologic Biblio Keywords - *neutrophil extracellular traps Biblio Keywords - *Paraneoplastic Syndromes Biblio Keywords - *Peptide Library Biblio Keywords - *Pregnancy Complications, Infectious Biblio Keywords - *RNA Interference Biblio Keywords - *SARS-CoV-2/genetics/immunology Biblio Keywords - *septic shock Biblio Keywords - *Soil Microbiology Biblio Keywords - *Spike Glycoprotein, Coronavirus/genetics/immunology Biblio Keywords - *Stomach/chemistry Biblio Keywords - *Stress, Psychological Biblio Keywords - *Xenograft Model Antitumor Assays Biblio Keywords - *Zika Virus Biblio Keywords - *Zika Virus Infection Biblio Keywords - 0300 ATMOSPHERIC COMPOSITION AND STRUCTURE Biblio Keywords - 0310 Airglow and aurora Biblio Keywords - 0328 Exosphere Biblio Keywords - 0335 Ion chemistry of the atmosphere (2419 Biblio Keywords - 0340 Middle atmosphere: composition and chemistry Biblio Keywords - 0342) Biblio Keywords - 0350 Pressure Biblio Keywords - 0355 ATMOSPHERIC COMPOSITION AND STRUCTURE Thermosphere: composition and chemistry Biblio Keywords - 0355 Thermosphere: composition and chemistry Biblio Keywords - 0394 Instruments and techniques Biblio Keywords - 0640:Sustainability Biblio Keywords - 0729:Architecture Biblio Keywords - 0999:Urban planning Biblio Keywords - 1-Methyl-3-isobutylxanthine Biblio Keywords - 2,4-Dinitrophenol Biblio Keywords - 2-Amino-5-phosphonovalerate Biblio Keywords - 2-Aminopurine Biblio Keywords - 2-Hydroxypropyl-beta-cyclodextrin Biblio Keywords - 2419 Ion chemistry and composition (0335) Biblio Keywords - 2427 Ionosphere/atmosphere interactions (0335) Biblio Keywords - 2427) Biblio Keywords - 3' Untranslated Regions Biblio Keywords - 3',5'-Cyclic-AMP Phosphodiesterases Biblio Keywords - 3',5'-Cyclic-GMP Phosphodiesterases Biblio Keywords - 3,4-Dihydroxyphenylacetic Acid Biblio Keywords - 3-Hydroxyanthranilate 3,4-Dioxygenase Biblio Keywords - 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester Biblio Keywords - 3300 ATMOSPHERIC PROCESSES Biblio Keywords - 3319 General circulation (1223) Biblio Keywords - 3332 Mesospheric dynamics Biblio Keywords - 3334 Middle atmosphere dynamics (0341 Biblio Keywords - 3337 Global climate models (1626 Biblio Keywords - 3360 Remote sensing Biblio Keywords - 3364 Synoptic-scale meteorology Biblio Keywords - 3384 Acoustic-gravity waves Biblio Keywords - 3389 Tides and planetary waves Biblio Keywords - 3394 Instruments and techniques Biblio Keywords - 3D remote sensing Biblio Keywords - 3T3 Cells Biblio Keywords - 4-Aminobutyrate Transaminase Biblio Keywords - 4928) Biblio Keywords - 5' Flanking Region Biblio Keywords - 6-Cyano-7-nitroquinoxaline-2,3-dione Biblio Keywords - 6-Phytase Biblio Keywords - 6-Phytase/*metabolism Biblio Keywords - 6-Phytase/*pharmacology Biblio Keywords - A Kinase Anchor Proteins Biblio Keywords - Abnormalities, Drug-Induced Biblio Keywords - Abnormalities, Multiple Biblio Keywords - Abortion, Criminal Biblio Keywords - Abortion, Induced Biblio Keywords - Absorbable Implants Biblio Keywords - Absorptiometry, Photon Biblio Keywords - Absorption Biblio Keywords - Academic Medical Centers Biblio Keywords - Academies and Institutes Biblio Keywords - Acculturation Biblio Keywords - Acetazolamide Biblio Keywords - Acetonitriles Biblio Keywords - Acetylation Biblio Keywords - Acetylcholine Biblio Keywords - Achievement Biblio Keywords - Acid Phosphatase Biblio Keywords - Aconitine Biblio Keywords - Acoustic niche hypothesis Biblio Keywords - Acoustic Stimulation Biblio Keywords - Acoustic-gravity waves Biblio Keywords - Acquired Immunodeficiency Syndrome Biblio Keywords - Acridine Orange Biblio Keywords - Acrocephalosyndactylia Biblio Keywords - Acrylamides Biblio Keywords - Actin Cytoskeleton Biblio Keywords - Actinobacteria Biblio Keywords - Actins Biblio Keywords - Actins/metabolism Biblio Keywords - Action Potentials Biblio Keywords - Activating Transcription Factor 1 Biblio Keywords - Active Transport, Cell Nucleus Biblio Keywords - Acute Disease Biblio Keywords - Acute Kidney Injury Biblio Keywords - Acyclovir Biblio Keywords - Acyl Carrier Protein Biblio Keywords - Acylation Biblio Keywords - Acyltransferases Biblio Keywords - ADAM Proteins Biblio Keywords - Adaptation, Physiological Biblio Keywords - Adaptation, Psychological Biblio Keywords - Adaptive Immunity Biblio Keywords - Adaptor Protein Complex alpha Subunits Biblio Keywords - Adaptor Proteins, Signal Transducing Biblio Keywords - Adaptor Proteins, Signal Transducing/genetics/*immunology Biblio Keywords - Adaptor Proteins, Vesicular Transport Biblio Keywords - Adenocarcinoma Biblio Keywords - Adenocarcinoma, Mucinous/*drug therapy/genetics/pathology Biblio Keywords - Adenocarcinoma/*epidemiology Biblio Keywords - Adenocarcinoma/epidemiology/mortality/pathology Biblio Keywords - Adenosine Deaminase Biblio Keywords - Adenosine Diphosphate Biblio Keywords - Adenosine Triphosphatases Biblio Keywords - Adenosine Triphosphatases/genetics/*metabolism Biblio Keywords - Adenosine Triphosphatases/genetics/*physiology Biblio Keywords - Adenosine Triphosphate Biblio Keywords - Adenoviridae Biblio Keywords - Adenylate Cyclase Biblio Keywords - Adherens Junctions Biblio Keywords - Adhesiveness Biblio Keywords - Adipocytes Biblio Keywords - Adiponectin Biblio Keywords - Adipose Tissue Biblio Keywords - Adiposity Biblio Keywords - Adjuvants, Immunologic Biblio Keywords - Administration, Inhalation Biblio Keywords - Administration, Oral Biblio Keywords - Administration, Rectal Biblio Keywords - Administration, Sublingual Biblio Keywords - Administration, Topical Biblio Keywords - Adolescent Biblio Keywords - Adolescent Behavior Biblio Keywords - Adolescent Health Services Biblio Keywords - Adoptive Transfer Biblio Keywords - ADP-ribosyl Cyclase 1/analysis Biblio Keywords - Adrenal Glands Biblio Keywords - Adrenal Medulla Biblio Keywords - Adrenergic Agents Biblio Keywords - Adrenergic Agents/*metabolism Biblio Keywords - Adrenergic alpha-2 Receptor Agonists Biblio Keywords - Adrenergic alpha-2 Receptor Antagonists Biblio Keywords - Adrenergic alpha-Antagonists Biblio Keywords - Adrenergic beta-2 Receptor Antagonists Biblio Keywords - Adrenergic beta-Agonists Biblio Keywords - Adrenergic beta-Antagonists Biblio Keywords - Adrenergic beta-Antagonists/pharmacology Biblio Keywords - Adrenergic beta-Antagonists/pharmacology/therapeutic use Biblio Keywords - Adrenocorticotropic Hormone Biblio Keywords - Adrenomedullin Biblio Keywords - Adsorption Biblio Keywords - Adult Biblio Keywords - Adult asthma patients Biblio Keywords - Adult Stem Cells Biblio Keywords - Aerosols Biblio Keywords - Affect Biblio Keywords - Afferent Pathways Biblio Keywords - Africa Biblio Keywords - Africa South of the Sahara Biblio Keywords - Africa, Western Biblio Keywords - African Americans Biblio Keywords - African climate Biblio Keywords - African Continental Ancestry Group Biblio Keywords - African Continental Ancestry Group/statistics & numerical data Biblio Keywords - African development Biblio Keywords - African flood events Biblio Keywords - African monsoon Biblio Keywords - Age Distribution Biblio Keywords - Age Factors Biblio Keywords - Age of Onset Biblio Keywords - Aged Biblio Keywords - Aged, 80 and over Biblio Keywords - Aggrecans Biblio Keywords - Aggression Biblio Keywords - Aging Biblio Keywords - Agnosia Biblio Keywords - Agrobacterium tumefaciens Biblio Keywords - AIDS Dementia Complex Biblio Keywords - AIDS Vaccines Biblio Keywords - AIDS-Related Opportunistic Infections Biblio Keywords - Air Biblio Keywords - air chemistry Biblio Keywords - Air Pollutants Biblio Keywords - Air Pollution Biblio Keywords - air pressure Biblio Keywords - Air-sea interaction Biblio Keywords - Alanine Biblio Keywords - Albinism, Oculocutaneous Biblio Keywords - Alcohol Drinking Biblio Keywords - Alcoholism Biblio Keywords - Aldehyde Dehydrogenase Biblio Keywords - Aldehydes Biblio Keywords - Aldosterone Biblio Keywords - Alginates Biblio Keywords - Algorithms Biblio Keywords - Alien plants Biblio Keywords - Alkaline Phosphatase Biblio Keywords - Alkaloids Biblio Keywords - Alkalosis Biblio Keywords - Alkanes Biblio Keywords - Alkylating Agents Biblio Keywords - Alkylation Biblio Keywords - Alkynes Biblio Keywords - Alleles Biblio Keywords - Allergens Biblio Keywords - Allosteric Regulation Biblio Keywords - Allosteric Site Biblio Keywords - Allyl Compounds Biblio Keywords - Allylglycine Biblio Keywords - alpha Karyopherins Biblio Keywords - alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid Biblio Keywords - alpha-enolase Biblio Keywords - alpha-Fetoproteins Biblio Keywords - alpha-Tocopherol Biblio Keywords - alpha7 Nicotinic Acetylcholine Receptor Biblio Keywords - Alphapapillomavirus Biblio Keywords - Alternative Splicing Biblio Keywords - Altitude Biblio Keywords - Alu Elements Biblio Keywords - Alzheimer Disease Biblio Keywords - Amber Biblio Keywords - Ambulatory Care Biblio Keywords - Americas Biblio Keywords - Amides Biblio Keywords - Amikacin Biblio Keywords - Amiloride Biblio Keywords - Amines Biblio Keywords - Amino Acid Chloromethyl Ketones Biblio Keywords - Amino Acid Metabolism, Inborn Errors Biblio Keywords - Amino Acid Motifs Biblio Keywords - Amino Acid Oxidoreductases Biblio Keywords - Amino Acid Sequence Biblio Keywords - Amino Acid Substitution Biblio Keywords - Amino Acid Transport Systems Biblio Keywords - Amino Acid Transport Systems, Neutral Biblio Keywords - Amino Acids Biblio Keywords - Aminobutyrates Biblio Keywords - Aminoglycosides Biblio Keywords - Aminoisobutyric Acids Biblio Keywords - Aminolevulinic Acid Biblio Keywords - Aminoquinolines Biblio Keywords - Amniotic Band Syndrome Biblio Keywords - Amoxicillin Biblio Keywords - Amphetamine Biblio Keywords - Ampicillin Biblio Keywords - Amplified Fragment Length Polymorphism Analysis Biblio Keywords - Amplifiers, Electronic Biblio Keywords - Amygdala Biblio Keywords - Amyloid Biblio Keywords - Amyloid beta-Protein Precursor Biblio Keywords - Amyloid Precursor Protein Secretases Biblio Keywords - Amyloidogenic Proteins Biblio Keywords - Anabolic Agents Biblio Keywords - Analgesics Biblio Keywords - Analgesics, Opioid Biblio Keywords - analysis Biblio Keywords - Analysis of Variance Biblio Keywords - and temperature Biblio Keywords - Androstadienes Biblio Keywords - Androstane-3,17-diol Biblio Keywords - Anemia, Aplastic Biblio Keywords - Anemia, Diamond-Blackfan Biblio Keywords - Anemia/*etiology Biblio Keywords - Anencephaly Biblio Keywords - Anesthesia Biblio Keywords - Anesthesia, General Biblio Keywords - Anesthesia, Inhalation Biblio Keywords - Anesthesia, Intravenous Biblio Keywords - Anesthesiology Biblio Keywords - Anesthetics Biblio Keywords - Anesthetics, Inhalation Biblio Keywords - Anesthetics, Intravenous Biblio Keywords - Anesthetics, Local Biblio Keywords - Aneuploidy Biblio Keywords - Angiogenesis Inducing Agents Biblio Keywords - Angiogenesis Inhibitors Biblio Keywords - Angiogenesis Inhibitors/*pharmacology Biblio Keywords - Angiogenesis Inhibitors/*therapeutic use Biblio Keywords - Angiogenesis Inhibitors/therapeutic use Biblio Keywords - Angiotensin I Biblio Keywords - Angiotensin II Biblio Keywords - Angiotensin II Type 1 Receptor Blockers Biblio Keywords - Angiotensin Receptor Antagonists Biblio Keywords - Angiotensin-Converting Enzyme Inhibitors Biblio Keywords - Angiotensinogen Biblio Keywords - Angiotensins Biblio Keywords - Angola-Namibia river flows Biblio Keywords - Aniline Compounds Biblio Keywords - animal Biblio Keywords - Animal Biblio Keywords - Animal Communication Biblio Keywords - animal epidemiology Biblio Keywords - Animal Husbandry Biblio Keywords - animal microbiology Biblio Keywords - Animal: microbiology Biblio Keywords - Animals Biblio Keywords - animals Biblio Keywords - Animals, Congenic Biblio Keywords - Animals, Genetically Modified Biblio Keywords - Animals, Newborn Biblio Keywords - Anions Biblio Keywords - Anisomycin Biblio Keywords - annual cycle Biblio Keywords - Anoikis Biblio Keywords - Anopheles Biblio Keywords - Anoxia Biblio Keywords - Antarctic Regions Biblio Keywords - Anterior Horn Cells Biblio Keywords - Anthozoa Biblio Keywords - Anti-Anxiety Agents Biblio Keywords - Anti-Arrhythmia Agents Biblio Keywords - Anti-Bacterial Agents Biblio Keywords - Anti-DFS Biblio Keywords - Anti-HIV Agents Biblio Keywords - Anti-Infective Agents Biblio Keywords - Anti-Infective Agents, Local Biblio Keywords - Anti-Inflammatory Agents Biblio Keywords - Anti-Inflammatory Agents, Non-Steroidal Biblio Keywords - Anti-Inflammatory Agents, Non-Steroidal/chemistry/metabolism/*pharmacology Biblio Keywords - Anti-Retroviral Agents Biblio Keywords - Anti-Ulcer Agents Biblio Keywords - Antibiosis Biblio Keywords - Antibiotics, Antineoplastic Biblio Keywords - Antibodies Biblio Keywords - Antibodies, Anti-Idiotypic Biblio Keywords - Antibodies, Anticardiolipin Biblio Keywords - Antibodies, Antinuclear/blood/*immunology Biblio Keywords - Antibodies, Blocking Biblio Keywords - Antibodies, Helminth Biblio Keywords - Antibodies, Heterophile Biblio Keywords - Antibodies, Monoclonal Biblio Keywords - Antibodies, Monoclonal, Humanized Biblio Keywords - Antibodies, Monoclonal, Murine-Derived Biblio Keywords - Antibodies, Monoclonal/administration & dosage Biblio Keywords - Antibodies, Monoclonal/pharmacology/therapeutic use Biblio Keywords - Antibodies, Monoclonal/therapeutic use Biblio Keywords - Antibodies, Neoplasm Biblio Keywords - Antibodies, Neutralizing Biblio Keywords - Antibodies, Neutralizing/pharmacology Biblio Keywords - Antibodies, Protozoan/*immunology Biblio Keywords - Antibodies, Viral Biblio Keywords - Antibody Affinity Biblio Keywords - Antibody Formation Biblio Keywords - Antibody Specificity Biblio Keywords - Antibody Specificity/*immunology Biblio Keywords - Anticancer agents Biblio Keywords - Anticoagulants Biblio Keywords - Anticonvulsants Biblio Keywords - Antidepressive Agents Biblio Keywords - Antidepressive Agents, Second-Generation Biblio Keywords - Antiemetics Biblio Keywords - Antifungal Agents Biblio Keywords - Antigen delivery Biblio Keywords - Antigen Presentation Biblio Keywords - Antigen-Antibody Complex Biblio Keywords - Antigen-Presenting Cells Biblio Keywords - Antigens Biblio Keywords - Antigens, CD Biblio Keywords - Antigens, CD11c Biblio Keywords - Antigens, CD14 Biblio Keywords - Antigens, CD19 Biblio Keywords - Antigens, CD274 Biblio Keywords - Antigens, CD29 Biblio Keywords - Antigens, CD3 Biblio Keywords - Antigens, CD31/biosynthesis Biblio Keywords - Antigens, CD31/metabolism Biblio Keywords - Antigens, CD34 Biblio Keywords - Antigens, CD4 Biblio Keywords - Antigens, CD40 Biblio Keywords - Antigens, CD44 Biblio Keywords - Antigens, CD56 Biblio Keywords - Antigens, CD80 Biblio Keywords - Antigens, CD86 Biblio Keywords - Antigens, Differentiation Biblio Keywords - Antigens, Differentiation, T-Lymphocyte Biblio Keywords - Antigens, Fungal Biblio Keywords - Antigens, Helminth Biblio Keywords - Antigens, Neoplasm Biblio Keywords - Antigens, Surface Biblio Keywords - Antigens, Viral Biblio Keywords - Antihypertensive Agents Biblio Keywords - Antilles climate Biblio Keywords - Antilymphocyte Serum Biblio Keywords - Antimalarials Biblio Keywords - Antimetabolites Biblio Keywords - Antimetabolites, Antineoplastic Biblio Keywords - Antimicrobial Cationic Peptides Biblio Keywords - Antineoplastic Agents Biblio Keywords - Antineoplastic Agents, Alkylating Biblio Keywords - Antineoplastic Agents, Phytogenic Biblio Keywords - Antineoplastic Agents/*pharmacology Biblio Keywords - Antineoplastic Agents/metabolism/pharmacology Biblio Keywords - Antineoplastic Agents/pharmacokinetics/pharmacology Biblio Keywords - Antineoplastic Agents/pharmacology Biblio Keywords - Antineoplastic Agents/therapeutic use Biblio Keywords - Antineoplastic Combined Chemotherapy Protocols Biblio Keywords - Antineoplastic Combined Chemotherapy Protocols/*pharmacology Biblio Keywords - Antineoplastic Combined Chemotherapy Protocols/*therapeutic use Biblio Keywords - Antineoplastic Combined Chemotherapy Protocols/therapeutic use Biblio Keywords - Antinuclear autoantibodies Biblio Keywords - Antioxidants Biblio Keywords - Antiretroviral Therapy, Highly Active Biblio Keywords - Antirheumatic Agents Biblio Keywords - Antithrombins Biblio Keywords - Antiviral Agents Biblio Keywords - Anura Biblio Keywords - Anus Neoplasms/*epidemiology/*mortality/pathology Biblio Keywords - Anus Neoplasms/*epidemiology/ethnology/mortality Biblio Keywords - Anus, Imperforate Biblio Keywords - Anxiety Biblio Keywords - Anxiety Disorders Biblio Keywords - Aorta Biblio Keywords - Aorta, Thoracic Biblio Keywords - Aortic Diseases Biblio Keywords - Aortic Valve Biblio Keywords - Apamin Biblio Keywords - Aplysia Biblio Keywords - Apoptosis Biblio Keywords - Apoptosis Regulatory Proteins Biblio Keywords - Apoptosis Regulatory Proteins/analysis Biblio Keywords - Apoptosis/*genetics Biblio Keywords - Apoptosis/drug effects Biblio Keywords - Appetite Biblio Keywords - Appetitive Behavior Biblio Keywords - aprendizaje Biblio Keywords - Aptamers, Nucleotide Biblio Keywords - Aptamers, Nucleotide/*therapeutic use Biblio Keywords - Arabinan Biblio Keywords - Arachidonic Acid Biblio Keywords - Arachidonic Acids Biblio Keywords - Archaea Biblio Keywords - Architecture Biblio Keywords - Area Under Curve Biblio Keywords - Arecbio Observatory Biblio Keywords - Arecibo observatory Biblio Keywords - Argentina Biblio Keywords - Arginine Biblio Keywords - Arginine Vasopressin Biblio Keywords - Arizona Biblio Keywords - Arousal Biblio Keywords - Arrestins Biblio Keywords - Arrhythmias, Cardiac Biblio Keywords - Arsenic Biblio Keywords - Arsenicals Biblio Keywords - Arsenites Biblio Keywords - Artemisinins Biblio Keywords - Arterial Pressure Biblio Keywords - Arteries Biblio Keywords - Arthritis, Rheumatoid Biblio Keywords - Arthropod Antennae Biblio Keywords - Arthropods Biblio Keywords - Aryl Hydrocarbon Hydroxylases Biblio Keywords - Arylformamidase Biblio Keywords - Ascaris Biblio Keywords - Ascitic Fluid Biblio Keywords - Ascomycota Biblio Keywords - Ascorbic Acid Biblio Keywords - Asia Biblio Keywords - Asian Americans Biblio Keywords - Asparagine Biblio Keywords - Aspartate Aminotransferases Biblio Keywords - Aspartic Acid Endopeptidases Biblio Keywords - Assessment Biblio Keywords - Association Learning Biblio Keywords - Astacoidea Biblio Keywords - Asthenopia Biblio Keywords - Asthma Biblio Keywords - Asthma/*therapy Biblio Keywords - Astrocytes Biblio Keywords - Astrocytoma Biblio Keywords - Astrophysics - Astrophysics of Galaxies Biblio Keywords - Astrophysics - High Energy Astrophysical Phenomena Biblio Keywords - Astrophysics - Solar and Stellar Astrophysics Biblio Keywords - Ataxia Telangiectasia Mutated Proteins Biblio Keywords - Atherosclerosis Biblio Keywords - Athletes Biblio Keywords - Atlantic multidecadal oscillation Biblio Keywords - Atlantic storms Biblio Keywords - Atmosphere-land interaction Biblio Keywords - Atmosphere-ocean interaction Biblio Keywords - atmospheric Biblio Keywords - atmospheric structure Biblio Keywords - atmospheric variability Biblio Keywords - Atmospheric waves Biblio Keywords - Atovaquone Biblio Keywords - ATP-Binding Cassette Transporters Biblio Keywords - ATP-Binding Cassette Transporters/genetics/*physiology Biblio Keywords - Atrial Natriuretic Factor Biblio Keywords - Atrioventricular Node Biblio Keywords - Atropine Biblio Keywords - Attention Biblio Keywords - attitude Biblio Keywords - Attitude of Health Personnel Biblio Keywords - Attitude to Health Biblio Keywords - Auditory Cortex Biblio Keywords - Auditory Pathways Biblio Keywords - Auditory Perception Biblio Keywords - Aurora Kinases Biblio Keywords - Autistic Disorder Biblio Keywords - Autoanalysis Biblio Keywords - autoantibodies Biblio Keywords - Autoantigens Biblio Keywords - Autoimmunity Biblio Keywords - Autonomic Nerve Block Biblio Keywords - Autophagy Biblio Keywords - Autophagy/*genetics Biblio Keywords - Autopsy Biblio Keywords - Autoradiography Biblio Keywords - Avidin Biblio Keywords - Avoidance Learning Biblio Keywords - Axonal Transport Biblio Keywords - Axons Biblio Keywords - Axotomy Biblio Keywords - Azacitidine Biblio Keywords - Azides Biblio Keywords - B-Lymphocytes Biblio Keywords - Bacillus subtilis Biblio Keywords - Back Pain Biblio Keywords - Baclofen Biblio Keywords - Bacteremia Biblio Keywords - Bacteria Biblio Keywords - Bacteria/*metabolism Biblio Keywords - Bacterial Biblio Keywords - bacterial Biblio Keywords - Bacterial Adhesion Biblio Keywords - bacterial genetics Biblio Keywords - Bacterial Infections Biblio Keywords - Bacterial Outer Membrane Proteins Biblio Keywords - Bacterial Outer Membrane Proteins/chemistry/*genetics/*metabolism Biblio Keywords - Bacterial Proteins Biblio Keywords - Bacterial Proteins: genetics Biblio Keywords - Bacterial Translocation Biblio Keywords - bacterial typing techniques Biblio Keywords - Bacterial Typing Techniques Biblio Keywords - bacterial typing techniques veterinary Biblio Keywords - Bacterial: chemistry Biblio Keywords - Bacterial: genetics Biblio Keywords - Bacteriophages Biblio Keywords - Bacteroides Biblio Keywords - Bardet-Biedl Syndrome Biblio Keywords - Barium Compounds Biblio Keywords - baroclinic tides Biblio Keywords - Basal Ganglia Biblio Keywords - Base Sequence Biblio Keywords - Basic Helix-Loop-Helix Leucine Zipper Transcription Factors Biblio Keywords - Basic Helix-Loop-Helix Transcription Factors Biblio Keywords - Basic-Leucine Zipper Transcription Factors Biblio Keywords - Basidiomycota Biblio Keywords - Bathing Beaches Biblio Keywords - Batrachotoxins Biblio Keywords - bcl-2-Associated X Protein Biblio Keywords - bcl-2-Associated X Protein/genetics/metabolism Biblio Keywords - bcl-X Protein Biblio Keywords - bcl-X Protein/genetics/metabolism Biblio Keywords - Beach erosion Biblio Keywords - beach use Biblio Keywords - Beckwith-Wiedemann Syndrome Biblio Keywords - Beetles Biblio Keywords - Behavior Biblio Keywords - Behavior Therapy Biblio Keywords - Behavior, Addictive Biblio Keywords - Behavior, Animal Biblio Keywords - Benguela Biblio Keywords - Benguela fish catch Biblio Keywords - Benzazepines/pharmacology Biblio Keywords - Benzeneacetamides Biblio Keywords - Benzenesulfonates Biblio Keywords - Benzocaine Biblio Keywords - Benzodiazepines Biblio Keywords - Benzofurans Biblio Keywords - Benzophenones Biblio Keywords - Benzopyrans Biblio Keywords - Bereavement Biblio Keywords - beta Catenin Biblio Keywords - beta Karyopherins Biblio Keywords - beta-Cyclodextrins Biblio Keywords - beta-Endorphin Biblio Keywords - beta-Galactosidase Biblio Keywords - beta-Lactam Resistance Biblio Keywords - beta-Lactamases Biblio Keywords - Bicarbonates Biblio Keywords - Bicuspid Biblio Keywords - Bicyclo Compounds, Heterocyclic Biblio Keywords - Bimetallic molecules Biblio Keywords - Binding Sites Biblio Keywords - Binding Sites, Antibody Biblio Keywords - Binding, Competitive Biblio Keywords - Binge-Eating Disorder Biblio Keywords - Bioacoustics Biblio Keywords - Biocatalysis Biblio Keywords - Biochemistry Biblio Keywords - Biocompatible Materials Biblio Keywords - Biodegradation, Environmental Biblio Keywords - Biodeterioration Biblio Keywords - Biodiversity Biblio Keywords - biodiversity and governance Biblio Keywords - biodiversity assessment Biblio Keywords - biodiversity; green infrastructure; residential yards; social-ecological systems; socioeconomic; sustainability; tropical; urban Biblio Keywords - Bioengineering Biblio Keywords - Biofilms Biblio Keywords - Biofouling Biblio Keywords - Biofuels Biblio Keywords - Biogenic Monoamines Biblio Keywords - Biogeography Biblio Keywords - Biological Assay Biblio Keywords - Biological Availability Biblio Keywords - Biological Clocks Biblio Keywords - Biological Evolution Biblio Keywords - biological invasions Biblio Keywords - Biological Markers Biblio Keywords - Biological Products Biblio Keywords - Biological Transport Biblio Keywords - Biological Transport, Active Biblio Keywords - Biomass Biblio Keywords - Biomechanical Phenomena Biblio Keywords - Biomedical Research Biblio Keywords - Biomimetic Materials Biblio Keywords - Biomimetics Biblio Keywords - Biomphalaria Biblio Keywords - Biophysical Phenomena Biblio Keywords - Biophysics Biblio Keywords - Biopolymers Biblio Keywords - Bioprospect Biblio Keywords - Biopsy Biblio Keywords - Biopsy, Fine-Needle Biblio Keywords - Bioreactors Biblio Keywords - Biotechnology Biblio Keywords - biotic change Biblio Keywords - Biotic homogenization Biblio Keywords - Biotin Biblio Keywords - Biotinylation Biblio Keywords - Biphenyl Compounds Biblio Keywords - Bipolar Disorder Biblio Keywords - Bird Diseases Biblio Keywords - Birds Biblio Keywords - Birth Rate Biblio Keywords - Birth Weight Biblio Keywords - Bisbenzimidazole Biblio Keywords - Bivalvia Biblio Keywords - Blastoderm Biblio Keywords - Bleeding Time Biblio Keywords - Bleomycin Biblio Keywords - Blood Biblio Keywords - Blood Cell Count Biblio Keywords - Blood Cells Biblio Keywords - Blood Flow Velocity Biblio Keywords - Blood Glucose Biblio Keywords - Blood Platelets/immunology Biblio Keywords - Blood Preservation Biblio Keywords - Blood Pressure Biblio Keywords - Blood Proteins Biblio Keywords - Blood Transfusion Biblio Keywords - Blood-Brain Barrier Biblio Keywords - Blotting, Northern Biblio Keywords - Blotting, Southern Biblio Keywords - Blotting, Western Biblio Keywords - Body Fat Distribution Biblio Keywords - Body Mass Index Biblio Keywords - Body Size Biblio Keywords - Body Water Biblio Keywords - Body Weight Biblio Keywords - Body Weights and Measures Biblio Keywords - Bone and Bones Biblio Keywords - Bone Development Biblio Keywords - Bone Diseases Biblio Keywords - Bone Marrow Biblio Keywords - Bone Marrow Cells Biblio Keywords - Bone Marrow Diseases Biblio Keywords - Bone Marrow Transplantation Biblio Keywords - Bone Matrix Biblio Keywords - Bone Morphogenetic Protein 2 Biblio Keywords - Bone Morphogenetic Proteins Biblio Keywords - Bone Neoplasms Biblio Keywords - Bone Neoplasms/prevention & control/*secondary Biblio Keywords - Bone Regeneration Biblio Keywords - Bone Substitutes Biblio Keywords - Bone Transplantation Biblio Keywords - Borates Biblio Keywords - Boron Compounds Biblio Keywords - botanical and zoological species Biblio Keywords - Boundary currents Biblio Keywords - Boundary layer Biblio Keywords - boundary-layer fluxes Biblio Keywords - Brachyura Biblio Keywords - Bradykinin Biblio Keywords - Brain Biblio Keywords - Brain Chemistry Biblio Keywords - Brain Injuries Biblio Keywords - Brain Mapping Biblio Keywords - Brain Neoplasms Biblio Keywords - Brain Stem Biblio Keywords - Brain-Derived Neurotrophic Factor Biblio Keywords - BRCA1 Protein Biblio Keywords - BRCA2 Protein Biblio Keywords - Breast Biblio Keywords - Breast Neoplasms Biblio Keywords - Breeding Biblio Keywords - Bridged Compounds Biblio Keywords - Bromeliads Biblio Keywords - Bromides Biblio Keywords - Bromodeoxyuridine Biblio Keywords - Bronchi Biblio Keywords - Bronchoscopy Biblio Keywords - Bryostatins Biblio Keywords - Bucladesine Biblio Keywords - Budgets Biblio Keywords - Buffers Biblio Keywords - Bufo marinus Biblio Keywords - Bumetanide Biblio Keywords - Bungarotoxins Biblio Keywords - Bupivacaine Biblio Keywords - Bursera simaruba Biblio Keywords - Busulfan Biblio Keywords - Butadienes Biblio Keywords - Butterflies Biblio Keywords - CA1 Region, Hippocampal Biblio Keywords - cabinet distribution unit Biblio Keywords - Cactaceae/*microbiology Biblio Keywords - Cadaverine Biblio Keywords - Cadherins Biblio Keywords - Cadherins/metabolism Biblio Keywords - Cadmium Biblio Keywords - Cadmium sulfide Biblio Keywords - Caenorhabditis elegans Biblio Keywords - Caenorhabditis elegans Proteins Biblio Keywords - Caesalpinia Biblio Keywords - Caffeine Biblio Keywords - Caicos Island wind wake Biblio Keywords - Calbindins Biblio Keywords - Calcification, Physiologic Biblio Keywords - Calcimimetic Agents Biblio Keywords - Calcineurin Biblio Keywords - Calcinosis Biblio Keywords - Calcitriol Biblio Keywords - Calcium Biblio Keywords - Calcium Carbonate Biblio Keywords - Calcium Channel Agonists Biblio Keywords - Calcium Channel Blockers Biblio Keywords - Calcium Channels Biblio Keywords - Calcium Channels, L-Type Biblio Keywords - Calcium Ionophores Biblio Keywords - Calcium Isotopes Biblio Keywords - Calcium Radioisotopes Biblio Keywords - Calcium Signaling Biblio Keywords - Calcium Sulfate Biblio Keywords - Calcium-Binding Proteins Biblio Keywords - Calcium-Calmodulin-Dependent Protein Kinases Biblio Keywords - Calibration Biblio Keywords - California Biblio Keywords - Calmodulin Biblio Keywords - Calmodulin-Binding Proteins Biblio Keywords - Calorimetry Biblio Keywords - Calorimetry, Differential Scanning Biblio Keywords - Canada Biblio Keywords - Cancer Biblio Keywords - cancer biomarker Biblio Keywords - Cancer Patients Biblio Keywords - cancer stem cells Biblio Keywords - Cancer vaccine Biblio Keywords - Candida albicans Biblio Keywords - Candy Biblio Keywords - Cannabis Biblio Keywords - Cape Frio Biblio Keywords - Cape Town Biblio Keywords - Caproates Biblio Keywords - Capsid Proteins Biblio Keywords - Captopril Biblio Keywords - Carbachol Biblio Keywords - Carbamazepine Biblio Keywords - Carbazoles Biblio Keywords - Carbohydrate Metabolism Biblio Keywords - Carbohydrate Sequence Biblio Keywords - Carbohydrates Biblio Keywords - Carbon Biblio Keywords - Carbon Cycle Biblio Keywords - Carbon Dioxide Biblio Keywords - Carbon Monoxide Biblio Keywords - Carbon-Oxygen Lyases Biblio Keywords - Carbon-Sulfur Lyases Biblio Keywords - Carbonic Acid Biblio Keywords - Carbonic Anhydrase Inhibitors Biblio Keywords - Carbonic Anhydrases Biblio Keywords - Carboxypeptidase H Biblio Keywords - Carboxypeptidases Biblio Keywords - Carcinogenesis Biblio Keywords - Carcinogenicity Tests Biblio Keywords - Carcinoid Tumor Biblio Keywords - Carcinoma Biblio Keywords - Carcinoma, Hepatocellular Biblio Keywords - Carcinoma, Non-Small-Cell Lung Biblio Keywords - Carcinoma, Squamous Cell Biblio Keywords - Carcinoma, Squamous Cell/*epidemiology Biblio Keywords - Carcinoma, Squamous Cell/epidemiology/mortality/pathology Biblio Keywords - Carcinoma/*blood supply/pathology/*physiopathology/radiography Biblio Keywords - Carcinoma/*drug therapy/pathology Biblio Keywords - Carcinoma/chemistry/*genetics Biblio Keywords - Carcinoma/drug therapy/genetics/metabolism Biblio Keywords - Carcinoma/metabolism/*pathology/*surgery Biblio Keywords - Cardiac Catheterization Biblio Keywords - Cardiac Complexes, Premature Biblio Keywords - Cardiac Output, Low Biblio Keywords - Cardiomegaly Biblio Keywords - Cardiomyopathies Biblio Keywords - Cardiomyopathy, Dilated Biblio Keywords - Cardiotonic Agents Biblio Keywords - Cardiovascular Abnormalities Biblio Keywords - Cardiovascular Diseases Biblio Keywords - Career Choice Biblio Keywords - Career Mobility Biblio Keywords - Caribbean Biblio Keywords - Caribbean Antilles Biblio Keywords - Caribbean island Biblio Keywords - Caribbean Region Biblio Keywords - Cariostatic Agents Biblio Keywords - Carotid Arteries Biblio Keywords - Carotid Intima-Media Thickness Biblio Keywords - Carrier Proteins Biblio Keywords - Cartilage Biblio Keywords - Cartilage Oligomeric Matrix Protein Biblio Keywords - Cartilage, Articular Biblio Keywords - Case Management Biblio Keywords - Case-Control Studies Biblio Keywords - Caspase 3 Biblio Keywords - Caspase 8 Biblio Keywords - Caspases Biblio Keywords - Caspases/metabolism Biblio Keywords - Catalase Biblio Keywords - Catalysis Biblio Keywords - Catechin Biblio Keywords - Catechin/pharmacology/*therapeutic use Biblio Keywords - Catecholamines Biblio Keywords - Catecholamines/pharmacology/physiology Biblio Keywords - Catenins Biblio Keywords - Catenins/genetics/metabolism Biblio Keywords - caterpillar-butterfly irruption Biblio Keywords - Cathepsin B Biblio Keywords - Catheterization Biblio Keywords - Catheterization, Swan-Ganz Biblio Keywords - Cathode material Biblio Keywords - Cation Transport Proteins Biblio Keywords - Cation Transport Proteins/genetics/*metabolism Biblio Keywords - Cations Biblio Keywords - Cations, Divalent Biblio Keywords - Cats Biblio Keywords - Cattle Biblio Keywords - cattle Biblio Keywords - cattle diseases Biblio Keywords - Cattle Diseases Biblio Keywords - cattle diseases epidemiology Biblio Keywords - cattle diseases microbiology Biblio Keywords - Cattle Diseases: microbiology Biblio Keywords - Caulobacter crescentus Biblio Keywords - Causality Biblio Keywords - Cause of Death Biblio Keywords - Caveolin 1 Biblio Keywords - Caveolin 2 Biblio Keywords - Caveolins Biblio Keywords - Caves Biblio Keywords - CCAAT-Enhancer-Binding Protein-beta Biblio Keywords - CCAAT-Enhancer-Binding Proteins Biblio Keywords - CCN Intercellular Signaling Proteins Biblio Keywords - CD4 Lymphocyte Count Biblio Keywords - CD4-CD8 Ratio Biblio Keywords - CD4-Positive T-Lymphocytes Biblio Keywords - CD40 Ligand Biblio Keywords - CD47 Antigen/metabolism Biblio Keywords - CD8-Positive T-Lymphocytes Biblio Keywords - Cebus Biblio Keywords - Cefotaxime Biblio Keywords - Ceftriaxone Biblio Keywords - Cell Adhesion Biblio Keywords - Cell Adhesion Molecules Biblio Keywords - Cell Adhesion/drug effects Biblio Keywords - Cell Aging Biblio Keywords - Cell Biology Biblio Keywords - Cell Communication Biblio Keywords - Cell Compartmentation Biblio Keywords - Cell Count Biblio Keywords - Cell Culture Techniques Biblio Keywords - Cell Cycle Biblio Keywords - Cell Cycle Proteins Biblio Keywords - Cell Cycle/drug effects Biblio Keywords - Cell Cycle/genetics Biblio Keywords - Cell Death Biblio Keywords - Cell Degranulation Biblio Keywords - Cell Differentiation Biblio Keywords - Cell Division Biblio Keywords - Cell Fractionation Biblio Keywords - Cell Fusion Biblio Keywords - Cell Growth Processes Biblio Keywords - Cell Hypoxia Biblio Keywords - Cell Line Biblio Keywords - Cell Line, Transformed Biblio Keywords - Cell Line, Tumor Biblio Keywords - Cell Line, Tumor/drug effects Biblio Keywords - Cell Lineage Biblio Keywords - Cell Membrane Biblio Keywords - Cell Membrane Permeability Biblio Keywords - Cell Membrane/chemistry/metabolism Biblio Keywords - Cell Membrane/metabolism Biblio Keywords - Cell Movement Biblio Keywords - Cell Movement/*drug effects Biblio Keywords - Cell Movement/drug effects Biblio Keywords - Cell Nucleus Biblio Keywords - Cell Physiological Phenomena Biblio Keywords - Cell Polarity Biblio Keywords - Cell Proliferation Biblio Keywords - Cell Proliferation/drug effects Biblio Keywords - Cell Separation Biblio Keywords - Cell Shape Biblio Keywords - Cell Size Biblio Keywords - Cell Survival Biblio Keywords - cell survival Biblio Keywords - Cell Survival/drug effects Biblio Keywords - Cell Tracking Biblio Keywords - Cell Transformation, Neoplastic Biblio Keywords - Cell Wall Biblio Keywords - Cell- and Tissue-Based Therapy Biblio Keywords - Cell-free expression system Biblio Keywords - Cell-Free System Biblio Keywords - Cells, Cultured Biblio Keywords - Cellular Microenvironment Biblio Keywords - Cellular Phone Biblio Keywords - Censuses Biblio Keywords - Centers for Disease Control and Prevention (U.S.) Biblio Keywords - Central Nervous System Biblio Keywords - Central Nervous System Agents Biblio Keywords - Central Nervous System Stimulants Biblio Keywords - Centrifugation Biblio Keywords - Centrifugation, Density Gradient Biblio Keywords - Centrosome Biblio Keywords - Cercopithecus aethiops Biblio Keywords - Cerebral Angiography Biblio Keywords - Cerebral Arteries Biblio Keywords - Cerebral Cortex Biblio Keywords - Cerebral Hemorrhage Biblio Keywords - Cerebrospinal Fluid Biblio Keywords - Cerebrovascular Circulation Biblio Keywords - Cerebrovascular Disorders Biblio Keywords - Cervix Uteri Biblio Keywords - Cesium Biblio Keywords - Characterization Biblio Keywords - Checklist Biblio Keywords - Cheek Biblio Keywords - Chelating Agents Biblio Keywords - Chemical Fractionation Biblio Keywords - Chemical kinetic and photochemical properties Biblio Keywords - Chemistry Biblio Keywords - Chemistry, Physical Biblio Keywords - Chemistry: Physical Biblio Keywords - Chemokine CCL4 Biblio Keywords - Chemokine CX3CL1 Biblio Keywords - Chemokine CXCL12 Biblio Keywords - Chemokines Biblio Keywords - chemokines Biblio Keywords - Chemokines, CC Biblio Keywords - Chemoreceptor Cells Biblio Keywords - chemoresistance Biblio Keywords - Chemotaxis Biblio Keywords - Chemotaxis, Leukocyte Biblio Keywords - Chi-Square Distribution Biblio Keywords - Chick Embryo Biblio Keywords - Chickenpox Vaccine Biblio Keywords - Chickens Biblio Keywords - Child Biblio Keywords - Child Abuse Biblio Keywords - Child Behavior Biblio Keywords - Child Day Care Centers Biblio Keywords - Child Development Biblio Keywords - Child Health Services Biblio Keywords - Child Welfare Biblio Keywords - Child, Preschool Biblio Keywords - children Biblio Keywords - Chile Biblio Keywords - China Biblio Keywords - Chitin Biblio Keywords - Chitin Synthase Biblio Keywords - Chitinase Biblio Keywords - Chitosan Biblio Keywords - Chlamydia Biblio Keywords - Chlamydia Infections Biblio Keywords - Chlamydia trachomatis Biblio Keywords - Chloramines Biblio Keywords - Chloramphenicol O-Acetyltransferase Biblio Keywords - Chlorides Biblio Keywords - Chlorine Biblio Keywords - Chlorine Compounds Biblio Keywords - Chlorisondamine Biblio Keywords - Chlorobenzoates Biblio Keywords - Chloroflexi Biblio Keywords - Chlorophyll Biblio Keywords - Chloroplasts Biblio Keywords - Chloroquine Biblio Keywords - CHO Cells Biblio Keywords - Choice Behavior Biblio Keywords - Cholecystokinin Biblio Keywords - Cholera Toxin Biblio Keywords - Cholesterol Biblio Keywords - Cholinergic Agonists Biblio Keywords - Cholinergic Fibers Biblio Keywords - Cholinergic Neurons Biblio Keywords - Chondrocytes Biblio Keywords - Chondrogenesis Biblio Keywords - Chondrus Biblio Keywords - Christianity Biblio Keywords - Chromaffin Cells Biblio Keywords - Chromatin Biblio Keywords - Chromatin Assembly and Disassembly Biblio Keywords - Chromatin Immunoprecipitation Biblio Keywords - Chromatography Biblio Keywords - Chromatography, Affinity Biblio Keywords - Chromatography, Affinity/methods Biblio Keywords - Chromatography, Gel Biblio Keywords - Chromatography, High Pressure Liquid Biblio Keywords - Chromatography, Ion Exchange Biblio Keywords - Chromatography, Liquid Biblio Keywords - Chromatography, Paper Biblio Keywords - Chromatography, Thin Layer Biblio Keywords - Chromium Radioisotopes Biblio Keywords - Chromium/chemistry/*metabolism Biblio Keywords - Chromones Biblio Keywords - Chromosomal Instability Biblio Keywords - Chromosome Aberrations Biblio Keywords - Chromosome Deletion Biblio Keywords - Chromosome Disorders Biblio Keywords - Chromosome Mapping Biblio Keywords - Chromosomes Biblio Keywords - Chromosomes, Artificial, Bacterial Biblio Keywords - Chromosomes, Bacterial Biblio Keywords - Chromosomes, Human, Pair 12 Biblio Keywords - Chromosomes, Human, Pair 19 Biblio Keywords - Chromosomes, Human, Pair 20 Biblio Keywords - Chromosomes, Human, Pair 3 Biblio Keywords - Chromosomes, Human, Pair 4 Biblio Keywords - Chromosomes, Human, Pair 7 Biblio Keywords - Chromosomes, Human, Pair 8 Biblio Keywords - Chromosomes, Mammalian Biblio Keywords - Chronic Disease Biblio Keywords - Ciencias del Sistema Terrestre Biblio Keywords - Ciencias Terrestres y del Espacio Biblio Keywords - Ciliary Neurotrophic Factor Biblio Keywords - Circadian Rhythm Biblio Keywords - Circular Dichroism Biblio Keywords - circulation index Biblio Keywords - Circulation/dynamics Biblio Keywords - Cisplatin Biblio Keywords - Cisplatin/*pharmacology Biblio Keywords - Cisplatin/metabolism/pharmacology Biblio Keywords - Cisplatin/pharmacokinetics/pharmacology Biblio Keywords - Citrus Biblio Keywords - Classification Biblio Keywords - Clathrin Biblio Keywords - Clathrin-Coated Vesicles Biblio Keywords - Clavulanic Acid Biblio Keywords - Cleft Lip Biblio Keywords - Cleft Palate Biblio Keywords - Climate Biblio Keywords - Climate change Biblio Keywords - Climate Change Biblio Keywords - climate change Biblio Keywords - climate change models Biblio Keywords - climate diagnostics Biblio Keywords - climate influence Biblio Keywords - climate predictability Biblio Keywords - Climate prediction Biblio Keywords - climate prediction Biblio Keywords - Climate trends Biblio Keywords - climate variability Biblio Keywords - climate variability and trend Biblio Keywords - climatic change Biblio Keywords - Climatic factors Biblio Keywords - CLIMATIC TRENDS Biblio Keywords - Clinical Laboratory Techniques Biblio Keywords - Clinical Protocols Biblio Keywords - Clinical Trials as Topic Biblio Keywords - CLOCK Proteins Biblio Keywords - Clone Cells Biblio Keywords - Clonidine Biblio Keywords - Cloning, Molecular Biblio Keywords - Cluster Analysis Biblio Keywords - CMIP5 simulations Biblio Keywords - Co-Repressor Proteins Biblio Keywords - Coamo Biblio Keywords - Coastal flooding Biblio Keywords - Coastal flows Biblio Keywords - coastal seiches Biblio Keywords - Coastal system Biblio Keywords - Coastal upwelling Biblio Keywords - Coated Materials, Biocompatible Biblio Keywords - Coated Pits, Cell-Membrane Biblio Keywords - Coated Vesicles Biblio Keywords - Cobalt Biblio Keywords - Cocaine Biblio Keywords - Cocaine-Related Disorders Biblio Keywords - Cochlear Nerve Biblio Keywords - Cockroaches Biblio Keywords - Coculture Techniques Biblio Keywords - Codon Biblio Keywords - Codon, Nonsense Biblio Keywords - Cognition Biblio Keywords - Cognition Disorders Biblio Keywords - Cognitive Therapy Biblio Keywords - Cohort Studies Biblio Keywords - COI Biblio Keywords - Coin cell Biblio Keywords - Cold Temperature Biblio Keywords - Colforsin Biblio Keywords - Coliphages Biblio Keywords - Colitis Biblio Keywords - Collagen Biblio Keywords - Collagen Type I Biblio Keywords - Collagen Type II Biblio Keywords - Collagen Type X Biblio Keywords - Colombia Biblio Keywords - Colonoscopy Biblio Keywords - Color Biblio Keywords - Colorado Biblio Keywords - Colorectal Neoplasms Biblio Keywords - Coloring Agents Biblio Keywords - Combinatorial Chemistry Techniques Biblio Keywords - Combined Modality Therapy Biblio Keywords - Commitment of Mentally Ill Biblio Keywords - Common Variable Immunodeficiency Biblio Keywords - communicable diseases Biblio Keywords - Communication Biblio Keywords - Communication and the arts Biblio Keywords - Communication Barriers Biblio Keywords - community Biblio Keywords - Community Biblio Keywords - Community Mental Health Services Biblio Keywords - Community Psychiatry Biblio Keywords - Community-Based Participatory Research Biblio Keywords - Comorbidity Biblio Keywords - comparative genomic hybridization Biblio Keywords - comparison metrics Biblio Keywords - Complement C3 Biblio Keywords - Complement C4 Biblio Keywords - COMPOSITE ANALYSIS Biblio Keywords - Compromiso organizacional y Empresas multinacionales Biblio Keywords - Computational Biology Biblio Keywords - Computer Simulation Biblio Keywords - Computer Systems Biblio Keywords - Computer Terminals Biblio Keywords - Computers Biblio Keywords - Conditioning (Psychology) Biblio Keywords - Conditioning, Classical Biblio Keywords - Conditioning, Operant Biblio Keywords - Condoms Biblio Keywords - Conductometry Biblio Keywords - Confidence Intervals Biblio Keywords - Confidentiality Biblio Keywords - conflict resolution Biblio Keywords - Congenital Abnormalities Biblio Keywords - Congenital Hypothyroidism Biblio Keywords - Congresses as Topic Biblio Keywords - Conjunctiva Biblio Keywords - Connexin 43 Biblio Keywords - Connexins Biblio Keywords - Conotoxins Biblio Keywords - Consciousness Biblio Keywords - Consensus Biblio Keywords - Consensus Sequence Biblio Keywords - conservation Biblio Keywords - Conserved Sequence Biblio Keywords - Construction Materials/*analysis Biblio Keywords - Consumer Participation Biblio Keywords - Continental Population Groups Biblio Keywords - Contraception Biblio Keywords - Contraception Behavior Biblio Keywords - Contraceptive Biblio Keywords - Contraceptives, Oral, Hormonal Biblio Keywords - Controlled asthma Biblio Keywords - convection Biblio Keywords - Convulsants Biblio Keywords - Cooperative Behavior Biblio Keywords - COP-Coated Vesicles Biblio Keywords - Copper Biblio Keywords - Copulation Biblio Keywords - coral proxy record Biblio Keywords - cord blood Biblio Keywords - Cordotomy Biblio Keywords - Core Binding Factor Alpha 1 Subunit Biblio Keywords - Corneal Transplantation Biblio Keywords - Coronary Disease Biblio Keywords - coronavirus Biblio Keywords - Corpus Striatum Biblio Keywords - correlation patterns Biblio Keywords - Corrosion Biblio Keywords - Corticosterone Biblio Keywords - Corticotropin-Releasing Hormone Biblio Keywords - COS Cells Biblio Keywords - Cost-Benefit Analysis Biblio Keywords - Costa Rica Biblio Keywords - COVID-19 Biblio Keywords - Covid-19 Biblio Keywords - COVID-19 Testing Biblio Keywords - COVID-19/blood/*drug therapy/pathology Biblio Keywords - COVID-19/complications/*transmission Biblio Keywords - CpG Islands Biblio Keywords - Craniofacial Abnormalities Biblio Keywords - Craniosynostoses Biblio Keywords - Creatinine Biblio Keywords - Cricetinae Biblio Keywords - Cricetulus Biblio Keywords - Critical Illness Biblio Keywords - Crk-Associated Substrate Protein Biblio Keywords - Crk-Associated Substrate Protein/*genetics Biblio Keywords - Crk-Associated Substrate Protein/physiology Biblio Keywords - Cross Infection Biblio Keywords - Cross Reactions Biblio Keywords - Cross-Cultural Comparison Biblio Keywords - Cross-Linking Reagents Biblio Keywords - Cross-Sectional Studies Biblio Keywords - Cryopreservation Biblio Keywords - Cryoprotective Agents Biblio Keywords - Cryptococcosis Biblio Keywords - Cryptococcus Biblio Keywords - Cryptococcus gattii/*classification/genetics/*isolation & purification Biblio Keywords - Cryptococcus neoformans Biblio Keywords - Crystallization Biblio Keywords - Crystallography, X-Ray Biblio Keywords - CTLA-4 Antigen Biblio Keywords - Cues Biblio Keywords - Culicidae Biblio Keywords - Cultural Characteristics Biblio Keywords - Cultural Competency Biblio Keywords - Cultural Diversity Biblio Keywords - Culture Biblio Keywords - Culture Media Biblio Keywords - Culture Media, Conditioned Biblio Keywords - Culture Techniques Biblio Keywords - Curcumin/*pharmacology Biblio Keywords - Curriculum Biblio Keywords - Cuscuta Biblio Keywords - Cyanides Biblio Keywords - Cyanobacteria Biblio Keywords - cyber-attacks Biblio Keywords - Cyclic AMP Biblio Keywords - Cyclic AMP Response Element-Binding Protein Biblio Keywords - Cyclic AMP-Dependent Protein Kinases Biblio Keywords - Cyclic AMP-Dependent Protein Kinases/metabolism Biblio Keywords - Cyclic AMP-Dependent Protein Kinases/physiology Biblio Keywords - Cyclic AMP/metabolism Biblio Keywords - Cyclic GMP Biblio Keywords - Cyclic N-Oxides Biblio Keywords - Cyclic Nucleotide Phosphodiesterases, Type 5 Biblio Keywords - Cyclic Nucleotide-Gated Cation Channels Biblio Keywords - Cyclin D1 Biblio Keywords - Cyclin-Dependent Kinase 4 Biblio Keywords - cycloaromatization Biblio Keywords - Cyclohexanones Biblio Keywords - Cyclooxygenase 2 Biblio Keywords - Cyclophilins Biblio Keywords - Cyclophosphamide Biblio Keywords - Cyclopropanes Biblio Keywords - Cystatin B Biblio Keywords - Cystatin C Biblio Keywords - Cysteine Biblio Keywords - Cystic Fibrosis Biblio Keywords - Cystic Fibrosis Transmembrane Conductance Regulator Biblio Keywords - Cystitis Biblio Keywords - Cytochrome c Group/metabolism Biblio Keywords - Cytochrome P-450 CYP2C19 Biblio Keywords - Cytochrome P-450 CYP2D6 Biblio Keywords - Cytochrome P450 Family 7 Biblio Keywords - Cytokines Biblio Keywords - cytokines Biblio Keywords - Cytokines/*immunology Biblio Keywords - Cytokines/*metabolism Biblio Keywords - Cytokines/blood Biblio Keywords - Cytokinesis Biblio Keywords - Cytological Techniques Biblio Keywords - Cytomegalovirus Infections Biblio Keywords - Cytopathogenic Effect, Viral Biblio Keywords - Cytoplasm Biblio Keywords - Cytoplasmic Structures Biblio Keywords - Cytoskeletal Proteins Biblio Keywords - Cytoskeleton Biblio Keywords - Cytosol Biblio Keywords - Cytosol/chemistry Biblio Keywords - Cytotoxicity, Immunologic Biblio Keywords - Dactinomycin Biblio Keywords - dairying Biblio Keywords - Dark Adaptation Biblio Keywords - Darkness Biblio Keywords - Data Collection Biblio Keywords - Data Interpretation, Statistical Biblio Keywords - databases Biblio Keywords - Databases, Factual Biblio Keywords - Databases, Genetic Biblio Keywords - DEAD-box RNA Helicases Biblio Keywords - Deamino Arginine Vasopressin Biblio Keywords - Decision Making Biblio Keywords - Decision Theory Biblio Keywords - Deep Brain Stimulation Biblio Keywords - Defective Viruses Biblio Keywords - Defensins Biblio Keywords - Dehydration Biblio Keywords - Delivery of Health Care/statistics & numerical data Biblio Keywords - Deltaretrovirus Antibodies Biblio Keywords - Demography Biblio Keywords - Dendrites Biblio Keywords - Dendritic Cells Biblio Keywords - Denervation Biblio Keywords - Dengue Biblio Keywords - dengue Biblio Keywords - Dengue Virus Biblio Keywords - Denmark Biblio Keywords - Dense fine speckles Biblio Keywords - density Biblio Keywords - Dental Caries Biblio Keywords - Dental Caries Activity Tests Biblio Keywords - Dental Prosthesis Biblio Keywords - Dentate Gyrus Biblio Keywords - Deoxycytidine Biblio Keywords - Deoxyribonuclease IV (Phage T4-Induced) Biblio Keywords - Deoxyribonucleases, Type II Site-Specific Biblio Keywords - Deoxyribonucleosides Biblio Keywords - Dependency (Psychology) Biblio Keywords - Dependovirus Biblio Keywords - Depression Biblio Keywords - Depression/physiopathology Biblio Keywords - Depressive Disorder Biblio Keywords - Depressive Disorder, Major Biblio Keywords - Dermis Biblio Keywords - Desempeño Biblio Keywords - Desert Climate Biblio Keywords - Desoxycorticosterone Biblio Keywords - detect detection Biblio Keywords - Detergents Biblio Keywords - Deuterium Biblio Keywords - Developed Countries Biblio Keywords - Developing Countries Biblio Keywords - development Biblio Keywords - Development Biblio Keywords - Developmental Biology Biblio Keywords - Developmental Disabilities Biblio Keywords - Dexamethasone Biblio Keywords - DFS70 Biblio Keywords - Diabetes Complications Biblio Keywords - Diabetes Insipidus Biblio Keywords - Diabetes Mellitus Biblio Keywords - Diabetes Mellitus, Experimental Biblio Keywords - Diabetes Mellitus, Type 1 Biblio Keywords - Diabetes Mellitus, Type 1/*genetics Biblio Keywords - Diabetes Mellitus, Type 2 Biblio Keywords - Diabetic Angiopathies Biblio Keywords - Diabetic Foot Biblio Keywords - Diagnosis Biblio Keywords - Diagnosis, Differential Biblio Keywords - Diagnostic and Statistical Manual of Mental Disorders Biblio Keywords - Diagnostic Errors Biblio Keywords - Diagnostic Imaging Biblio Keywords - Diagnostic Techniques, Neurological Biblio Keywords - Dialysis Biblio Keywords - Diarrhea Biblio Keywords - Diarrhea, Infantile Biblio Keywords - Diastole Biblio Keywords - Dibucaine Biblio Keywords - Dicarboxylic Acids Biblio Keywords - Dichloroacetic Acid Biblio Keywords - Dicyclomine Biblio Keywords - Diet Biblio Keywords - Diet, Sodium-Restricted Biblio Keywords - Dietary Fats Biblio Keywords - Dietary Proteins Biblio Keywords - Dietary Supplements Biblio Keywords - Diffusion Biblio Keywords - Diffusion Chambers, Culture Biblio Keywords - Diffusion of Innovation Biblio Keywords - Diffusion Tensor Imaging Biblio Keywords - Digestive System Biblio Keywords - Digitonin Biblio Keywords - Digoxigenin Biblio Keywords - Dihydro-beta-Erythroidine Biblio Keywords - Dihydrotestosterone Biblio Keywords - Dihydroxyphenylalanine Biblio Keywords - Dimerization Biblio Keywords - Dimethyl Sulfoxide Biblio Keywords - Dimethylnitrosamine Biblio Keywords - Dimethylphenylpiperazinium Iodide Biblio Keywords - Dimethylpolysiloxanes Biblio Keywords - Dinitrophenols Biblio Keywords - Dinoprostone Biblio Keywords - Dinuclear complexes Biblio Keywords - Dinucleoside Phosphates Biblio Keywords - Dioxygenases Biblio Keywords - Diploidy Biblio Keywords - diradical Biblio Keywords - direct detection Biblio Keywords - Disasters Biblio Keywords - discriminación Biblio Keywords - Discrimination Learning Biblio Keywords - Disease Biblio Keywords - Disease Models, Animal Biblio Keywords - Disease Outbreaks Biblio Keywords - Disease Progression Biblio Keywords - Disease Reservoirs Biblio Keywords - Disease Susceptibility Biblio Keywords - Disease-Free Survival Biblio Keywords - Disinfectants Biblio Keywords - Disinfection Biblio Keywords - Distance education Biblio Keywords - Diterpenes Biblio Keywords - Dithioles Biblio Keywords - Dithionite Biblio Keywords - Diuresis Biblio Keywords - Diuretics Biblio Keywords - diurnal Biblio Keywords - Diversity Biblio Keywords - Dizocilpine Maleate Biblio Keywords - DMF Index Biblio Keywords - DNA Biblio Keywords - dna Biblio Keywords - Dna Biblio Keywords - DNA Adducts Biblio Keywords - DNA Adducts/drug effects Biblio Keywords - DNA Breaks, Double-Stranded Biblio Keywords - DNA Copy Number Variations Biblio Keywords - DNA Damage Biblio Keywords - DNA Fingerprinting Biblio Keywords - DNA Fragmentation Biblio Keywords - DNA Helicases Biblio Keywords - DNA Methylation Biblio Keywords - DNA Mutational Analysis Biblio Keywords - DNA Polymerase I Biblio Keywords - DNA Polymerase III Biblio Keywords - DNA Primers Biblio Keywords - DNA Primers/*genetics Biblio Keywords - DNA Probes Biblio Keywords - DNA Repair Biblio Keywords - DNA Repair Enzymes Biblio Keywords - DNA Replication Biblio Keywords - DNA Restriction Enzymes Biblio Keywords - DNA Transposable Elements Biblio Keywords - DNA, Archaeal/analysis/genetics Biblio Keywords - DNA, Bacterial Biblio Keywords - DNA, Bacterial/analysis/genetics Biblio Keywords - DNA, Circular Biblio Keywords - DNA, Complementary Biblio Keywords - DNA, Fungal Biblio Keywords - DNA, Helminth Biblio Keywords - DNA, Mitochondrial Biblio Keywords - DNA, Protozoan Biblio Keywords - DNA, Recombinant Biblio Keywords - DNA, Ribosomal Biblio Keywords - DNA, Single-Stranded Biblio Keywords - DNA, Superhelical Biblio Keywords - DNA, Viral Biblio Keywords - DNA-(Apurinic or Apyrimidinic Site) Lyase Biblio Keywords - DNA-Binding Proteins Biblio Keywords - DNA-Directed DNA Polymerase Biblio Keywords - DNA-Directed DNA Polymerase/*genetics Biblio Keywords - docetaxel Biblio Keywords - docetaxel resistance Biblio Keywords - Documentation Biblio Keywords - Dogs Biblio Keywords - Dominican Republic Biblio Keywords - Dopamine Biblio Keywords - Dopamine Agents Biblio Keywords - Dopamine Agents/pharmacology Biblio Keywords - Dopamine Agonists Biblio Keywords - Dopamine Antagonists Biblio Keywords - Dopamine Uptake Inhibitors Biblio Keywords - Dopamine/*pharmacology/physiology Biblio Keywords - Dopaminergic Neurons Biblio Keywords - Doping in Sports Biblio Keywords - Dose-Response Relationship, Drug Biblio Keywords - Dose-Response Relationship, Immunologic Biblio Keywords - Dose-Response Relationship, Radiation Biblio Keywords - Double-Blind Method Biblio Keywords - Down-Regulation Biblio Keywords - Doxylamine Biblio Keywords - Dronabinol Biblio Keywords - Drosophila Biblio Keywords - Drosophila melanogaster Biblio Keywords - Drosophila Proteins Biblio Keywords - DROUGHT Biblio Keywords - drought Biblio Keywords - Drug absorption Biblio Keywords - Drug Administration Routes Biblio Keywords - Drug Administration Schedule Biblio Keywords - Drug Carriers Biblio Keywords - Drug Combinations Biblio Keywords - Drug Contamination Biblio Keywords - Drug Delivery Systems Biblio Keywords - Drug Design Biblio Keywords - Drug Discovery Biblio Keywords - Drug Evaluation Biblio Keywords - Drug Evaluation, Preclinical Biblio Keywords - Drug Hypersensitivity Biblio Keywords - Drug Implants Biblio Keywords - Drug Industry Biblio Keywords - Drug Interactions Biblio Keywords - Drug Resistance Biblio Keywords - drug resistance Biblio Keywords - Drug Resistance, Bacterial Biblio Keywords - Drug Resistance, Fungal Biblio Keywords - Drug Resistance, Microbial Biblio Keywords - Drug Resistance, Multiple Biblio Keywords - Drug Resistance, Neoplasm Biblio Keywords - Drug Resistance, Neoplasm/*genetics Biblio Keywords - Drug Resistance, Neoplasm/genetics Biblio Keywords - Drug Resistance, Viral Biblio Keywords - Drug Screening Assays, Antitumor Biblio Keywords - Drug Synergism Biblio Keywords - Drug Therapy, Combination Biblio Keywords - Drug Tolerance Biblio Keywords - Drug-Related Side Effects and Adverse Reactions Biblio Keywords - Dry Eye Syndromes Biblio Keywords - Dry forest Biblio Keywords - Drywall Biblio Keywords - Dual Specificity Phosphatase 1 Biblio Keywords - Duodenal Ulcer Biblio Keywords - Dynamin II Biblio Keywords - Dynamin III Biblio Keywords - Dynamins Biblio Keywords - Dynorphins Biblio Keywords - Ear Biblio Keywords - Early Diagnosis Biblio Keywords - Earth and Space Science Education Biblio Keywords - Earth Systems Sciences Biblio Keywords - East Africa Biblio Keywords - east-west climate gradient Biblio Keywords - EASTERLY WAVE DISTURBANCES Biblio Keywords - Eating Biblio Keywords - Economics Biblio Keywords - Ecosystem Biblio Keywords - Ecosystem-based management Biblio Keywords - Edetic Acid Biblio Keywords - educación Biblio Keywords - educación ambiental Biblio Keywords - educación en Puerto Rico Biblio Keywords - Education Biblio Keywords - Education, Graduate Biblio Keywords - Education, Medical Biblio Keywords - Education, Medical, Graduate Biblio Keywords - Educational Status Biblio Keywords - EF1a Biblio Keywords - Efferent Pathways Biblio Keywords - Egg tempera Biblio Keywords - Egg-oil emulsion Biblio Keywords - Egtazic Acid Biblio Keywords - El Nino impacts Biblio Keywords - El Nino Southern Oscillation Biblio Keywords - Elasticity Biblio Keywords - Electric Conductivity Biblio Keywords - Electric Organ Biblio Keywords - Electric Stimulation Biblio Keywords - Electrocardiography Biblio Keywords - Electrochemistry Biblio Keywords - Electrodes, Implanted Biblio Keywords - Electroencephalography Biblio Keywords - Electrolytes Biblio Keywords - Electromyography Biblio Keywords - Electron Spin Resonance Spectroscopy Biblio Keywords - Electron Transport Biblio Keywords - Electron Transport Chain Complex Proteins Biblio Keywords - Electron Transport Complex III Biblio Keywords - Electrophoresis Biblio Keywords - electrophoresis Biblio Keywords - Electrophoresis, Agar Gel Biblio Keywords - Electrophoresis, Gel, Pulsed-Field Biblio Keywords - Electrophoresis, Gel, Two-Dimensional Biblio Keywords - Electrophoresis, Polyacrylamide Gel Biblio Keywords - Electrophoretic Mobility Shift Assay Biblio Keywords - Electrophysiological Phenomena Biblio Keywords - Electrophysiology Biblio Keywords - Electroretinography Biblio Keywords - Electroshock Biblio Keywords - electrospun vascular scaffold Biblio Keywords - Eleutherodactylus Biblio Keywords - Elution Biblio Keywords - Embryo Culture Techniques Biblio Keywords - Embryo, Mammalian Biblio Keywords - Embryo, Nonmammalian Biblio Keywords - Embryonic Development Biblio Keywords - Embryonic Induction Biblio Keywords - Embryonic Stem Cells Biblio Keywords - Emergency response Biblio Keywords - Emergency room use Biblio Keywords - Emergency Service, Hospital/*statistics & numerical data Biblio Keywords - emerging Biblio Keywords - emerging veterinary Biblio Keywords - Emigrants and Immigrants Biblio Keywords - Emigration and Immigration Biblio Keywords - Emotions Biblio Keywords - Employment Biblio Keywords - Enalapril Biblio Keywords - Enalaprilat Biblio Keywords - Encephalitis Biblio Keywords - Encephalocele Biblio Keywords - Encephalomyelitis, Autoimmune, Experimental Biblio Keywords - Endangered Species Act Biblio Keywords - Endemic Diseases Biblio Keywords - Endocytosis Biblio Keywords - Endodeoxyribonucleases Biblio Keywords - Endogenous Retroviruses Biblio Keywords - Endometriosis Biblio Keywords - Endometrium Biblio Keywords - Endonucleases Biblio Keywords - Endopeptidase K Biblio Keywords - Endopeptidases Biblio Keywords - Endoplasmic Reticulum Biblio Keywords - Endosomal Sorting Complexes Required for Transport Biblio Keywords - Endosomes Biblio Keywords - Endothelial Cells Biblio Keywords - Endothelial Cells/drug effects/metabolism Biblio Keywords - Endothelin-1 Biblio Keywords - Endothelium Biblio Keywords - Endothelium, Vascular Biblio Keywords - Endothelium, Vascular/drug effects Biblio Keywords - Endotoxins Biblio Keywords - enediyne Biblio Keywords - energy delivery systems Biblio Keywords - Energy Metabolism Biblio Keywords - Energy Metabolism/*genetics Biblio Keywords - English Biblio Keywords - Enhancer Elements, Genetic Biblio Keywords - Enkephalin, Ala(2)-MePhe(4)-Gly(5)- Biblio Keywords - Enkephalin, Leucine Biblio Keywords - Enkephalin, Methionine Biblio Keywords - Enkephalins Biblio Keywords - ENO1 Biblio Keywords - enseñanza de lengua extranjera Biblio Keywords - enseñanza de lenguas extranjera Biblio Keywords - ENSO Biblio Keywords - Enterobacteriaceae Biblio Keywords - Enterococcus Biblio Keywords - Enterococcus faecalis Biblio Keywords - Entorhinal Cortex Biblio Keywords - Entropy Biblio Keywords - Environment Biblio Keywords - environmental conflicts Biblio Keywords - Environmental Exposure Biblio Keywords - Environmental governance Biblio Keywords - environmental lobby Biblio Keywords - environmental microbiology Biblio Keywords - Environmental Monitoring Biblio Keywords - Environmental Pollutants Biblio Keywords - Enzyme Activation Biblio Keywords - Enzyme Activation/drug effects Biblio Keywords - Enzyme Activators Biblio Keywords - Enzyme Induction Biblio Keywords - Enzyme Inhibitors Biblio Keywords - Enzyme Inhibitors/*therapeutic use Biblio Keywords - Enzyme Inhibitors/pharmacology Biblio Keywords - Enzyme Stability Biblio Keywords - Enzyme-Linked Immunosorbent Assay Biblio Keywords - Enzyme-Linked Immunosorbent Assay/methods Biblio Keywords - Enzymes Biblio Keywords - Eosine I Bluish Biblio Keywords - Ephrins Biblio Keywords - epidemics Biblio Keywords - Epidemiologic Methods Biblio Keywords - Epidemiologic Studies Biblio Keywords - epidemiological curve Biblio Keywords - epidemiological model Biblio Keywords - Epidemiological Monitoring Biblio Keywords - Epidermal Growth Factor Biblio Keywords - Epidermis Biblio Keywords - Epididymis Biblio Keywords - Epigenesis, Genetic Biblio Keywords - Epilepsy Biblio Keywords - Epilepsy, Absence Biblio Keywords - Epilepsy, Temporal Lobe Biblio Keywords - Epinephrine Biblio Keywords - Epinephrine/*pharmacology Biblio Keywords - Epinephrine/metabolism Biblio Keywords - Epistasis, Genetic Biblio Keywords - Epithelial Cells Biblio Keywords - Epithelial-Mesenchymal Transition Biblio Keywords - Epithelium Biblio Keywords - Epitope Mapping Biblio Keywords - Epitopes Biblio Keywords - Epitopes, T-Lymphocyte Biblio Keywords - Epoxy Compounds Biblio Keywords - Equine Biblio Keywords - Equipment and Supplies Biblio Keywords - Equipment Design Biblio Keywords - Equipment Failure Analysis Biblio Keywords - Equol Biblio Keywords - ER Stress Biblio Keywords - erradicación de Rattus rattus Biblio Keywords - Erythrocebus patas Biblio Keywords - Erythrocyte Aging Biblio Keywords - Erythrocyte Membrane Biblio Keywords - Erythrocyte Volume Biblio Keywords - Erythrocytes Biblio Keywords - Erythrocytes/*immunology/parasitology Biblio Keywords - Erythromycin Biblio Keywords - Escape Reaction Biblio Keywords - Escherichia coli Biblio Keywords - Escherichia coli Proteins Biblio Keywords - Escherichia coli Proteins/chemistry/*genetics/*metabolism Biblio Keywords - Escherichia coli/genetics Biblio Keywords - Escherichia coli/genetics/metabolism Biblio Keywords - Esomeprazole Biblio Keywords - Esophageal Atresia Biblio Keywords - Esophagus Biblio Keywords - Estradiol Biblio Keywords - Estradiol Congeners Biblio Keywords - Estradiol/*pharmacology Biblio Keywords - Estrogen Antagonists Biblio Keywords - Estrogen Receptor alpha Biblio Keywords - Estrogen Receptor alpha/genetics/metabolism Biblio Keywords - Estrogen Receptor beta Biblio Keywords - Estrogen Receptor Modulators Biblio Keywords - Estrogens Biblio Keywords - Estrogens/*pharmacology Biblio Keywords - Estrous Cycle Biblio Keywords - Estrous Cycle/*physiology Biblio Keywords - Ethanol Biblio Keywords - Ethiopia Biblio Keywords - Ethiopian highlands Biblio Keywords - Ethiopian highlands rainfall Biblio Keywords - Ethnic Groups Biblio Keywords - Ethology Biblio Keywords - Etoposide Biblio Keywords - Eukaryotic Initiation Factor-2 Biblio Keywords - Eukaryotic Initiation Factor-4E Biblio Keywords - Eukaryotic Initiation Factor-4G Biblio Keywords - Eunica talita Biblio Keywords - Eunica tatila Biblio Keywords - European Continental Ancestry Group Biblio Keywords - European Continental Ancestry Group/statistics & numerical data Biblio Keywords - evaluation of satellite-model proxies Biblio Keywords - Evaluation Studies as Topic Biblio Keywords - Evidence-Based Medicine Biblio Keywords - Evidence-Based Practice Biblio Keywords - Evoked Potentials Biblio Keywords - Evoked Potentials, Auditory Biblio Keywords - Evoked Potentials, Motor Biblio Keywords - Evoked Potentials, Somatosensory Biblio Keywords - evolution Biblio Keywords - Evolution, Molecular Biblio Keywords - Excitatory Amino Acid Agonists Biblio Keywords - Excitatory Amino Acid Antagonists Biblio Keywords - Excitatory Amino Acids Biblio Keywords - Excitatory Postsynaptic Potentials Biblio Keywords - executive orders Biblio Keywords - Exocytosis Biblio Keywords - Exons Biblio Keywords - Expatriate and Organizational Commitment and Multinational Corporations Biblio Keywords - Exploratory Behavior Biblio Keywords - Expressed Emotion Biblio Keywords - Expressed Sequence Tags Biblio Keywords - extinction Biblio Keywords - Extinction, Psychological Biblio Keywords - extirpation Biblio Keywords - Extracellular Fluid Biblio Keywords - Extracellular Matrix Biblio Keywords - Extracellular Matrix Proteins Biblio Keywords - Extracellular Signal-Regulated MAP Kinases Biblio Keywords - Extracellular Space Biblio Keywords - Extracellular Traps/*drug effects Biblio Keywords - Extremities Biblio Keywords - Exudates and Transudates Biblio Keywords - Eye Biblio Keywords - Eye Diseases Biblio Keywords - Eye Proteins/*pharmacology Biblio Keywords - Face Biblio Keywords - Facies Biblio Keywords - Factor Analysis, Statistical Biblio Keywords - Factor VIII Biblio Keywords - False Positive Reactions Biblio Keywords - Family Biblio Keywords - Family Characteristics Biblio Keywords - Family Planning Policy Biblio Keywords - Family Planning Services Biblio Keywords - Family Practice Biblio Keywords - Family Relations Biblio Keywords - Fanconi Anemia Biblio Keywords - Fas Ligand Protein Biblio Keywords - Fasciola hepatica Biblio Keywords - Fasciola hepatica/*chemistry/metabolism Biblio Keywords - Fasciola hepatica/*immunology Biblio Keywords - Fasciola hepatica/genetics/*metabolism Biblio Keywords - Fascioliasis Biblio Keywords - Fascioliasis/genetics Biblio Keywords - Fatal Outcome Biblio Keywords - Fats Biblio Keywords - Fatty Acid Synthases Biblio Keywords - Fatty Acid Transport Proteins Biblio Keywords - Fatty Acid-Binding Proteins Biblio Keywords - Fatty Acid-Binding Proteins/*administration & dosage Biblio Keywords - Fatty Acid-Binding Proteins/chemistry/isolation & Biblio Keywords - Fatty Acids Biblio Keywords - Fatty Acids, Omega-3 Biblio Keywords - Fatty Acids, Unsaturated Biblio Keywords - Fatty Acids/analysis Biblio Keywords - Fatty Alcohols Biblio Keywords - Fear Biblio Keywords - Feasibility Studies Biblio Keywords - Feces Biblio Keywords - feces Biblio Keywords - feces microbiology Biblio Keywords - Feedback, Physiological Biblio Keywords - Feedback, Sensory Biblio Keywords - Feeding Behavior Biblio Keywords - Fellowships and Scholarships Biblio Keywords - Female Biblio Keywords - Femur Biblio Keywords - Fentanyl Biblio Keywords - Fermentation Biblio Keywords - Ferric Compounds Biblio Keywords - Ferrous Compounds Biblio Keywords - Fertilins Biblio Keywords - Fertility Biblio Keywords - Fertilization Biblio Keywords - Fetal Alcohol Spectrum Disorders Biblio Keywords - Fetal Blood/virology Biblio Keywords - Fetal Growth Retardation Biblio Keywords - Fetus Biblio Keywords - Fever Biblio Keywords - Fibrinolytic Agents Biblio Keywords - Fibroblast Growth Factor 2 Biblio Keywords - Fibroblast Growth Factors Biblio Keywords - Fibroblasts Biblio Keywords - Fibromyalgia Biblio Keywords - Fibronectins Biblio Keywords - Fibrosarcoma Biblio Keywords - Fibrosis Biblio Keywords - Fingers Biblio Keywords - Fish catch variability Biblio Keywords - Fisheries Biblio Keywords - Fishes Biblio Keywords - Flagella Biblio Keywords - Flavonoids Biblio Keywords - FLOOD RAINFALL Biblio Keywords - Florida Biblio Keywords - Flow Cytometry Biblio Keywords - FLUCTUATIONS Biblio Keywords - Flunitrazepam Biblio Keywords - Fluorescein-5-isothiocyanate Biblio Keywords - Fluoresceins Biblio Keywords - Fluorescence Biblio Keywords - Fluorescence Recovery After Photobleaching Biblio Keywords - Fluorescence Resonance Energy Transfer Biblio Keywords - Fluorescent Antibody Technique Biblio Keywords - Fluorescent Antibody Technique, Indirect Biblio Keywords - Fluorescent Dyes Biblio Keywords - Fluorescent Dyes/pharmacology Biblio Keywords - Fluorodeoxyglucose F18 Biblio Keywords - Fluoxetine Biblio Keywords - FMRFamide Biblio Keywords - Focal Adhesion Kinase 1 Biblio Keywords - Focal Adhesion Protein-Tyrosine Kinases Biblio Keywords - Focal Adhesion Protein-Tyrosine Kinases/*metabolism Biblio Keywords - Focal Adhesions Biblio Keywords - Focal Dermal Hypoplasia Biblio Keywords - Focus Groups Biblio Keywords - Folate Receptors, GPI-Anchored Biblio Keywords - Folic Acid Biblio Keywords - Folic Acid Deficiency Biblio Keywords - Follow-Up Studies Biblio Keywords - Food Additives Biblio Keywords - Food Analysis Biblio Keywords - Food, Fortified Biblio Keywords - Foodborne Diseases Biblio Keywords - Foodborne Diseases: epidemiology Biblio Keywords - Foodborne Diseases: microbiology Biblio Keywords - Foot Deformities, Congenital Biblio Keywords - Forecasting Biblio Keywords - Foreign Bodies Biblio Keywords - foreign language Biblio Keywords - Foreign-Body Reaction Biblio Keywords - Forelimb Biblio Keywords - Forensic Psychiatry Biblio Keywords - Formaldehyde Biblio Keywords - Fosfomycin Biblio Keywords - Fosmid library Biblio Keywords - Fossils Biblio Keywords - Fovea Centralis Biblio Keywords - Fractures, Bone Biblio Keywords - France Biblio Keywords - Free Radical Scavengers Biblio Keywords - Freeze Fracturing Biblio Keywords - Freezing Biblio Keywords - Freezing Reaction, Cataleptic Biblio Keywords - Fresh Water Biblio Keywords - Frontotemporal Dementia Biblio Keywords - Fruit Biblio Keywords - Fumarates Biblio Keywords - Funaria Biblio Keywords - Funaria hygrometrica Biblio Keywords - Functional Biblio Keywords - Functional Laterality Biblio Keywords - Functional Neuroimaging Biblio Keywords - Fungal Capsules Biblio Keywords - Fungal Proteins Biblio Keywords - Fungi Biblio Keywords - Fura-2 Biblio Keywords - Fusion Proteins, gag-pol Biblio Keywords - G2 Phase Biblio Keywords - GABA Agonists Biblio Keywords - GABA Antagonists Biblio Keywords - GABA Modulators Biblio Keywords - GABA-A Receptor Agonists Biblio Keywords - gag Gene Products, Human Immunodeficiency Virus Biblio Keywords - Gait Biblio Keywords - Galactose Biblio Keywords - Galanin Biblio Keywords - Galvanic Skin Response Biblio Keywords - Gametogenesis Biblio Keywords - gamma-Aminobutyric Acid Biblio Keywords - Ganglia Biblio Keywords - Ganglia, Invertebrate Biblio Keywords - Ganglia, Sensory Biblio Keywords - Ganglia, Spinal Biblio Keywords - Ganglia, Sympathetic Biblio Keywords - Ganoderma Biblio Keywords - Gap Junctions Biblio Keywords - GAP-43 Protein Biblio Keywords - Garlic Biblio Keywords - Gas Chromatography-Mass Spectrometry Biblio Keywords - Gastritis Biblio Keywords - Gastroenteritis Biblio Keywords - Gastroesophageal Reflux Biblio Keywords - Gastrointestinal Neoplasms Biblio Keywords - Gastrointestinal Tract Biblio Keywords - Gel Biblio Keywords - gel Biblio Keywords - Gels Biblio Keywords - Gene Amplification Biblio Keywords - Gene Deletion Biblio Keywords - Gene Dosage Biblio Keywords - Gene Expression Biblio Keywords - Gene Expression Profiling Biblio Keywords - Gene Expression Regulation Biblio Keywords - Gene Expression Regulation, Bacterial Biblio Keywords - Gene Expression Regulation, Developmental Biblio Keywords - Gene Expression Regulation, Enzymologic Biblio Keywords - Gene Expression Regulation, Fungal Biblio Keywords - Gene Expression Regulation, Leukemic Biblio Keywords - Gene Expression Regulation, Neoplastic Biblio Keywords - Gene Expression Regulation, Neoplastic/drug effects Biblio Keywords - Gene Expression Regulation, Plant Biblio Keywords - Gene Expression Regulation, Viral Biblio Keywords - Gene Expression Regulation/*drug effects Biblio Keywords - Gene Frequency Biblio Keywords - Gene Knock-In Techniques Biblio Keywords - Gene Knockdown Techniques Biblio Keywords - Gene Library Biblio Keywords - Gene Order Biblio Keywords - Gene Products, env Biblio Keywords - Gene Products, gag Biblio Keywords - Gene Products, nef Biblio Keywords - Gene Products, vpr Biblio Keywords - Gene Regulatory Networks Biblio Keywords - Gene Silencing Biblio Keywords - Gene Targeting Biblio Keywords - Gene Transfer Biblio Keywords - Gene Transfer Techniques Biblio Keywords - Genes Biblio Keywords - genes Biblio Keywords - Genes, Bacterial Biblio Keywords - Genes, BRCA1 Biblio Keywords - Genes, Dominant Biblio Keywords - Genes, Fungal Biblio Keywords - Genes, gag Biblio Keywords - Genes, Helminth Biblio Keywords - Genes, Insect Biblio Keywords - Genes, MDR Biblio Keywords - Genes, Mitochondrial Biblio Keywords - Genes, myc Biblio Keywords - Genes, Neoplasm Biblio Keywords - Genes, Plant Biblio Keywords - Genes, Protozoan Biblio Keywords - Genes, Reporter Biblio Keywords - Genes, Retinoblastoma Biblio Keywords - Genes, rev Biblio Keywords - Genes, Tumor Suppressor Biblio Keywords - Genes, Viral Biblio Keywords - Genes, vpr Biblio Keywords - genetic Biblio Keywords - Genetic Association Studies Biblio Keywords - Genetic Complementation Test Biblio Keywords - Genetic Counseling Biblio Keywords - Genetic Diseases, Inborn Biblio Keywords - Genetic Engineering Biblio Keywords - Genetic Enhancement Biblio Keywords - Genetic Linkage Biblio Keywords - Genetic Loci Biblio Keywords - Genetic Markers Biblio Keywords - Genetic Predisposition to Disease Biblio Keywords - Genetic Testing Biblio Keywords - Genetic Therapy Biblio Keywords - Genetic Variation Biblio Keywords - Genetic Vectors Biblio Keywords - Genetics, Medical Biblio Keywords - Genetics, Population Biblio Keywords - Genistein Biblio Keywords - Genistein/*pharmacology Biblio Keywords - Genitalia, Female Biblio Keywords - Genome Biblio Keywords - genome Biblio Keywords - Genome, Bacterial Biblio Keywords - Genome, Fungal Biblio Keywords - Genome, Human Biblio Keywords - Genome, Viral Biblio Keywords - Genome-Wide Association Study Biblio Keywords - Genomic Islands Biblio Keywords - Genomic Library Biblio Keywords - Genomics Biblio Keywords - Genotype Biblio Keywords - Gentamicins Biblio Keywords - Geographic location/entity Biblio Keywords - Geography Biblio Keywords - Geologic Sediments Biblio Keywords - Geologic Sediments/*microbiology Biblio Keywords - Geologic Sediments/microbiology Biblio Keywords - Georgia Biblio Keywords - Germ Cells Biblio Keywords - Germ Cells, Plant Biblio Keywords - Gestational Age Biblio Keywords - Ghrelin Biblio Keywords - GIS Biblio Keywords - Glass Biblio Keywords - Glial Fibrillary Acidic Protein Biblio Keywords - Glioma Biblio Keywords - global Biblio Keywords - Global Health Biblio Keywords - Global positioning systems (GPS) Biblio Keywords - Glomerular Filtration Rate Biblio Keywords - Glomerulonephritis Biblio Keywords - Glucagon-Like Peptide 1 Biblio Keywords - Glucan Endo-1,3-beta-D-Glucosidase Biblio Keywords - Glucocorticoids Biblio Keywords - Glucose Biblio Keywords - Glucuronic Acid Biblio Keywords - Glucuronidase Biblio Keywords - Glutamate Decarboxylase Biblio Keywords - Glutamate Dehydrogenase Biblio Keywords - Glutamate-Cysteine Ligase Biblio Keywords - Glutamates Biblio Keywords - Glutamic Acid Biblio Keywords - Glutamine/*metabolism Biblio Keywords - Glutathione Biblio Keywords - Glutathione Disulfide Biblio Keywords - Glutathione Peroxidase Biblio Keywords - Glutathione Reductase Biblio Keywords - Glutathione Synthase Biblio Keywords - Glutathione Transferase Biblio Keywords - Glutathione Transferase/*immunology Biblio Keywords - Glycerol Biblio Keywords - Glycine Biblio Keywords - Glycolates Biblio Keywords - Glycols Biblio Keywords - Glycoproteins Biblio Keywords - Glycosaminoglycans Biblio Keywords - Glycosylation Biblio Keywords - GMC Biblio Keywords - Goats Biblio Keywords - Gold Biblio Keywords - Gold Colloid Biblio Keywords - Gold complexes Biblio Keywords - Golgi Apparatus Biblio Keywords - Golgi Apparatus/metabolism Biblio Keywords - Gonadal Steroid Hormones Biblio Keywords - Gonadotropin-Releasing Hormone Biblio Keywords - Gonads Biblio Keywords - Gonorrhea Biblio Keywords - Government Agencies Biblio Keywords - Graft Survival Biblio Keywords - Graft vs Host Disease Biblio Keywords - Gram-Negative Bacterial Infections Biblio Keywords - Gram-Positive Bacteria Biblio Keywords - Granulation Tissue Biblio Keywords - Granulocyte Colony-Stimulating Factor Biblio Keywords - Granulocyte-Macrophage Colony-Stimulating Factor Biblio Keywords - Granulocytes Biblio Keywords - Granuloma Biblio Keywords - Granzymes Biblio Keywords - Great Britain Biblio Keywords - green area loss Biblio Keywords - Green Fluorescent Proteins Biblio Keywords - Greenhouse gases Biblio Keywords - Grief Biblio Keywords - Groundwater dynamics Biblio Keywords - Groundwater/*chemistry Biblio Keywords - Group II Chaperonins Biblio Keywords - Growth Cones Biblio Keywords - Growth Disorders Biblio Keywords - Growth Hormone Biblio Keywords - Growth Inhibitors Biblio Keywords - Growth Plate Biblio Keywords - Growth Substances Biblio Keywords - GTP Phosphohydrolases Biblio Keywords - GTP-Binding Proteins Biblio Keywords - GTPase Biblio Keywords - GTPase-Activating Proteins Biblio Keywords - Guanica Dry Forest Biblio Keywords - Guanosine Biblio Keywords - Guanosine 5'-O-(3-Thiotriphosphate) Biblio Keywords - Guanosine Diphosphate Biblio Keywords - Guanosine Triphosphate Biblio Keywords - Guanylate Cyclase Biblio Keywords - guard cell Biblio Keywords - Guided Tissue Regeneration Biblio Keywords - Guinea Pigs Biblio Keywords - Gyrus Cinguli Biblio Keywords - Habituation, Psychophysiologic Biblio Keywords - Hair Biblio Keywords - Hair Cells, Auditory Biblio Keywords - Half-Life Biblio Keywords - Halobacterium/genetics Biblio Keywords - Halogenation Biblio Keywords - Halothane Biblio Keywords - Hand Biblio Keywords - Hand Deformities, Congenital Biblio Keywords - Hand Disinfection Biblio Keywords - Haploidy Biblio Keywords - Haplorhini Biblio Keywords - Haptens Biblio Keywords - Hawaii Biblio Keywords - Hazardous Substances Biblio Keywords - Hazardous Waste Biblio Keywords - Hazardous waves Biblio Keywords - Head and Neck Neoplasms Biblio Keywords - Health Behavior Biblio Keywords - Health Care Surveys Biblio Keywords - Health Education Biblio Keywords - Health Knowledge, Attitudes, Practice Biblio Keywords - Health Literacy Biblio Keywords - Health Personnel Biblio Keywords - Health Planning Biblio Keywords - Health Priorities Biblio Keywords - Health Promotion Biblio Keywords - Health Resources Biblio Keywords - Health Services Biblio Keywords - Health Services Accessibility Biblio Keywords - Health Services Needs and Demand Biblio Keywords - Health Services Research Biblio Keywords - Health Status Disparities Biblio Keywords - Health Surveys Biblio Keywords - Health Transition Biblio Keywords - Healthcare Disparities Biblio Keywords - Heart Biblio Keywords - Heart Atria Biblio Keywords - Heart Conduction System Biblio Keywords - Heart Defects, Congenital Biblio Keywords - Heart Diseases Biblio Keywords - Heart Failure Biblio Keywords - Heart Injuries Biblio Keywords - Heart Rate Biblio Keywords - Heart Ventricles Biblio Keywords - Heat-Shock Proteins Biblio Keywords - Hedgehog Proteins Biblio Keywords - HEK293 Cells Biblio Keywords - HeLa Cells Biblio Keywords - Helicobacter Infections Biblio Keywords - Helicobacter pylori Biblio Keywords - Helix-Loop-Helix Motifs Biblio Keywords - Helminth Proteins Biblio Keywords - Helminth Proteins/*administration & dosage Biblio Keywords - Helminth Proteins/*immunology Biblio Keywords - Helminth Proteins/chemistry/isolation & purification/metabolism/*pharmacology Biblio Keywords - Helminth Proteins/genetics Biblio Keywords - Helminthiasis, Animal Biblio Keywords - Helplessness, Learned Biblio Keywords - Hemagglutination Inhibition Tests Biblio Keywords - Hemangioma Biblio Keywords - Hematocrit Biblio Keywords - Hematologic Neoplasms Biblio Keywords - Hematopoietic Stem Cell Transplantation Biblio Keywords - Hematopoietic Stem Cells Biblio Keywords - Heme Biblio Keywords - Hemeproteins Biblio Keywords - Hemiplegia Biblio Keywords - Hemiptera Biblio Keywords - Hemodynamics Biblio Keywords - Hemoglobin, Sickle Biblio Keywords - Hemoglobins Biblio Keywords - Hemoglobins, Abnormal Biblio Keywords - Hemoglobinuria, Paroxysmal Biblio Keywords - Hemophilia A Biblio Keywords - Hemostatics Biblio Keywords - Hepacivirus Biblio Keywords - Heparin Biblio Keywords - Heparin-binding EGF-like Growth Factor Biblio Keywords - Hepatic Veno-Occlusive Disease Biblio Keywords - Hepatitis A Biblio Keywords - Hepatitis B Biblio Keywords - Hepatitis B virus Biblio Keywords - Hepatitis C Biblio Keywords - Hepatitis C, Chronic Biblio Keywords - Hepatitis, Chronic Biblio Keywords - Hepatocyte Growth Factor Biblio Keywords - Hepatocytes Biblio Keywords - Heptanoates Biblio Keywords - Heptanoic Acids Biblio Keywords - herbivoría de insectos Biblio Keywords - Hermanski-Pudlak Syndrome Biblio Keywords - Hernia, Diaphragmatic Biblio Keywords - Hernia, Inguinal Biblio Keywords - Hernia, Umbilical Biblio Keywords - Heroin Biblio Keywords - Heroin Dependence Biblio Keywords - Herpes Genitalis Biblio Keywords - Herpes Simplex Biblio Keywords - Herpesviridae Infections Biblio Keywords - Herpesvirus 1, Cercopithecine Biblio Keywords - Heterozygote Biblio Keywords - Heterozygote Detection Biblio Keywords - Hexamethonium Biblio Keywords - Hexamethonium Compounds Biblio Keywords - Hexanols Biblio Keywords - Hexosyltransferases Biblio Keywords - Hexuronic Acids Biblio Keywords - Hiccup Biblio Keywords - High-Throughput Nucleotide Sequencing Biblio Keywords - High-Throughput Screening Assays Biblio Keywords - hindcast datasets Biblio Keywords - Hindlimb Biblio Keywords - Hinduism Biblio Keywords - Hippocampus Biblio Keywords - Hirschsprung Disease Biblio Keywords - Hispanic Americans Biblio Keywords - Hispanic Americans/statistics & numerical data Biblio Keywords - Histamine Biblio Keywords - Histocompatibility Antigens Class I Biblio Keywords - Histocompatibility Antigens Class II Biblio Keywords - Histocompatibility Testing Biblio Keywords - Histocytochemistry Biblio Keywords - Histological Techniques Biblio Keywords - Histone-Lysine N-Methyltransferase Biblio Keywords - Histone-Lysine N-Methyltransferase/genetics/*physiology Biblio Keywords - Histones Biblio Keywords - History, 19th Century Biblio Keywords - History, 20th Century Biblio Keywords - History, 21st Century Biblio Keywords - HIV Biblio Keywords - HIV Antibodies Biblio Keywords - HIV Antigens Biblio Keywords - HIV Core Protein p24 Biblio Keywords - HIV Envelope Protein gp120 Biblio Keywords - HIV Envelope Protein gp160 Biblio Keywords - HIV Infections Biblio Keywords - HIV Long Terminal Repeat Biblio Keywords - HIV Reverse Transcriptase Biblio Keywords - HIV Seronegativity Biblio Keywords - HIV Seropositivity Biblio Keywords - HIV-1 Biblio Keywords - HIV-2 Biblio Keywords - HL-60 Cells Biblio Keywords - HLA-A2 Antigen Biblio Keywords - HLA-DR Antigens Biblio Keywords - Holoprosencephaly Biblio Keywords - Homeless Persons Biblio Keywords - Homeodomain Proteins Biblio Keywords - Homeostasis Biblio Keywords - Homocysteine Biblio Keywords - homogalacturonan Biblio Keywords - Homovanillic Acid Biblio Keywords - Homozygote Biblio Keywords - Honduras Biblio Keywords - Horizontal Biblio Keywords - Hormone Replacement Therapy Biblio Keywords - Hormones Biblio Keywords - Horseradish Peroxidase Biblio Keywords - Hospitalization/*statistics & numerical data Biblio Keywords - Hospitalizations Biblio Keywords - Hospitals, Proprietary Biblio Keywords - Hospitals, Public Biblio Keywords - Hospitals, University Biblio Keywords - Host-Parasite Interactions Biblio Keywords - Host-Pathogen Interactions Biblio Keywords - Hot Temperature Biblio Keywords - Housing Biblio Keywords - HSP40 Heat-Shock Proteins Biblio Keywords - HSP70 Heat-Shock Proteins Biblio Keywords - HT29 Cells Biblio Keywords - Human dimension Biblio Keywords - Human Engineering Biblio Keywords - Human Genome Project Biblio Keywords - Human papillomavirus 16 Biblio Keywords - Human Umbilical Vein Endothelial Cells Biblio Keywords - Humans Biblio Keywords - Humic Substances Biblio Keywords - Huntington Disease Biblio Keywords - Hyaluronic Acid Biblio Keywords - Hybridomas Biblio Keywords - Hydantoins Biblio Keywords - Hydro-Lyases Biblio Keywords - hydro-meteorology Biblio Keywords - hydro-meteorology monitoring systems Biblio Keywords - Hydrochlorothiazide Biblio Keywords - Hydrogel Biblio Keywords - Hydrogels Biblio Keywords - Hydrogen Biblio Keywords - Hydrogen Bonding Biblio Keywords - Hydrogen Peroxide Biblio Keywords - Hydrogen Sulfide Biblio Keywords - Hydrogen Sulfide/*metabolism Biblio Keywords - Hydrogen-Ion Concentration Biblio Keywords - Hydrolases Biblio Keywords - hydrological modelling Biblio Keywords - Hydrolysis Biblio Keywords - Hydroxamic Acids Biblio Keywords - Hydroxyindoleacetic Acid Biblio Keywords - Hydroxyl Radical Biblio Keywords - Hyperalgesia Biblio Keywords - Hypercapnia Biblio Keywords - Hyperglycemia Biblio Keywords - Hyperkinesis Biblio Keywords - Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels Biblio Keywords - Hypersensitivity Biblio Keywords - Hypertelorism Biblio Keywords - Hypertension Biblio Keywords - Hypertension, Pulmonary Biblio Keywords - Hypertension, Renal Biblio Keywords - Hypertonic Solutions Biblio Keywords - Hypertrophy Biblio Keywords - Hypertrophy, Left Ventricular Biblio Keywords - Hypoglycemic Agents Biblio Keywords - Hypokalemia Biblio Keywords - Hypospadias Biblio Keywords - Hypothalamic Hormones Biblio Keywords - Hypothalamo-Hypophyseal System Biblio Keywords - Hypothalamus Biblio Keywords - Hypothalamus, Middle Biblio Keywords - Hypothyroidism Biblio Keywords - Hypotonic Solutions Biblio Keywords - Hypoxia-Inducible Factor 1 Biblio Keywords - Hypoxia-Inducible Factor 1, alpha Subunit Biblio Keywords - I-kappa B Kinase Biblio Keywords - IBD interactome Biblio Keywords - Illumina Biblio Keywords - Image Processing, Computer-Assisted Biblio Keywords - Imaging, Three-Dimensional Biblio Keywords - Imidazoles Biblio Keywords - Imidoesters Biblio Keywords - Imines Biblio Keywords - Immediate-Early Proteins Biblio Keywords - Immobilized Proteins Biblio Keywords - Immune Evasion Biblio Keywords - Immune Reconstitution Inflammatory Syndrome Biblio Keywords - Immune Sera Biblio Keywords - Immune System Biblio Keywords - Immune Tolerance Biblio Keywords - Immunity Biblio Keywords - Immunity, Cellular Biblio Keywords - Immunity, Humoral Biblio Keywords - Immunity, Innate Biblio Keywords - Immunity, Mucosal Biblio Keywords - Immunization Biblio Keywords - Immunization Programs Biblio Keywords - Immunization Schedule Biblio Keywords - Immunization, Secondary Biblio Keywords - Immunoassay Biblio Keywords - Immunoblotting Biblio Keywords - Immunoblotting/methods Biblio Keywords - Immunocompromised Host Biblio Keywords - Immunoconjugates Biblio Keywords - Immunodiffusion Biblio Keywords - Immunoenzyme Techniques Biblio Keywords - Immunoglobulin A Biblio Keywords - Immunoglobulin Class Switching Biblio Keywords - Immunoglobulin Constant Regions Biblio Keywords - Immunoglobulin E Biblio Keywords - Immunoglobulin G Biblio Keywords - Immunoglobulin M Biblio Keywords - Immunoglobulin Variable Region Biblio Keywords - Immunoglobulins Biblio Keywords - Immunoglobulins, Intravenous Biblio Keywords - Immunohistochemistry Biblio Keywords - immunolabelling Biblio Keywords - immunolocalization Biblio Keywords - Immunologic Deficiency Syndromes Biblio Keywords - Immunologic Factors Biblio Keywords - Immunologic Memory Biblio Keywords - Immunologic Techniques Biblio Keywords - Immunomodulation Biblio Keywords - Immunomodulator Biblio Keywords - Immunophenotyping Biblio Keywords - Immunoprecipitation Biblio Keywords - Immunosorbent Techniques Biblio Keywords - Immunosuppressive Agents Biblio Keywords - Immunotherapy Biblio Keywords - Impacts on resources Biblio Keywords - Implants, Experimental Biblio Keywords - Implosive Therapy Biblio Keywords - In Situ Hybridization Biblio Keywords - In Situ Hybridization, Fluorescence Biblio Keywords - In Situ Nick-End Labeling Biblio Keywords - In Vitro Techniques Biblio Keywords - Incidence Biblio Keywords - Inclusion Bodies Biblio Keywords - Inclusion Bodies, Viral Biblio Keywords - INDEL Mutation Biblio Keywords - Indenes Biblio Keywords - India Biblio Keywords - Indian Ocean Biblio Keywords - Indicator Dilution Techniques Biblio Keywords - Indicators and Reagents Biblio Keywords - Individuality Biblio Keywords - Individualized Medicine Biblio Keywords - Indoles Biblio Keywords - Induced Pluripotent Stem Cells Biblio Keywords - Industry Biblio Keywords - Infant Biblio Keywords - Infant Food Biblio Keywords - Infant Mortality Biblio Keywords - Infant, Newborn Biblio Keywords - Infant, Newborn, Diseases Biblio Keywords - Infant, Newborn, Diseases/diagnosis/etiology/*virology Biblio Keywords - Infarction, Middle Cerebral Artery Biblio Keywords - Infection Biblio Keywords - Infectious Disease Transmission, Vertical Biblio Keywords - Infertility Biblio Keywords - Infertility, Female Biblio Keywords - Infertility, Male Biblio Keywords - Inflammation Biblio Keywords - Inflammation Mediators Biblio Keywords - Inflammatory Bowel Diseases Biblio Keywords - Inflammatory Breast Neoplasms Biblio Keywords - Inflammatory Breast Neoplasms/*genetics/*pathology Biblio Keywords - Influenza A virus Biblio Keywords - Informal Science Education Biblio Keywords - Information Systems Biblio Keywords - Infusions, Intravenous Biblio Keywords - Infusions, Parenteral Biblio Keywords - inglés Biblio Keywords - Inhalation Biblio Keywords - Inhalation Exposure Biblio Keywords - Inhibitor of Apoptosis Proteins Biblio Keywords - Inhibitor of Differentiation Protein 2 Biblio Keywords - inhibitors/*physiology Biblio Keywords - inhibitors/genetics/metabolism Biblio Keywords - Inhibitory Postsynaptic Potentials Biblio Keywords - Injections Biblio Keywords - Injections, Intramuscular Biblio Keywords - Injections, Intraperitoneal Biblio Keywords - Injections, Intravenous Biblio Keywords - Injections, Intraventricular Biblio Keywords - Injections, Subcutaneous Biblio Keywords - inner-ring suburbs Biblio Keywords - Inosine Biblio Keywords - Inositol Phosphates Biblio Keywords - Inpatients Biblio Keywords - Insect Control Biblio Keywords - insect herbivory Biblio Keywords - Insect Proteins Biblio Keywords - Insects Biblio Keywords - Insemination, Artificial, Heterologous Biblio Keywords - Insulin Biblio Keywords - Insulin Resistance Biblio Keywords - Insulin-Secreting Cells Biblio Keywords - Insulinoma Biblio Keywords - Insurance Coverage Biblio Keywords - Insurance, Health Biblio Keywords - integrase binding domain Biblio Keywords - Integrases Biblio Keywords - Integrated coastal management Biblio Keywords - Integrin alpha2beta1 Biblio Keywords - Integrin alpha5beta1 Biblio Keywords - Integrin alpha6beta1 Biblio Keywords - Integrin alphaVbeta3/*antagonists & inhibitors/genetics/metabolism Biblio Keywords - Integrin alphaXbeta2 Biblio Keywords - Integrins Biblio Keywords - Integumentary System Biblio Keywords - Inteins Biblio Keywords - inteligencia emocional Biblio Keywords - inteligencia interpersonal Biblio Keywords - inteligencia intrapersonal Biblio Keywords - Inteligencia naturalista Biblio Keywords - inteligencia verbal lingüística Biblio Keywords - inteligencias múltiples Biblio Keywords - Intellectual Disability Biblio Keywords - Intellectual Property Biblio Keywords - Intelligence Tests Biblio Keywords - Intensive Care Biblio Keywords - Intention Biblio Keywords - inter-Americas Biblio Keywords - inter-annual climate variability Biblio Keywords - inter-annual climatic fluctuations Biblio Keywords - inter-annual variability Biblio Keywords - interacción depredador-presa Biblio Keywords - Interacting partners Biblio Keywords - interannual rainfall variability Biblio Keywords - interannual variability Biblio Keywords - Intercalating Agents Biblio Keywords - Intercellular Adhesion Molecule-1 Biblio Keywords - Intercellular Junctions Biblio Keywords - Intercellular Signaling Peptides and Proteins Biblio Keywords - Interdisciplinary Communication Biblio Keywords - Interferon Regulatory Factor-7 Biblio Keywords - Interferon Type I Biblio Keywords - Interferon-alpha Biblio Keywords - Interferon-gamma Biblio Keywords - Interferons Biblio Keywords - Interinstitutional Relations Biblio Keywords - Interior Design and Furnishings Biblio Keywords - Interleukin 1 Receptor Antagonist Protein Biblio Keywords - Interleukin-1 Biblio Keywords - Interleukin-10 Biblio Keywords - Interleukin-12 Biblio Keywords - Interleukin-12 Subunit p40 Biblio Keywords - Interleukin-13 Biblio Keywords - Interleukin-15 Biblio Keywords - Interleukin-18 Biblio Keywords - Interleukin-1beta Biblio Keywords - Interleukin-1beta/genetics/immunology Biblio Keywords - Interleukin-2 Biblio Keywords - Interleukin-3 Receptor alpha Subunit Biblio Keywords - Interleukin-4 Biblio Keywords - Interleukin-6 Biblio Keywords - Interleukin-6/*antagonists & inhibitors/blood/immunology Biblio Keywords - Interleukin-6/*biosynthesis/metabolism Biblio Keywords - Interleukin-6/physiology Biblio Keywords - Interleukin-8 Biblio Keywords - Interleukin-8/*genetics/metabolism Biblio Keywords - Interleukins Biblio Keywords - Intermediate Filament Proteins Biblio Keywords - internal solitary waves Biblio Keywords - internal waves Biblio Keywords - International Cooperation Biblio Keywords - Interneurons Biblio Keywords - Interphase Biblio Keywords - Interprofessional Relations Biblio Keywords - Interspersed Repetitive Sequences Biblio Keywords - intervention Biblio Keywords - interventions Biblio Keywords - Interview, Psychological Biblio Keywords - Interviews as Topic Biblio Keywords - Intestinal Absorption Biblio Keywords - Intestinal Absorption/physiology Biblio Keywords - Intestinal Mucosa Biblio Keywords - Intestinal Mucosa/drug effects/*physiology Biblio Keywords - Intestinal Obstruction Biblio Keywords - intra-seasonal climate Biblio Keywords - INTRA-SEASONAL EVENTS Biblio Keywords - intra-seasonal oscillations Biblio Keywords - Intracellular Fluid Biblio Keywords - Intracellular Membranes Biblio Keywords - Intracellular Signaling Peptides and Proteins Biblio Keywords - Intracellular Space Biblio Keywords - Intraocular Pressure Biblio Keywords - Intraoperative Complications Biblio Keywords - intraseasonal oscillations Biblio Keywords - Intraseasonal rainfall variability Biblio Keywords - Introns Biblio Keywords - Intubation, Gastrointestinal Biblio Keywords - Intubation, Intratracheal Biblio Keywords - Invasiveness Biblio Keywords - Inventions Biblio Keywords - Inventores Biblio Keywords - Inventors Biblio Keywords - Inventos Biblio Keywords - Invertebrate Hormones Biblio Keywords - Invertebrates Biblio Keywords - Iodine Radioisotopes Biblio Keywords - Iodoacetamide Biblio Keywords - Ion Channel Gating Biblio Keywords - Ion Channels Biblio Keywords - Ion Exchange Resins Biblio Keywords - Ionomycin Biblio Keywords - Ionosphere Biblio Keywords - Ionospheric disturbances and irregularities Biblio Keywords - Iron Biblio Keywords - irrupción de mariposa-oruga Biblio Keywords - Ischemia Biblio Keywords - Ischemic Attack, Transient Biblio Keywords - Islam Biblio Keywords - Islets of Langerhans Biblio Keywords - Islets of Langerhans Transplantation Biblio Keywords - Isoelectric Focusing Biblio Keywords - Isoelectric Point Biblio Keywords - Isoenzymes Biblio Keywords - Isoflavones Biblio Keywords - Isoflavones/*pharmacology Biblio Keywords - Isomerism Biblio Keywords - Isometric Contraction Biblio Keywords - Isoniazid Biblio Keywords - Isoproterenol Biblio Keywords - Isoproterenol/agonists Biblio Keywords - Isoquinolines Biblio Keywords - Isothiuronium Biblio Keywords - Isotonic Solutions Biblio Keywords - Isotretinoin Biblio Keywords - Italy Biblio Keywords - Jamaica Biblio Keywords - Janus Kinase 2 Biblio Keywords - Janus Kinases Biblio Keywords - Japan Biblio Keywords - Jejunum Biblio Keywords - JNK Mitogen-Activated Protein Kinases Biblio Keywords - Job Application Biblio Keywords - joint modes Biblio Keywords - Joints Biblio Keywords - Jumonji Domain-Containing Histone Demethylases Biblio Keywords - Jurkat Cells Biblio Keywords - K562 Cells Biblio Keywords - Kainic Acid Biblio Keywords - Kanamycin Biblio Keywords - Kaplan-Meier Estimate Biblio Keywords - Karyopherins Biblio Keywords - Karyotyping Biblio Keywords - Kenya Biblio Keywords - Keratinocytes Biblio Keywords - Ketones Biblio Keywords - Key outcomes: ocean observations and maize yield Biblio Keywords - Ki-67 Antigen Biblio Keywords - Ki-67 Antigen/metabolism Biblio Keywords - Kidney Biblio Keywords - Kidney Concentrating Ability Biblio Keywords - Kidney Cortex Biblio Keywords - Kidney Diseases Biblio Keywords - Kidney Function Tests Biblio Keywords - Kidney Glomerulus Biblio Keywords - Kidney Neoplasms Biblio Keywords - Kidney Tubules Biblio Keywords - Kidney/drug effects/physiology Biblio Keywords - Killer Cells, Natural Biblio Keywords - Kinetics Biblio Keywords - Korea Biblio Keywords - Kruppel-Like Transcription Factors Biblio Keywords - Kv1.1 Potassium Channel Biblio Keywords - Kv1.4 Potassium Channel Biblio Keywords - Kwa-Zulu Natal Biblio Keywords - Kynurenine Biblio Keywords - Laboratories Biblio Keywords - Lactic Acid Biblio Keywords - Lactic Acid/*metabolism/pharmacology Biblio Keywords - Lactones Biblio Keywords - LADAR Biblio Keywords - lake level Biblio Keywords - Lakes Biblio Keywords - Laminin Biblio Keywords - Lamivudine Biblio Keywords - land-sea transition Biblio Keywords - land-use science Biblio Keywords - Language Biblio Keywords - Lanthanum Biblio Keywords - Large-Conductance Calcium-Activated Potassium Channel beta Subunits Biblio Keywords - Large-Conductance Calcium-Activated Potassium Channels Biblio Keywords - Larva Biblio Keywords - larval morphology Biblio Keywords - Laryngeal Masks Biblio Keywords - Laryngeal Neoplasms Biblio Keywords - Lasers Biblio Keywords - Latin America Biblio Keywords - LDL-Receptor Related Proteins Biblio Keywords - Lead Biblio Keywords - Learning Biblio Keywords - Learning Disorders Biblio Keywords - Least-Squares Analysis Biblio Keywords - Lecithins Biblio Keywords - Lectins Biblio Keywords - Lectins, C-Type Biblio Keywords - LEDGF/p75 Biblio Keywords - Leg Biblio Keywords - Length of Stay Biblio Keywords - lengua extranjera Biblio Keywords - Lentivirus Biblio Keywords - Lentivirus Infections Biblio Keywords - LEOPARD Syndrome Biblio Keywords - Leptin Biblio Keywords - Lethal Dose 50 Biblio Keywords - Leukemia Biblio Keywords - Leukemia, Lymphoid Biblio Keywords - Leukemia, Myelogenous, Chronic, BCR-ABL Positive Biblio Keywords - Leukemia, Myeloid Biblio Keywords - Leukemia, Myeloid, Acute Biblio Keywords - Leukemia, Myelomonocytic, Juvenile Biblio Keywords - Leukemia, Promyelocytic, Acute Biblio Keywords - Leukocyte Common Antigens Biblio Keywords - Leukocyte Count Biblio Keywords - Leukocyte Migration-Inhibitory Factors Biblio Keywords - Leukocytes Biblio Keywords - Leukocytes, Mononuclear Biblio Keywords - Library Biblio Keywords - LIDAR Biblio Keywords - Lidocaine Biblio Keywords - Life Change Events Biblio Keywords - Life Cycle Stages Biblio Keywords - Life Style Biblio Keywords - Ligands Biblio Keywords - Ligases Biblio Keywords - Ligation Biblio Keywords - Light Biblio Keywords - light-rail Biblio Keywords - Lighting Biblio Keywords - LIM Domain Proteins Biblio Keywords - Limb Deformities, Congenital Biblio Keywords - Limbic System Biblio Keywords - Limit of Detection Biblio Keywords - Limpopo Valley Biblio Keywords - Linear Models Biblio Keywords - linear regression Biblio Keywords - Linguistics Biblio Keywords - Linkage Disequilibrium Biblio Keywords - Lip Biblio Keywords - Lipase/metabolism Biblio Keywords - Lipid Metabolism Biblio Keywords - Lipid Peroxidation Biblio Keywords - Lipids Biblio Keywords - Lipopolysaccharides Biblio Keywords - Lipopolysaccharides/*antagonists & inhibitors/pharmacology Biblio Keywords - Lipopolysaccharides/*immunology Biblio Keywords - Liposomes Biblio Keywords - Lipoylation Biblio Keywords - Listeria monocytogenes Biblio Keywords - Listeria monocytogenes: genetics Biblio Keywords - Listeria monocytogenes: isolation & purification Biblio Keywords - Listeria monocytogenes: pathogenicity Biblio Keywords - Lithium Biblio Keywords - Lithium batteries Biblio Keywords - Lithium Carbonate Biblio Keywords - Lithium Chloride Biblio Keywords - Little Rock Biblio Keywords - Liver Biblio Keywords - Liver Cirrhosis Biblio Keywords - Liver Diseases Biblio Keywords - Liver Failure Biblio Keywords - Liver Function Tests Biblio Keywords - Liver Neoplasms Biblio Keywords - Liver Neoplasms, Experimental Biblio Keywords - Liver Neoplasms, Experimental/prevention & control/*secondary Biblio Keywords - Liver/*metabolism Biblio Keywords - Liver/drug effects/physiology Biblio Keywords - LM13 Biblio Keywords - LM19 Biblio Keywords - LM6 Biblio Keywords - Locomotion Biblio Keywords - Lod Score Biblio Keywords - Logistic Models Biblio Keywords - logistic models Biblio Keywords - Long Interspersed Nucleotide Elements Biblio Keywords - Long QT Syndrome Biblio Keywords - Long-range climate prediction in southern Africa Biblio Keywords - Long-Term Potentiation Biblio Keywords - Longitudinal Studies Biblio Keywords - Lopinavir Biblio Keywords - Lordosis Biblio Keywords - Los Angeles Biblio Keywords - Losartan Biblio Keywords - LOX-1 Biblio Keywords - Luciferases Biblio Keywords - Luciferases, Firefly Biblio Keywords - Lumbar Vertebrae Biblio Keywords - Luminescent Measurements Biblio Keywords - Luminescent Proteins Biblio Keywords - Lung Biblio Keywords - Lung Neoplasms Biblio Keywords - Lupus Erythematosus, Cutaneous Biblio Keywords - Lupus Erythematosus, Systemic Biblio Keywords - Lupus Nephritis Biblio Keywords - Lutetium Biblio Keywords - Lyases/chemistry/*genetics/*metabolism Biblio Keywords - Lycopersicon esculentum Biblio Keywords - Lymph Nodes Biblio Keywords - Lymphocyte Activation Biblio Keywords - Lymphocyte Count Biblio Keywords - Lymphocyte Culture Test, Mixed Biblio Keywords - Lymphocyte Subsets Biblio Keywords - Lymphocytes Biblio Keywords - Lymphoid Tissue Biblio Keywords - Lymphokines Biblio Keywords - Lymphoma Biblio Keywords - Lymphoma, Large B-Cell, Diffuse Biblio Keywords - Lymphoma, T-Cell, Cutaneous Biblio Keywords - Lysosomal-Associated Membrane Protein 1 Biblio Keywords - Lysosomes Biblio Keywords - Macaca Biblio Keywords - Macaca fascicularis Biblio Keywords - Macaca mulatta Biblio Keywords - Macaca nemestrina Biblio Keywords - Macromolecular Substances Biblio Keywords - Macrophage Activation Biblio Keywords - Macrophages Biblio Keywords - Macrophages, Peritoneal Biblio Keywords - Macrophages, Peritoneal/*drug effects/*physiology Biblio Keywords - Macrophages/cytology/drug effects/immunology Biblio Keywords - Macrophages/drug effects/*physiology Biblio Keywords - Macula Lutea Biblio Keywords - Madagascar Biblio Keywords - Magnesium Biblio Keywords - Magnetic Fields Biblio Keywords - Magnetic Resonance Imaging Biblio Keywords - Magnetic Resonance Spectroscopy Biblio Keywords - Magnetics Biblio Keywords - Malabsorption Syndromes Biblio Keywords - Malaria Biblio Keywords - Malaria, Falciparum Biblio Keywords - Malaria, Falciparum/*complications/immunology Biblio Keywords - Malawi Biblio Keywords - Male Biblio Keywords - Maleimides Biblio Keywords - Malodors Biblio Keywords - malware Biblio Keywords - Mammary Neoplasms, Experimental Biblio Keywords - Mammary Neoplasms, Experimental/*drug therapy/pathology Biblio Keywords - Managed Care Programs Biblio Keywords - Mandible Biblio Keywords - Manganese Biblio Keywords - Mannitol Biblio Keywords - Mannose-Binding Lectins Biblio Keywords - MAP Kinase Kinase 1 Biblio Keywords - MAP Kinase Kinase 3 Biblio Keywords - MAP Kinase Kinase 6 Biblio Keywords - MAP Kinase Kinase Kinase 1 Biblio Keywords - MAP Kinase Kinase Kinase 4 Biblio Keywords - MAP Kinase Kinase Kinases Biblio Keywords - MAP Kinase Signaling System Biblio Keywords - Marine Biology Biblio Keywords - marine climate Biblio Keywords - Marine ecosystem Biblio Keywords - Marine environment Biblio Keywords - Marker Biblio Keywords - Markov Chains Biblio Keywords - Marriage Biblio Keywords - Maryland Biblio Keywords - Mass Screening Biblio Keywords - Mass Spectrometry Biblio Keywords - Mastocytosis Biblio Keywords - Materials Testing Biblio Keywords - Maternal Age Biblio Keywords - Maternal Welfare Biblio Keywords - Maternal-Fetal Exchange Biblio Keywords - Mathematics Biblio Keywords - Mating Preference, Animal Biblio Keywords - Matrilin Proteins Biblio Keywords - Matrix Metalloproteinase 10 Biblio Keywords - Matrix Metalloproteinase 13 Biblio Keywords - Matrix Metalloproteinase 2 Biblio Keywords - Matrix Metalloproteinase 9 Biblio Keywords - Matrix Metalloproteinases/physiology Biblio Keywords - Maximum likelihood estimation Biblio Keywords - Maze Learning Biblio Keywords - MCF-7 Cells Biblio Keywords - MDR Biblio Keywords - Meat Products Biblio Keywords - Mecamylamine Biblio Keywords - Mechanical Phenomena Biblio Keywords - mechanical properties Biblio Keywords - Mechanisms Biblio Keywords - Mechanoreceptors Biblio Keywords - Mechanotransduction, Cellular Biblio Keywords - Mediastinitis Biblio Keywords - Medical Secretaries Biblio Keywords - Medicine, Traditional Biblio Keywords - Meditation Biblio Keywords - Mefloquine Biblio Keywords - Melanins Biblio Keywords - Melanocyte-Stimulating Hormones Biblio Keywords - Melanoma Biblio Keywords - Membrane Fusion Biblio Keywords - Membrane Glycoproteins Biblio Keywords - Membrane Glycoproteins/analysis Biblio Keywords - Membrane Lipids Biblio Keywords - Membrane Microdomains Biblio Keywords - Membrane Potentials Biblio Keywords - Membrane Proteins Biblio Keywords - Membrane Proteins/analysis Biblio Keywords - Membrane Transport Modulators Biblio Keywords - Membrane Transport Proteins Biblio Keywords - Membrane Transport Proteins/genetics/*physiology Biblio Keywords - Membranes Biblio Keywords - Membranes, Artificial Biblio Keywords - Memory Biblio Keywords - Memory Disorders Biblio Keywords - Memory, Long-Term Biblio Keywords - Memory, Short-Term Biblio Keywords - Meningitis Biblio Keywords - Meningitis, Cryptococcal Biblio Keywords - Meningoencephalitis Biblio Keywords - Menisci, Tibial Biblio Keywords - menores refugiados Biblio Keywords - Mental Disorders Biblio Keywords - Mental Health Services Biblio Keywords - Mental Recall Biblio Keywords - Meprobamate Biblio Keywords - Mercaptoethanol Biblio Keywords - Mercury Biblio Keywords - Mesalamine Biblio Keywords - Mesencephalon Biblio Keywords - Mesenchymal Stromal Cells Biblio Keywords - Mesenteric Arteries Biblio Keywords - Mesoclimate Biblio Keywords - Mesocricetus Biblio Keywords - mesopause dynamics Biblio Keywords - mesopause temperature Biblio Keywords - Mesoscale processes Biblio Keywords - Mesoscale systems Biblio Keywords - mesosphere dynamics Biblio Keywords - mesosphere temperature Biblio Keywords - Mesospheric dynamics Biblio Keywords - Mesothelioma Biblio Keywords - Metabolic Syndrome X Biblio Keywords - Metagenome Biblio Keywords - Metagenomics Biblio Keywords - metal layers Biblio Keywords - Metal Nanoparticles Biblio Keywords - Metalloproteases Biblio Keywords - Metallothionein Biblio Keywords - Metallothionein/*genetics Biblio Keywords - Metals Biblio Keywords - Metals, Heavy Biblio Keywords - Metamorphosis, Biological Biblio Keywords - meteotsunami Biblio Keywords - Methacrylates Biblio Keywords - Methadone Biblio Keywords - Methamphetamine Biblio Keywords - Methanol Biblio Keywords - Methicillin Resistance Biblio Keywords - Methionine Biblio Keywords - Methods Biblio Keywords - Methotrexate Biblio Keywords - Methyl Methanesulfonate Biblio Keywords - Methyl-CpG-Binding Protein 2 Biblio Keywords - Methyl-CpG-Binding Protein 2/*immunology Biblio Keywords - Methylcellulose Biblio Keywords - Methylene Blue Biblio Keywords - Methylenetetrahydrofolate Dehydrogenase (NADP) Biblio Keywords - Methylenetetrahydrofolate Reductase (NADPH2) Biblio Keywords - Methyltestosterone Biblio Keywords - Metronidazole Biblio Keywords - Mexican Americans Biblio Keywords - Mexico Biblio Keywords - Mice Biblio Keywords - Mice models Biblio Keywords - Mice, Inbred BALB C Biblio Keywords - Mice, Inbred C3H Biblio Keywords - Mice, Inbred C57BL Biblio Keywords - Mice, Inbred CBA Biblio Keywords - Mice, Inbred ICR Biblio Keywords - Mice, Inbred NOD Biblio Keywords - Mice, Inbred Strains Biblio Keywords - Mice, Knockout Biblio Keywords - Mice, Mutant Strains Biblio Keywords - Mice, Neurologic Mutants Biblio Keywords - Mice, Nude Biblio Keywords - Mice, SCID Biblio Keywords - Mice, Transgenic Biblio Keywords - Miconazole Biblio Keywords - Micro-Electrical-Mechanical Systems Biblio Keywords - Microarray Analysis Biblio Keywords - Microbial Sensitivity Tests Biblio Keywords - microbial sensitivity tests Biblio Keywords - microbial sensitivity tests veterinary Biblio Keywords - Microbial Viability Biblio Keywords - Microbiology Biblio Keywords - Microbiome Biblio Keywords - Microbiota Biblio Keywords - Microbubbles Biblio Keywords - Microclimatology Biblio Keywords - Microcystis Biblio Keywords - Microdialysis Biblio Keywords - Microdissection Biblio Keywords - Microelectrodes Biblio Keywords - Microfilament Proteins Biblio Keywords - Microfluidic Analytical Techniques Biblio Keywords - Microfluidics Biblio Keywords - Microglia Biblio Keywords - Microinjections Biblio Keywords - Micromanipulation Biblio Keywords - MicroRNAs Biblio Keywords - Microsatellite Repeats Biblio Keywords - Microscopy Biblio Keywords - Microscopy, Atomic Force Biblio Keywords - Microscopy, Confocal Biblio Keywords - Microscopy, Electron Biblio Keywords - Microscopy, Electron, Scanning Biblio Keywords - Microscopy, Electron, Transmission Biblio Keywords - Microscopy, Fluorescence Biblio Keywords - Microscopy, Phase-Contrast Biblio Keywords - Microscopy, Polarization Biblio Keywords - Microscopy, Video Biblio Keywords - Microspheres Biblio Keywords - Microtubule-Associated Proteins Biblio Keywords - Microtubule-Associated Proteins/analysis Biblio Keywords - Microvessels Biblio Keywords - Microvessels/drug effects Biblio Keywords - Microvessels/drug effects/pathology/physiology Biblio Keywords - MICROWAVE Biblio Keywords - Middle Aged Biblio Keywords - Middle atmosphere dynamics Biblio Keywords - Middle atmosphere: composition and chemistry Biblio Keywords - Middle atmosphere: constituent transport and chemistry Biblio Keywords - Midline Thalamic Nuclei Biblio Keywords - Mineralocorticoid Receptor Antagonists Biblio Keywords - Minerals Biblio Keywords - Mining Biblio Keywords - Minority Groups Biblio Keywords - Minority Health Biblio Keywords - Miro Biblio Keywords - Missouri Biblio Keywords - mitigation Biblio Keywords - mitigation strategies Biblio Keywords - Mitochondria Biblio Keywords - mitochondria Biblio Keywords - Mitochondria, Liver Biblio Keywords - Mitochondrial Proteins Biblio Keywords - Mitochondrial Proton-Translocating ATPases/metabolism Biblio Keywords - Mitochondrial Turnover Biblio Keywords - Mitogen-Activated Protein Kinase 3 Biblio Keywords - Mitogen-Activated Protein Kinase 8 Biblio Keywords - Mitogen-Activated Protein Kinases Biblio Keywords - Mitogen-Activated Protein Kinases/antagonists & inhibitors/metabolism Biblio Keywords - Mitomycin Biblio Keywords - Mitosis Biblio Keywords - Mixed Function Oxygenases Biblio Keywords - Mixed layer Biblio Keywords - Mixed-valent complexes Biblio Keywords - model simulation and intercomparison Biblio Keywords - Modeling Observation Biblio Keywords - Models, Animal Biblio Keywords - Models, Biological Biblio Keywords - Models, Cardiovascular Biblio Keywords - Models, Chemical Biblio Keywords - Models, Genetic Biblio Keywords - Models, Immunological Biblio Keywords - Models, Molecular Biblio Keywords - Models, Neurological Biblio Keywords - Models, Organizational Biblio Keywords - Models, Psychological Biblio Keywords - Models, Statistical Biblio Keywords - Models, Theoretical Biblio Keywords - modern-era Biblio Keywords - Modified carbon paste electrode Biblio Keywords - Molar Biblio Keywords - molecular Biblio Keywords - Molecular Biology Biblio Keywords - Molecular Chaperones Biblio Keywords - Molecular Conformation Biblio Keywords - Molecular Epidemiology Biblio Keywords - Molecular Epidemiology: methods Biblio Keywords - Molecular Imaging Biblio Keywords - Molecular Mimicry Biblio Keywords - Molecular Sequence Annotation Biblio Keywords - Molecular Sequence Data Biblio Keywords - Molecular Structure Biblio Keywords - Molecular Targeted Therapy Biblio Keywords - Molecular Typing Biblio Keywords - Molecular Typing: methods Biblio Keywords - Molecular Weight Biblio Keywords - Moles Biblio Keywords - Mollusca Biblio Keywords - Mollusk Venoms Biblio Keywords - Monitoring, Physiologic Biblio Keywords - Monkey Diseases Biblio Keywords - Monocytes Biblio Keywords - Monocytes/*pathology Biblio Keywords - Monomeric GTP-Binding Proteins Biblio Keywords - Monophenol Monooxygenase Biblio Keywords - monsoon Biblio Keywords - Monte Carlo Method Biblio Keywords - Morbidity Biblio Keywords - Morbidity/trends Biblio Keywords - Morphine Biblio Keywords - Morphine Dependence Biblio Keywords - Morphogenesis Biblio Keywords - Morpholines Biblio Keywords - moss Biblio Keywords - mosses Biblio Keywords - Mother-Child Relations Biblio Keywords - Motivation Biblio Keywords - Motor Activity Biblio Keywords - Motor Cortex Biblio Keywords - Motor Endplate Biblio Keywords - Motor Neurons Biblio Keywords - Mountain wake Biblio Keywords - Mouth Biblio Keywords - Mouth Diseases Biblio Keywords - Mouth Mucosa Biblio Keywords - Mouth Neoplasms Biblio Keywords - Movement Biblio Keywords - Mozambique Biblio Keywords - Mozambique Channel Biblio Keywords - MRE11 Homologue Protein Biblio Keywords - Mucous Membrane Biblio Keywords - Multidrug Resistance-Associated Proteins Biblio Keywords - Multienzyme Complexes Biblio Keywords - Multifactorial Inheritance Biblio Keywords - Multigene Family Biblio Keywords - Multilingualism Biblio Keywords - Multimodal Imaging Biblio Keywords - multiple Biblio Keywords - multiple intelligences Biblio Keywords - Multiple Organ Failure Biblio Keywords - Multiprotein Complexes Biblio Keywords - Multitarget therapy Biblio Keywords - Multivariate Analysis Biblio Keywords - Muramoylpentapeptide Carboxypeptidase Biblio Keywords - Muscarinic Agonists Biblio Keywords - Muscarinic Antagonists Biblio Keywords - Muscimol Biblio Keywords - Muscle Cells Biblio Keywords - Muscle Contraction Biblio Keywords - Muscle Development Biblio Keywords - Muscle Proteins Biblio Keywords - Muscle Tonus Biblio Keywords - Muscle Weakness Biblio Keywords - Muscle, Skeletal Biblio Keywords - Muscle, Smooth Biblio Keywords - Muscle, Smooth, Vascular Biblio Keywords - Muscles Biblio Keywords - Muscular Diseases Biblio Keywords - Mutagenesis Biblio Keywords - Mutagenesis, Insertional Biblio Keywords - Mutagenesis, Site-Directed Biblio Keywords - Mutagens Biblio Keywords - Mutation Biblio Keywords - Mutation, Missense Biblio Keywords - Myasthenic Syndromes, Congenital Biblio Keywords - Mycobacterium Infections Biblio Keywords - Mycobacterium tuberculosis Biblio Keywords - Mycoplasma Infections Biblio Keywords - Mycosis Fungoides Biblio Keywords - Myelin Sheath Biblio Keywords - Myeloablative Agonists Biblio Keywords - Myelodysplastic Syndromes Biblio Keywords - Myeloid Cells Biblio Keywords - Myeloid-Lymphoid Leukemia Protein Biblio Keywords - Myoblasts Biblio Keywords - Myoblasts, Skeletal Biblio Keywords - Myocardial Contraction Biblio Keywords - Myocardial Infarction Biblio Keywords - Myocardial Ischemia Biblio Keywords - Myocardial Reperfusion Injury Biblio Keywords - Myocardium Biblio Keywords - Myocytes, Cardiac Biblio Keywords - Myocytes, Smooth Muscle Biblio Keywords - Myofibrils Biblio Keywords - Myofibroblasts Biblio Keywords - Myogenin Biblio Keywords - Myoglobin Biblio Keywords - myosin Biblio Keywords - Myosin Heavy Chains Biblio Keywords - Myosin Light Chains Biblio Keywords - Myosin Type II Biblio Keywords - Myosin Type V Biblio Keywords - Myosins Biblio Keywords - N-Methylaspartate Biblio Keywords - N-Methylscopolamine Biblio Keywords - NADH electrooxidation Biblio Keywords - NADP Biblio Keywords - NADPH Dehydrogenase Biblio Keywords - Naloxone Biblio Keywords - Nandrolone Biblio Keywords - Nanocapsules Biblio Keywords - Nanofibers Biblio Keywords - Nanoparticles Biblio Keywords - Nanostructures Biblio Keywords - Nanotechnology Biblio Keywords - Nanotubes, Carbon Biblio Keywords - Naphthalenes Biblio Keywords - Narcotics Biblio Keywords - Nasal Cavity Biblio Keywords - National Health Programs Biblio Keywords - National Institutes of Health (U.S.) Biblio Keywords - native plants Biblio Keywords - Natriuresis Biblio Keywords - Natriuretic Peptide, Brain Biblio Keywords - naturalized plants Biblio Keywords - nature conservation Biblio Keywords - Nausea Biblio Keywords - Nebraska Biblio Keywords - Neck Pain Biblio Keywords - Necrosis Biblio Keywords - Needle Sharing Biblio Keywords - Needs Assessment Biblio Keywords - nef Gene Products, Human Immunodeficiency Virus Biblio Keywords - neighborhood decline Biblio Keywords - Neisseria gonorrhoeae Biblio Keywords - Nematoda Biblio Keywords - neonatal Biblio Keywords - Neonatal Screening Biblio Keywords - Neoplasm Invasiveness Biblio Keywords - Neoplasm Metastasis Biblio Keywords - Neoplasm Metastasis/*prevention & control Biblio Keywords - Neoplasm Proteins Biblio Keywords - Neoplasm Recurrence, Local Biblio Keywords - Neoplasm Staging Biblio Keywords - Neoplasm Transplantation Biblio Keywords - Neoplasm, Residual Biblio Keywords - Neoplasms Biblio Keywords - Neoplasms, Experimental Biblio Keywords - Neoplasms, Experimental/genetics/metabolism/pathology Biblio Keywords - Neoplasms, Glandular and Epithelial/blood/*complications/drug therapy Biblio Keywords - Neoplasms/*economics/*mortality Biblio Keywords - Neoplasms/*epidemiology Biblio Keywords - Neoplasms/*epidemiology/mortality Biblio Keywords - Neoplasms/blood supply/pathology Biblio Keywords - Neoplasms/immunology/*pathology Biblio Keywords - Neoplasms/immunology/pathology/*physiopathology Biblio Keywords - Neoplastic Cells, Circulating Biblio Keywords - Neoplastic Stem Cells Biblio Keywords - Neostigmine Biblio Keywords - Neostriatum Biblio Keywords - Neovascularization, Pathologic Biblio Keywords - Neovascularization, Pathologic/*drug therapy/metabolism Biblio Keywords - Neovascularization, Pathologic/*drug therapy/metabolism/pathology Biblio Keywords - Neovascularization, Pathologic/*pathology Biblio Keywords - Neovascularization, Pathologic/*physiopathology Biblio Keywords - Neovascularization, Pathologic/immunology/*pathology Biblio Keywords - Neovascularization, Pathologic/pathology Biblio Keywords - Neovascularization, Physiologic Biblio Keywords - Nephrectomy Biblio Keywords - Nephrons Biblio Keywords - Nerve Crush Biblio Keywords - Nerve Degeneration Biblio Keywords - Nerve Fibers Biblio Keywords - Nerve Fibers, Myelinated Biblio Keywords - Nerve Growth Factor Biblio Keywords - Nerve Growth Factors Biblio Keywords - Nerve Growth Factors/*pharmacology Biblio Keywords - Nerve Net Biblio Keywords - Nerve Regeneration Biblio Keywords - Nerve Tissue Biblio Keywords - Nerve Tissue Proteins Biblio Keywords - Nervous System Biblio Keywords - Nervous System Diseases Biblio Keywords - Nervous System Physiological Phenomena Biblio Keywords - Neural Cell Adhesion Molecules Biblio Keywords - Neural Conduction Biblio Keywords - Neural Crest Biblio Keywords - Neural Inhibition Biblio Keywords - Neural Networks (Computer) Biblio Keywords - Neural Pathways Biblio Keywords - Neural Stem Cells Biblio Keywords - Neural Tube Defects Biblio Keywords - Neuralgia Biblio Keywords - Neurites Biblio Keywords - Neurobiology Biblio Keywords - Neuroblastoma Biblio Keywords - Neurodegenerative Diseases Biblio Keywords - Neuroendocrine Tumors Biblio Keywords - Neurofibrillary Tangles Biblio Keywords - Neurofilament Proteins Biblio Keywords - Neurogenesis Biblio Keywords - Neuroglia Biblio Keywords - Neuroimmunomodulation/immunology/physiology Biblio Keywords - Neuromuscular Junction Biblio Keywords - Neuronal Plasticity Biblio Keywords - Neurons Biblio Keywords - Neurons, Afferent Biblio Keywords - Neuropeptide Y Biblio Keywords - Neuropeptides Biblio Keywords - Neurophysiology Biblio Keywords - Neuropil Biblio Keywords - Neuroprotective Agents Biblio Keywords - Neuropsychological Tests Biblio Keywords - Neurosciences Biblio Keywords - Neurosecretory Systems/immunology/*pathology Biblio Keywords - Neurosecretory Systems/immunology/*physiopathology Biblio Keywords - Neurotensin Biblio Keywords - Neurotransmitter Agents Biblio Keywords - Neurotransmitter Uptake Inhibitors Biblio Keywords - Neurotrophin 3 Biblio Keywords - neutral metal layers Biblio Keywords - Neutral Red Biblio Keywords - Neutralization Tests Biblio Keywords - Neutrophils Biblio Keywords - Neutrophils/*drug effects Biblio Keywords - New York Biblio Keywords - new york Biblio Keywords - New York City Biblio Keywords - new york epidemiology Biblio Keywords - Newport Biblio Keywords - NF-kappa B Biblio Keywords - NF-kappa B p50 Subunit Biblio Keywords - NF-kappa B/*immunology Biblio Keywords - NF-kappa B/*metabolism Biblio Keywords - NFATC Transcription Factors Biblio Keywords - NG-Nitroarginine Methyl Ester Biblio Keywords - Nickel Biblio Keywords - Nicotinamide Phosphoribosyltransferase Biblio Keywords - Nicotine Biblio Keywords - Nicotinic Agonists Biblio Keywords - Nicotinic Antagonists Biblio Keywords - Nictitating Membrane Biblio Keywords - Nifedipine Biblio Keywords - NIH 3T3 Cells Biblio Keywords - Nile River flow variability Biblio Keywords - Nitrates Biblio Keywords - Nitric Oxide Biblio Keywords - Nitric Oxide Synthase Biblio Keywords - Nitric Oxide Synthase Type I Biblio Keywords - Nitric Oxide Synthase Type II Biblio Keywords - Nitric Oxide Synthase Type III Biblio Keywords - Nitriles Biblio Keywords - Nitrilotriacetic Acid Biblio Keywords - Nitrites Biblio Keywords - Nitro Compounds Biblio Keywords - Nitroarginine Biblio Keywords - Nitrobenzoates Biblio Keywords - Nitrogen Biblio Keywords - Nitrosamines Biblio Keywords - NK Cell Lectin-Like Receptor Subfamily K Biblio Keywords - Nociceptors Biblio Keywords - non-inocent Biblio Keywords - Nootropic Agents Biblio Keywords - Norepinephrine Biblio Keywords - Norepinephrine/*metabolism Biblio Keywords - Norepinephrine/*pharmacology Biblio Keywords - Norepinephrine/metabolism Biblio Keywords - Norepinephrine/pharmacology Biblio Keywords - North America Biblio Keywords - North Atlantic Oscillation Biblio Keywords - northern Namibia Biblio Keywords - Nuclear Envelope Biblio Keywords - Nuclear Family Biblio Keywords - Nuclear Localization Signals Biblio Keywords - Nuclear Magnetic Resonance, Biomolecular Biblio Keywords - Nuclear Pore Biblio Keywords - Nuclear Pore Complex Proteins Biblio Keywords - Nuclear Proteins Biblio Keywords - Nuclear Receptor Subfamily 4, Group A, Member 2 Biblio Keywords - Nucleic Acid Amplification Techniques Biblio Keywords - Nucleic Acid Conformation Biblio Keywords - Nucleic Acid Heteroduplexes Biblio Keywords - Nucleic Acid Hybridization Biblio Keywords - Nucleic Acid Synthesis Inhibitors Biblio Keywords - Nucleocytoplasmic Transport Proteins Biblio Keywords - nucleophilic addition Biblio Keywords - Nucleoplasmins Biblio Keywords - Nucleotides Biblio Keywords - Nucleotides, Cyclic Biblio Keywords - Nucleus Accumbens Biblio Keywords - Nurse's Role Biblio Keywords - Nutrition Disorders Biblio Keywords - Nutrition Surveys Biblio Keywords - Nutritional Requirements Biblio Keywords - Nymph Biblio Keywords - Obesity Biblio Keywords - Obsessive-Compulsive Disorder Biblio Keywords - Obstetrics and Gynecology Department, Hospital Biblio Keywords - Occupational Diseases Biblio Keywords - Occupational Exposure Biblio Keywords - Ocean swells Biblio Keywords - ocean-atmosphere interaction Biblio Keywords - ocean-atmosphere interactions Biblio Keywords - oceanography Biblio Keywords - Octamer Transcription Factor-3 Biblio Keywords - Octanols Biblio Keywords - Octopamine Biblio Keywords - Odds Ratio Biblio Keywords - Oils Biblio Keywords - Old Age Assistance Biblio Keywords - Olfactory Mucosa Biblio Keywords - Olfactory Pathways Biblio Keywords - Oligodeoxyribonucleotides Biblio Keywords - Oligodeoxyribonucleotides, Antisense Biblio Keywords - Oligonucleotide Array Sequence Analysis Biblio Keywords - Oligonucleotides Biblio Keywords - Oligonucleotides, Antisense Biblio Keywords - Oligopeptides Biblio Keywords - Oncogene Proteins v-fos Biblio Keywords - Oncogene Proteins, Fusion Biblio Keywords - Oncogene Proteins, Viral Biblio Keywords - Oocysts Biblio Keywords - Oocytes Biblio Keywords - Open Reading Frames Biblio Keywords - Operon Biblio Keywords - Ophthalmic Solutions Biblio Keywords - Opossums Biblio Keywords - Optic Nerve Biblio Keywords - Optic Nerve Injuries Biblio Keywords - Optical Imaging Biblio Keywords - Optics and Photonics Biblio Keywords - Optogenetics Biblio Keywords - Orbit Biblio Keywords - Orchiectomy Biblio Keywords - Organ Culture Techniques Biblio Keywords - Organ of Corti Biblio Keywords - Organ Size Biblio Keywords - Organ Specificity Biblio Keywords - Organelles Biblio Keywords - Organic Chemicals Biblio Keywords - organic farming Biblio Keywords - Organizational Case Studies Biblio Keywords - Organizational Innovation Biblio Keywords - Organizational Objectives Biblio Keywords - Organogenesis Biblio Keywords - Organometallic Compounds Biblio Keywords - Organophosphonates Biblio Keywords - Organoplatinum Compounds/administration & dosage/pharmacology Biblio Keywords - Organosilicon Compounds Biblio Keywords - Orientation Biblio Keywords - Ornithine Decarboxylase Biblio Keywords - Orographic effects Biblio Keywords - Osmolar Concentration Biblio Keywords - Osmosis Biblio Keywords - Osmotic Pressure Biblio Keywords - Osseointegration Biblio Keywords - Osteitis Deformans Biblio Keywords - Osteoarthritis Biblio Keywords - Osteoarthritis, Knee Biblio Keywords - Osteoblasts Biblio Keywords - Osteocalcin Biblio Keywords - Osteoclasts Biblio Keywords - Osteogenesis Biblio Keywords - Osteopontin Biblio Keywords - Osteosarcoma Biblio Keywords - Otitis Externa Biblio Keywords - Ouabain Biblio Keywords - outer membrane Biblio Keywords - OUTGOING LONGWAVE RADIATION Biblio Keywords - Outpatients Biblio Keywords - Ovalbumin Biblio Keywords - Ovarian Neoplasms Biblio Keywords - Ovarian Neoplasms/*blood supply/metabolism/pathology Biblio Keywords - Ovarian Neoplasms/*blood supply/pathology Biblio Keywords - Ovarian Neoplasms/*blood supply/pathology/*physiopathology/radiography Biblio Keywords - Ovarian Neoplasms/*drug therapy Biblio Keywords - Ovarian Neoplasms/*drug therapy/*genetics/metabolism Biblio Keywords - Ovarian Neoplasms/*drug therapy/genetics/pathology Biblio Keywords - Ovarian Neoplasms/*drug therapy/metabolism Biblio Keywords - Ovarian Neoplasms/*drug therapy/pathology Biblio Keywords - Ovarian Neoplasms/*genetics/metabolism/pathology Biblio Keywords - Ovarian Neoplasms/*metabolism Biblio Keywords - Ovarian Neoplasms/*pathology Biblio Keywords - Ovarian Neoplasms/blood supply/*drug therapy/metabolism Biblio Keywords - Ovarian Neoplasms/blood supply/*pathology/therapy Biblio Keywords - Ovarian Neoplasms/blood/*complications/drug therapy Biblio Keywords - Ovarian Neoplasms/chemistry/*genetics Biblio Keywords - Ovarian Neoplasms/drug therapy/*enzymology/mortality/*pathology Biblio Keywords - Ovarian Neoplasms/genetics/*metabolism/pathology Biblio Keywords - Ovarian Neoplasms/genetics/*pathology/therapy Biblio Keywords - Ovarian Neoplasms/genetics/pathology/*therapy Biblio Keywords - Ovarian Neoplasms/metabolism/*pathology/*surgery Biblio Keywords - Ovariectomy Biblio Keywords - Overweight Biblio Keywords - Ovum Biblio Keywords - Oxazines/*pharmacology Biblio Keywords - Oxidants Biblio Keywords - Oxidants, Photochemical Biblio Keywords - Oxidation-Reduction Biblio Keywords - Oxidative Phosphorylation Biblio Keywords - Oxidative Stress Biblio Keywords - Oxides Biblio Keywords - Oxidoreductases Biblio Keywords - Oxidoreductases Acting on CH-CH Group Donors Biblio Keywords - Oxidoreductases Acting on CH-NH Group Donors Biblio Keywords - Oximes Biblio Keywords - Oxygen Biblio Keywords - Oxygen Consumption Biblio Keywords - Oxygenases Biblio Keywords - Oxyhemoglobins Biblio Keywords - Oxymetazoline Biblio Keywords - Oxytocin Biblio Keywords - Ozone Biblio Keywords - p-benzyne Biblio Keywords - p21-Activated Kinases Biblio Keywords - p38 Mitogen-Activated Protein Kinases Biblio Keywords - Paclitaxel Biblio Keywords - Paclitaxel/administration & dosage Biblio Keywords - Pain Biblio Keywords - Pain Measurement Biblio Keywords - Palaemonidae Biblio Keywords - Paleontology Biblio Keywords - Palinuridae Biblio Keywords - palm weevils Biblio Keywords - Palmitoyl Coenzyme A Biblio Keywords - palmitylation Biblio Keywords - Pamphlets Biblio Keywords - Pancreas Biblio Keywords - Pancreatic Neoplasms Biblio Keywords - Pancreatic Polypeptide Biblio Keywords - Pancytopenia Biblio Keywords - pandemics Biblio Keywords - Panic Disorder Biblio Keywords - Papanicolaou Test Biblio Keywords - Papaverine Biblio Keywords - Papillary Muscles Biblio Keywords - Papillomaviridae Biblio Keywords - Papillomavirus E7 Proteins Biblio Keywords - Papillomavirus Infections Biblio Keywords - Parabens Biblio Keywords - Paracrine Communication Biblio Keywords - Paragonimus Biblio Keywords - Paraquat Biblio Keywords - Parasitemia Biblio Keywords - Parasitic Sensitivity Tests Biblio Keywords - Parasitology Biblio Keywords - Parasympatholytics Biblio Keywords - Parathyroid Hormone Biblio Keywords - Parathyroid Hormone-Related Protein Biblio Keywords - Paratuberculosis Biblio Keywords - Paraventricular Hypothalamic Nucleus Biblio Keywords - Pargyline Biblio Keywords - Parity Biblio Keywords - Parkinson Disease Biblio Keywords - Particle Size Biblio Keywords - Particulate Matter Biblio Keywords - Patch-Clamp Techniques Biblio Keywords - Patentes Biblio Keywords - Patents Biblio Keywords - Paternal Age Biblio Keywords - Patient Acceptance of Health Care Biblio Keywords - Patient Acceptance of Health Care/*statistics & numerical data Biblio Keywords - Patient Admission Biblio Keywords - Patient Care Team Biblio Keywords - Patient Compliance Biblio Keywords - Patient Education as Topic Biblio Keywords - Patient Participation Biblio Keywords - Patient Preference Biblio Keywords - Patient Satisfaction Biblio Keywords - Patient Selection Biblio Keywords - Patients Biblio Keywords - PCL Biblio Keywords - PDMS Biblio Keywords - pectin Biblio Keywords - Pedigree Biblio Keywords - Pelvic Inflammatory Disease Biblio Keywords - Pelvis Biblio Keywords - Penicillin G Biblio Keywords - Penicillin G Procaine Biblio Keywords - Penicillin Resistance Biblio Keywords - Penicillin-Binding Proteins Biblio Keywords - Penicillins Biblio Keywords - Penile Neoplasms Biblio Keywords - Penile Neoplasms/*epidemiology/ethnology Biblio Keywords - Pentostatin Biblio Keywords - Pepsin A Biblio Keywords - Peptide encapsulation Biblio Keywords - Peptide Fragments Biblio Keywords - Peptide Hormones Biblio Keywords - Peptide Hydrolases Biblio Keywords - Peptide Initiation Factors Biblio Keywords - Peptide Mapping Biblio Keywords - Peptide YY Biblio Keywords - Peptides Biblio Keywords - Peptides, Cyclic Biblio Keywords - Peptidyl Transferases Biblio Keywords - Peptidyl-Dipeptidase A Biblio Keywords - Peptococcaceae/drug effects/genetics/growth & development Biblio Keywords - Perception Biblio Keywords - Perchlorates Biblio Keywords - Perforin Biblio Keywords - performance Biblio Keywords - Performance Biblio Keywords - Perfusion Biblio Keywords - Pericytes/*drug effects/metabolism Biblio Keywords - Pericytes/drug effects/metabolism Biblio Keywords - Period Circadian Proteins Biblio Keywords - Periodicals as Topic Biblio Keywords - Periodicity Biblio Keywords - Periodontal Diseases Biblio Keywords - Peripheral Nerves Biblio Keywords - Peripherins Biblio Keywords - Periplaneta Biblio Keywords - Permeability Biblio Keywords - Peroxidase Biblio Keywords - Peroxiredoxins Biblio Keywords - Personal experiences 1995-2005 Biblio Keywords - Personality Assessment Biblio Keywords - Personality Inventory Biblio Keywords - Pertussis Toxin Biblio Keywords - PFA4 Biblio Keywords - Phaeophyta Biblio Keywords - Phagocytes Biblio Keywords - Phagocytosis Biblio Keywords - Pharmaceutical Biblio Keywords - Pharmaceutical Preparations Biblio Keywords - Pharmaceutical Vehicles Biblio Keywords - Pharmacogenetics Biblio Keywords - Pharyngeal Neoplasms Biblio Keywords - Pharynx Biblio Keywords - Phenazocine Biblio Keywords - Phencyclidine Biblio Keywords - Phenobarbital Biblio Keywords - Phenols Biblio Keywords - Phenothiazines Biblio Keywords - Phenotype Biblio Keywords - Phentolamine Biblio Keywords - Phenyl Ethers Biblio Keywords - Phenylalanine Biblio Keywords - Phenylephrine Biblio Keywords - Phenylketonurias Biblio Keywords - Phenylmercuric Acetate Biblio Keywords - Phenylurea Compounds/pharmacology Biblio Keywords - Pheochromocytoma Biblio Keywords - Philadelphia Biblio Keywords - Phloem Biblio Keywords - Phorbol 12,13-Dibutyrate Biblio Keywords - Phosphates Biblio Keywords - Phosphatidylcholines Biblio Keywords - Phosphatidylcholines/pharmacology Biblio Keywords - Phosphatidylethanolamines Biblio Keywords - Phosphatidylinositol 3-Kinases Biblio Keywords - Phosphatidylinositol 3-Kinases/analysis Biblio Keywords - Phosphatidylinositol Phosphates Biblio Keywords - Phosphatidylserines/*immunology Biblio Keywords - Phosphodiesterase Inhibitors Biblio Keywords - Phospholipases Biblio Keywords - Phospholipases A Biblio Keywords - Phospholipases A2 Biblio Keywords - Phospholipids Biblio Keywords - Phosphoprotein Phosphatases Biblio Keywords - Phosphoproteins Biblio Keywords - Phosphopyruvate Hydratase Biblio Keywords - Phosphoric Monoester Hydrolases Biblio Keywords - Phosphorus Biblio Keywords - Phosphorus Radioisotopes Biblio Keywords - Phosphorylation Biblio Keywords - Phosphorylation/drug effects Biblio Keywords - Phosphoserine Biblio Keywords - Phosphoserine/metabolism Biblio Keywords - Phosphotyrosine Biblio Keywords - Photic Stimulation Biblio Keywords - Photo Production Biblio Keywords - Photobacterium Biblio Keywords - Photobleaching Biblio Keywords - Photochemical Processes Biblio Keywords - Photochemistry Biblio Keywords - Photography Biblio Keywords - Photolysis Biblio Keywords - Photons Biblio Keywords - Photoreceptor Cells, Invertebrate Biblio Keywords - Phthalazines/pharmacology Biblio Keywords - Phthalic Acids Biblio Keywords - Phycoerythrin Biblio Keywords - Phylogeny Biblio Keywords - Physical Chromosome Mapping Biblio Keywords - Physical meteorology and climatology Biblio Keywords - Physical oceanography Biblio Keywords - Physical Stimulation Biblio Keywords - Physician-Patient Relations Biblio Keywords - Physicians' Offices Biblio Keywords - Physicochemical Phenomena Biblio Keywords - Physics: Molecular Biblio Keywords - Physics: Optics Biblio Keywords - Physiology Biblio Keywords - Phytoestrogens Biblio Keywords - Phytohemagglutinins Biblio Keywords - Phytotelma Biblio Keywords - Phytotherapy Biblio Keywords - Pichia Biblio Keywords - Picrotoxin Biblio Keywords - Pilocarpine Biblio Keywords - Pilot Projects Biblio Keywords - Pinus Biblio Keywords - Piperazines Biblio Keywords - Piperazines/*therapeutic use Biblio Keywords - Piperidines Biblio Keywords - Pirenzepine Biblio Keywords - Pituitary Hormones Biblio Keywords - Pituitary-Adrenal System Biblio Keywords - Placenta Biblio Keywords - Placenta/virology Biblio Keywords - Planarians Biblio Keywords - Planning Biblio Keywords - planning and forecasting Biblio Keywords - Plant Bark Biblio Keywords - plant cell wall Biblio Keywords - Plant Development Biblio Keywords - Plant Diseases Biblio Keywords - Plant Extracts Biblio Keywords - Plant Leaves Biblio Keywords - Plant Proteins Biblio Keywords - Plant Roots Biblio Keywords - Plants Biblio Keywords - Plants, Genetically Modified Biblio Keywords - Plants, Medicinal Biblio Keywords - Plants, Toxic Biblio Keywords - Plaque, Atherosclerotic Biblio Keywords - Plasma Biblio Keywords - Plasma Cells Biblio Keywords - Plasmacytoma Biblio Keywords - Plasmids Biblio Keywords - Plasmids: genetics Biblio Keywords - Plasmodium berghei Biblio Keywords - Plasmodium falciparum Biblio Keywords - Plasmodium falciparum/*physiology Biblio Keywords - Plasmodium vivax Biblio Keywords - Plasmodium yoelii Biblio Keywords - Platelet Activating Factor Biblio Keywords - Platelet Count Biblio Keywords - Plesiomonas Biblio Keywords - Pleural Neoplasms Biblio Keywords - Pluripotent Stem Cells Biblio Keywords - PMN-MDSCs Biblio Keywords - Pneumonia, Aspiration Biblio Keywords - Point Mutation Biblio Keywords - Pokeweed Mitogens Biblio Keywords - Pol1 Transcription Initiation Complex Proteins Biblio Keywords - polar blocking Biblio Keywords - Policy Biblio Keywords - políticas sobre relaciones románticas en el trabajo Biblio Keywords - políticas sobre relaciones románticas en el trabajo. Biblio Keywords - Politics Biblio Keywords - pollution Biblio Keywords - Poly A Biblio Keywords - Poly(ethylene-oxide) Biblio Keywords - Polyamines Biblio Keywords - Polychlorinated Biphenyls Biblio Keywords - Polycomb Repressive Complex 2 Biblio Keywords - Polydactyly Biblio Keywords - Polydeoxyribonucleotides Biblio Keywords - Polyesters Biblio Keywords - Polyethylene Glycols Biblio Keywords - Polyethylene Terephthalates Biblio Keywords - Polyketide Synthases Biblio Keywords - Polylysine Biblio Keywords - Polymerase Chain Reaction Biblio Keywords - Polymerase Chain Reaction/*methods Biblio Keywords - Polymers Biblio Keywords - Polymers/*metabolism/pharmacology Biblio Keywords - Polymethacrylic Acids Biblio Keywords - Polymorphism Biblio Keywords - Polymorphism, Genetic Biblio Keywords - Polymorphism, Single Nucleotide Biblio Keywords - Polyphenols Biblio Keywords - Polyphosphates Biblio Keywords - Polyploidy Biblio Keywords - Polypyrimidine Tract-Binding Protein Biblio Keywords - Polyribosomes Biblio Keywords - Polysaccharides Biblio Keywords - Polystyrenes Biblio Keywords - Ponta do Ouro Biblio Keywords - Population Biblio Keywords - Population Characteristics Biblio Keywords - Population Density Biblio Keywords - Population Dynamics Biblio Keywords - Population Groups Biblio Keywords - Population Growth Biblio Keywords - Population Surveillance Biblio Keywords - population surveillance Biblio Keywords - Population Surveillance/*methods Biblio Keywords - Porifera Biblio Keywords - Porins Biblio Keywords - Porosity Biblio Keywords - port city Biblio Keywords - Portraits as Topic Biblio Keywords - Positron-Emission Tomography Biblio Keywords - Post-Exposure Prophylaxis Biblio Keywords - Postpartum Period Biblio Keywords - Postural Balance Biblio Keywords - Potassium Biblio Keywords - Potassium Channel Blockers Biblio Keywords - Potassium Channels Biblio Keywords - Potassium Channels, Calcium-Activated Biblio Keywords - Potassium Channels, Voltage-Gated Biblio Keywords - Potassium Chloride Biblio Keywords - Potassium layer Biblio Keywords - potassium lidar Biblio Keywords - POU Domain Factors Biblio Keywords - Poverty Biblio Keywords - power distribution unit Biblio Keywords - Practice Guidelines as Topic Biblio Keywords - Prazosin Biblio Keywords - Precancerous Conditions Biblio Keywords - precipitation Biblio Keywords - Precipitin Tests Biblio Keywords - Preconception Care Biblio Keywords - Precursor Cell Lymphoblastic Leukemia-Lymphoma Biblio Keywords - predator-prey interaction Biblio Keywords - Predatory Behavior Biblio Keywords - predictability Biblio Keywords - prediction model Biblio Keywords - Predictive Value of Tests Biblio Keywords - Prefrontal Cortex Biblio Keywords - Pregnancy Biblio Keywords - Pregnancy Complications Biblio Keywords - Pregnancy Complications, Infectious Biblio Keywords - Pregnancy Complications, Infectious/*virology Biblio Keywords - Pregnancy in Diabetics Biblio Keywords - Pregnancy Outcome Biblio Keywords - Pregnancy Tests Biblio Keywords - Pregnancy Trimester, First Biblio Keywords - Pregnancy, Multiple Biblio Keywords - Pregnant Women Biblio Keywords - Pregnenolone Carbonitrile Biblio Keywords - Prejudice Biblio Keywords - Prenatal Care Biblio Keywords - Prenatal Diagnosis Biblio Keywords - Prenatal Exposure Delayed Effects Biblio Keywords - Prenylation Biblio Keywords - Preoperative Care Biblio Keywords - Preoptic Area Biblio Keywords - Pressure Biblio Keywords - Presynaptic Terminals Biblio Keywords - Prevalence Biblio Keywords - prevalence Biblio Keywords - Primaquine Biblio Keywords - Primary Cell Culture Biblio Keywords - Primary Health Care Biblio Keywords - Primates Biblio Keywords - Principal Component Analysis Biblio Keywords - principle component analysis Biblio Keywords - Printing Biblio Keywords - Prions Biblio Keywords - Prisoners Biblio Keywords - Probability Biblio Keywords - Procaine Biblio Keywords - Product Surveillance, Postmarketing Biblio Keywords - Professional Competence Biblio Keywords - Professional-Patient Relations Biblio Keywords - Progesterone Biblio Keywords - Progesterone Congeners Biblio Keywords - Prognosis Biblio Keywords - Program Development Biblio Keywords - Program Evaluation Biblio Keywords - Programmed Cell Death 1 Ligand 2 Protein Biblio Keywords - Prolactin Biblio Keywords - Proliferating Cell Nuclear Antigen Biblio Keywords - Proliferating Cell Nuclear Antigen/metabolism Biblio Keywords - Proline Biblio Keywords - Proline-Rich Protein Domains Biblio Keywords - Promoter Regions, Genetic Biblio Keywords - Propanolamines Biblio Keywords - Propanols Biblio Keywords - Prophages Biblio Keywords - Prophages: genetics Biblio Keywords - Propidium Biblio Keywords - Propiedad Intelectual Biblio Keywords - Propionates Biblio Keywords - Propionibacterium Biblio Keywords - Proportional Hazards Models Biblio Keywords - Propranolol Biblio Keywords - Propranolol/pharmacology Biblio Keywords - Prospective Studies Biblio Keywords - Prostaglandin D2 Biblio Keywords - Prostaglandins Biblio Keywords - Prostaglandins E Biblio Keywords - Prostaglandins E, Synthetic Biblio Keywords - Prostate Biblio Keywords - prostate cancer Biblio Keywords - Prostate-Specific Antigen Biblio Keywords - Prostatectomy Biblio Keywords - Prostatic Neoplasms Biblio Keywords - Prostatic Neoplasms/*drug therapy Biblio Keywords - Prostatic Neoplasms/*epidemiology/mortality Biblio Keywords - Prostatic Neoplasms/*etiology/*psychology Biblio Keywords - Prostatitis Biblio Keywords - Prostheses and Implants Biblio Keywords - Protamines Biblio Keywords - Protease Inhibitors Biblio Keywords - Protease Nexins Biblio Keywords - protein Biblio Keywords - Protein Array Analysis Biblio Keywords - Protein Binding Biblio Keywords - Protein Binding/immunology Biblio Keywords - Protein Biosynthesis Biblio Keywords - Protein C Biblio Keywords - Protein Carbonylation Biblio Keywords - Protein Conformation Biblio Keywords - Protein Conformation, alpha-Helical Biblio Keywords - Protein Conformation, beta-Strand Biblio Keywords - Protein Deficiency Biblio Keywords - Protein Denaturation Biblio Keywords - Protein Engineering Biblio Keywords - Protein Engineering/*methods Biblio Keywords - Protein Folding Biblio Keywords - Protein Footprinting Biblio Keywords - Protein Inhibitors of Activated STAT Biblio Keywords - Protein Interaction Domains and Motifs Biblio Keywords - Protein Interaction Mapping Biblio Keywords - Protein Isoforms Biblio Keywords - Protein Kinase C Biblio Keywords - Protein Kinase C-alpha Biblio Keywords - Protein Kinase Inhibitors Biblio Keywords - Protein Kinase Inhibitors/administration & dosage/pharmacology Biblio Keywords - Protein Kinases Biblio Keywords - Protein Modification, Translational Biblio Keywords - Protein Multimerization Biblio Keywords - Protein Phosphatase 1 Biblio Keywords - Protein Phosphatase 2 Biblio Keywords - Protein Precursors Biblio Keywords - Protein Processing, Post-Translational Biblio Keywords - Protein Sorting Signals Biblio Keywords - Protein Stability Biblio Keywords - Protein Structure, Quaternary Biblio Keywords - Protein Structure, Secondary Biblio Keywords - Protein Structure, Tertiary Biblio Keywords - Protein Subunits Biblio Keywords - Protein Synthesis Inhibitors Biblio Keywords - Protein Transport Biblio Keywords - Protein Tyrosine Phosphatase, Non-Receptor Type 11 Biblio Keywords - Protein Tyrosine Phosphatases Biblio Keywords - Protein-Serine-Threonine Kinases Biblio Keywords - Protein-Serine-Threonine Kinases/*antagonists & inhibitors Biblio Keywords - Protein-Tyrosine Kinases Biblio Keywords - Protein-Tyrosine Kinases/*genetics/physiology Biblio Keywords - Proteins Biblio Keywords - Proteinuria Biblio Keywords - Proteobacteria Biblio Keywords - Proteolysis Biblio Keywords - Proteome Biblio Keywords - Proteomics Biblio Keywords - Proteus Infections Biblio Keywords - Proteus mirabilis Biblio Keywords - Proto-Oncogene Protein c-ets-1 Biblio Keywords - Proto-Oncogene Proteins Biblio Keywords - Proto-Oncogene Proteins c-akt Biblio Keywords - Proto-Oncogene Proteins c-akt/analysis Biblio Keywords - Proto-Oncogene Proteins c-akt/metabolism Biblio Keywords - Proto-Oncogene Proteins c-bcl-2 Biblio Keywords - Proto-Oncogene Proteins c-ets Biblio Keywords - Proto-Oncogene Proteins c-fos Biblio Keywords - Proto-Oncogene Proteins c-fos/*genetics/metabolism Biblio Keywords - Proto-Oncogene Proteins c-kit Biblio Keywords - Proto-Oncogene Proteins c-mdm2 Biblio Keywords - Proto-Oncogene Proteins c-myc Biblio Keywords - Proto-Oncogene Proteins c-myc/genetics/metabolism Biblio Keywords - Proto-Oncogene Proteins c-raf Biblio Keywords - Proto-Oncogene Proteins c-sis/*antagonists & inhibitors Biblio Keywords - Proto-Oncogene Proteins c-vav Biblio Keywords - Proto-Oncogene Proteins pp60(c-src) Biblio Keywords - Proto-Oncogene Proteins/*genetics/physiology Biblio Keywords - Proton-Coupled Folate Transporter Biblio Keywords - Proton-Translocating ATPases Biblio Keywords - Protoplasts Biblio Keywords - Protozoan Proteins Biblio Keywords - Proviruses Biblio Keywords - Prunus Biblio Keywords - Pseudomonas aeruginosa Biblio Keywords - Pseudomonas/drug effects/genetics/growth & development Biblio Keywords - PSIP1 Biblio Keywords - Psychiatric Nursing Biblio Keywords - Psychiatry Biblio Keywords - Psychological Theory Biblio Keywords - Psychometrics Biblio Keywords - Psychomotor Disorders Biblio Keywords - Psychomotor Performance Biblio Keywords - Psychoneuroimmunology Biblio Keywords - Psychophysics Biblio Keywords - Psychotherapy Biblio Keywords - Psychotic Disorders Biblio Keywords - PTEN Phosphohydrolase Biblio Keywords - Pterins Biblio Keywords - Puberty, Precocious Biblio Keywords - Public Health Biblio Keywords - Public Health Administration Biblio Keywords - Public Opinion Biblio Keywords - Public Policy Biblio Keywords - Public transit Biblio Keywords - Puerperal Disorders Biblio Keywords - Puerto Rico Biblio Keywords - Puerto Rico index Biblio Keywords - Puerto Rico/epidemiology Biblio Keywords - Puerto Rico/epidemiology/ethnology Biblio Keywords - Pulmonary Artery Biblio Keywords - Pulmonary Disease, Chronic Obstructive Biblio Keywords - Pulsatile Flow Biblio Keywords - Pulse Biblio Keywords - Pulse Radiolysis Biblio Keywords - pulsed field Biblio Keywords - pulsed field veterinary Biblio Keywords - Pulsed-Field Biblio Keywords - purification/metabolism/*pharmacology Biblio Keywords - Purinergic P1 Receptor Agonists Biblio Keywords - Purinergic P1 Receptor Antagonists Biblio Keywords - Purinergic P2 Receptor Agonists Biblio Keywords - Purines Biblio Keywords - Purinones Biblio Keywords - Purkinje Cells Biblio Keywords - Purkinje Fibers Biblio Keywords - Putrescine Biblio Keywords - Pyramidal Cells Biblio Keywords - Pyramidal Tracts Biblio Keywords - Pyrazoles Biblio Keywords - Pyridines Biblio Keywords - Pyridines/*pharmacology Biblio Keywords - Pyridines/pharmacology Biblio Keywords - Pyridoxine Biblio Keywords - Pyrimethamine Biblio Keywords - Pyrimidines Biblio Keywords - Pyrimidines/administration & dosage/*pharmacology Biblio Keywords - Pyrroles Biblio Keywords - Pyrrolidines Biblio Keywords - Pyruvate Kinase Biblio Keywords - Qa-SNARE Proteins Biblio Keywords - Qa-SNARE Proteins/metabolism Biblio Keywords - Quail Biblio Keywords - Qualitative Research Biblio Keywords - Quality Assurance, Health Care Biblio Keywords - Quality Control Biblio Keywords - Quality of Health Care Biblio Keywords - Quality of Life Biblio Keywords - Quantitative Trait Loci Biblio Keywords - Quantitative Trait, Heritable Biblio Keywords - Quantum Dots Biblio Keywords - Quantum Theory Biblio Keywords - quasi-biennial oscillation Biblio Keywords - Quaternary Ammonium Compounds Biblio Keywords - Quercetin Biblio Keywords - Questionnaires Biblio Keywords - Quinazolines Biblio Keywords - Quinolines Biblio Keywords - Quinolinium Compounds Biblio Keywords - quinolinium salts Biblio Keywords - Quinoxalines Biblio Keywords - Quinpirole Biblio Keywords - Quinuclidinyl Benzilate Biblio Keywords - Quisqualic Acid Biblio Keywords - Quorum Sensing Biblio Keywords - R-SNARE Proteins Biblio Keywords - R-SNARE Proteins/metabolism Biblio Keywords - rab GTP-Binding Proteins Biblio Keywords - rab4 GTP-Binding Proteins Biblio Keywords - Rabbits Biblio Keywords - Rabies Biblio Keywords - Rabies Vaccines Biblio Keywords - Rabies virus Biblio Keywords - rac GTP-Binding Proteins Biblio Keywords - rac1 GTP-Binding Protein Biblio Keywords - racismo Biblio Keywords - Raclopride Biblio Keywords - Rad51 Recombinase Biblio Keywords - Rad52 DNA Repair and Recombination Protein Biblio Keywords - Radiation Dosage Biblio Keywords - Radiation Tolerance Biblio Keywords - Radioimmunoassay Biblio Keywords - Radioimmunotherapy Biblio Keywords - Radioisotopes Biblio Keywords - Radioligand Assay Biblio Keywords - Radiometry Biblio Keywords - Radius Biblio Keywords - Rain Biblio Keywords - rainfall Biblio Keywords - RAINFALL Biblio Keywords - Rainfall change Biblio Keywords - rainfall index Biblio Keywords - rainfall variability Biblio Keywords - Rainwater isotopic analysis Biblio Keywords - Ralstonia solanacearum Biblio Keywords - ran GTP-Binding Protein Biblio Keywords - Rana pipiens Biblio Keywords - Random Allocation Biblio Keywords - Randomized Controlled Trials as Topic Biblio Keywords - Rank–abundance curve Biblio Keywords - Raphe Nuclei Biblio Keywords - Rats Biblio Keywords - Rats, Brattleboro Biblio Keywords - Rats, Inbred Dahl Biblio Keywords - Rats, Inbred F344 Biblio Keywords - Rats, Inbred Lew Biblio Keywords - Rats, Inbred SHR Biblio Keywords - Rats, Inbred Strains Biblio Keywords - Rats, Inbred WF Biblio Keywords - Rats, Long-Evans Biblio Keywords - Rats, Mutant Strains Biblio Keywords - Rats, Sprague-Dawley Biblio Keywords - Rats, Transgenic Biblio Keywords - Rats, Wistar Biblio Keywords - Rattus rattus eradication Biblio Keywords - RAW 264.7 Cells Biblio Keywords - Raynaud Disease Biblio Keywords - Reaction Time Biblio Keywords - Reactive Oxygen Species Biblio Keywords - Reagent Kits, Diagnostic Biblio Keywords - Real-Time Polymerase Chain Reaction Biblio Keywords - Receptor Cross-Talk Biblio Keywords - Receptor Protein-Tyrosine Kinases Biblio Keywords - Receptor, Angiotensin, Type 1 Biblio Keywords - Receptor, Angiotensin, Type 2 Biblio Keywords - Receptor, Cannabinoid, CB1 Biblio Keywords - Receptor, Cannabinoid, CB2 Biblio Keywords - Receptor, EphA2 Biblio Keywords - Receptor, EphA4 Biblio Keywords - Receptor, EphB4 Biblio Keywords - Receptor, Epidermal Growth Factor Biblio Keywords - Receptor, ErbB-2 Biblio Keywords - Receptor, ErbB-3 Biblio Keywords - Receptor, IGF Type 1 Biblio Keywords - Receptor, Insulin Biblio Keywords - Receptor, Metabotropic Glutamate 5 Biblio Keywords - Receptor, PAR-1 Biblio Keywords - Receptor, trkB Biblio Keywords - Receptor, trkC Biblio Keywords - Receptor-Like Protein Tyrosine Phosphatases, Class 5 Biblio Keywords - Receptors, Adrenergic Biblio Keywords - Receptors, Adrenergic, alpha Biblio Keywords - Receptors, Adrenergic, alpha-1 Biblio Keywords - Receptors, Adrenergic, alpha-2 Biblio Keywords - Receptors, Adrenergic, beta Biblio Keywords - Receptors, Adrenergic, beta-2 Biblio Keywords - Receptors, Adrenergic, beta/*metabolism Biblio Keywords - Receptors, Adrenergic, beta/drug effects/metabolism Biblio Keywords - Receptors, Adrenergic, beta/metabolism Biblio Keywords - Receptors, Adrenomedullin Biblio Keywords - Receptors, AMPA Biblio Keywords - Receptors, Androgen Biblio Keywords - Receptors, Angiotensin Biblio Keywords - Receptors, Antigen, T-Cell Biblio Keywords - Receptors, Aryl Hydrocarbon Biblio Keywords - Receptors, Atrial Natriuretic Factor Biblio Keywords - Receptors, Biogenic Amine Biblio Keywords - Receptors, CCR5 Biblio Keywords - Receptors, Cell Surface Biblio Keywords - Receptors, Cholinergic Biblio Keywords - Receptors, CXCR Biblio Keywords - Receptors, CXCR4 Biblio Keywords - Receptors, Cytoplasmic and Nuclear Biblio Keywords - Receptors, Dopamine Biblio Keywords - Receptors, Dopamine D1 Biblio Keywords - Receptors, Dopamine D2 Biblio Keywords - Receptors, Dopamine D3 Biblio Keywords - Receptors, Dopamine/metabolism Biblio Keywords - Receptors, Eph Family Biblio Keywords - Receptors, Estrogen Biblio Keywords - Receptors, Fibroblast Growth Factor Biblio Keywords - Receptors, Fibronectin Biblio Keywords - Receptors, G-Protein-Coupled Biblio Keywords - Receptors, GABA-A Biblio Keywords - Receptors, GABA-B Biblio Keywords - Receptors, Ghrelin Biblio Keywords - Receptors, Glutamate Biblio Keywords - Receptors, Guanylate Cyclase-Coupled Biblio Keywords - Receptors, Immunologic Biblio Keywords - Receptors, Interleukin Biblio Keywords - Receptors, Interleukin-10 Biblio Keywords - Receptors, Interleukin-12 Biblio Keywords - Receptors, Interleukin-3 Biblio Keywords - Receptors, Interleukin-6/deficiency Biblio Keywords - Receptors, KIR Biblio Keywords - Receptors, KIR3DL1 Biblio Keywords - Receptors, LDL Biblio Keywords - Receptors, Metabotropic Glutamate Biblio Keywords - Receptors, Mineralocorticoid Biblio Keywords - Receptors, Muscarinic Biblio Keywords - Receptors, N-Methyl-D-Aspartate Biblio Keywords - Receptors, Neurokinin-1 Biblio Keywords - Receptors, Neuropeptide Y Biblio Keywords - Receptors, Neurotensin Biblio Keywords - Receptors, Neurotransmitter Biblio Keywords - Receptors, Nicotinic Biblio Keywords - Receptors, Opioid Biblio Keywords - Receptors, Opioid, delta Biblio Keywords - Receptors, Opioid, mu Biblio Keywords - Receptors, Peptide Biblio Keywords - Receptors, Progesterone Biblio Keywords - Receptors, Progesterone/genetics/metabolism Biblio Keywords - Receptors, Purinergic P2 Biblio Keywords - Receptors, Purinergic P2Y2 Biblio Keywords - Receptors, Serotonin Biblio Keywords - Receptors, Serotonin, 5-HT1 Biblio Keywords - Receptors, Serotonin, 5-HT2 Biblio Keywords - Receptors, Steroid Biblio Keywords - Receptors, TNF-Related Apoptosis-Inducing Ligand Biblio Keywords - Receptors, Transferrin Biblio Keywords - Receptors, Transforming Growth Factor beta Biblio Keywords - Receptors, Tumor Necrosis Factor Biblio Keywords - Receptors, Tumor Necrosis Factor, Type I Biblio Keywords - Receptors, Tumor Necrosis Factor, Type II Biblio Keywords - Receptors, Vitronectin Biblio Keywords - Recognition (Psychology) Biblio Keywords - Recombinant Fusion Proteins Biblio Keywords - Recombinant Fusion Proteins/chemistry/genetics/metabolism Biblio Keywords - Recombinant Proteins Biblio Keywords - Recombinant Proteins/administration & dosage Biblio Keywords - recombination Biblio Keywords - Recombination, Genetic Biblio Keywords - Recovery of Function Biblio Keywords - Recreation Biblio Keywords - Rectum Biblio Keywords - rectum Biblio Keywords - rectum microbiology Biblio Keywords - Recurrence Biblio Keywords - redox state Biblio Keywords - Reference Standards Biblio Keywords - Reference Values Biblio Keywords - Referral and Consultation Biblio Keywords - Reflector dish Biblio Keywords - Reflex, Stretch Biblio Keywords - Refractometry Biblio Keywords - Refractory Period, Electrophysiological Biblio Keywords - refugees Biblio Keywords - refugiados Biblio Keywords - Regeneration Biblio Keywords - Regenerative Medicine Biblio Keywords - Regional Blood Flow Biblio Keywords - REGIONAL METEOROLOGICAL FORCING Biblio Keywords - regional trend patterns Biblio Keywords - Registries Biblio Keywords - Regression Analysis Biblio Keywords - Regulatory Sequences, Nucleic Acid Biblio Keywords - Reinfection Biblio Keywords - Reinforcement Schedule Biblio Keywords - Reishi Biblio Keywords - Reishi/*chemistry Biblio Keywords - Relaciones románticas en el trabajo Biblio Keywords - Religion Biblio Keywords - Remission Induction Biblio Keywords - Remote sensing Biblio Keywords - Renal Circulation Biblio Keywords - Renin Biblio Keywords - Renin-Angiotensin System Biblio Keywords - reorganization Biblio Keywords - Reperfusion Injury Biblio Keywords - Repetitive Sequences, Amino Acid Biblio Keywords - Repetitive Sequences, Nucleic Acid Biblio Keywords - Replication Origin Biblio Keywords - Repressor Proteins Biblio Keywords - Reproducibility of Results Biblio Keywords - Reproduction Biblio Keywords - Research Biblio Keywords - Research Design Biblio Keywords - Residence Characteristics Biblio Keywords - resonance lidar Biblio Keywords - Resource Allocation Biblio Keywords - Respiration Disorders Biblio Keywords - Respiratory failure Biblio Keywords - Respiratory Function Tests Biblio Keywords - Respiratory Physiological Phenomena Biblio Keywords - Respiratory System Biblio Keywords - Response Elements Biblio Keywords - Rest Biblio Keywords - Restraint, Physical Biblio Keywords - Restraint, Physical/psychology Biblio Keywords - Retention (Psychology) Biblio Keywords - Reticulocyte Count Biblio Keywords - Retina Biblio Keywords - Retinal Degeneration Biblio Keywords - Retinal Ganglion Cells Biblio Keywords - Retinal Neoplasms Biblio Keywords - Retinal Pigment Epithelium Biblio Keywords - Retinal Vessels Biblio Keywords - Retinoblastoma Biblio Keywords - Retinoblastoma Protein Biblio Keywords - Retroelements Biblio Keywords - Retrospective Studies Biblio Keywords - Retroviridae Biblio Keywords - Retroviridae Proteins Biblio Keywords - Retroviruses, Simian Biblio Keywords - Rett Syndrome Biblio Keywords - Reverse Transcriptase Inhibitors Biblio Keywords - Reverse Transcriptase Polymerase Chain Reaction Biblio Keywords - Review Biblio Keywords - Reward Biblio Keywords - Rhabdomyosarcoma Biblio Keywords - rhamnogalacturonan Biblio Keywords - Rheology Biblio Keywords - Rhizobiaceae Biblio Keywords - rho GTP-Binding Proteins Biblio Keywords - rho-Associated Kinases Biblio Keywords - Rhodamines Biblio Keywords - Rhodanine Biblio Keywords - Rhodobacter sphaeroides/genetics/*growth & development/metabolism Biblio Keywords - Ribavirin Biblio Keywords - Ribes Biblio Keywords - Ribonucleases Biblio Keywords - Ribonucleoproteins Biblio Keywords - Ribosomal Proteins Biblio Keywords - Ribosome Inactivating Proteins, Type 1 Biblio Keywords - ridership Biblio Keywords - Rifampin Biblio Keywords - Risk Biblio Keywords - Risk Assessment Biblio Keywords - Risk assessment Biblio Keywords - Risk Factors Biblio Keywords - Risk Reduction Behavior Biblio Keywords - Risk-Taking Biblio Keywords - Ritonavir Biblio Keywords - Rituximab Biblio Keywords - Rivers Biblio Keywords - RNA Biblio Keywords - RNA Cap-Binding Proteins Biblio Keywords - RNA Editing Biblio Keywords - RNA Interference Biblio Keywords - RNA Precursors Biblio Keywords - RNA sequencing Biblio Keywords - RNA Splicing Biblio Keywords - RNA, Antisense Biblio Keywords - RNA, Bacterial Biblio Keywords - RNA, Double-Stranded Biblio Keywords - RNA, Fungal Biblio Keywords - RNA, Messenger Biblio Keywords - RNA, Messenger/*genetics Biblio Keywords - RNA, Messenger/genetics/metabolism Biblio Keywords - RNA, Neoplasm Biblio Keywords - RNA, Plant Biblio Keywords - RNA, Protozoan Biblio Keywords - RNA, Ribosomal Biblio Keywords - RNA, Ribosomal, 16S Biblio Keywords - RNA, Ribosomal, 16S/*genetics Biblio Keywords - RNA, Ribosomal, 16S/metabolism Biblio Keywords - RNA, Small Interfering Biblio Keywords - RNA, Small Interfering/*pharmacology Biblio Keywords - RNA, Small Interfering/administration & dosage/*genetics Biblio Keywords - RNA, Small Interfering/metabolism Biblio Keywords - RNA, Viral Biblio Keywords - RNA, Viral/blood/urine Biblio Keywords - RNA-Binding Proteins Biblio Keywords - RNA-Directed DNA Polymerase Biblio Keywords - Robotics Biblio Keywords - ROC Curve Biblio Keywords - Romance at work Biblio Keywords - romance en el trabajo Biblio Keywords - Romantic Relationships Biblio Keywords - rootkits Biblio Keywords - Rossby waves Biblio Keywords - Rotavirus Biblio Keywords - Rubella Biblio Keywords - Rubella Syndrome, Congenital Biblio Keywords - Rubella Vaccine Biblio Keywords - Rubidium Biblio Keywords - Rural Health Biblio Keywords - Rural Population Biblio Keywords - Ruthenium complex mediator Biblio Keywords - Ryanodine Receptor Calcium Release Channel Biblio Keywords - S Phase Biblio Keywords - Saccharomyces cerevisiae Biblio Keywords - Saccharomyces cerevisiae Proteins Biblio Keywords - Saccharomycetales Biblio Keywords - Safety Biblio Keywords - SAIDS Vaccines Biblio Keywords - Salicylamides Biblio Keywords - Saliva Biblio Keywords - Salmonella Biblio Keywords - salmonella Biblio Keywords - salmonella classification Biblio Keywords - Salmonella enterica Biblio Keywords - salmonella enterica Biblio Keywords - salmonella enterica classification Biblio Keywords - salmonella enterica drug effects Biblio Keywords - salmonella enterica isolation & purification Biblio Keywords - salmonella enterica pathogenicity Biblio Keywords - Salmonella enterica: classification Biblio Keywords - Salmonella enterica: genetics Biblio Keywords - Salmonella enterica: isolation & purification Biblio Keywords - salmonella genetics Biblio Keywords - Salmonella Infections Biblio Keywords - salmonella infections Biblio Keywords - Salmonella Infections: epidemiology Biblio Keywords - Salmonella Infections: microbiology Biblio Keywords - Salmonella, toxin Biblio Keywords - Salmonella: classification Biblio Keywords - Salmonella: genetics Biblio Keywords - Salmonella: isolation & purification Biblio Keywords - Salmonella: pathogenicity Biblio Keywords - Salts Biblio Keywords - Sample Size Biblio Keywords - Sampling Studies Biblio Keywords - Santonin Biblio Keywords - Saposin-like protein-2 Biblio Keywords - Saposins Biblio Keywords - Saposins/*chemical synthesis/genetics Biblio Keywords - Sarcolemma Biblio Keywords - Sarcomeres Biblio Keywords - Sarcoplasmic Reticulum Biblio Keywords - Sarcoplasmic Reticulum Calcium-Transporting ATPases Biblio Keywords - SARS-CoV-2 Biblio Keywords - SARS-CoV-2/genetics Biblio Keywords - SARS-CoV-2/isolation & purification Biblio Keywords - SATELLITE Biblio Keywords - satellite era Biblio Keywords - SATELLITE VEGETATION Biblio Keywords - Satellite vegetation patterns Biblio Keywords - Scalp Biblio Keywords - Scattering, Radiation Biblio Keywords - Schistosoma japonicum Biblio Keywords - Schistosoma mansoni Biblio Keywords - Schistosomiasis Biblio Keywords - Schizophrenia Biblio Keywords - Schizosaccharomyces pombe Proteins Biblio Keywords - Schools, Medical Biblio Keywords - Schwann Cells Biblio Keywords - Scopolamine Derivatives Biblio Keywords - Scyphophorus yuccae Biblio Keywords - Sea level rise Biblio Keywords - sea surface height Biblio Keywords - sea surface temperature Biblio Keywords - Sea-breeze confluence Biblio Keywords - Seasons Biblio Keywords - Seawater Biblio Keywords - Second Messenger Systems Biblio Keywords - Secondary structure Biblio Keywords - Secretory Vesicles Biblio Keywords - seiches Biblio Keywords - Seizures Biblio Keywords - selection Biblio Keywords - selectivity Biblio Keywords - Selenium Biblio Keywords - Selenomethionine Biblio Keywords - Self Administration Biblio Keywords - Semen Biblio Keywords - Sense Organs Biblio Keywords - Sensitivity and Specificity Biblio Keywords - Sensory Gating Biblio Keywords - Sensory Receptor Cells Biblio Keywords - Sentinel Surveillance Biblio Keywords - Sepharose Biblio Keywords - sepsis Biblio Keywords - Sepsis Biblio Keywords - Sequence Alignment Biblio Keywords - sequence analysis Biblio Keywords - Sequence Analysis Biblio Keywords - Sequence Analysis, DNA Biblio Keywords - Sequence Analysis, Protein Biblio Keywords - Sequence Deletion Biblio Keywords - Sequence Homology, Amino Acid Biblio Keywords - Sequence Homology, Nucleic Acid Biblio Keywords - Serine Biblio Keywords - Serine Endopeptidases Biblio Keywords - Serine Proteinase Inhibitors Biblio Keywords - Seroepidemiologic Studies Biblio Keywords - Serologic Tests Biblio Keywords - Serotonergic Neurons Biblio Keywords - Serotonin Biblio Keywords - serotyping Biblio Keywords - Serotyping Biblio Keywords - Serpin E2 Biblio Keywords - Serpins Biblio Keywords - Serpins/*pharmacology Biblio Keywords - Serum Biblio Keywords - Serum Albumin, Bovine Biblio Keywords - Sesquiterpenes Biblio Keywords - Sesquiterpenes, Eudesmane Biblio Keywords - Severity of Illness Index Biblio Keywords - Sewage Biblio Keywords - Sex Biblio Keywords - Sex Attractants Biblio Keywords - Sex Characteristics Biblio Keywords - Sex Differentiation Biblio Keywords - Sex Distribution Biblio Keywords - Sex Factors Biblio Keywords - Sexual Behavior Biblio Keywords - Sexual Behavior, Animal Biblio Keywords - Sexual Maturation Biblio Keywords - Sexual Partners Biblio Keywords - sexualidad en el trabajo Biblio Keywords - Sexually Transmitted Diseases Biblio Keywords - Sezary Syndrome Biblio Keywords - Shab Potassium Channels Biblio Keywords - Sheep Biblio Keywords - Sheep Diseases Biblio Keywords - Shewanella Biblio Keywords - Shock, Septic Biblio Keywords - Shock, Septic/*immunology Biblio Keywords - Shock, Septic/*pathology Biblio Keywords - short-term climate change Biblio Keywords - Shotgun sequencing Biblio Keywords - Sialic Acid Binding Ig-like Lectin 1 Biblio Keywords - Sialoglycoproteins Biblio Keywords - Siblings Biblio Keywords - Signal Transduction Biblio Keywords - Signal Transduction/*immunology Biblio Keywords - Signal Transduction/drug effects Biblio Keywords - Signal Transduction/genetics Biblio Keywords - Silanes Biblio Keywords - Silicon Biblio Keywords - Silicon Dioxide Biblio Keywords - Silicones Biblio Keywords - Silver Staining Biblio Keywords - Simian Acquired Immunodeficiency Syndrome Biblio Keywords - Simian immunodeficiency virus Biblio Keywords - Simian T-lymphotropic virus 1 Biblio Keywords - Simian virus 40 Biblio Keywords - simple network management protocol Biblio Keywords - Simplexvirus Biblio Keywords - Single Nucleotide Biblio Keywords - Single-Blind Method Biblio Keywords - Single-Strand Specific DNA and RNA Endonucleases Biblio Keywords - Singlet Oxygen Biblio Keywords - Sinoatrial Node Biblio Keywords - Sirolimus Biblio Keywords - Skin Biblio Keywords - Skin Diseases Biblio Keywords - Skin Neoplasms Biblio Keywords - Skin Physiological Phenomena Biblio Keywords - Skin Tests Biblio Keywords - Skull Biblio Keywords - Sleep Apnea, Central Biblio Keywords - Smad Proteins Biblio Keywords - Smad4 Protein Biblio Keywords - Small Ubiquitin-Related Modifier Proteins/*genetics/*physiology Biblio Keywords - Smallpox Vaccine Biblio Keywords - Smell Biblio Keywords - Smoking Biblio Keywords - Snails Biblio Keywords - Social Behavior Biblio Keywords - Social Change Biblio Keywords - Social Class Biblio Keywords - Social Conditions Biblio Keywords - Social Determinants of Health Biblio Keywords - Social Environment Biblio Keywords - Social Perception Biblio Keywords - Social Problems Biblio Keywords - Social sciences Biblio Keywords - Social Stigma Biblio Keywords - Social Support Biblio Keywords - Social Values Biblio Keywords - Social Work Biblio Keywords - social-ecological Biblio Keywords - socialization Biblio Keywords - socio-economic development Biblio Keywords - Socioeconomic Factors Biblio Keywords - Sodium Biblio Keywords - Sodium Channel Blockers Biblio Keywords - Sodium Channels Biblio Keywords - Sodium Chloride Biblio Keywords - Sodium Isotopes Biblio Keywords - sodium lidar Biblio Keywords - Sodium Radioisotopes Biblio Keywords - Sodium, Dietary Biblio Keywords - Sodium-Calcium Exchanger Biblio Keywords - Sodium-Hydrogen Antiporter Biblio Keywords - Sodium-Phosphate Cotransporter Proteins, Type I Biblio Keywords - Sodium-Potassium-Exchanging ATPase Biblio Keywords - Soft Tissue Neoplasms Biblio Keywords - Software Biblio Keywords - Soil Biblio Keywords - Soil metagenomics Biblio Keywords - Soil Microbiology Biblio Keywords - Soil Pollutants Biblio Keywords - Solid Phase Extraction Biblio Keywords - Solid Phase Microextraction Biblio Keywords - Solubility Biblio Keywords - Solutions Biblio Keywords - solvation Biblio Keywords - Solvents Biblio Keywords - Somatosensory Cortex Biblio Keywords - Somatostatin Biblio Keywords - Sotalol Biblio Keywords - Sound Biblio Keywords - South Africa Biblio Keywords - South Indian Ocean Biblio Keywords - SOUTH-AFRICA Biblio Keywords - south-eastern Africa Biblio Keywords - southeastern Antilles islands Biblio Keywords - southern Africa Biblio Keywords - Southern Africa Biblio Keywords - SOUTHERN AFRICA Biblio Keywords - SOXB1 Transcription Factors Biblio Keywords - Soybeans Biblio Keywords - Soybeans/*chemistry Biblio Keywords - Space Perception Biblio Keywords - Spain Biblio Keywords - Spatial Behavior Biblio Keywords - spatial correlations Biblio Keywords - Species richness Biblio Keywords - Species Specificity Biblio Keywords - Specific Pathogen-Free Organisms Biblio Keywords - Specimen Handling Biblio Keywords - Spectinomycin Biblio Keywords - Spectrometry, Fluorescence Biblio Keywords - Spectrometry, Mass, Electrospray Ionization Biblio Keywords - Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Biblio Keywords - Spectrophotometry Biblio Keywords - Spectrophotometry, Ultraviolet Biblio Keywords - Spectroscopy, Fourier Transform Infrared Biblio Keywords - Spectrum Analysis, Raman Biblio Keywords - speleothems Biblio Keywords - Sperm Motility Biblio Keywords - Sperm-Ovum Interactions Biblio Keywords - Spermatocidal Agents Biblio Keywords - Spermatogenesis Biblio Keywords - Spermatozoa Biblio Keywords - Spermidine Biblio Keywords - Spermine Biblio Keywords - Sphenophorus cubensis Biblio Keywords - Spheroids, Cellular Biblio Keywords - Spheroids, Cellular/drug effects/metabolism Biblio Keywords - Spheroplasts Biblio Keywords - Spinal Cord Biblio Keywords - Spinal Cord Injuries Biblio Keywords - Spinal Dysraphism Biblio Keywords - Spinal Nerve Roots Biblio Keywords - Spinal Nerves Biblio Keywords - Spindle Apparatus Biblio Keywords - Spine Biblio Keywords - Spiral Ganglion Biblio Keywords - Spiro Compounds Biblio Keywords - Spironolactone Biblio Keywords - Splanchnic Circulation Biblio Keywords - Spleen Biblio Keywords - Spleen/immunology Biblio Keywords - Spliceosomes Biblio Keywords - Spondylarthropathies Biblio Keywords - Spores, Fungal Biblio Keywords - Sporothrix Biblio Keywords - Sporozoites Biblio Keywords - src Homology Domains Biblio Keywords - src-Family Kinases Biblio Keywords - src-Family Kinases/*antagonists & inhibitors/genetics/metabolism Biblio Keywords - src-Family Kinases/*genetics/physiology Biblio Keywords - src-Family Kinases/*metabolism Biblio Keywords - src-Family Kinases/chemistry/*metabolism Biblio Keywords - Sri Lanka Biblio Keywords - Staff Development Biblio Keywords - Staining and Labeling Biblio Keywords - Staphylococcal Infections Biblio Keywords - Staphylococcus aureus Biblio Keywords - Staphylococcus epidermidis Biblio Keywords - STAT Transcription Factors Biblio Keywords - STAT1 Transcription Factor Biblio Keywords - STAT3 Transcription Factor/*metabolism Biblio Keywords - Static Electricity Biblio Keywords - statistical evaluation Biblio Keywords - statistical teleconnections Biblio Keywords - statistics Biblio Keywords - Statistics as Topic Biblio Keywords - Statistics, Nonparametric Biblio Keywords - Staurosporine Biblio Keywords - Stavudine Biblio Keywords - Stem Cell Transplantation Biblio Keywords - Stem Cells Biblio Keywords - Stereoisomerism Biblio Keywords - Stereotyped Behavior Biblio Keywords - Sterilization, Reproductive Biblio Keywords - Steroid Hydroxylases Biblio Keywords - Stifle Biblio Keywords - Stilbenes Biblio Keywords - STIMULATED GAIN SPECTROSCOPY Biblio Keywords - Stimulation, Chemical Biblio Keywords - Stomach Biblio Keywords - stomata Biblio Keywords - stomatal development Biblio Keywords - stomatal patterning Biblio Keywords - Storm environments Biblio Keywords - Street Drugs Biblio Keywords - streetcar Biblio Keywords - Streetcar Biblio Keywords - streetcars Biblio Keywords - Streptavidin Biblio Keywords - Streptococcus pneumoniae Biblio Keywords - Streptomycin Biblio Keywords - Streptozocin Biblio Keywords - Stress Disorders, Post-Traumatic Biblio Keywords - Stress, Mechanical Biblio Keywords - Stress, Physiological Biblio Keywords - Stress, Physiological/drug effects Biblio Keywords - Stress, Psychological Biblio Keywords - Stress, Psychological/*complications Biblio Keywords - Stress, Psychological/*pathology Biblio Keywords - Stress, Psychological/immunology/physiopathology Biblio Keywords - Stroke Biblio Keywords - Stroke, Lacunar Biblio Keywords - Stromal Cells Biblio Keywords - Strontium Biblio Keywords - Structural Homology, Protein Biblio Keywords - Structure-Activity Relationship Biblio Keywords - Students, Medical Biblio Keywords - sub-tropical Africa Biblio Keywords - Subcellular Fractions Biblio Keywords - Substance Abuse Detection Biblio Keywords - Substance Abuse, Intravenous Biblio Keywords - Substance P Biblio Keywords - Substance Withdrawal Syndrome Biblio Keywords - Substance-Related Disorders Biblio Keywords - Substantia Nigra Biblio Keywords - Substrate Specificity Biblio Keywords - Subtraction Technique Biblio Keywords - Subtropical Biblio Keywords - Subtropics Biblio Keywords - Succinates Biblio Keywords - Sucrose Biblio Keywords - Suicide, Attempted Biblio Keywords - Sulbactam Biblio Keywords - Sulfadoxine Biblio Keywords - Sulfatases Biblio Keywords - Sulfates Biblio Keywords - Sulfates/metabolism Biblio Keywords - Sulfhydryl Compounds Biblio Keywords - Sulfhydryl Compounds/metabolism Biblio Keywords - Sulfides/metabolism Biblio Keywords - Sulfites Biblio Keywords - Sulfonamides Biblio Keywords - Sulfones Biblio Keywords - Sulfotransferases Biblio Keywords - Sulfur Dioxide/chemistry Biblio Keywords - Sulfur disproportionation Biblio Keywords - Sulfur Radioisotopes Biblio Keywords - Sulfur/*chemistry Biblio Keywords - Sulpiride Biblio Keywords - summer rainfall Biblio Keywords - SUMO-1 Protein Biblio Keywords - Superior Colliculi Biblio Keywords - Superoxide Dismutase Biblio Keywords - Superoxides Biblio Keywords - Superoxides/metabolism Biblio Keywords - Supervisión Biblio Keywords - Supervisor Biblio Keywords - Suppressor of Cytokine Signaling Proteins Biblio Keywords - Suprachiasmatic Nucleus Biblio Keywords - surface air temperature Biblio Keywords - Surface Plasmon Resonance Biblio Keywords - Surface Properties Biblio Keywords - surface water deficit Biblio Keywords - Surgical Procedures, Operative Biblio Keywords - Survival Analysis Biblio Keywords - Survival Rate Biblio Keywords - Survival Rate/trends Biblio Keywords - Survivors Biblio Keywords - Sus scrofa Biblio Keywords - sustainability Biblio Keywords - Sustainability Biblio Keywords - Sustained release Biblio Keywords - suture retention strength Biblio Keywords - Swaziland Biblio Keywords - Sweetening Agents Biblio Keywords - Swimming Biblio Keywords - Swimming Pools Biblio Keywords - Swine Biblio Keywords - Swine/metabolism Biblio Keywords - Symbiosis Biblio Keywords - Sympathetic Nervous System Biblio Keywords - Synapses Biblio Keywords - Synapsins Biblio Keywords - Synaptic Membranes Biblio Keywords - Synaptic Transmission Biblio Keywords - Synaptic Vesicles Biblio Keywords - Synaptosomes Biblio Keywords - Syndactyly Biblio Keywords - Syndrome Biblio Keywords - Synovial Membrane Biblio Keywords - Synovitis Biblio Keywords - synthesis. Biblio Keywords - Syphilis Biblio Keywords - Systole Biblio Keywords - T-Lymphocyte Subsets Biblio Keywords - T-Lymphocytes Biblio Keywords - T-Lymphocytes, Cytotoxic Biblio Keywords - T-Lymphocytes, Helper-Inducer Biblio Keywords - Tachycardia Biblio Keywords - Tacrolimus Biblio Keywords - Tail Biblio Keywords - Talin Biblio Keywords - Tamoxifen Biblio Keywords - Tampa Biblio Keywords - Tandem Mass Spectrometry Biblio Keywords - Tanzania Biblio Keywords - Taq Polymerase/genetics Biblio Keywords - tau Proteins Biblio Keywords - tautomerism Biblio Keywords - Taxoids Biblio Keywords - Taxoids/administration & dosage Biblio Keywords - Taxoids/pharmacology Biblio Keywords - Teaching Biblio Keywords - Technology Biblio Keywords - Technology Assessment, Biomedical Biblio Keywords - Technology Assessment. Biblio Keywords - Tegmentum Mesencephali Biblio Keywords - Teicoplanin Biblio Keywords - teleconnections Biblio Keywords - Telemetry Biblio Keywords - Telephone Biblio Keywords - Television Biblio Keywords - Temperature Biblio Keywords - Templates, Genetic Biblio Keywords - Tensile Strength Biblio Keywords - Tephritidae Biblio Keywords - Teratocarcinoma Biblio Keywords - Teratogens Biblio Keywords - Terbutaline/agonists Biblio Keywords - Terminology as Topic Biblio Keywords - Testosterone Biblio Keywords - Testosterone Propionate Biblio Keywords - Tetrachlorodibenzodioxin Biblio Keywords - Tetracycline Biblio Keywords - Tetracycline Resistance Biblio Keywords - Tetracyclines Biblio Keywords - Tetradecanoylphorbol Acetate Biblio Keywords - Tetraethylammonium Biblio Keywords - Tetraethylammonium Compounds Biblio Keywords - Tetrahymena Biblio Keywords - Tetranychidae Biblio Keywords - Tetrazoles Biblio Keywords - Tetrodotoxin Biblio Keywords - Th1 Cells Biblio Keywords - Th2 Cells Biblio Keywords - Thalamus Biblio Keywords - Thalidomide Biblio Keywords - Thapsigargin Biblio Keywords - Theophylline Biblio Keywords - therapeutic target Biblio Keywords - therapeutic targeting Biblio Keywords - Therapeutics Biblio Keywords - Thermal spring Biblio Keywords - Thermodynamics Biblio Keywords - Thermosensing Biblio Keywords - thermosphere Biblio Keywords - thermosphere potassium lidar Biblio Keywords - Thermospheric dynamics Biblio Keywords - Thermotoga maritima Biblio Keywords - Theta Rhythm Biblio Keywords - Thiamine Biblio Keywords - Thiazepines Biblio Keywords - Thiazoles/administration & dosage/*pharmacology Biblio Keywords - Thiolester Hydrolases Biblio Keywords - Thionucleotides Biblio Keywords - Thioredoxins Biblio Keywords - Thiosulfates/chemistry Biblio Keywords - Thoracica Biblio Keywords - Thorax Biblio Keywords - THP-1 Cells Biblio Keywords - Thrombin Biblio Keywords - Thrombocytosis/*etiology Biblio Keywords - Thrombomodulin Biblio Keywords - Thrombopoietin/antagonists & inhibitors/blood Biblio Keywords - Thrombosis Biblio Keywords - Thumb Biblio Keywords - Thymidine Biblio Keywords - Thymidine Kinase Biblio Keywords - Thyrotropin Biblio Keywords - Tibia Biblio Keywords - tidal ion layers Biblio Keywords - Time Factors Biblio Keywords - Tin Biblio Keywords - Tinea Pedis Biblio Keywords - Tissue Culture Techniques Biblio Keywords - Tissue Distribution Biblio Keywords - Tissue Engineering Biblio Keywords - Tissue Scaffolds Biblio Keywords - Titanium Biblio Keywords - TNF-Related Apoptosis-Inducing Ligand Biblio Keywords - Tobacco Biblio Keywords - Toes Biblio Keywords - Tolbutamide Biblio Keywords - Toll-Like Receptor 2 Biblio Keywords - Toll-Like Receptor 3 Biblio Keywords - Toll-Like Receptor 4 Biblio Keywords - Toll-Like Receptor 4/antagonists & inhibitors/genetics/*immunology Biblio Keywords - Toll-Like Receptor 7 Biblio Keywords - Toll-Like Receptor 8 Biblio Keywords - Toll-Like Receptor 9 Biblio Keywords - Toll-Like Receptors Biblio Keywords - Tolonium Chloride Biblio Keywords - Tomography Biblio Keywords - Tomography, Optical Coherence Biblio Keywords - Tomography, Spiral Computed Biblio Keywords - Tomography, X-Ray Computed Biblio Keywords - Tongue Biblio Keywords - Tooth Eruption Biblio Keywords - Tooth Exfoliation Biblio Keywords - Tooth, Deciduous Biblio Keywords - Toothpastes Biblio Keywords - Topoisomerase II Inhibitors Biblio Keywords - TOR Serine-Threonine Kinases Biblio Keywords - Torpedo Biblio Keywords - Torture Biblio Keywords - Toxicity Tests Biblio Keywords - Toxins, Biological Biblio Keywords - Trace Elements Biblio Keywords - Trachea Biblio Keywords - Tracheoesophageal Fistula Biblio Keywords - tracking Biblio Keywords - Trade wind convection Biblio Keywords - tranquillity tourism Biblio Keywords - Trans-Activators Biblio Keywords - trans-Golgi Network Biblio Keywords - Transcranial Magnetic Stimulation Biblio Keywords - Transcription Factor AP-1 Biblio Keywords - Transcription Factor AP-2 Biblio Keywords - Transcription Factor RelA Biblio Keywords - Transcription Factor RelB Biblio Keywords - Transcription Factors Biblio Keywords - Transcription Factors, TFII Biblio Keywords - Transcription Factors/genetics/*immunology Biblio Keywords - Transcription, Genetic Biblio Keywords - Transcription, Genetic/*drug effects Biblio Keywords - Transcriptional Activation Biblio Keywords - Transcriptome Biblio Keywords - Transducers Biblio Keywords - Transduction, Genetic Biblio Keywords - Transfection Biblio Keywords - Transformation, Genetic Biblio Keywords - Transforming Growth Factor alpha Biblio Keywords - Transforming Growth Factor beta Biblio Keywords - Transforming Growth Factor beta1 Biblio Keywords - Transgenes Biblio Keywords - Transglutaminases Biblio Keywords - Transient Receptor Potential Channels Biblio Keywords - transit Biblio Keywords - Transition Temperature Biblio Keywords - Translational Medical Research Biblio Keywords - Translocation, Genetic Biblio Keywords - Transplantation Conditioning Biblio Keywords - Transplantation, Heterologous Biblio Keywords - Transplantation, Heterologous/pathology Biblio Keywords - Transplantation, Homologous Biblio Keywords - Trauma Severity Indices Biblio Keywords - Travel Biblio Keywords - Treatment Outcome Biblio Keywords - Trematoda Biblio Keywords - Treponema Biblio Keywords - Tretinoin Biblio Keywords - Triage Biblio Keywords - Triazoles Biblio Keywords - Trichechus manatus Biblio Keywords - Triclosan Biblio Keywords - Trihalomethanes Biblio Keywords - Trimethadione Biblio Keywords - Trimethylsilyl Compounds Biblio Keywords - Trinuclear complexes Biblio Keywords - Trisomy Biblio Keywords - Tritium Biblio Keywords - tropical Atlantic Biblio Keywords - Tropical Climate Biblio Keywords - Tropical cyclones Biblio Keywords - tropical cyclones Biblio Keywords - tropical maritime Biblio Keywords - tropical maritime climate Biblio Keywords - TROPICAL TEMPERATE TROUGHS Biblio Keywords - Troponin T Biblio Keywords - Trout Biblio Keywords - Trypsin Biblio Keywords - Tryptophan Biblio Keywords - Tuberculosis Biblio Keywords - Tuberculosis, Pulmonary Biblio Keywords - Tubocurarine Biblio Keywords - Tumor Burden Biblio Keywords - Tumor Burden/drug effects Biblio Keywords - Tumor Cells, Cultured Biblio Keywords - Tumor Markers, Biological Biblio Keywords - Tumor Microenvironment Biblio Keywords - Tumor Microenvironment/physiology Biblio Keywords - Tumor Necrosis Factor-alpha Biblio Keywords - Tumor Necrosis Factor-alpha/genetics/immunology Biblio Keywords - Tumor Suppressor Protein p53 Biblio Keywords - Tumor Suppressor Proteins Biblio Keywords - Tuna Biblio Keywords - Tunica Intima Biblio Keywords - Tunica Media Biblio Keywords - Twist Transcription Factor Biblio Keywords - Two-Hybrid System Techniques Biblio Keywords - Typhimurium Biblio Keywords - Tyrosine Biblio Keywords - Tyrosine 3-Monooxygenase Biblio Keywords - Tyrosine/metabolism Biblio Keywords - Ubiquitin Biblio Keywords - Ubiquitin-Conjugating Enzymes Biblio Keywords - Ubiquitin-Protein Ligases Biblio Keywords - Ultra-pH sensitive micelles Biblio Keywords - Ultrafiltration Biblio Keywords - Ultrasonics Biblio Keywords - ultrastructure Biblio Keywords - Ultraviolet Rays Biblio Keywords - Umbilical Veins Biblio Keywords - Unconsciousness Biblio Keywords - Uncontrolled asthma Biblio Keywords - Uncoupling Agents Biblio Keywords - United Arab Emirates Biblio Keywords - United States Biblio Keywords - United States Food and Drug Administration Biblio Keywords - United States/epidemiology Biblio Keywords - Unrelated Donors Biblio Keywords - Up-Regulation Biblio Keywords - urban dynamics Biblio Keywords - Urban Health Services Biblio Keywords - Urban heat island Biblio Keywords - urban impacts Biblio Keywords - urban planning Biblio Keywords - Urban planning Biblio Keywords - Urban Population Biblio Keywords - Urea Biblio Keywords - Ureaplasma Biblio Keywords - Ureaplasma Infections Biblio Keywords - Ureaplasma urealyticum Biblio Keywords - Urethane Biblio Keywords - Urethritis Biblio Keywords - Uridine Triphosphate Biblio Keywords - Urinary Bladder Biblio Keywords - Urinary Bladder Diseases Biblio Keywords - Urinary Bladder Neck Obstruction Biblio Keywords - Urine Biblio Keywords - Urogenital Abnormalities Biblio Keywords - Urothelium Biblio Keywords - Uterine Cervical Dysplasia Biblio Keywords - Uterine Cervical Neoplasms Biblio Keywords - Uterine Cervical Neoplasms/*epidemiology Biblio Keywords - Uterine Cervicitis Biblio Keywords - Vaal River Biblio Keywords - Vaccination Biblio Keywords - vaccines Biblio Keywords - Vaccines Biblio Keywords - Vaccines, Attenuated Biblio Keywords - Vaccines, DNA Biblio Keywords - Vaccinia virus Biblio Keywords - Vacuolar Proton-Translocating ATPases Biblio Keywords - Vacuoles Biblio Keywords - Vagina Biblio Keywords - Vaginal Creams, Foams, and Jellies Biblio Keywords - Vaginal Smears Biblio Keywords - Valerian Biblio Keywords - Valine Biblio Keywords - Valproic Acid Biblio Keywords - Vanadates Biblio Keywords - Vancomycin Resistance Biblio Keywords - Vanilmandelic Acid Biblio Keywords - Varicose Ulcer Biblio Keywords - Vas Deferens Biblio Keywords - Vascular Cell Adhesion Molecule-1 Biblio Keywords - Vascular Endothelial Growth Factor A Biblio Keywords - Vascular Endothelial Growth Factor A/*antagonists & Biblio Keywords - Vascular Endothelial Growth Factor A/antagonists & inhibitors Biblio Keywords - Vascular Endothelial Growth Factor A/antagonists & inhibitors/metabolism Biblio Keywords - Vascular Endothelial Growth Factor A/genetics/metabolism Biblio Keywords - Vascular Endothelial Growth Factor A/physiology Biblio Keywords - Vascular Endothelial Growth Factor Receptor-2/analysis/antagonists & Biblio Keywords - Vascular Resistance Biblio Keywords - Vasoconstriction Biblio Keywords - Vasoconstrictor Agents Biblio Keywords - Vasoconstrictor Agents/pharmacology Biblio Keywords - Vasodilation Biblio Keywords - Vasodilator Agents Biblio Keywords - Vasopressins Biblio Keywords - Vault Ribonucleoprotein Particles Biblio Keywords - Venezuela Biblio Keywords - Ventral Tegmental Area Biblio Keywords - Ventricular Function Biblio Keywords - Ventricular Function, Left Biblio Keywords - Ventricular Remodeling Biblio Keywords - Veratridine Biblio Keywords - Verdigris Biblio Keywords - Vero Cells Biblio Keywords - Versicans Biblio Keywords - Vertebrates Biblio Keywords - vertical transmission Biblio Keywords - Vesicular Transport Proteins Biblio Keywords - Veterans Biblio Keywords - Vibrio Biblio Keywords - Vibrio Infections Biblio Keywords - Vibrissae Biblio Keywords - Vidarabine Biblio Keywords - Video Recording Biblio Keywords - Videotape Recording Biblio Keywords - Vinca Biblio Keywords - Vinculin Biblio Keywords - Violence Biblio Keywords - Viral Biblio Keywords - Viral Core Proteins Biblio Keywords - Viral Envelope Proteins Biblio Keywords - Viral Interference Biblio Keywords - Viral Load Biblio Keywords - Viral Nonstructural Proteins Biblio Keywords - Viral Plaque Assay Biblio Keywords - Viral Proteins Biblio Keywords - viral proteins Biblio Keywords - Viral Vaccines Biblio Keywords - Viremia Biblio Keywords - Virion Biblio Keywords - Virology Biblio Keywords - virulence Biblio Keywords - Virulence Biblio Keywords - Virulence Factors Biblio Keywords - Virulence Factors, Bordetella Biblio Keywords - Virulence Factors: genetics Biblio Keywords - Virulence: genetics Biblio Keywords - Virus Activation Biblio Keywords - Virus Assembly Biblio Keywords - Virus Diseases Biblio Keywords - Virus Inactivation Biblio Keywords - Virus Integration Biblio Keywords - Virus Internalization Biblio Keywords - Virus Latency Biblio Keywords - Virus Replication Biblio Keywords - Viruses Biblio Keywords - Viscosity Biblio Keywords - Vision Disorders Biblio Keywords - Visual Acuity Biblio Keywords - Visual Pathways Biblio Keywords - Vitamin A Biblio Keywords - Vitamin B 12 Biblio Keywords - Vitamin B 12 Deficiency Biblio Keywords - Vitamin D Biblio Keywords - Vitamin E Biblio Keywords - Vitamin K Epoxide Reductases Biblio Keywords - Vitamins Biblio Keywords - Vitis Biblio Keywords - Volatile sulfur substances Biblio Keywords - von Willebrand Factor Biblio Keywords - Voriconazole Biblio Keywords - vpr Gene Products, Human Immunodeficiency Virus Biblio Keywords - Vulnerable Populations Biblio Keywords - Walking Biblio Keywords - Warfarin Biblio Keywords - Warming trend Biblio Keywords - Washington Biblio Keywords - Waste Disposal, Fluid Biblio Keywords - Waste Water Biblio Keywords - Water Biblio Keywords - Water Deprivation Biblio Keywords - Water Microbiology Biblio Keywords - Water Pollutants Biblio Keywords - Water Pollutants, Chemical Biblio Keywords - Water Pollution Biblio Keywords - Water Purification Biblio Keywords - Water Quality Biblio Keywords - water supplies Biblio Keywords - Water Supply Biblio Keywords - Water-Electrolyte Balance Biblio Keywords - wave-2 Biblio Keywords - Waves Biblio Keywords - Weaning Biblio Keywords - Weather Biblio Keywords - weather patterns Biblio Keywords - Wechsler Scales Biblio Keywords - Weight Loss Biblio Keywords - West Indies Biblio Keywords - West Nile Fever Biblio Keywords - West Nile virus Biblio Keywords - WET AND DRY SPELLS Biblio Keywords - wet spells Biblio Keywords - wetlands Biblio Keywords - Whole-Body Irradiation Biblio Keywords - Williams Syndrome Biblio Keywords - Wilms Tumor Biblio Keywords - Wind Biblio Keywords - Wnt Proteins Biblio Keywords - Wnt Signaling Pathway Biblio Keywords - Wolf-Hirschhorn Syndrome Biblio Keywords - Women's Health Biblio Keywords - Workplace Biblio Keywords - Wound Healing Biblio Keywords - Writing Biblio Keywords - X Chromosome Biblio Keywords - X-Ray Microtomography Biblio Keywords - X-ray structures Biblio Keywords - Xanthine Oxidase Biblio Keywords - Xanthomonas Biblio Keywords - Xenograft Model Antitumor Assays Biblio Keywords - Xenopus Biblio Keywords - Xenopus laevis Biblio Keywords - Xenopus Proteins Biblio Keywords - Xeroderma Pigmentosum Group D Protein Biblio Keywords - Xylella Biblio Keywords - Yeasts Biblio Keywords - Yohimbine Biblio Keywords - Young Adult Biblio Keywords - Yttrium Radioisotopes Biblio Keywords - Zambezi Valley Africa Biblio Keywords - Zebrafish Biblio Keywords - Zidovudine Biblio Keywords - ZIMBABWE Biblio Keywords - Zinc Biblio Keywords - Zinc Compounds Biblio Keywords - Zinc Fingers Biblio Keywords - Zinc Oxide Biblio Keywords - Zinc/metabolism/*pharmacology Biblio Keywords - Zinc/pharmacokinetics/*pharmacology Biblio Keywords - Zirconium Biblio Keywords - Zirconium phosphate Biblio Keywords - Zonula Occludens-1 Protein Year any Submitted 2023 2022 2021 2020 2019 2018 2017 2016 2015 2014 2013 2012 2011 2010 2009 2008 2007 2006 2005 2004 2003 2002 2001 2000 1999 1998 1997 1996 1995 1994 1993 1992 1991 1990 1989 1988 1987 1986 1985 1984 1983 1982 1981 1980 1979 1978 1977 1976 1975 1974 1973 1972 1970 1969 1967 1966 1965 1964 1959 1958 0 Keyword any "ICI 182,780" *Anoikis *Antigens, Bacterial/chemistry/genetics/metabolism *Bacillus anthracis/chemistry/metabolism *Bacterial Toxins/chemistry/genetics/metabolism *Bacteriophage T7 *cd38 *Cell Proliferation *covid-19 *COVID-19/genetics/immunology *cytokines *Dietary Supplements *Disease Models, Animal *Ecology *Efficiency *Environmental Microbiology *Epitopes/genetics/immunology *Fasciola hepatica *fatty acid binding protein *fostamatinib *Gastric Mucosa/metabolism *Gene Expression Regulation, Neoplastic *Gene Silencing *Health Status Disparities *Healthcare Disparities *Immunity, Humoral *immunothrombosis *Infectious Disease Transmission, Vertical *macrophages *Mutation *Neovascularization, Pathologic *neutrophil extracellular traps *Paraneoplastic Syndromes *Peptide Library *Pregnancy Complications, Infectious *RNA Interference *SARS-CoV-2/genetics/immunology *septic shock *Soil Microbiology *Spike Glycoprotein, Coronavirus/genetics/immunology *Stomach/chemistry *Stress, Psychological *Xenograft Model Antitumor Assays *Zika Virus *Zika Virus Infection 0300 ATMOSPHERIC COMPOSITION AND STRUCTURE 0310 Airglow and aurora 0328 Exosphere 0335 Ion chemistry of the atmosphere (2419 0340 Middle atmosphere: composition and chemistry 0342) 0350 Pressure 0355 ATMOSPHERIC COMPOSITION AND STRUCTURE Thermosphere: composition and chemistry 0355 Thermosphere: composition and chemistry 0394 Instruments and techniques 0640:Sustainability 0729:Architecture 0999:Urban planning 1-Methyl-3-isobutylxanthine 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine 1-Methyl-4-phenylpyridinium 2,4-Dinitrophenol 2-Amino-5-phosphonovalerate 2-Aminopurine 2-Hydroxypropyl-beta-cyclodextrin 2419 Ion chemistry and composition (0335) 2427 Ionosphere/atmosphere interactions (0335) 2427) 3' Untranslated Regions 3',5'-Cyclic-AMP Phosphodiesterases 3',5'-Cyclic-GMP Phosphodiesterases 3,4-Dihydroxyphenylacetic Acid 3-Hydroxyanthranilate 3,4-Dioxygenase 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester 3300 ATMOSPHERIC PROCESSES 3319 General circulation (1223) 3332 Mesospheric dynamics 3334 Middle atmosphere dynamics (0341 3337 Global climate models (1626 3360 Remote sensing 3364 Synoptic-scale meteorology 3384 Acoustic-gravity waves 3389 Tides and planetary waves 3394 Instruments and techniques 3D remote sensing 3T3 Cells 4-Aminobutyrate Transaminase 4928) 5' Untranslated Regions 6-Cyano-7-nitroquinoxaline-2,3-dione 6-Phytase 6-Phytase/*metabolism 6-Phytase/*pharmacology <!– Tag Not Handled –><keyword id="kw0130">Undisturbed soil columns á A Kinase Anchor Proteins Abnormalities, Drug-Induced Abnormalities, Multiple Abortion, Criminal Abortion, Induced Absorptiometry, Photon Absorption Academic Medical Centers Academies and Institutes Acculturation Acetazolamide Acetonitriles Acetylation Acetylcholine Achievement Acid Phosphatase Aconitine Acoustic niche hypothesis Acoustic Stimulation Acoustic-gravity waves Acquired Immunodeficiency Syndrome Acridine Orange Acrocephalosyndactylia Actin Cytoskeleton Actinobacteria Actins Actins/metabolism Action Potentials Activating Transcription Factor 1 Active Transport, Cell Nucleus Acute Disease Acute Kidney Injury Acyclovir Acyl Carrier Protein Acylation Acyltransferases ADAM Proteins Adaptation, Physiological Adaptation, Psychological Adaptive Immunity Adaptor Protein Complex alpha Subunits Adaptor Proteins, Signal Transducing Adaptor Proteins, Signal Transducing/genetics/*immunology Adaptor Proteins, Vesicular Transport Adenocarcinoma Adenocarcinoma, Mucinous/*drug therapy/genetics/pathology Adenocarcinoma/*epidemiology Adenocarcinoma/epidemiology/mortality/pathology Adenosine Deaminase Adenosine Diphosphate Adenosine Triphosphatases Adenosine Triphosphatases/genetics/*metabolism Adenosine Triphosphatases/genetics/*physiology Adenosine Triphosphate Adenoviridae Adenylate Cyclase Adiponectin Adipose Tissue Adiposity Adjuvants, Immunologic Administration, Inhalation Administration, Oral Administration, Rectal Administration, Sublingual Administration, Topical Adolescent Adolescent Behavior Adolescent Health Services Adoptive Transfer ADP-ribosyl Cyclase 1/analysis Adrenal Glands Adrenal Medulla Adrenergic Agents Adrenergic Agents/*metabolism Adrenergic alpha-2 Receptor Agonists Adrenergic alpha-2 Receptor Antagonists Adrenergic alpha-Antagonists Adrenergic beta-2 Receptor Antagonists Adrenergic beta-Agonists Adrenergic beta-Antagonists Adrenergic beta-Antagonists/pharmacology Adrenergic beta-Antagonists/pharmacology/therapeutic use Adrenergic Uptake Inhibitors Adrenocorticotropic Hormone Adrenomedullin Adsorption Adult Adult asthma patients Aedes Aerosols Affect Afferent Pathways Africa Africa South of the Sahara Africa, Western African Americans African climate African Continental Ancestry Group African Continental Ancestry Group/statistics & numerical data African development African flood events African monsoon Age Distribution Age Factors Age of Onset Aged Aged, 80 and over Aggression Aging Agnosia Agrobacterium tumefaciens AIDS Dementia Complex AIDS Vaccines AIDS-Related Opportunistic Infections Air air chemistry Air Pollutants Air Pollution air pressure Air-sea interaction Alanine Albinism, Oculocutaneous Albumins Alcohol Drinking Alcoholics Alcoholism Aldehyde Dehydrogenase Aldehydes Aldosterone Algorithms Alien plants Alkaloids Alkalosis Alkanes Alkylating Agents Alkylation Alkynes Alleles Allergens Allosteric Regulation Allosteric Site Allyl Compounds Allylglycine alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid alpha-enolase alpha-Fetoproteins alpha-Tocopherol alpha7 Nicotinic Acetylcholine Receptor Alphapapillomavirus Alternative Splicing Altitude Alzheimer Disease Amber Ambulatory Care Americas Amides Amikacin Amiloride Amines Amino Acid Chloromethyl Ketones Amino Acid Metabolism, Inborn Errors Amino Acid Motifs Amino Acid Oxidoreductases Amino Acid Sequence Amino Acid Substitution Amino Acid Transport Systems Amino Acid Transport Systems, Neutral Amino Acids Aminobutyrates Aminoglycosides Aminoisobutyric Acids Aminolevulinic Acid Aminoquinolines Amniotic Band Syndrome Amoxicillin Amphetamine Ampicillin Amplified Fragment Length Polymorphism Analysis Amplifiers, Electronic Amygdala Amyloid Amyloid beta-Protein Precursor Amyloid Precursor Protein Secretases Amyloidogenic Proteins Anabolic Agents Analgesics Analgesics, Opioid analysis Analysis of Variance Anaphase and temperature Androstadienes Androstane-3,17-diol Anemia, Aplastic Anemia, Diamond-Blackfan Anemia, Macrocytic Anemia/*etiology Anencephaly Anesthesia Anesthesia, General Anesthesia, Inhalation Anesthesia, Intravenous Anesthesiology Anesthetics Anesthetics, Inhalation Anesthetics, Intravenous Anesthetics, Local Aneuploidy Angiogenesis Inducing Agents Angiogenesis Inhibitors Angiogenesis Inhibitors/*pharmacology Angiogenesis Inhibitors/*therapeutic use Angiogenesis Inhibitors/therapeutic use Angiotensin I Angiotensin II Angiotensin II Type 1 Receptor Blockers Angiotensin Receptor Antagonists Angiotensin-Converting Enzyme Inhibitors Angiotensinogen Angiotensins Angola-Namibia river flows Aniline Compounds animal Animal Communication animal epidemiology Animal Husbandry animal microbiology Animal: microbiology Animals Animals, Congenic Animals, Genetically Modified Animals, Newborn Animals, Suckling Anions Anisomycin Annona annual cycle Anoikis Anopheles Anterior Cruciate Ligament Anterior Horn Cells Anthozoa Anti-Anxiety Agents Anti-Arrhythmia Agents Anti-Bacterial Agents Anti-DFS Anti-HIV Agents Anti-Infective Agents Anti-Infective Agents, Local Anti-Inflammatory Agents Anti-Inflammatory Agents, Non-Steroidal Anti-Inflammatory Agents, Non-Steroidal/chemistry/metabolism/*pharmacology Anti-Retroviral Agents Anti-Ulcer Agents Antibiosis Antibiotics, Antineoplastic Antibodies Antibodies, Anti-Idiotypic Antibodies, Anticardiolipin Antibodies, Antinuclear/blood/*immunology Antibodies, Blocking Antibodies, Helminth Antibodies, Heterophile Antibodies, Monoclonal Antibodies, Monoclonal, Humanized Antibodies, Monoclonal, Murine-Derived Antibodies, Monoclonal/administration & dosage Antibodies, Monoclonal/pharmacology/therapeutic use Antibodies, Monoclonal/therapeutic use Antibodies, Neoplasm Antibodies, Neutralizing Antibodies, Neutralizing/pharmacology Antibodies, Protozoan/*immunology Antibodies, Viral Antibody Affinity Antibody Formation Antibody Specificity Antibody Specificity/*immunology Anticancer agents Anticoagulants Anticonvulsants Anticonvulsants/pharmacology Antidepressive Agents Antidepressive Agents, Second-Generation Antiemetics Antifungal Agents Antigen delivery Antigen Presentation Antigen-Antibody Complex Antigen-Presenting Cells Antigens Antigens, CD Antigens, CD11c Antigens, CD14 Antigens, CD19 Antigens, CD274 Antigens, CD3 Antigens, CD31/biosynthesis Antigens, CD31/metabolism Antigens, CD34 Antigens, CD4 Antigens, CD40 Antigens, CD44 Antigens, CD56 Antigens, CD80 Antigens, CD86 Antigens, CD95 Antigens, Differentiation Antigens, Differentiation, T-Lymphocyte Antigens, Fungal Antigens, Helminth Antigens, Neoplasm Antigens, Surface Antigens, Viral Antihypertensive Agents Antilles climate Antilymphocyte Serum Antimalarials Antimetabolites Antimetabolites, Antineoplastic Antimicrobial Cationic Peptides Antineoplastic Agents Antineoplastic Agents, Alkylating Antineoplastic Agents, Phytogenic Antineoplastic Agents/*pharmacology Antineoplastic Agents/metabolism/pharmacology Antineoplastic Agents/pharmacokinetics/pharmacology Antineoplastic Agents/pharmacology Antineoplastic Agents/therapeutic use Antineoplastic Combined Chemotherapy Protocols Antineoplastic Combined Chemotherapy Protocols/*pharmacology Antineoplastic Combined Chemotherapy Protocols/*therapeutic use Antineoplastic Combined Chemotherapy Protocols/therapeutic use Antinuclear autoantibodies Antioxidants Antiretroviral Therapy, Highly Active Antirheumatic Agents Antithrombins Antiviral Agents Anura Anus Neoplasms/*epidemiology/*mortality/pathology Anus Neoplasms/*epidemiology/ethnology/mortality Anus, Imperforate Anxiety Anxiety Disorders Aorta Aorta, Thoracic Apamin Aplysia Apolipoprotein A-I Apoproteins Apoptosis Apoptosis Regulatory Proteins Apoptosis Regulatory Proteins/analysis Apoptosis/*genetics Apoptosis/drug effects Appetite Appetitive Behavior aprendizaje aprendizaje contextual Aptamers, Nucleotide Aptamers, Nucleotide/*therapeutic use Arabinan Arachidonic Acid Arachidonic Acids Archaea Architecture Area Under Curve Arecbio Observatory Arecibo observatory Argentina Arginine Arginine Vasopressin Arizona Arousal Arousal/physiology Arrestins Arrhythmias, Cardiac Arsenic Arsenicals Arsenites Artemisinins Arterial Pressure Arteries Arthritis, Rheumatoid Arthropod Antennae Arthropods Artifacts Aryl Hydrocarbon Hydroxylases Arylformamidase Ascaris Ascitic Fluid Ascomycota Ascorbic Acid Asia Asian Americans Asparagine Aspartate Aminotransferases aspergillosis Assessment Association Learning Astacoidea Asthenopia Asthma Asthma/*therapy Astrocytes Astrocytoma Astrophysics - Astrophysics of Galaxies Astrophysics - High Energy Astrophysical Phenomena Astrophysics - Solar and Stellar Astrophysics Ataxia Telangiectasia Mutated Proteins Atherosclerosis Athletes Atlantic multidecadal oscillation Atlantic storms Atmosphere-land interaction Atmosphere-ocean interaction atmospheric atmospheric structure atmospheric variability Atmospheric waves Atovaquone ATP-Binding Cassette Transporters ATP-Binding Cassette Transporters/genetics/*physiology Atrial Natriuretic Factor Atrioventricular Node Atropine Attention Attention Deficit Disorder with Hyperactivity attitude Attitude of Health Personnel Attitude to Health Auditory Cortex Auditory Pathways Auditory Perception Aurora Kinases Autistic Disorder autoantibodies Autoantigens Autoimmune diabetes Autoimmune Diseases Autoimmune Type 1 diabetes mellitus Autoimmunity Automation Autonomic Nerve Block Autonomic Nervous System Autophagy Autophagy/*genetics Autopsy Autoradiography Aviation Education Aviation Mechanics Avoidance Learning Axonal Transport Axons Axotomy Azathioprine Azides Azocines B-Lymphocytes Bacillus subtilis Back Pain Baclofen Bacteremia Bacteria Bacteria/*metabolism Bacterial Bacterial Adhesion Bacterial Capsules bacterial genetics Bacterial Infections Bacterial Outer Membrane Proteins Bacterial Outer Membrane Proteins/chemistry/*genetics/*metabolism Bacterial Proteins Bacterial Proteins: genetics Bacterial Translocation bacterial typing techniques bacterial typing techniques veterinary Bacterial: chemistry Bacterial: genetics Bacteriophages Bacteroides Bardet-Biedl Syndrome Barium Compounds baroclinic tides Basal Ganglia Base Composition Base Sequence Basic Helix-Loop-Helix Leucine Zipper Transcription Factors Basic Helix-Loop-Helix Transcription Factors Basic-Leucine Zipper Transcription Factors Basidiomycota Bathing Beaches Batrachotoxins bcl-2-Associated X Protein bcl-2-Associated X Protein/genetics/metabolism bcl-X Protein bcl-X Protein/genetics/metabolism Beach erosion beach use Beckwith-Wiedemann Syndrome Beetles Behavior Behavior Therapy Behavior, Addictive Behavior, Animal Behavior, Animal/physiology Behavior, Animal: drug effects Behavior, Animal: physiology Behavioral Research Behavioral sensitization Benguela Benguela fish catch Benzazepines/pharmacology Benzeneacetamides Benzenesulfonates Benzocaine Benzodiazepines Benzofurans Benzopyrans Benzoquinones Bereavement beta Catenin beta-Cyclodextrins beta-Endorphin beta-Galactosidase beta-Lactam Resistance beta-Lactamases Bicarbonates Bicuspid Bicyclo Compounds, Heterocyclic Bimetallic molecules Binding Sites Binding Sites, Antibody Binding, Competitive Binge-Eating Disorder bioacoustics Biocatalysis Biochemistry Biocompatible Materials Biodegradable material Biodegradation, Environmental Biodeterioration Biodiversity biodiversity and governance biodiversity assessment biodiversity; green infrastructure; residential yards; social-ecological systems; socioeconomic; sustainability; tropical; urban Biofilms Biofouling Biofuels Biogenic Monoamines Biogeography Biological Assay Biological Availability Biological Clocks Biological Evolution biological invasions Biological Markers Biological Products Biological Sciences Biological Transport Biological Transport, Active Biomass Biomechanical Phenomena Biomedical and Life Sciences Biomedical Research biophony Biophysical Phenomena Biopolymers Bioprospect Biopsy Biopsy, Fine-Needle Biopsy, Needle Bioreactors Biosensing Techniques Biotechnology biotic change Biotic homogenization Biotin Biotinylation Biotransformation Biphenyl Compounds Bipolar Disorder Bird Diseases Birds Birth Rate Birth Weight Bisbenzimidazole Bivalvia Bleeding Time Bleomycin Blood Blood Cell Count Blood Cells Blood Chemical Analysis Blood Coagulation Blood Flow Velocity Blood Glucose Blood Platelets/immunology Blood Pressure Blood Volume Blood-Brain Barrier Blotting, Northern Blotting, Southern Blotting, Western Body Burden Body Fat Distribution Body Mass Index Body Size Body Water Body Weight Body Weights and Measures Bombyx Bone and Bones Bone Development Bone Marrow Bone Marrow Cells Bone Marrow Diseases Bone Marrow Transplantation Bone Neoplasms Bone Neoplasms/prevention & control/*secondary Bone Regeneration Bone Substitutes Bone Transplantation Borates Boron Compounds botanical and zoological species Boundary currents Boundary layer boundary-layer fluxes Bradykinin Brain Brain Chemistry Brain Chemistry/drug effects/*genetics Brain Injuries Brain Mapping Brain Neoplasms Brain Stem Brain-Derived Neurotrophic Factor Brain/cytology/*metabolism Brain/drug effects/*metabolism Brain: drug effects Brain: metabolism Branchial Region Brazil BRCA1 Protein BRCA2 Protein Breast Breast Neoplasms Breeding Bridged Compounds Bromeliads Bromides Bromodeoxyuridine Bronchi Bronchoscopy Bryostatins Bucladesine Budgets Bufo marinus Bumetanide Bungarotoxins Bunyaviridae Bupivacaine Bursera simaruba Busulfan Butadienes Butterflies Butyrates CA1 Region, Hippocampal cabinet distribution unit Cactaceae/*microbiology Cadaverine Cadherins Cadherins/metabolism Cadmium Cadmium sulfide Caenorhabditis elegans Caenorhabditis elegans Proteins Caesalpinia Caffeine Caicos Island wind wake Calbindins Calcification, Physiologic Calcimimetic Agents Calcineurin Calcinosis Calcitriol Calcium Calcium Carbonate Calcium Channel Agonists Calcium Channel Blockers Calcium Channels Calcium Channels, L-Type Calcium Ionophores Calcium Isotopes Calcium Radioisotopes Calcium Signaling Calcium Sulfate Calcium-Binding Proteins Calcium-Calmodulin-Dependent Protein Kinase Type 2 Calcium-Calmodulin-Dependent Protein Kinases Calibration California Calmodulin Calmodulin-Binding Proteins Calorimetry Calorimetry, Differential Scanning Canada Cancer cancer biomarker Cancer Patients cancer stem cells Cancer vaccine Cancer Vaccines Candida albicans Candy Cannabis Cape Frio Cape Town Captopril Carbachol Carbamazepine Carbamazepine/pharmacology Carbazoles Carbohydrate Metabolism Carbohydrate Sequence Carbon Carbon Cycle Carbon Dioxide Carbon Isotopes Carbon Monoxide Carbon-Oxygen Lyases Carbon-Sulfur Lyases Carbonic Acid Carbonic Anhydrase Inhibitors Carbonic Anhydrases Carboxypeptidase H Carboxypeptidases Carcinogenesis Carcinogenicity Tests Carcinoid Tumor Carcinoma Carcinoma, Basal Cell Carcinoma, Ductal, Breast Carcinoma, Hepatocellular Carcinoma, Non-Small-Cell Lung Carcinoma, Pancreatic Ductal Carcinoma, Squamous Cell Carcinoma, Squamous Cell/*epidemiology Carcinoma, Squamous Cell/epidemiology/mortality/pathology Carcinoma/*blood supply/pathology/*physiopathology/radiography Carcinoma/*drug therapy/pathology Carcinoma/chemistry/*genetics Carcinoma/drug therapy/genetics/metabolism Carcinoma/metabolism/*pathology/*surgery Cardiac Catheterization Cardiac Complexes, Premature Cardiac Output, Low Cardiomegaly Cardiomyopathies Cardiomyopathy, Dilated Cardiotonic Agents Cardiovascular Abnormalities Cardiovascular Disease Cardiovascular Diseases Cardiovascular fluid dynamics Cardiovascular risks Career Choice Career Mobility Caribbean Caribbean Antilles Caribbean island Caribbean Region Cariostatic Agents Carotid Arteries Carotid Intima-Media Thickness Carrier Proteins Cartilage Cartilage Oligomeric Matrix Protein Cartilage, Articular Case Management Case-Control Studies Caspase 3 Caspase 7 Caspase 8 Caspases Caspases/metabolism Catalase Catalysis Catechin Catechin/pharmacology/*therapeutic use Catecholamines Catecholamines/pharmacology/physiology Catenins Catenins/genetics/metabolism caterpillar-butterfly irruption Cathepsin B Catheterization Catheterization, Swan-Ganz Catheters, Indwelling Cathode material Cation Transport Proteins Cation Transport Proteins/genetics/*metabolism Cations Cations, Divalent Cats Cattle cattle diseases cattle diseases epidemiology cattle diseases microbiology Cattle Diseases: microbiology Causality Cause of Death Caveolin 1 Caveolin 2 Caveolins Caves CCAAT-Enhancer-Binding Protein-beta CCAAT-Enhancer-Binding Proteins CCN Intercellular Signaling Proteins CD4 Lymphocyte Count CD4-CD8 Ratio CD4-Positive T-Lymphocytes CD40 Ligand CD47 Antigen/metabolism CD8-Positive T-Lymphocytes CDC28 Protein Kinase, S cerevisiae cdc42 GTP-Binding Protein cdc42 GTP-Binding Protein, Saccharomyces cerevisiae Cebus Cefotaxime Ceftriaxone Cell Adhesion Cell Adhesion Molecules Cell Adhesion/drug effects Cell Aging Cell Biology Cell Communication Cell Compartmentation Cell Count Cell Culture Techniques Cell Cycle Cell Cycle Proteins Cell Cycle/drug effects Cell Cycle/genetics Cell Death Cell Degranulation Cell Differentiation Cell Division Cell Extracts Cell Fractionation Cell Fusion Cell Growth Processes Cell Hypoxia Cell Line Cell Line, Transformed Cell Line, Tumor Cell Line, Tumor/drug effects Cell Lineage Cell Membrane Cell Membrane Permeability Cell Membrane/chemistry/metabolism Cell Membrane/metabolism Cell Movement Cell Movement/*drug effects Cell Movement/drug effects Cell Nucleus Cell Nucleus Structures Cell Physiological Phenomena Cell Polarity Cell Proliferation Cell Proliferation/drug effects Cell Separation Cell Size Cell Survival Cell Survival/drug effects Cell Tracking Cell Transformation, Neoplastic Cell Wall Cell-free expression system Cell-Free System Cells, Cultured Centers for Disease Control and Prevention (U.S.) Central Nervous System Central Nervous System Agents Central Nervous System Stimulants Central obesity Centrifugation Centrifugation, Density Gradient Centrosome Cercopithecus aethiops Cerebral Angiography Cerebral Arteries Cerebral Cortex Cerebral Hemorrhage Cerebrospinal Fluid Cerebrovascular Circulation Cerebrovascular Disorders Cervix Uteri Characterization Checklist Chelating Agents Chemical Fractionation Chemical kinetic and photochemical properties Chemistry, Pharmaceutical Chemistry, Physical Chemistry: Physical Chemokine CCL2 Chemokine CCL4 Chemokine CX3CL1 Chemokine CXCL12 Chemokines Chemokines, CC Chemoreceptor Cells chemoresistance Chemotaxis Chemotaxis, Leukocyte Chi-Square Distribution Chick Embryo Chickenpox Vaccine Chickens Child Child Abuse Child Behavior Child Day Care Centers Child Development Child Health Services Child Welfare Child, Preschool children Chile China Chitin Chitin Synthase Chitinase Chitosan Chlamydia Chlamydia Infections Chlamydia trachomatis Chlamydomonas reinhardtii Chloramines Chloramphenicol O-Acetyltransferase Chlorides Chlorine Chlorine Compounds Chlorisondamine Chlorobenzoates Chloroflexi Chlorophyll Chloroplasts Chloroquine CHO Cells Choice Behavior Cholecystokinin Cholera Toxin Cholesterol Cholinergic Agonists Cholinergic Fibers Cholinergic Neurons Chondrocytes Chondrus Christianity Chromaffin Cells Chromatin Chromatin Immunoprecipitation Chromatography Chromatography, Affinity Chromatography, Affinity/methods Chromatography, Gas Chromatography, Gel Chromatography, High Pressure Liquid Chromatography, Ion Exchange Chromatography, Liquid Chromatography, Paper Chromatography, Thin Layer Chromium Radioisotopes Chromium/chemistry/*metabolism Chromones Chromosomal Instability Chromosome Aberrations Chromosome Deletion Chromosome Disorders Chromosome Mapping Chromosomes Chromosomes, Bacterial Chromosomes, Human, Pair 12 Chromosomes, Human, Pair 19 Chromosomes, Human, Pair 20 Chromosomes, Human, Pair 3 Chromosomes, Human, Pair 4 Chromosomes, Human, Pair 7 Chromosomes, Human, Pair 8 Chromosomes, Mammalian Chronic Disease ciencia Ciencia Puerto Rico Ciencias del Sistema Terrestre Ciencias Terrestres y del Espacio Ciguatera Poisoning Ciguatoxins Ciliary Neurotrophic Factor Cimicifuga Circadian Rhythm Circadian Rhythm/*physiology Circadian Rhythm/genetics/*physiology Circular Dichroism circulation index Circulation/dynamics Cisplatin Cisplatin/*pharmacology Cisplatin/metabolism/pharmacology Cisplatin/pharmacokinetics/pharmacology Citrus Classification Clathrin Clathrin-Coated Vesicles Clavulanic Acid Cleft Lip Cleft Palate Climate Climate Change climate change models climate diagnostics climate influence climate predictability Climate prediction Climate trends climate variability climate variability and trend climatic change Climatic factors CLIMATIC TRENDS Clinical Laboratory Techniques Clinical Protocols clinical strain Clinical Trials as Topic CLOCK Proteins Clone Cells Clonidine Cloning, Molecular Cluster Analysis CMIP5 simulations Co-Repressor Proteins Coamo Coastal flooding Coastal flows coastal seiches Coastal system Coastal upwelling Coated Pits, Cell-Membrane Coated Vesicles Cobalt Cocaine Cocaine-Related Disorders Cocaine: pharmacology Cochlear Nerve Cockroaches Coculture Techniques Codon Codon, Initiator Codon, Nonsense Cognition Cognition Disorders Cognitive Therapy Cohort Studies COI Coin cell Cold Temperature Colforsin Coliphages Colitis Collagen Type II Collagen Type X College Science College Students Colombia Colon Colonic Neoplasms Colonoscopy Color Colorado Colorectal Neoplasms Coloring Agents Combinatorial Chemistry Techniques Combined Modality Therapy Commitment of Mentally Ill Common Variable Immunodeficiency Communicable Disease Control Communicable Diseases Communication Communication and the arts Communication Barriers Community Community Mental Health Services Community Psychiatry Community-Based Participatory Research Comorbidity comparative genomic hybridization comparison metrics Complement C3 Complement C4 complementary curriculum COMPOSITE ANALYSIS Compromiso organizacional y Empresas multinacionales Computational Biology Computer Simulation Computer Systems Computer Terminals Computers Conditioned place preference Conditioning (Psychology) Conditioning, Classical Conditioning, Operant Condoms Conductometry Confidence Intervals Confidentiality conflict resolution Congenital Abnormalities Congenital Hypothyroidism Congresses as Topic Conjunctiva Connexin 43 Connexins Conotoxins Consciousness Consensus Consensus Sequence conservation Conserved Sequence Construction Materials/*analysis Consumer Participation Context dependent learning contextualized learning Continental Population Groups Contraception Contraception Behavior Contraceptive Contraceptives, Oral, Hormonal Controlled asthma convection Convulsants Cooperative Behavior Copper Copper Sulfate Copulation coral proxy record cord blood Cordotomy Corneal Transplantation Coronary Disease coronavirus Corpus Striatum correlation patterns Corrosion Cortical hem Corticosterone Corticotropin-Releasing Hormone COS Cells Cost-Benefit Analysis Costa Rica Covid-19 COVID-19 Testing COVID-19/blood/*drug therapy/pathology COVID-19/complications/*transmission CpG Islands Craniofacial Abnormalities Craniosynostoses Creatinine Cricetinae Cricetulus Critical Illness Crk-Associated Substrate Protein Crk-Associated Substrate Protein/*genetics Crk-Associated Substrate Protein/physiology Crop, Avian Cross Infection Cross Reactions Cross-Cultural Comparison Cross-Linking Reagents Cross-Sectional Studies Cryopreservation Cryoprotective Agents Cryptochromes Cryptococcosis Cryptococcus Cryptococcus gattii/*classification/genetics/*isolation & purification Cryptococcus neoformans Crystallization Crystallography, X-Ray Cues Culicidae Cultural Characteristics Cultural Competency Cultural Diversity Cultural Influences cultural relevance Culturally Relevant Education Culture Culture Media Culture Media, Conditioned Culture Techniques Curcumin/*pharmacology currículo complementario Curriculum Cuscuta Cyanides Cyanobacteria cyber-attacks Cyclic AMP Cyclic AMP Response Element-Binding Protein Cyclic AMP-Dependent Protein Kinases Cyclic AMP-Dependent Protein Kinases/metabolism Cyclic AMP-Dependent Protein Kinases/physiology Cyclic AMP/metabolism Cyclic GMP Cyclic N-Oxides Cyclic Nucleotide Phosphodiesterases, Type 5 Cyclic Nucleotide-Gated Cation Channels Cyclin B Cyclin T Cyclin-Dependent Kinase 5 Cyclins cycloaromatization Cyclohexanones Cyclooxygenase 2 Cyclophilins Cyclophosphamide Cyclopropanes Cyclosporine Cystatin B Cystatin C Cystic Fibrosis Cystic Fibrosis Transmembrane Conductance Regulator Cystitis Cytochrome c Group/metabolism Cytochrome P-450 CYP2C19 Cytochrome P-450 CYP2D6 Cytochrome P-450 CYP3A Cytochrome P-450 Enzyme System Cytochrome P450 Family 7 Cytochromes c Cytokines Cytokines/*immunology Cytokines/*metabolism Cytokines/blood Cytokinesis Cytological Techniques Cytomegalovirus Infections Cytopathogenic Effect, Viral Cytoplasm Cytoplasmic Granules Cytoplasmic Streaming Cytoplasmic Structures Cytoprotection Cytoskeletal Proteins Cytoskeleton Cytosol Cytosol/chemistry Cytotoxicity, Immunologic Dactinomycin dairying Dark Adaptation Darkness Data Collection Data Interpretation, Statistical Data Mining databases Databases, Factual Databases, Genetic dawn and dusk chorus DEAD-box RNA Helicases Deamino Arginine Vasopressin Decanoic Acids Decision Making Decision Theory Deep Brain Stimulation Defective Viruses Defense Mechanisms Defensins Dehydration Delayed-Action Preparations Delivery of Health Care/statistics & numerical data Deltaretrovirus Antibodies Demography Dendrites Dendritic Cells Dendritic Spines Denervation Dengue Dengue Virus Denmark Dense fine speckles Densitometry density Dental Caries Dental Caries Activity Tests Dental Prosthesis Dentate Gyrus Deoxycytidine Deoxyglucose Deoxyribonuclease IV (Phage T4-Induced) Deoxyribonucleases Deoxyribonucleosides Dependency (Psychology) Dependovirus Depression Depression/physiopathology Depressive Disorder Depressive Disorder, Major Dermis Desempeño Desert Climate Design Desoxycorticosterone detect detection Detergents Deuterium Developed Countries Developing Countries Development Developmental Biology Developmental Disabilities Dexamethasone DFS70 Diabetes Diabetes Complications Diabetes Insipidus Diabetes mellitus Diabetes Mellitus, Experimental Diabetes Mellitus, Type 1 Diabetes Mellitus, Type 1/*genetics Diabetes Mellitus, Type 2 Diabetic Angiopathies Diabetic Foot Diagnosis Diagnosis, Differential Diagnostic and Statistical Manual of Mental Disorders Diagnostic Errors Diagnostic Imaging Diagnostic Techniques, Neurological Dialysis Diarrhea Diarrhea, Infantile Diastole Dibucaine Dicarboxylic Acids Dichloroacetic Acid Dicyclomine Diet Diet, Sodium-Restricted Dietary Fats Dietary Proteins Dietary Supplements Diffusion Diffusion Chambers, Culture Diffusion of Innovation Diffusion Tensor Imaging Digestive System Dihydro-beta-Erythroidine Dihydrotestosterone Dihydroxyphenylalanine Dimerization Dimethyl Sulfoxide Dimethylnitrosamine Dimethylphenylpiperazinium Iodide Dimethylpolysiloxanes Dinitrophenols Dinoprostone Dinuclear complexes Dinucleoside Phosphates Dioxygenases Diphtheria Toxin Diploidy diradical direct detection Disasters discriminación Discrimination Learning Disease Disease Models, Animal Disease Outbreaks Disease Progression Disease Reservoirs Disease Susceptibility Disease-Free Survival Disinfectants Disinfection disparity Distance education Disulfides Diterpenes Dithioles Diuresis Diuretics diurnal diversity Dizocilpine Maleate DMF Index DNA DNA Adducts DNA Adducts/drug effects DNA Breaks, Double-Stranded DNA Copy Number Variations DNA Damage DNA Fingerprinting DNA Helicases DNA Methylation DNA Mutational Analysis DNA Polymerase III DNA Primers DNA Primers/*genetics DNA Repair DNA Repair Enzymes DNA Replication DNA Shuffling DNA Transposable Elements DNA, Archaeal/analysis/genetics DNA, Bacterial DNA, Bacterial/analysis/genetics DNA, Circular DNA, Complementary DNA, Fungal DNA, Helminth DNA, Mitochondrial DNA, Protozoan DNA, Recombinant DNA, Ribosomal DNA, Single-Stranded DNA, Superhelical DNA, Viral DNA-(Apurinic or Apyrimidinic Site) Lyase DNA-Binding Proteins DNA-Directed DNA Polymerase DNA-Directed DNA Polymerase/*genetics DNA-Directed RNA Polymerases docetaxel docetaxel resistance Documentation Dogs Dominican Republic Dopamine Dopamine Agents Dopamine Agents/pharmacology Dopamine Agonists Dopamine Antagonists Dopamine Uptake Inhibitors Dopamine Uptake Inhibitors: pharmacology Dopamine/*pharmacology/physiology Dopaminergic Neurons Doping in Sports Dose-Response Relationship, Drug Dose-Response Relationship, Immunologic Dose-Response Relationship, Radiation Double-Blind Method Down-Regulation Doxylamine Dronabinol Drosophila Drosophila melanogaster Drosophila melanogaster/*physiology Drosophila melanogaster/cytology/genetics/*physiol Drosophila melanogaster/genetics/*metabolism Drosophila Proteins Drosophila Proteins/drug effects/genetics/*metabol Drosophila Proteins/genetics/metabolism drought Drug absorption Drug Administration Routes Drug Administration Schedule Drug Carriers Drug Combinations Drug Contamination Drug delivery Drug Delivery Systems Drug Design Drug Discovery Drug Evaluation Drug Evaluation, Preclinical Drug Hypersensitivity Drug Implants Drug Industry Drug Interactions Drug Resistance Drug Resistance, Bacterial Drug Resistance, Fungal Drug Resistance, Microbial Drug Resistance, Multiple Drug Resistance, Neoplasm Drug Resistance, Neoplasm/*genetics Drug Resistance, Neoplasm/genetics Drug Resistance, Viral Drug Screening Assays, Antitumor Drug Stability Drug Synergism Drug targeting Drug Therapy, Combination Drug Tolerance Drug-Related Side Effects and Adverse Reactions Drugs of abuse Dry Eye Syndromes Dry forest Drywall Duodenal Ulcer Dynamin II Dynamin III Dynamins Dyneins Dynorphins Dystrophin Ear Early Diagnosis Earth and Space Science Education Earth Systems Sciences East Africa east-west climate gradient EASTERLY WAVE DISTURBANCES Eating Ebf2 Echocardiography Economics Ecosystem Ecosystem-based management Edetic Acid educación educación ambiental educación en Puerto Rico Education Education, Graduate Education, Medical Education, Medical, Graduate Educational Status Educational Strategies EF1a Efferent Pathways Egg tempera Egg-oil emulsion Egtazic Acid El Nino impacts El Nino Southern Oscillation Electric Conductivity Electric Organ Electric Stimulation Electrocardiography Electrochemical Techniques Electrochemistry Electrodes, Implanted Electroencephalography Electrolytes Electromyography Electron Spin Resonance Spectroscopy Electron Transport Electron Transport Chain Complex Proteins Electron Transport Complex III electrophoresis Electrophoresis, Agar Gel Electrophoresis, Gel, Pulsed-Field Electrophoresis, Gel, Two-Dimensional Electrophoresis, Polyacrylamide Gel Electrophoretic Mobility Shift Assay Electrophysiological Phenomena Electrophysiology Electroretinography Electroshock electrospun vascular scaffold Elementary School Science Elementary Secondary Education Eleutherodactylus Elution Embryo, Mammalian Embryo, Nonmammalian Embryonic Development Embryonic Induction Embryonic Stem Cells Emergency response Emergency room use Emergency Service, Hospital/*statistics & numerical data emerging emerging pathogen emerging veterinary Emigrants and Immigrants Emigration and Immigration Emotions Employment Enalapril Enalaprilat Encephalitis Encephalocele Encephalomyelitis, Autoimmune, Experimental Encephalomyocarditis virus Endangered Species Act Endemic Diseases Endocrine Disruptors Endocytosis Endodeoxyribonucleases Endogenous Retroviruses Endometriosis Endometrium Endonucleases Endoplasmic Reticulum Endoribonucleases Endosomal Sorting Complexes Required for Transport Endosomes Endothelial Cells Endothelial Cells/drug effects/metabolism Endothelin-1 Endothelium Endothelium, Vascular Endothelium, Vascular/drug effects Endothelium-derived factors Endotoxins Endpoint Determination enediyne Energy energy delivery systems Energy Metabolism Energy Metabolism/*genetics English Enhancer Elements, Genetic Enkephalin, Ala(2)-MePhe(4)-Gly(5)- Enkephalin, Leucine Enkephalin, Methionine Enkephalins ENO1 enseñanza de lengua extranjera enseñanza de lenguas extranjera ENSO Enterobacteriaceae Enterococcus Enterococcus faecalis Entorhinal Cortex Entropy env Gene Products, Human Immunodeficiency Virus Environment environmental conflicts Environmental Exposure Environmental governance environmental lobby environmental microbiology Environmental Monitoring Environmental Pollutants Enzyme Activation Enzyme Activation/drug effects Enzyme Activators Enzyme Induction Enzyme Inhibitors Enzyme Inhibitors/*therapeutic use Enzyme Inhibitors/pharmacology Enzyme Stability Enzyme-Linked Immunosorbent Assay Enzyme-Linked Immunosorbent Assay/methods Enzymes Eosine I Bluish Ephrins epidemics Epidemiologic Methods Epidemiologic Studies epidemiological curve epidemiological model Epidemiological Monitoring Epidermal Growth Factor Epidermis Epididymis Epigenesis, Genetic Epilepsy Epilepsy, Absence Epilepsy, Temporal Lobe Epinephrine Epinephrine/*pharmacology Epinephrine/metabolism Epistasis, Genetic Epithelial Cells Epithelial-Mesenchymal Transition Epithelium Epitope Mapping Epitopes Epitopes, T-Lymphocyte Epstein-Barr Virus Infections Equine Equipment and Supplies Equipment Design Equipment Failure Analysis Equol ER Stress Ergocalciferols erradicación de Rattus rattus Erythrocebus patas Erythrocyte Aging Erythrocyte Membrane Erythrocyte Volume Erythrocytes Erythrocytes/*immunology/parasitology Erythromycin Escape Reaction Escherichia coli Escherichia coli Proteins Escherichia coli Proteins/chemistry/*genetics/*metabolism Escherichia coli/genetics Escherichia coli/genetics/metabolism Esomeprazole Esophageal Atresia Esters Estradiol Estradiol Congeners Estradiol/*pharmacology Estradiol: metabolism Estrogen Antagonists Estrogen Receptor alpha Estrogen Receptor alpha/genetics/metabolism Estrogen Receptor beta Estrogen Receptor Modulators Estrogen receptors Estrogens Estrogens/*pharmacology Estrous Cycle Estrous Cycle/*physiology Estrus Ethanol Ethiopia Ethiopian highlands Ethiopian highlands rainfall Ethnic Groups ethnicity Ethology Etoposide Eukaryotic Initiation Factor-2 Eukaryotic Initiation Factor-4E Eukaryotic Initiation Factor-4G Eunica talita Eunica tatila Europe European Continental Ancestry Group European Continental Ancestry Group/statistics & numerical data evaluation of satellite-model proxies Evaluation Studies as Topic Evidence-Based Medicine Evidence-Based Practice Evoked Potentials Evoked Potentials, Auditory Evoked Potentials, Motor Evoked Potentials, Somatosensory evolution Evolution, Molecular Excitatory Amino Acid Agonists Excitatory Amino Acid Antagonists Excitatory Amino Acids Excitatory postsynaptic current Excitatory Postsynaptic Potentials executive orders Exocytosis Exons Expatriate and Organizational Commitment and Multinational Corporations Expectation Exploratory Behavior Expressed Emotion Expressed Sequence Tags extinction Extinction, Psychological extirpation Extracellular Fluid Extracellular Matrix Extracellular Matrix Proteins Extracellular Signal-Regulated MAP Kinases Extracellular Space Extracellular Traps/*drug effects Exudates and Transudates Eye Eye Diseases Eye Proteins Eye Proteins/*pharmacology Eye Proteins/metabolism Face Facies Factor Analysis, Statistical Factor VIII False Positive Reactions Family Family Characteristics Family Health Family Planning Policy Family Planning Services Family Practice Family Relations Fanconi Anemia Fanconi Anemia Complementation Group C Protein Fanconi Anemia Complementation Group D2 Protein Fanconi Anemia Complementation Group L Protein Fanconi Anemia Complementation Group Proteins Fas Ligand Protein Fasciola hepatica Fasciola hepatica/*chemistry/metabolism Fasciola hepatica/*immunology Fasciola hepatica/genetics/*metabolism Fascioliasis Fascioliasis/genetics Fatal Outcome Fats Fatty Acid Synthases Fatty Acid Transport Proteins Fatty Acid-Binding Proteins Fatty Acid-Binding Proteins/*administration & dosage Fatty Acid-Binding Proteins/chemistry/isolation & Fatty Acids Fatty Acids, Omega-3 Fatty Acids, Unsaturated Fatty Acids/analysis Fatty Alcohols Fear Feasibility Studies feces feces microbiology Federal Government Feed-forward inhibition Feedback, Sensory Feeding Behavior Fellowships and Scholarships Female Females Femoral Artery Femur Fentanyl Fermentation Ferric Compounds Ferritins Ferromagnetic implant Ferrous Compounds Fertilins Fertility Fertilization Fetal Alcohol Spectrum Disorders Fetal Blood/virology Fetal Growth Retardation Fetus Fever Fibrinolytic Agents Fibroblast Growth Factor 2 Fibroblast Growth Factors Fibroblasts Fibroins Fibromyalgia Fibrosis Field Studies Fingers Fish catch variability Fish Proteins Fisheries Fishes Flagella Flavonoids FLOOD RAINFALL Florida Flow Cytometry FLUCTUATIONS Flunitrazepam Fluorescein-5-isothiocyanate Fluoresceins Fluorescence Fluorescence Resonance Energy Transfer Fluorescent Antibody Technique Fluorescent Antibody Technique, Indirect Fluorescent Dyes Fluorescent Dyes/pharmacology Fluorodeoxyglucose F18 Fluoxetine Focal Adhesion Protein-Tyrosine Kinases Focal Adhesion Protein-Tyrosine Kinases/*metabolism Focal Adhesions Focal Dermal Hypoplasia Focus Groups Folic Acid Folic Acid Deficiency Follow-Up Studies Food Additives Food Analysis Food Deprivation Food, Fortified Foodborne Diseases Foodborne Diseases: epidemiology Foodborne Diseases: microbiology Foot Deformities, Congenital Forecasting Foreign Bodies foreign language Forelimb Forensic Psychiatry Forkhead Transcription Factors Formaldehyde Fosfomycin Fosmid library Fossils Fourier Analysis Fovea Centralis France Free Radical Scavengers Freeze Fracturing Freezing Reaction, Cataleptic Fresh Water Frontotemporal Dementia Fruit Fumarates Funaria Funaria hygrometrica Functional Functional Laterality Functional Neuroimaging Fungal Capsules Fungal Proteins Fungi Fura-2 Fusion Proteins, gag-pol G2 Phase GABA Agonists GABA Antagonists GABA Modulators GABA-A Receptor Agonists Gait Galactose Galanin Galvanic Skin Response Gametogenesis gamma-Aminobutyric Acid gamma-Aminobutyric Acid/*metabolism Ganglia Ganglia, Invertebrate Ganglia, Sensory Ganglia, Spinal Ganglia, Sympathetic Ganoderma Gap Junctions GAP-43 Protein Gas Chromatography-Mass Spectrometry Gastritis Gastroenteritis Gastroesophageal Reflux Gastrointestinal Diseases Gastrointestinal Neoplasms Gastrointestinal Tract gel Gender Bias Gene Amplification Gene Deletion Gene Dosage Gene Expression Gene Expression Profiling Gene Expression Regulation Gene Expression Regulation, Bacterial Gene Expression Regulation, Developmental Gene Expression Regulation, Enzymologic Gene Expression Regulation, Fungal Gene Expression Regulation, Leukemic Gene Expression Regulation, Neoplastic Gene Expression Regulation, Neoplastic/drug effects Gene Expression Regulation, Plant Gene Expression Regulation, Viral Gene Expression Regulation/*drug effects Gene Frequency Gene Knock-In Techniques Gene Knockdown Techniques Gene Library Gene Order Gene Products, env Gene Products, gag Gene Products, nef Gene Products, tat Gene Products, vpr Gene Regulatory Networks Gene Silencing Gene Targeting Gene Therapy Gene Transfer Gene Transfer Techniques Gene Transfer, Horizontal Genes Genes, Bacterial Genes, BRCA1 Genes, Dominant Genes, Fungal Genes, gag Genes, Helminth Genes, Homeobox Genes, Insect Genes, MDR Genes, MHC Class II Genes, Mitochondrial Genes, myc Genes, p53 Genes, Plant Genes, Protozoan Genes, Recessive Genes, Reporter Genes, Retinoblastoma Genes, rev Genes, Viral Genes, vpr genetic Genetic Association Studies Genetic Complementation Test Genetic Counseling Genetic Diseases, Inborn Genetic Engineering Genetic Linkage Genetic Loci Genetic Markers Genetic Predisposition to Disease Genetic Techniques Genetic Testing Genetic Therapy Genetic Variation Genetic Vectors Genetics, Medical Genetics, Population Genistein Genistein/*pharmacology Genitalia, Female Genome Genome, Bacterial Genome, Fungal Genome, Human Genome, Insect Genome, Viral Genome-Wide Association Study Genomic Islands Genomics Genotype Gentamicins Geographic location/entity Geography Geologic Sediments Geologic Sediments/*microbiology Geologic Sediments/microbiology Geology Georgia Germ Cells Germ Cells, Plant Germ-Line Mutation Gestational Age Ghrelin GIS Glial Fibrillary Acidic Protein Glioma global Global Health Global positioning systems (GPS) Globins Glomerular Filtration Rate Glomerulonephritis Glucagon-Like Peptide 1 Glucan Endo-1,3-beta-D-Glucosidase Glucocorticoids Glucose Glucuronidase Glutamate Decarboxylase Glutamate Dehydrogenase Glutamate-Cysteine Ligase Glutamates Glutamic Acid Glutamine/*metabolism Glutathione Glutathione Disulfide Glutathione Peroxidase Glutathione Reductase Glutathione Synthase Glutathione Transferase Glutathione Transferase/*immunology Glyceraldehyde-3-Phosphate Dehydrogenases Glycerol Glycine Glycolates Glycoproteins Glycosylation GMC Goats Gold Colloid Gold complexes Golgi Apparatus Golgi Apparatus/metabolism Gonadal Steroid Hormones Gonadotropin-Releasing Hormone Gonads Gonorrhea Government Agencies Graft Survival Graft vs Host Disease Gram-Negative Bacterial Infections Gram-Positive Bacteria Granulation Tissue Granulocyte Colony-Stimulating Factor Granulocyte-Macrophage Colony-Stimulating Factor Granulocytes Granuloma Granzymes Great Britain green area loss Green fluorescent protein Green Fluorescent Proteins Greenhouse gases Grief Groundwater dynamics Groundwater/*chemistry Group II Chaperonins Growth Cones Growth Disorders Growth Hormone Growth Inhibitors Growth Plate Growth Substances GTP Phosphohydrolases GTP-Binding Protein alpha Subunits GTP-Binding Proteins GTPase Guanica Dry Forest Guanine Nucleotide Exchange Factors Guanosine Guanosine 5'-O-(3-Thiotriphosphate) Guanosine Diphosphate Guanosine Triphosphate Guanylate Cyclase guard cell Guided Tissue Regeneration Guinea Pigs Gyrus Cinguli Habituation, Psychophysiologic Hair Hair Cells, Auditory Half-Life Halobacterium/genetics Halogenated Diphenyl Ethers Halogenation Halothane Hand Hand Deformities, Congenital Hand Disinfection Hands on Science Haploidy Haplorhini Haplotypes Hawaii Hazardous Substances Hazardous Waste Hazardous waves Head and Neck Neoplasms Health Behavior Health Care Surveys Health Education Health Knowledge, Attitudes, Practice Health Literacy Health Personnel Health Planning Health Priorities Health Promotion Health Resources Health Services Health Services Accessibility Health Services Needs and Demand Health Services Research Health Status Disparities Health Surveys Health Transition Healthcare Disparities Heart Heart Atria Heart Catheterization Heart Conduction System Heart Defects, Congenital Heart Diseases Heart Failure Heart Injuries Heart Rate Heart Ventricles Heat Heat-Shock Proteins Hedgehog Proteins HEK293 Cells HeLa Cells Helicobacter Infections Helicobacter pylori Helix-Loop-Helix Motifs Helminth Proteins Helminth Proteins/*administration & dosage Helminth Proteins/*immunology Helminth Proteins/chemistry/isolation & purification/metabolism/*pharmacology Helminth Proteins/genetics Helminthiasis, Animal Helplessness, Learned Hemagglutination Inhibition Tests Hemangioma Hematocrit Hematologic Diseases Hematologic Neoplasms Hematologic Tests Hematopoietic Stem Cell Transplantation Hematopoietic Stem Cells Heme Hemeproteins Hemiplegia Hemiptera Hemodynamics Hemoglobin, Sickle Hemoglobins Hemoglobins, Abnormal Hemoglobinuria, Paroxysmal Hemophilia A Hemostatics Hepacivirus Heparin Heparin-binding EGF-like Growth Factor Hepatic Veno-Occlusive Disease Hepatitis A Hepatitis B Hepatitis B virus Hepatitis C Hepatitis C, Chronic Hepatitis Delta Virus Hepatitis, Chronic Hepatocytes Heptanoates Heptanoic Acids herbivoría de insectos Hermanski-Pudlak Syndrome Hernia, Diaphragmatic Hernia, Inguinal Hernia, Umbilical Heroin Heroin Dependence Herpes Genitalis Herpes Simplex Herpesviridae Infections Herpesvirus 1, Cercopithecine Herpesvirus 4, Human Heterochromatin Heterogeneous-Nuclear Ribonucleoprotein Group F-H Heterozygote Heterozygote Detection Hexamethonium Hexamethonium Compounds Hexanes Hexanols Hexosyltransferases HGMS Hiccup High gradient magnetic separation High Schools High-Throughput Nucleotide Sequencing High-Throughput Screening Assays hindcast datasets Hindlimb Hinduism Hippocampus Hirschsprung Disease Hispanic Americans Hispanic Americans/statistics & numerical data Hispanic/Latino Health Hispanics Histamine Histocompatibility Antigens Class I Histocompatibility Antigens Class II Histocompatibility Testing Histocytochemistry Histological Techniques Histone Deacetylase Inhibitors Histone-Lysine N-Methyltransferase Histone-Lysine N-Methyltransferase/genetics/*physiology Histones History, 19th Century History, 20th Century History, 21st Century HIV HIV Antibodies HIV Core Protein p24 HIV Envelope Protein gp120 HIV Envelope Protein gp160 HIV Infections HIV Long Terminal Repeat HIV Reverse Transcriptase HIV Seronegativity HIV Seropositivity HIV-1 HIV-2 HL-60 Cells HLA haplotypes HLA-A2 Antigen HLA-DR Antigens Holoprosencephaly Homeless Persons Homeodomain Proteins Homeostasis Homocysteine homogalacturonan Homovanillic Acid Homozygote Honduras Horizontal Hormone Replacement Therapy Hormones Horseradish Peroxidase Hospitalization/*statistics & numerical data Hospitalizations Hospitals, Proprietary Hospitals, Public Hospitals, University Host-Parasite Interactions Host-Pathogen Interactions Hot Temperature Housing HSP70 Heat-Shock Proteins HSP90 Heat-Shock Proteins HT29 Cells Human dimension Human Engineering Human Genome Project Human papillomavirus 16 Human Umbilical Vein Endothelial Cells Humans Humic Substances Huntington Disease Hyaluronic Acid Hybridomas Hydantoins Hydro-Lyases hydro-meteorology hydro-meteorology monitoring systems Hydrochlorothiazide Hydrogen Hydrogen Bonding Hydrogen Peroxide Hydrogen Sulfide Hydrogen Sulfide/*metabolism Hydrogen-Ion Concentration Hydrolases hydrological modelling Hydrolysis Hydroxyindoleacetic Acid Hydroxyl Radical Hydroxylation Hydroxyurea Hyperalgesia Hypercapnia Hyperglycemia Hyperkinesis Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels Hypersensitivity Hypertelorism Hypertension Hypertension, Pulmonary Hypertension, Renal Hypertonic Solutions Hypertrophy Hypertrophy, Left Ventricular Hyphae Hypoglycemic Agents Hypokalemia Hypospadias Hypothalamic Hormones Hypothalamo-Hypophyseal System Hypothalamus Hypothalamus, Middle Hypothyroidism Hypotonic Solutions Hypoxia-Inducible Factor 1, alpha Subunit I-kappa B Kinase IBD interactome Idazoxan Identification Illumina Image Processing, Computer-Assisted Imaging, Three-Dimensional Imidazoles Imines Immune Evasion Immune Reconstitution Inflammatory Syndrome Immune Sera Immune System Immune Tolerance Immunity Immunity, Cellular Immunity, Humoral Immunity, Innate Immunity, Mucosal Immunization Immunization Programs Immunization Schedule Immunization, Secondary Immunoblotting Immunoblotting/methods Immunochemistry Immunocompromised Host Immunoconjugates Immunodiffusion Immunoenzyme Techniques Immunoglobulin A Immunoglobulin Class Switching Immunoglobulin Constant Regions Immunoglobulin E Immunoglobulin G Immunoglobulin M Immunoglobulin Variable Region Immunoglobulins Immunoglobulins, Intravenous Immunohistochemistry immunolabelling immunolocalization Immunologic Deficiency Syndromes Immunologic Factors Immunologic Memory Immunologic Techniques Immunologic Tests Immunomodulation Immunomodulator Immunophenotyping Immunoprecipitation Immunosorbent Techniques Immunosuppressive Agents Immunotherapy Impacts on resources Implant assisted magnetic drug targeting Implant assisted-magnetic drug targeting Implosive Therapy In Situ Hybridization In Situ Nick-End Labeling In vitro In Vitro Techniques Incidence Inclusion Bodies Inclusion Bodies, Viral INDEL Mutation Indenes India Indian Ocean Indicator Dilution Techniques Indicators and Reagents Individuality Individualized Medicine Indoles Induced Pluripotent Stem Cells Industry Infant Infant Food Infant Mortality Infant, Newborn Infant, Newborn, Diseases Infant, Newborn, Diseases/diagnosis/etiology/*virology Infarction, Middle Cerebral Artery Infection Infectious Anemia Virus, Equine Infectious Disease Transmission, Vertical Infertility Infertility, Female Infertility, Male Inflammation Inflammation Mediators Inflammatory Bowel Diseases Inflammatory Breast Neoplasms Inflammatory Breast Neoplasms/*genetics/*pathology Influenza A virus Informal Science Education Information Systems Infusion Pumps, Implantable Infusions, Intravenous Infusions, Parenteral inglés Inhalation Inhalation Exposure Inhibitor of Apoptosis Proteins Inhibitor of Differentiation Protein 2 inhibitors/*physiology inhibitors/genetics/metabolism Inhibitory postsynaptic current Injections Injections, Intramuscular Injections, Intraperitoneal Injections, Intravenous Injections, Intraventricular Injections, Subcutaneous inner-ring suburbs Inosine Inositol Phosphates Inpatients Inquiry Insect Control insect herbivory Insect Proteins Insect Vectors Insects Insemination, Artificial, Heterologous Insulin Insulin resistance Insulin sensitivity Insulin therapy Insulin-Like Growth Factor I Insulinoma Insurance Coverage Insurance, Health integrase binding domain Integrases Integrated coastal management Integrin alphaVbeta3/*antagonists & inhibitors/genetics/metabolism Integrin alphaXbeta2 Integrins Integumentary System inteligencia emocional inteligencia interpersonal inteligencia intrapersonal Inteligencia naturalista inteligencia verbal lingüística inteligencias múltiples Intellectual Disability Intellectual Property Intelligence Tests Intensive Care Intensive insulin therapy Intention inter-Americas inter-annual climate variability inter-annual climatic fluctuations inter-annual variability interacción depredador-presa Interacting partners interannual rainfall variability interannual variability Intercalating Agents Intercellular Adhesion Molecule-1 Intercellular Junctions Intercellular Signaling Peptides and Proteins Interdisciplinary Communication Interferon Regulatory Factor-7 Interferon Type I Interferon-alpha Interferon-gamma Interferons Interinstitutional Relations Interior Design and Furnishings Interleukin 1 Receptor Antagonist Protein Interleukin-1 Interleukin-10 Interleukin-12 Interleukin-12 Subunit p40 Interleukin-13 Interleukin-15 Interleukin-18 Interleukin-1beta Interleukin-1beta/genetics/immunology Interleukin-2 Interleukin-3 Receptor alpha Subunit Interleukin-4 Interleukin-6 Interleukin-6/*antagonists & inhibitors/blood/immunology Interleukin-6/*biosynthesis/metabolism Interleukin-6/physiology Interleukin-8 Interleukin-8/*genetics/metabolism Interleukins Intermediate Filament Proteins internal solitary waves internal waves International Cooperation Internet Interneurons Interprofessional Relations Interspersed Repetitive Sequences intervention interventions Interview, Psychological Interviews as Topic Intestinal Absorption Intestinal Absorption/physiology Intestinal Mucosa Intestinal Mucosa/drug effects/*physiology Intestinal Obstruction Intestine, Small Intestines intra-seasonal climate INTRA-SEASONAL EVENTS intra-seasonal oscillations Intracellular Fluid Intracellular Membranes Intracellular Signaling Peptides and Proteins Intracellular Space Intraocular Pressure Intraoperative Complications intraseasonal oscillations Intraseasonal rainfall variability Introns Intubation, Gastrointestinal Intubation, Intratracheal Invasiveness Inventions Inventores Inventors Inventos Invertebrate Hormones Investigations Iodides Iodine Radioisotopes Iodoacetamide Ion Channel Gating Ion Channels Ion Exchange Resins Ionomycin Ionosphere Ionospheric disturbances and irregularities Iridoids Iron irrupción de mariposa-oruga Ischemia Ischemic Attack, Transient Islam Islets of Langerhans Isoelectric Focusing Isoelectric Point Isoenzymes Isoflavones Isoflavones/*pharmacology Isolated organ perfusion Isomerism Isometric Contraction Isoniazid Isoproterenol Isoproterenol/agonists Isoquinolines Isothiuronium Isotonic Solutions Isotopes Isotretinoin Italy Item Analysis Jamaica Janus Kinase 2 Janus Kinases Japan JC Virus Jejunum JNK Mitogen-Activated Protein Kinases Job Application joint modes Jugular Veins Jumonji Domain-Containing Histone Demethylases K562 Cells Kainic Acid Kanamycin Kaplan-Meier Estimate Karyotyping Keratinocytes Ketones Key outcomes: ocean observations and maize yield Ki-67 Antigen Ki-67 Antigen/metabolism Kidney Kidney Concentrating Ability Kidney Cortex Kidney Diseases Kidney Function Tests Kidney Glomerulus Kidney Neoplasms Kidney Transplantation Kidney Tubules Kidney/drug effects/physiology Killer Cells, Natural Kinetics Korea Kruppel-Like Transcription Factors Kv1.1 Potassium Channel Kv1.4 Potassium Channel Kwa-Zulu Natal Kynurenine Laboratories Lactation Lactic Acid/*metabolism/pharmacology Lactones LADAR lake level Lakes Lamivudine land-sea transition land-use science Language Lanthanum Large-Conductance Calcium-Activated Potassium Channel beta Subunits Large-Conductance Calcium-Activated Potassium Channels Larva larval morphology Laryngeal Masks Laryngeal Neoplasms Lasers Latin America Latin Americans Latinos Layer 1 LDL-Receptor Related Proteins Lead Learner Engagement Learning Learning Disorders Lecithins Lectins Lectins, C-Type LEDGF/p75 Leg Length of Stay lengua extranjera Lentivirus Lentivirus Infections LEOPARD Syndrome Leptin Lethal Dose 50 Leukemia Leukemia Virus, Feline Leukemia, Lymphoid Leukemia, Myelogenous, Chronic, BCR-ABL Positive Leukemia, Myeloid Leukemia, Myeloid, Acute Leukemia, Myelomonocytic, Juvenile Leukemia, Promyelocytic, Acute Leukocyte Common Antigens Leukocyte Count Leukocyte Migration-Inhibitory Factors Leukocytes Leukocytes, Mononuclear Leukoencephalopathy, Progressive Multifocal Library LIDAR Lidocaine Life Change Events Life Cycle Stages Life Style Ligands Ligases Ligation Light light-rail Lighting LIM Domain Proteins Limb Deformities, Congenital Limbic System Limit of Detection Limpopo Valley Linear Models linear regression Linguistics Linkage Disequilibrium Lip Lipase/metabolism Lipid Metabolism Lipid Peroxidation Lipids Lipopolysaccharides Lipopolysaccharides/*antagonists & inhibitors/pharmacology Lipopolysaccharides/*immunology Liposomes Lipoylation Liquid Crystal Polymers Listeria Listeria monocytogenes Listeria monocytogenes: genetics Listeria monocytogenes: isolation & purification Listeria monocytogenes: pathogenicity Lithium Lithium batteries Lithium Carbonate Lithium Chloride Little Rock Liver Liver Cirrhosis Liver Diseases Liver Failure Liver Function Tests Liver Neoplasms Liver Neoplasms, Experimental Liver Neoplasms, Experimental/prevention & control/*secondary Liver/*metabolism Liver/drug effects/physiology LM13 LM19 LM6 Locomotion Lod Score Logistic Models Long QT Syndrome Long-range climate prediction in southern Africa Long-Term Potentiation Long-Term Synaptic Depression Longitudinal Studies Lopinavir Lordosis Los Angeles Losartan LOX-1 Luciferases Luciferases, Firefly Lumbar Vertebrae Luminescent Measurements Luminescent Proteins Lung Lung Neoplasms Lupus Erythematosus, Cutaneous Lupus Erythematosus, Systemic Lupus Nephritis Lutetium Lyases/chemistry/*genetics/*metabolism Lycopersicon esculentum Lymph Nodes Lymphocyte Activation Lymphocyte Count Lymphocyte Culture Test, Mixed Lymphocyte Subsets Lymphocytes Lymphoid Tissue Lymphokines Lymphoma Lymphoma, Large B-Cell, Diffuse Lymphoma, T-Cell, Cutaneous Lysine Lysosomal-Associated Membrane Protein 1 Lysosomes Macaca Macaca fascicularis Macaca mulatta Macaca nemestrina Macrophage Activation Macrophages Macrophages, Peritoneal Macrophages, Peritoneal/*drug effects/*physiology Macrophages/cytology/drug effects/immunology Macrophages/drug effects/*physiology Macula Lutea Madagascar Magnesium Magnetic drug carrier particles Magnetic Fields Magnetic nanoparticles Magnetic Resonance Imaging Magnetic Resonance Spectroscopy Magnetic stent Magnetics Magnetite Malabsorption Syndromes Malaria Malaria, Falciparum Malaria, Falciparum/*complications/immunology Malawi Male Maleimides Malodors malware Mammals/physiology Mammary Neoplasms, Experimental Mammary Neoplasms, Experimental/*drug therapy/pathology Managed Care Programs Mandible Manganese Mannitol Mannose-Binding Lectins MAP Kinase Kinase 1 MAP Kinase Kinase 3 MAP Kinase Kinase 6 MAP Kinase Kinase Kinase 1 MAP Kinase Kinase Kinase 4 MAP Kinase Kinase Kinases MAP Kinase Signaling System Marginal zone Marine Biology marine climate Marine ecosystem Marine environment Marine Toxins Marker Markov Chains Marriage Maryland Mass Media Use Mass Screening Mass Spectrometry Mast Cells Mastocytosis Materials Testing Maternal Age Maternal Behavior Maternal Welfare Maternal-Fetal Exchange Mathematics Mating Preference, Animal mating type Matrilin Proteins Matrix Metalloproteinase 10 Matrix Metalloproteinase 13 Matrix Metalloproteinase 2 Matrix Metalloproteinase 9 Matrix Metalloproteinases/physiology Maximum likelihood estimation Maze Learning MCF-7 Cells MDCP MDCPs MDR MDT Meat Products Mecamylamine mechanical properties Mechanisms Mechanoreceptors Mechanotransduction, Cellular Mediastinitis Medical Secretaries Medicine, Traditional Meditation Medulla Oblongata Mefloquine Meiosis Melanins Melanocyte-Stimulating Hormones Melanoma Melanoma, Experimental Membrane Fusion Membrane Glycoproteins Membrane Glycoproteins/analysis Membrane Lipids Membrane Microdomains Membrane Potential, Mitochondrial Membrane Potentials Membrane Proteins Membrane Proteins/analysis Membrane Transport Proteins Membrane Transport Proteins/genetics/*physiology Membranes Memory Memory Disorders Memory, Long-Term Memory, Short-Term Meningitis Meningitis, Cryptococcal Meningoencephalitis menores refugiados Mental Disorders Mental Health Services Mental Recall Meprobamate Mercaptoethanol Mercury Mesalamine Mesencephalon Mesenteric Arteries Mesoclimate Mesocricetus Mesoderm mesopause dynamics mesopause temperature Mesoscale processes Mesoscale systems mesosphere dynamics mesosphere temperature Mesospheric dynamics Mesothelioma Metabolic Syndrome X Metabolism Metagenome Metagenomics metal layers Metal Nanoparticles Metalloproteases Metallothionein Metallothionein/*genetics Metals Metals, Heavy Metamorphosis, Biological meteotsunami Methadone Methamphetamine Methanol Methicillin Resistance Methionine Methotrexate Methyl Methanesulfonate Methyl-CpG-Binding Protein 2 Methyl-CpG-Binding Protein 2/*immunology Methylation Methylene Blue Methylenetetrahydrofolate Dehydrogenase (NADP) Methylenetetrahydrofolate Reductase (NADPH2) Methylphenidate Methylprednisolone Methyltestosterone Methyltransferases Metronidazole Mexican Americans Mexico Mice Mice models Mice, Inbred BALB C Mice, Inbred C3H Mice, Inbred C57BL Mice, Inbred CBA Mice, Inbred ICR Mice, Inbred NOD Mice, Inbred Strains Mice, Knockout Mice, Mutant Strains Mice, Neurologic Mutants Mice, Nude Mice, SCID Mice, Transgenic Miconazole Microarray Analysis microbial sensitivity tests microbial sensitivity tests veterinary Microbial Viability Microbiology Microbiome Microbiota Microbubbles Microclimatology Microcystis Microdialysis Microdissection Microelectrodes Microfilament Proteins Microfluidic Analytical Techniques Microglia Microinjections MicroRNAs Microsatellite Repeats Microscopy Microscopy, Confocal Microscopy, Electron Microscopy, Electron, Scanning Microscopy, Electron, Transmission Microscopy, Fluorescence Microscopy, Immunoelectron Microscopy, Polarization Microscopy, Video Microsomes Microsomes, Liver Microspheres Microtubule-Associated Proteins Microtubule-Associated Proteins/analysis Microtubules Microvessels Microvessels/drug effects Microvessels/drug effects/pathology/physiology MICROWAVE Microwaves Midazolam Middle Aged Middle atmosphere dynamics Middle atmosphere: composition and chemistry Middle atmosphere: constituent transport and chemistry Midline Thalamic Nuclei Mineralocorticoid Receptor Antagonists Mining minority Minority Groups Minority Health Miro Missouri mitigation mitigation strategies Mitochondria Mitochondria, Liver Mitochondrial Proteins Mitochondrial Proton-Translocating ATPases/metabolism Mitochondrial Turnover Mitogen-Activated Protein Kinase 13 Mitogen-Activated Protein Kinase 3 Mitogen-Activated Protein Kinase 8 Mitogen-Activated Protein Kinases Mitogen-Activated Protein Kinases/antagonists & inhibitors/metabolism Mitosis Mitotic Spindle Apparatus Mixed Function Oxygenases Mixed layer Mixed-valent complexes MNP model simulation and intercomparison Modeling Observation Models Models, Animal Models, Biological Models, Cardiovascular Models, Chemical Models, Genetic Models, Immunological Models, Molecular Models, Neurological Models, Organizational Models, Psychological Models, Statistical Models, Theoretical modern-era Modified carbon paste electrode Molar molecular Molecular Biology Molecular Biology/methods Molecular Chaperones Molecular Conformation Molecular Epidemiology Molecular Epidemiology: methods Molecular Imaging Molecular Probe Techniques Molecular Sequence Annotation Molecular Sequence Data Molecular Structure Molecular Targeted Therapy Molecular Typing Molecular Typing: methods Molecular Weight Mollusca Mollusk Venoms Molybdenum Monkey Diseases Monocytes Monocytes/*pathology Monophenol Monooxygenase monsoon Monte Carlo Method Morbidity Morbidity/trends Morphine Morphine Dependence Morphogenesis Morpholines moss mosses Mossy Fibers, Hippocampal Mother-Child Relations Mothers Motivation Motor Activity Motor Activity/genetics/*physiology Motor Cortex Motor Endplate Motor Neurons Motor Vehicles Mountain wake Mouth Mouth Diseases Mouth Mucosa Mouth Neoplasms Movement Mozambique Mozambique Channel MRE11 Homologue Protein Mucin-4 Mucins Mucous Membrane Multidrug Resistance-Associated Proteins Multienzyme Complexes Multifactorial Inheritance Multigene Family Multilingualism Multimodal Imaging multiple multiple intelligences Multiple Organ Failure Multiple Sclerosis Multiprotein Complexes Multitarget therapy Multivariate Analysis Muramoylpentapeptide Carboxypeptidase Muscarinic Agonists Muscarinic Antagonists Muscimol Muscle Cells Muscle Contraction Muscle Development Muscle Proteins Muscle Tonus Muscle Weakness Muscle, Skeletal Muscle, Smooth Muscle, Smooth, Vascular Muscles Muscular Diseases Mutagenesis Mutagenesis, Insertional Mutagenesis, Site-Directed Mutagens Mutation Mutation, Missense Mutation/genetics Myasthenic Syndromes, Congenital Mycobacterium Infections Mycobacterium tuberculosis Mycoplasma Infections Mycorrhizae Mycosis Fungoides Myelin Sheath Myeloablative Agonists Myelodysplastic Syndromes Myeloid Cells Myeloid-Lymphoid Leukemia Protein Myocardial Contraction Myocardial Infarction Myocardial Ischemia Myocardial Reperfusion Injury Myocardium Myocytes, Cardiac Myocytes, Smooth Muscle Myofibrils Myofibroblasts myosin Myosin Heavy Chains Myosin Type II Myosin Type V Myosins N-Methylaspartate N-Methylscopolamine NADH electrooxidation NADP NADPH Dehydrogenase Naloxone Nandrolone Nanocapsules Nanocomposites Nanoparticles Nanotechnology Naphthalenes Narcotic Antagonists Narcotics Nasal Cavity National Health Programs National Institutes of Health (U.S.) native plants Natriuresis Natriuretic Peptide, Brain naturalized plants nature conservation nature deficit disorder Nausea Nebraska Neck Pain Necrosis Needle Sharing Needs Assessment nef Gene Products, Human Immunodeficiency Virus neighborhood decline Neisseria gonorrhoeae Nematoda Neocortex neonatal Neonatal Screening Neoplasm Invasiveness Neoplasm Metastasis Neoplasm Metastasis/*prevention & control Neoplasm Proteins Neoplasm Recurrence, Local Neoplasm Staging Neoplasm Transplantation Neoplasm, Residual Neoplasms Neoplasms, Experimental Neoplasms, Experimental/genetics/metabolism/pathology Neoplasms, Glandular and Epithelial/blood/*complications/drug therapy Neoplasms, Multiple Primary Neoplasms/*economics/*mortality Neoplasms/*epidemiology Neoplasms/*epidemiology/mortality Neoplasms/blood supply/pathology Neoplasms/immunology/*pathology Neoplasms/immunology/pathology/*physiopathology Neoplastic Cells, Circulating Neoplastic Stem Cells Neostigmine Neostriatum Neovascularization, Pathologic Neovascularization, Pathologic/*drug therapy/metabolism Neovascularization, Pathologic/*drug therapy/metabolism/pathology Neovascularization, Pathologic/*pathology Neovascularization, Pathologic/*physiopathology Neovascularization, Pathologic/immunology/*pathology Neovascularization, Pathologic/pathology Neovascularization, Physiologic Nephrectomy Nephrons Nerve Crush Nerve Degeneration Nerve Fibers Nerve Fibers, Myelinated Nerve Growth Factor Nerve Growth Factors Nerve Growth Factors/*pharmacology Nerve Net Nerve Regeneration Nerve Tissue Nerve Tissue Proteins Nervous System Nervous System Diseases Nervous System Physiological Phenomena Network connectivity Neural Cell Adhesion Molecules Neural Conduction Neural Crest Neural Inhibition Neural Networks (Computer) Neural Pathways Neural Pathways/cytology/metabolism Neural Plate Neural Tube Defects Neuralgia Neurites Neurobiology Neuroblastoma Neurodegenerative Diseases Neuroendocrine Tumors Neurofibrillary Tangles Neurofilament Proteins Neurogenesis Neuroglia Neuroimmunomodulation/immunology/physiology Neuromuscular Junction Neuronal Plasticity Neurons Neurons, Afferent Neurons/cytology/*metabolism Neurons/cytology/*physiology Neurons/drug effects/metabolism Neuropeptide Y Neuropeptides Neuropeptides/genetics/metabolism Neuropeptides/metabolism Neurophysiology Neuropil Neuroprotective Agents Neuropsychological Tests Neurosciences Neurosecretory Systems/immunology/*pathology Neurosecretory Systems/immunology/*physiopathology Neurotensin Neurotoxins Neurotransmitter Agents Neurotransmitter Uptake Inhibitors Neurotrophin 3 neutral metal layers Neutral Red Neutralization Tests Neutrophils Neutrophils/*drug effects new york New York City new york epidemiology Newport Newspapers NF-kappa B NF-kappa B p50 Subunit NF-kappa B/*immunology NF-kappa B/*metabolism NFATC Transcription Factors NFI Transcription Factors NG-Nitroarginine Methyl Ester Nickel Nicotinamide Phosphoribosyltransferase Nicotine Nicotinic Agonists Nicotinic Antagonists Nictitating Membrane Nifedipine NIH 3T3 Cells Nile River flow variability Nitrates Nitric Oxide Nitric Oxide Synthase Nitric Oxide Synthase Type I Nitric Oxide Synthase Type II Nitric Oxide Synthase Type III Nitriles Nitrites Nitro Compounds Nitroarginine Nitrobenzoates Nitrogen Nitrosamines NK Cell Lectin-Like Receptor Subfamily K Nociceptors Nocodazole non-inocent Nonmajors Nootropic Agents Norepinephrine Norepinephrine/*metabolism Norepinephrine/*pharmacology Norepinephrine/metabolism Norepinephrine/pharmacology North America North Atlantic Oscillation northern Namibia Notochord Nuclear Envelope Nuclear Family Nuclear Magnetic Resonance, Biomolecular Nuclear Pore Nuclear Proteins Nuclear Receptor Subfamily 4, Group A, Member 2 Nucleic Acid Conformation Nucleic Acid Heteroduplexes Nucleic Acid Hybridization Nucleic Acid Synthesis Inhibitors Nucleocapsid nucleophilic addition Nucleotides, Cyclic Nucleus Accumbens Nurse's Role Nutrition Disorders Nutrition Surveys Nutritional Requirements Nymph Obesity Object Attachment Obsessive-Compulsive Disorder Obstetrics and Gynecology Department, Hospital Occupational Diseases Occupational Exposure Ocean swells ocean-atmosphere interaction ocean-atmosphere interactions oceanography Octamer Transcription Factor-3 Octanols Octopamine Odds Ratio Odors Oils Old Age Assistance Olea Olfactory Mucosa Olfactory Pathways Oligodeoxyribonucleotides Oligodeoxyribonucleotides, Antisense Oligonucleotide Array Sequence Analysis Oligonucleotide Probes Oligonucleotides Oligonucleotides, Antisense Oligopeptides Oncogene Proteins v-fos Oncogene Proteins, Fusion Oncogene Proteins, Viral Oocysts Oocytes Open Reading Frames Operon Ophthalmic Solutions Opioid Peptides Opossums Optic Nerve Optic Nerve Injuries Optical Imaging Optics and Photonics Optogenetics Orbit Orchiectomy Organ Culture Techniques Organ of Corti Organ Size Organ Specificity Organelles Organic Chemicals organic farming Organizational Case Studies Organizational Innovation Organizational Objectives organizations Organogenesis Organometallic Compounds Organophosphonates Organoplatinum Compounds/administration & dosage/pharmacology Organosilicon Compounds Orientation Ornithine Decarboxylase Orographic effects Orphan Nuclear Receptors Osmolar Concentration Osmosis Osmotic Pressure Osteitis Deformans Osteoarthritis Osteoarthritis, Knee Osteoblasts Osteoclasts Osteogenesis Otitis Externa Ouabain outer membrane OUTGOING LONGWAVE RADIATION Outpatients Ovalbumin Ovarian Neoplasms Ovarian Neoplasms/*blood supply/metabolism/pathology Ovarian Neoplasms/*blood supply/pathology Ovarian Neoplasms/*blood supply/pathology/*physiopathology/radiography Ovarian Neoplasms/*drug therapy Ovarian Neoplasms/*drug therapy/*genetics/metabolism Ovarian Neoplasms/*drug therapy/genetics/pathology Ovarian Neoplasms/*drug therapy/metabolism Ovarian Neoplasms/*drug therapy/pathology Ovarian Neoplasms/*genetics/metabolism/pathology Ovarian Neoplasms/*metabolism Ovarian Neoplasms/*pathology Ovarian Neoplasms/blood supply/*drug therapy/metabolism Ovarian Neoplasms/blood supply/*pathology/therapy Ovarian Neoplasms/blood/*complications/drug therapy Ovarian Neoplasms/chemistry/*genetics Ovarian Neoplasms/drug therapy/*enzymology/mortality/*pathology Ovarian Neoplasms/genetics/*metabolism/pathology Ovarian Neoplasms/genetics/*pathology/therapy Ovarian Neoplasms/genetics/pathology/*therapy Ovarian Neoplasms/metabolism/*pathology/*surgery Ovariectomized Ovariectomy Ovary Overweight Ovum Oxazines/*pharmacology Oxidants Oxidants, Photochemical Oxidation-Reduction Oxidative Phosphorylation Oxidative Stress Oxides Oxidoreductases Oxidoreductases Acting on CH-CH Group Donors Oxidoreductases Acting on CH-NH Group Donors Oximes Oxocins Oxygen Oxygen Consumption Oxygenases Oxymetazoline Oxytocin Ozone p-benzyne p21-Activated Kinases p38 Mitogen-Activated Protein Kinases Pacific Islanders Paclitaxel Paclitaxel/administration & dosage Pain Pain Measurement Palaemonidae Paleontology Palinuridae palm weevils Palmitoyl Coenzyme A Pamphlets Pancreas Pancreatic Neoplasms Pancreatic Polypeptide Pancytopenia pandemics Panic Disorder Papanicolaou Test Papaverine Papillary Muscles Papillomaviridae Papillomavirus E7 Proteins Papillomavirus Infections Papillomavirus Vaccines Parabens Paracrine Communication Paragonimus Paraquat Parasitemia Parasitic Sensitivity Tests Parasitology Parasympatholytics Parathyroid Hormone Parathyroid Hormone-Related Protein Paratuberculosis Paraventricular Hypothalamic Nucleus Pargyline Parity Parkinson Disease Particle Size Particulate Matter Parvalbumins Patch-Clamp Techniques Patentes Patents Paternal Age Patient Acceptance of Health Care Patient Acceptance of Health Care/*statistics & numerical data Patient Admission Patient Care Team Patient Compliance Patient Education as Topic Patient Participation Patient Preference Patient Satisfaction Patient Selection Patients Pattern Recognition, Automated PCL PDMS pectin Pedigree Pelvic Inflammatory Disease Pelvis Penicillin G Penicillin G Procaine Penicillin Resistance Penicillin-Binding Proteins Penicillins Penile Neoplasms Penile Neoplasms/*epidemiology/ethnology Pentostatin Pepsin A Peptide encapsulation Peptide Fragments Peptide Hormones Peptide Hydrolases Peptide Initiation Factors Peptide YY Peptides Peptides, Cyclic Peptidyl Transferases Peptidyl-Dipeptidase A Peptococcaceae/drug effects/genetics/growth & development Percent body fat Perception Perchlorates Perforin performance Pericytes/*drug effects/metabolism Pericytes/drug effects/metabolism Period Circadian Proteins Periodicals as Topic Periodicity Periodontal Diseases Peripheral Nerves Peripherins Periplaneta Permeability Peroxidase Peroxiredoxins Personal experiences 1995-2005 Personality Assessment Personality Inventory Pertussis Toxin Phaeophyta Phagocytes Phagocytosis Phagosomes Pharmaceutical Pharmaceutical Preparations Pharmacogenetics Pharyngeal Neoplasms Pharynx Phenazocine Phencyclidine Phenobarbital Phenols Phenothiazines Phenotype Phentolamine Phenyl Ethers Phenylephrine Phenylketonurias Phenylmercuric Acetate Phenylurea Compounds/pharmacology Pheochromocytoma Philadelphia Phloem Phorbol 12,13-Dibutyrate Phosphates Phosphatidylcholines Phosphatidylcholines/pharmacology Phosphatidylethanolamines Phosphatidylinositol 3-Kinase Phosphatidylinositol 3-Kinases Phosphatidylinositol 3-Kinases/analysis Phosphatidylinositol Phosphates Phosphatidylserines/*immunology Phosphodiesterase Inhibitors Phospholipases Phospholipases A Phospholipases A2 Phospholipases A2, Cytosolic Phosphoprotein Phosphatases Phosphoproteins Phosphopyruvate Hydratase Phosphoric Monoester Hydrolases Phosphorus Phosphorus Radioisotopes Phosphorylation Phosphorylation/drug effects Phosphoserine Phosphoserine/metabolism Photic Stimulation Photo Production Photobacterium Photobleaching Photochemical Processes Photochemistry Photography Photolysis Photons Photoreceptor Cells Photoreceptor Cells, Invertebrate Photoreceptor Cells, Invertebrate/metabolism Phthalazines/pharmacology Phthalic Acids Phycoerythrin Phylogeny Physical Chromosome Mapping Physical meteorology and climatology Physical oceanography Physical Sciences Physical Stimulation Physician-Patient Relations Physicians' Offices Physicochemical Phenomena Physics Physics: Molecular Physics: Optics Physiology Phytoestrogens Phytohemagglutinins Phytotelma Phytotherapy Pichia Picornaviridae Picornaviridae Infections Picrotoxin Pilocarpine Pilot Projects Pineal Gland Pinus Piperazines Piperazines/*therapeutic use Piperidines Pirenzepine Pituitary Hormones Pituitary-Adrenal System Placenta Placenta/virology Planarians Planning planning and forecasting Plant Bark plant cell wall Plant Development Plant Diseases Plant Extracts Plant Leaves Plant Proteins Plant Roots Plants Plants, Genetically Modified Plants, Medicinal Plants, Toxic Plasma Plasma Cells Plasmacytoma Plasmids Plasmids: genetics Plasmodium berghei Plasmodium falciparum Plasmodium falciparum/*physiology Plasmodium vivax Plasmodium yoelii Platelet Activating Factor Platelet Count Plesiomonas Pleural Neoplasms PMN-MDSCs Pneumonia, Aspiration Point Mutation Pokeweed Mitogens polar blocking Policy Poliovirus políticas sobre relaciones románticas en el trabajo Politics pollution Poly A Poly(A)-Binding Proteins Poly(ethylene-oxide) Polyamines Polyanhydrides Polybrominated Biphenyls Polychlorinated Biphenyls Polycomb Repressive Complex 2 Polydactyly Polydeoxyribonucleotides Polyesters Polyethylene Glycols Polyketide Synthases Polymer nanocomposite Polymerase Chain Reaction Polymerase Chain Reaction/*methods Polymers Polymers/*metabolism/pharmacology Polymethacrylic Acids Polymorphism Polymorphism, Genetic Polymorphism, Single Nucleotide Polyomavirus Infections Polyphenols Polyphosphates Polypyrimidine Tract-Binding Protein Polyribosomes Polysaccharides Ponta do Ouro Population Population Characteristics Population Density Population Dynamics Population Groups Population Growth population surveillance Population Surveillance/*methods Porifera port city Portraits as Topic Positron-Emission Tomography Post-Exposure Prophylaxis postdocs Postpartum Period Postural Balance Potassium Potassium Channel Blockers Potassium Channels Potassium Channels, Calcium-Activated Potassium Channels, Voltage-Gated Potassium Chloride Potassium layer potassium lidar POU Domain Factors Poverty power distribution unit Practice Guidelines as Topic Prazosin Precancerous Conditions precipitation Precipitin Tests Preconception Care Precursor Cell Lymphoblastic Leukemia-Lymphoma predator-prey interaction Predatory Behavior predictability prediction model Predictive Value of Tests Prefrontal Cortex Pregnancy Pregnancy Complications Pregnancy Complications, Infectious Pregnancy Complications, Infectious/*virology Pregnancy in Diabetics Pregnancy Outcome Pregnancy Tests Pregnancy Trimester, First Pregnancy, Multiple Pregnant Women Pregnenolone Carbonitrile Prejudice Premenopausal women Prenatal Care Prenatal Diagnosis Prenatal Exposure Delayed Effects Prenylation Preoperative Care Preoptic Area Pressure Presynaptic Terminals Prevalence Primaquine Primary Cell Culture Primary Health Care Primates Principal component analysis principle component analysis Prisoners Probability Probability Sampling Problem Solving Procaine Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase Product Surveillance, Postmarketing Professional Competence Professional-Patient Relations Progesterone Progesterone Congeners Progestins Prognosis Program Development Program Evaluation Programmed Cell Death 1 Ligand 2 Protein Prolactin Proliferating Cell Nuclear Antigen Proliferating Cell Nuclear Antigen/metabolism Proline Proline-Rich Protein Domains Promoter Regions, Genetic Propanolamines Propanols Prophages Prophages: genetics Propidium Propiedad Intelectual Propionates Propionibacterium Proportional Hazards Models Propranolol Propranolol/pharmacology Prosencephalon Prosopis Prospective Studies Prostaglandin D2 Prostaglandins Prostaglandins E Prostaglandins E, Synthetic Prostate prostate cancer Prostate-Specific Antigen Prostatectomy Prostatic Neoplasms Prostatic Neoplasms/*drug therapy Prostatic Neoplasms/*epidemiology/mortality Prostatic Neoplasms/*etiology/*psychology Prostatitis Protamines Protease Inhibitors Protease Nexins Proteasome Endopeptidase Complex protein Protein Array Analysis Protein Binding Protein Binding/immunology Protein Biosynthesis Protein C Protein Carbonylation Protein Conformation Protein Conformation, alpha-Helical Protein Conformation, beta-Strand Protein Deficiency Protein Denaturation Protein Engineering Protein Engineering/*methods Protein Folding Protein Footprinting Protein Inhibitors of Activated STAT Protein Interaction Domains and Motifs Protein Interaction Mapping Protein Isoforms Protein Kinase C Protein Kinase C-alpha Protein Kinase Inhibitors Protein Kinase Inhibitors/administration & dosage/pharmacology Protein Kinases Protein Multimerization Protein Phosphatase 2 Protein Precursors Protein Processing, Post-Translational Protein Sorting Signals Protein Stability Protein Structure, Quaternary Protein Structure, Secondary Protein Structure, Tertiary Protein Subunits Protein Synthesis Inhibitors Protein Transport Protein Tyrosine Phosphatase, Non-Receptor Type 11 Protein Tyrosine Phosphatases Protein-Serine-Threonine Kinases Protein-Serine-Threonine Kinases/*antagonists & inhibitors Protein-Tyrosine Kinases Protein-Tyrosine Kinases/*genetics/physiology Proteins Proteinuria Proteobacteria Proteolysis Proteome Proteomics Proteus Infections Proteus mirabilis Proto-Oncogene Protein c-ets-1 Proto-Oncogene Proteins Proto-Oncogene Proteins c-akt Proto-Oncogene Proteins c-akt/analysis Proto-Oncogene Proteins c-akt/metabolism Proto-Oncogene Proteins c-bcl-2 Proto-Oncogene Proteins c-ets Proto-Oncogene Proteins c-fos Proto-Oncogene Proteins c-fos/*genetics/metabolism Proto-Oncogene Proteins c-kit Proto-Oncogene Proteins c-mdm2 Proto-Oncogene Proteins c-myc Proto-Oncogene Proteins c-myc/genetics/metabolism Proto-Oncogene Proteins c-raf Proto-Oncogene Proteins c-sis/*antagonists & inhibitors Proto-Oncogene Proteins c-vav Proto-Oncogene Proteins pp60(c-src) Proto-Oncogene Proteins/*genetics/physiology Proton-Coupled Folate Transporter Proton-Translocating ATPases Protons Protoplasts Protozoan Proteins Proviruses Prunus Pseudomonas aeruginosa Pseudomonas Infections Pseudomonas/drug effects/genetics/growth & development PSIP1 Psychiatric Nursing Psychiatry Psychogenic vomiting Psychological Theory Psychometrics Psychomotor Disorders Psychomotor Performance Psychoneuroimmunology Psychophysics Psychotherapy Psychotic Disorders PTEN Phosphohydrolase Puberty, Precocious Public Health Public Health Administration Public Opinion Public Policy Public transit Puerperal Disorders Puerto Rico Puerto Rico index Puerto Rico/epidemiology Puerto Rico/epidemiology/ethnology Pulmonary Artery Pulmonary Disease, Chronic Obstructive Pulsatile Flow Pulse Pulse Radiolysis pulsed field pulsed field veterinary Pulsed-Field purification/metabolism/*pharmacology Purinergic P1 Receptor Agonists Purinergic P1 Receptor Antagonists Purinergic P2 Receptor Agonists Purines Purinones Purkinje Cells Purkinje Fibers Putrescine Pyramidal Cells Pyramidal Tracts Pyrans Pyrazoles Pyridines Pyridines/*pharmacology Pyridines/pharmacology Pyridoxine Pyrimethamine Pyrimidines Pyrimidines/administration & dosage/*pharmacology Pyrroles Pyrrolidines Pyruvate Kinase Qa-SNARE Proteins Qa-SNARE Proteins/metabolism Qualitative Research Quality Assurance, Health Care Quality Control Quality of Health Care Quality of Life Quantitative Trait Loci Quantitative Trait, Heritable Quantum Theory quasi-biennial oscillation Quaternary Ammonium Compounds Quercetin Questionnaires Quinazolines Quinolines Quinolinium Compounds quinolinium salts Quinoxalines Quinpirole Quinuclidinyl Benzilate Quisqualic Acid Quorum Sensing R-SNARE Proteins R-SNARE Proteins/metabolism rab GTP-Binding Proteins rab4 GTP-Binding Proteins Rabbits Rabies Rabies Vaccines Rabies virus rac GTP-Binding Proteins rac1 GTP-Binding Protein racismo Raclopride Rad52 DNA Repair and Recombination Protein Radiation Dosage Radiation Tolerance Radioimmunoassay Radioimmunotherapy Radioisotopes Radioligand Assay Radiometry Radius Rain rainfall Rainfall change rainfall index rainfall variability Rainwater isotopic analysis Ralstonia solanacearum Rana pipiens Random Allocation Randomized Controlled Trials as Topic Rank–abundance curve rap GTP-Binding Proteins Raphe Nuclei ras Proteins Rat Rats Rats, Brattleboro Rats, Inbred Dahl Rats, Inbred F344 Rats, Inbred Lew Rats, Inbred SHR Rats, Inbred Strains Rats, Inbred WF Rats, Long-Evans Rats, Mutant Strains Rats, Sprague-Dawley Rats, Transgenic Rats, Wistar Rattus rattus eradication RAW 264.7 Cells Raynaud Disease Reaction Time Reaction Time/genetics Reactive Oxygen Species Reagent Kits, Diagnostic Real-Time Polymerase Chain Reaction Receptor Protein-Tyrosine Kinases Receptor, Angiotensin, Type 1 Receptor, Angiotensin, Type 2 Receptor, Cannabinoid, CB1 Receptor, Cannabinoid, CB2 Receptor, EphA2 Receptor, EphA4 Receptor, EphB4 Receptor, Epidermal Growth Factor Receptor, ErbB-2 Receptor, ErbB-3 Receptor, Fibroblast Growth Factor, Type 1 Receptor, Fibroblast Growth Factor, Type 2 Receptor, IGF Type 1 Receptor, Insulin Receptor, Macrophage Colony-Stimulating Factor Receptor, Metabotropic Glutamate 5 Receptor, Muscarinic M2 Receptor, Muscarinic M4 Receptor, Notch1 Receptor, PAR-1 Receptor, TIE-2 Receptor, trkB Receptor, trkC Receptor-Like Protein Tyrosine Phosphatases, Class 2 Receptor-Like Protein Tyrosine Phosphatases, Class 5 Receptors, Adrenergic Receptors, Adrenergic, alpha Receptors, Adrenergic, alpha-1 Receptors, Adrenergic, alpha-2 Receptors, Adrenergic, beta Receptors, Adrenergic, beta-2 Receptors, Adrenergic, beta/*metabolism Receptors, Adrenergic, beta/drug effects/metabolism Receptors, Adrenergic, beta/metabolism Receptors, Adrenomedullin Receptors, AMPA Receptors, Androgen Receptors, Angiotensin Receptors, Antigen, T-Cell Receptors, Aryl Hydrocarbon Receptors, Atrial Natriuretic Factor Receptors, Biogenic Amine Receptors, CCR5 Receptors, Cell Surface Receptors, Cholinergic Receptors, CXCR Receptors, CXCR4 Receptors, Cytoplasmic and Nuclear Receptors, Dopamine Receptors, Dopamine D1 Receptors, Dopamine D2 Receptors, Dopamine D3 Receptors, Dopamine/metabolism Receptors, Eph Family Receptors, Estrogen Receptors, Fibroblast Growth Factor Receptors, G-Protein-Coupled Receptors, GABA Receptors, GABA-A Receptors, GABA-A/drug effects/genetics/*metabolis Receptors, GABA-B Receptors, Ghrelin Receptors, Glutamate Receptors, Guanylate Cyclase-Coupled Receptors, Immunologic Receptors, Interleukin Receptors, Interleukin-1 Type I Receptors, Interleukin-10 Receptors, Interleukin-12 Receptors, Interleukin-3 Receptors, Interleukin-6/deficiency Receptors, Interleukin-7 Receptors, KIR Receptors, KIR3DL1 Receptors, LDL Receptors, Metabotropic Glutamate Receptors, Mineralocorticoid Receptors, Muscarinic Receptors, N-Methyl-D-Aspartate Receptors, Neurokinin-1 Receptors, Neuropeptide Y Receptors, Neurotensin Receptors, Neurotransmitter Receptors, Nicotinic Receptors, Notch Receptors, Opioid Receptors, Opioid, delta Receptors, Opioid, mu Receptors, Oxytocin Receptors, Peptide Receptors, Progesterone Receptors, Progesterone/genetics/metabolism Receptors, Purinergic P2 Receptors, Purinergic P2Y2 Receptors, Serotonin Receptors, Serotonin, 5-HT1 Receptors, Serotonin, 5-HT2 Receptors, Steroid Receptors, TNF-Related Apoptosis-Inducing Ligand Receptors, Transferrin Receptors, Transforming Growth Factor beta Receptors, Tumor Necrosis Factor Receptors, Tumor Necrosis Factor, Type I Receptors, Tumor Necrosis Factor, Type II Receptors, Vasopressin Recognition (Psychology) Recombinant Fusion Proteins Recombinant Fusion Proteins/chemistry/genetics/metabolism Recombinant Proteins Recombinant Proteins/administration & dosage recombination Recombination, Genetic Recovery of Function Recreation rectum rectum microbiology Recurrence redox state Reelin Reference Standards Reference Values Referral and Consultation Reflector dish Refractometry Refractory Period, Electrophysiological refugees refugiados Regeneration Regional Blood Flow REGIONAL METEOROLOGICAL FORCING regional trend patterns Registries Regression Analysis Regulatory Sequences, Nucleic Acid Regulatory Sequences, Ribonucleic Acid Reinfection Reinforcement Schedule Reishi Reishi/*chemistry Relaciones románticas en el trabajo relevancia cultural Religion Remission Induction Remote sensing Renal Circulation Renin Renin-Angiotensin System reorganization Repetitive Sequences, Nucleic Acid Replication Origin Repressor Proteins Reproducibility of Results Reproduction Research Research Design Residence Characteristics resonance lidar Resource Allocation Respiration Disorders Respiratory failure Respiratory Function Tests Respiratory Physiological Phenomena Respiratory System Response Elements Rest Restraint, Physical Restraint, Physical/psychology Retention (Psychology) Reticulocyte Count Retina Retinal Degeneration Retinal Ganglion Cells Retinal Neoplasms Retinal Pigment Epithelium Retinal Rod Photoreceptor Cells Retinal Vessels Retinaldehyde Retinoblastoma Retinoblastoma Protein Retrospective Studies Retroviridae Proteins Retroviruses, Simian Rett Syndrome Reversal Learning Reverse Transcriptase Inhibitors Reverse Transcriptase Polymerase Chain Reaction Review Reward Rhabdomyosarcoma rhamnogalacturonan Rheology Rhizobiaceae Rhizosphere rho GTP-Binding Proteins Rhodamines Rhodobacter sphaeroides/genetics/*growth & development/metabolism Rhodopsin Rhombencephalon Ribavirin Ribes Ribonucleases Ribonucleoprotein, U1 Small Nuclear Ribosomal Proteins Ribosome Inactivating Proteins, Type 1 Ribosomes ridership Rifampin Right ventricle Risk Risk Assessment Risk Factors Risk Reduction Behavior Risk-Taking Ritonavir Rituximab Rivers RNA RNA Caps RNA Editing RNA Helicases RNA Interference RNA Isoforms RNA Polymerase II RNA Polymerase III RNA Precursors RNA sequencing RNA Splice Sites RNA Splicing RNA, Antisense RNA, Bacterial RNA, Double-Stranded RNA, Fungal RNA, Messenger RNA, Messenger/*genetics RNA, Messenger/genetics/metabolism RNA, Neoplasm RNA, Plant RNA, Protozoan RNA, Ribosomal RNA, Ribosomal, 16S RNA, Ribosomal, 16S/*genetics RNA, Ribosomal, 16S/metabolism RNA, Small Interfering RNA, Small Interfering/*pharmacology RNA, Small Interfering/administration & dosage/*genetics RNA, Small Interfering/metabolism RNA, Viral RNA, Viral/blood/urine RNA-Binding Protein FUS RNA-Binding Proteins RNA-Directed DNA Polymerase Robotics ROC Curve Rod Opsins romance en el trabajo rootkits Rossby waves Rotavirus Rubella Rubella Syndrome, Congenital Rubella Vaccine Rubidium Rural Health Ruthenium complex mediator Ryanodine Receptor Calcium Release Channel S Phase Saccharomyces cerevisiae Saccharomyces cerevisiae Proteins Saccharomycetales Safety SAIDS Vaccines Salicylamides Saliva Salmonella salmonella classification Salmonella enterica salmonella enterica classification salmonella enterica drug effects salmonella enterica isolation & purification salmonella enterica pathogenicity Salmonella enterica: classification Salmonella enterica: genetics Salmonella enterica: isolation & purification salmonella genetics Salmonella Infections Salmonella Infections, Animal Salmonella Infections: epidemiology Salmonella Infections: microbiology Salmonella typhimurium Salmonella: classification Salmonella: genetics Salmonella: isolation & purification Salmonella: pathogenicity Salts Sample Size Sampling Diverse Populations Sampling Studies San Francisco Santonin Saposin-like protein-2 Saposins Saposins/*chemical synthesis/genetics Sarcolemma Sarcoplasmic Reticulum Sarcoplasmic Reticulum Calcium-Transporting ATPases SARS-CoV-2 SARS-CoV-2/genetics SARS-CoV-2/isolation & purification SATELLITE satellite era SATELLITE VEGETATION Satellite vegetation patterns Scalp Scattering, Radiation Schistosoma japonicum Schistosoma mansoni Schistosomiasis Schizophrenia Schizosaccharomyces pombe Proteins Schools, Medical Science Science Activities Science Curriculum Science Education Science Instruction Science Projects Science Teachers Scientists Scopolamine Derivatives Scyphophorus yuccae Sea level rise sea surface height sea surface temperature Sea Urchins Sea-breeze confluence Seasons Seawater Sebum Second Messenger Systems Secondary School Science Secondary structure Secretory Vesicles seiches Seizures selection selectivity Selenium Selenomethionine Self Administration Semen Sensation Sense Organs Sensitivity and Specificity Sensory Gating Sensory Receptor Cells Sentinel Surveillance Sepsis Sequence Alignment Sequence Analysis Sequence Analysis, DNA Sequence Analysis, Protein Sequence Analysis, RNA Sequence Deletion Sequence Homology Sequence Homology, Amino Acid Sequence Homology, Nucleic Acid Serine Serine Endopeptidases Serine Proteinase Inhibitors Seroepidemiologic Studies Serologic Tests Serotonergic Neurons Serotonin Serotonin Uptake Inhibitors serotyping Serpin E2 Serpins/*pharmacology Serum Serum Albumin Sesquiterpenes Sesquiterpenes, Eudesmane Set (Psychology) Severity of Illness Index Sewage Sex Sex Attractants Sex Characteristics Sex Differentiation Sex Distribution Sex Factors Sexual Behavior Sexual Behavior, Animal Sexual Maturation Sexual Partners sexualidad en el trabajo Sexually Transmitted Diseases Sezary Syndrome Shab Potassium Channels Shaker Superfamily of Potassium Channels Sheep Sheep Diseases Shewanella Shock, Septic Shock, Septic/*immunology Shock, Septic/*pathology short-term climate change Shotgun sequencing Sialic Acid Binding Ig-like Lectin 1 Siblings Sigma Factor Signal Transduction Signal Transduction/*immunology Signal Transduction/drug effects Signal Transduction/genetics Silanes Silencer Elements, Transcriptional Silica Silicon Silicon Dioxide Silicones Silk Silver Staining Simian Acquired Immunodeficiency Syndrome Simian immunodeficiency virus Simian T-lymphotropic virus 1 Simian virus 40 simple network management protocol Simplexvirus Single Nucleotide Single-Blind Method Single-Strand Specific DNA and RNA Endonucleases Singlet Oxygen Sinoatrial Node Sirolimus Skin Skin Diseases Skin Neoplasms Skin Physiological Phenomena Skin Tests Skull Sleep Apnea, Central Sleep/*physiology Sleep/drug effects/*genetics Smad4 Protein Small Ubiquitin-Related Modifier Proteins/*genetics/*physiology Smallpox Vaccine Smell Smoking Snails Social Behavior Social Change Social Class Social Conditions Social Determinants of Health Social Environment Social Perception Social policy Social Problems Social sciences Social Stigma Social Support Social Values Social Work social-ecological socialization Societies, Scientific socio-economic development Socioeconomic Factors Sodium Sodium Channel Blockers Sodium Channels Sodium Chloride Sodium Isotopes sodium lidar Sodium Radioisotopes Sodium, Dietary Sodium-Calcium Exchanger Sodium-Hydrogen Antiporter Sodium-Phosphate Cotransporter Proteins, Type I Sodium-Potassium-Exchanging ATPase Soft Tissue Neoplasms Software Soil Soil metagenomics Soil Microbiology Soil Pollutants Solid Phase Extraction Solid Phase Microextraction Solubility Solutions solvation Solvents Somatosensory Cortex Somatostatin Sotalol Sound soundscapes soundscapes á acoustic analysis South Africa South Indian Ocean SOUTH-AFRICA south-eastern Africa southeastern Antilles islands Southern Africa SOXB1 Transcription Factors Soybeans Soybeans/*chemistry Space Perception Spain Spatial Behavior spatial correlations Species richness Species Specificity Specific Pathogen-Free Organisms Specimen Handling Spectinomycin spectrograms á entropy á Spectrometry, Fluorescence Spectrometry, Mass, Electrospray Ionization Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Spectrophotometry Spectrophotometry, Infrared Spectrophotometry, Ultraviolet Spectroscopy, Fourier Transform Infrared Spectrum Analysis Spectrum Analysis, Raman speleothems Sperm Motility Sperm-Ovum Interactions Spermatocidal Agents Spermatogenesis Spermatozoa Spermidine Spermine Sphenophorus cubensis Spheroids, Cellular/drug effects/metabolism Sphingomyelin Phosphodiesterase Spinal Cord Spinal Cord Injuries Spinal Dysraphism Spinal Nerve Roots Spinal Nerves Spindle Apparatus Spine Spiral Ganglion Spiro Compounds Spironolactone Splanchnic Circulation Spleen Spleen/immunology Spliceosomes Spondylarthropathies Spores, Fungal Sporothrix Sporotrichosis Sporozoites src Homology Domains src-Family Kinases src-Family Kinases/*antagonists & inhibitors/genetics/metabolism src-Family Kinases/*genetics/physiology src-Family Kinases/*metabolism src-Family Kinases/chemistry/*metabolism Sri Lanka Staff Development Staining and Labeling Staphylococcal Infections Staphylococcus aureus Staphylococcus epidermidis STAT Transcription Factors STAT1 Transcription Factor STAT3 Transcription Factor/*metabolism Static Electricity Statistical Analysis statistical evaluation statistical teleconnections statistics Statistics as Topic Statistics, Nonparametric Staurosporine Stavudine Stem Cell Transplantation Stem Cells Stereoisomerism Stereotyped Behavior Sterilization, Reproductive Steroid Hydroxylases Steroids Stilbenes STIMULATED GAIN SPECTROSCOPY Stimulation, Chemical Stomach stomata stomatal development stomatal patterning Storm environments Street Drugs streetcar streetcars Streptavidin Streptococcus pneumoniae Streptomycin Streptozocin Stress Disorders, Post-Traumatic Stress, Mechanical Stress, Physiological Stress, Physiological/drug effects Stress, Psychological Stress, Psychological/*complications Stress, Psychological/*pathology Stress, Psychological/immunology/physiopathology Stroke Stromal Cells Strontium Structural Homology, Protein Structure-Activity Relationship Student Attitudes Student Surveys Students, Medical sub-tropical Africa Subcellular Fractions Substance Abuse Detection Substance Abuse, Intravenous Substance P Substance Withdrawal Syndrome Substance-Related Disorders Substantia Nigra substrate Substrate Specificity Subtraction Technique Subtropical Subtropics Succinates Sucrose Suicide, Attempted Sulbactam Sulfadoxine Sulfatases Sulfates Sulfates/metabolism Sulfhydryl Compounds/metabolism Sulfides/metabolism Sulfites Sulfonamides Sulfones Sulfotransferases Sulfur Dioxide/chemistry Sulfur disproportionation Sulfur Radioisotopes Sulfur/*chemistry summer rainfall SUMO-1 Protein Superior Colliculi Superoxide Dismutase Superoxides Superoxides/metabolism Supervisión Supervisor Suppressor of Cytokine Signaling Proteins Suprachiasmatic Nucleus surface air temperature Surface Plasmon Resonance Surface Properties surface water deficit Surgical Procedures, Operative Survival Analysis Survival Rate Survival Rate/trends Survivors sustainability Sustained release suture retention strength Swaziland Sweetening Agents Swimming Swimming Pools Swine Swine Diseases Swine/metabolism Symbiosis Sympathetic Nervous System Synapses Synapsins Synaptic Membranes Synaptic Transmission Synaptic Transmission/physiology Synaptic Vesicles Synaptosomes Syndactyly Syndrome Synovial Membrane Synovitis synthesis. Syphilis Systole T-Lymphocyte Subsets T-Lymphocytes T-Lymphocytes, Cytotoxic T-Lymphocytes, Helper-Inducer Tachycardia Tacrolimus Tail Tamoxifen Tampa Tandem Mass Spectrometry Tanzania Taq Polymerase/genetics tat Gene Products, Human Immunodeficiency Virus tau Proteins Tauopathies tautomerism Taxoids Taxoids/administration & dosage Taxoids/pharmacology Teaching Teaching Methods Technology Technology Assessment. 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Found 45 results Author Title Type
[ Year
]
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2012
O. ; Isayev , Crespo-Hernández, C. E. , Gorb, L. ; , Hill, F. C. ; , and Leszczynski, J.
, “ In silico structure-function analysis of E. cloacae nitroreductase ”
, ProteinsProteins
, vol. 80, pp. 2728-2741, 2012.
R. A. ; Vogt , Gray, T. G. ; , and Crespo-Hernández, C. E.
, “ Subpicosecond intersystem crossing in mono- and di-(organophosphine)gold(I) naphthalene derivatives in solution ”
, J. Am. Chem. Soc.J. Am. Chem. Soc.
, vol. 134, pp. 14808-14817, 2012.
2011
C. ; Reichardt , Guo, C. ; , and Crespo-Hernández, C. E.
, “ Excited-state dynamics in 6-thioguanosine from the femtosecond to microsecond time scale ”
, J. Phys. Chem. BJ. Phys. Chem. B
, vol. 115, pp. 3263-3270, 2011.
L. ; Dodson , Vogt, R. A. ; , Reichardt, C. ; , Marks, J. , and Crespo-Hernández, C. E.
, “ Photophysical and photochemical properties of the pharmaceutical compound salbutamol in aqueous solutions ”
, ChemosphereChemosphere
, vol. 83, pp. 1513-1523, 2011.
Y. ; Díaz-Espinosa , Crespo-Hernández, C. E. , Alegría, A. E. ; , and García, C.
, “ Quenching enhancement of the singlet excited state of pheophorbide-a by DNA in the presence of the quinone carboquone ”
, Photochem. Photobiol.Photochem. Photobiol.
, vol. 87, pp. 275-283, 2011.
J. ; Santos-Pérez , Crespo-Hernández, C. E. , Reichardt, C. ; , Cabrera, C. R. ; , Feliciano-Ramos, I. ; , Arroyo-Ramírez, L. ; , and
Meador, M. A.
, “ Synthesis, Optical Characterization, and Electrochemical Properties of Isomeric Tetraphenylbenzodifurans Containing Electron Acceptor Groups ”
, J. Phys. Chem. AJournal of Physical Chemistry A
, vol. 115, pp. 4157-4168, 2011.
2010
R. A. ; Vogt , Peay, M. A. ; , Gray, T. G. ; , and Crespo-Hernández, C. E.
, “ Excited-state dynamics of (organophosphine)gold(I) pyrenyl isomers ”
, J. Phys. Chem. Lett.J. Phys. Chem. Lett.
, vol. 1, pp. 1205-1211, 2010.
C. ; Reichardt and Crespo-Hernández, C. E.
, “ Room-temperature phosphorescence of the DNA monomer analogue 4-thiothymidine in aqueous solution after UVA excitation ”
, J. Phys. Chem. Lett.J. Phys. Chem. Lett.
, vol. 1, pp. 2239-2243, 2010.
C. ; Reichardt and Crespo-Hernández, C. E.
, “ Ultrafast spin crossover in 4-thiothymidine in an ionic liquid ”
, Chem. Comm.Chem. Comm.
, vol. 46, pp. 5963-5965, 2010.
2009
K. ; De La Harpe , Crespo-Hernández, C. E. , and Kohler, B.
, “ Deuterium isotope effect on excited-state dynamics in an alternating GC oligonucleotide ”
, J. Am. Chem. Soc.J. Am. Chem. Soc.
, vol. 131, pp. 17557-17559, 2009.
C. T. ; Middleton , De La Harpe, K. ; , Su, C. ; , Law, Y. K. ; , Crespo-Hernández, C. E. , and Kohler, B.
, “ DNA excited-state dynamics: from single bases to the double helix ”
, Annu. Rev. Phys. Chem.Annu. Rev. Phys. Chem.
, vol. 60, pp. 217-239, 2009.
K. ; De La Harpe , Crespo-Hernández, C. E. , and Kohler, B.
, “ The excited-state lifetimes in a G×C DNA duplex are nearly independent of helix conformation and base-pairing motif ”
, ChemPhysChemChemPhysChem
, vol. 10, pp. 1421-1425, 2009.
C. ; Reichardt , Vogt, R. A. ; , and Crespo-Hernández, C. E.
, “ On the origin of ultrafast nonradiative transitions in nitro-polycyclic aromatic hydrocarbons: excited-state dynamics in 1-nitronaphthalene ”
, J. Chem. Phys.J. Chem. Phys.
, vol. 131, p. 224518, 2009.
R. A. ; Vogt , Rahman, S. ; , and Crespo-Hernández, C. E.
, “ Structure-Activity Relationships in Nitro-Aromatic Compounds ”
, in Practical Aspects of Computational Chemistry
, J. ; Leszczynski and Shukla, M. K. , Eds.
Netherlands: Springer Science+Business Media, 2009, pp. 217-240.
2008
C. E. Crespo-Hernández , Burdzinski, G. ; , and Arce, R.
, “ Environmental photochemistry of nitro-PAHs: direct observation of ultrafast intersystem crossing in 1-nitropyrene ”
, J. Phys. Chem. AJournal of Physical Chemistry A
, vol. 112, pp. 6313-6319, 2008.
C. E. Crespo-Hernández , De La Harpe, K. ; , and Kohler, B.
, “ Ground-state recovery following UV excitation is much slower in G×C-DNA duplexes and hairpins than in mononucleotides ”
, J. Am. Chem. Soc.J. Am. Chem. Soc.
, vol. 130, pp. 10844-10845, 2008.
D. M. ; Close , Crespo-Hernández, C. E. , Gorb, L. ; , and Leszczynski, J.
, “ Ionization energy thresholds of microhydrated adenine and its tautomers ”
, J. Phys. Chem. AJournal of Physical Chemistry A
, vol. 112, pp. 12702-12706, 2008.
Y. K. ; Law , Azadi, J. ; , Crespo-Hernández, C. E. , Olmon, E. ; , and Kohler, B.
, “ Predicting thymine dimerization yields from molecular dynamics simulations ”
, Biophys. J.Biophys. J.
, vol. 94, pp. 3590-3600, 2008.
D. M. ; Close , Crespo-Hernández, C. E. , Gorb, L. ; , and Leszczynski, J.
, “ Theoretical elucidation of conflicting experimental data on vertical ionization potentials of microhydrated thymine ”
, J. Phys. Chem. AJournal of Physical Chemistry A
, vol. 112, pp. 4405-4409, 2008.
T. ; Takaya , Su, C. ; , De La Harpe, K. ; , Crespo-Hernández, C. E. , and Kohler, B.
, “ UV excitation of single DNA and RNA strands produces high yields of exciplex states between two stacked bases ”
, Proc. Natl. Acad. Sci. USAProc. Natl. Acad. Sci. USA
, vol. 105, pp. 10285-10290, 2008.
2007
C. E. Crespo-Hernández , Close, D. M. ; , Gorb, L. ; , and Leszczynski, J.
, “ Determination of redox potentials for the Watson-Crick base pairs, DNA nucleosides, and relevant nucleoside analogues ”
, J. Phys. Chem. BJ. Phys. Chem. B
, vol. 111, pp. 5386-5395, 2007.
P. M. ; Hare , Crespo-Hernández, C. E. , and Kohler, B.
, “ Internal conversion to the electronic ground state occurs via two distinct pathways for pyrimidine bases in aqueous solution ”
, Proc. Natl. Acad. Sci. USAProc. Natl. Acad. Sci. USA
, vol. 104, pp. 435-440, 2007.
W. J. ; Schreier , Schrader, T. E. ; , Koller, F. O. ; , Gilch, P. ; , Crespo-Hernández, C. E. , Swaminathan, V. N. ; , Carell, T. ; , Zinth, W. ; , and Kohler, B.
, “ Thymine dimerization in DNA is an ultrafast photoreaction ”
, ScienceScience
, vol. 315, pp. 625-629, 2007.
C. E. Crespo-Hernández and Marai, C. N. J.
, “ Vertical singlet excitations energies on adenine dimer: a time dependent density functional study ”
, AIP Conference ProceedingsAIP Conference Proceedings
, vol. 963, pp. 607-610, 2007.
2006
C. E. Crespo-Hernández , Cohen, B. ; , and Kohler, B.
, “ Complexity of excited-state dynamics in DNA ”
, NatureNature
, vol. 441, p. E8, 2006.
Pages 1 2 next › last » | https://www.cienciapr.org/en/user/217/biblio?f%5Btg%5D=L |
Test Extracorporeal Photopheresis (ECP) Treatment Before/After Allogeneic Bone Marrow Transplant (BMT) or Peripheral Blood Stem Cell (PBSC) Transplant to Prevent Graft Versus Host Disease - Full Text View - ClinicalTrials.gov
Test Extracorporeal Photopheresis (ECP) Treatment Before/After Allogeneic Bone Marrow Transplant (BMT) or Peripheral Blood Stem Cell (PBSC) Transplant to Prevent Graft Versus Host Disease
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government.
Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT01174940 Recruitment Status :
Completed First Posted : August 4, 2010 Last Update Posted : January 9, 2017
Sponsor:
University of Kansas Medical Center
Mallinckrodt
Information provided by (Responsible Party):
University of Kansas Medical Center
Study Details
Study Description
Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information
Brief Summary:
To study the effect of ECP with Uvadex® in conjunction with a standard myeloablative conditioning regimen on the incidence of acute and chronic GvHD in patients undergoing an allogeneic related or unrelated BMT or PBSC transplant, for treatment of hematologic or lymphoproliferative malignancies.
Condition or disease Intervention/treatment Phase Stem Cell Leukemia of Unclear Lineage Graft Versus Host Disease Drug: extracorporeal photopheresis Early Phase 1
Detailed Description:
This study is to test the concept that using ECP treatment prior to and after an allogeneic bone marrow transplant (BMT) or peripheral blood stem cell (PBSC) transplant will prevent the development of GvHD. This study is not designed to detect a specific treatment effect. However, some statements about the outcome of the study are possible. A sample size of n = 21 patients could detect a statistically significant difference between the expected rate of GvHD in an untreated population, 60%, and our hypothesized rate, 30%, for the matched-unrelated recipients. This calculation is based on a one-sample, two-sided chi-square test at the 5% level of significance with 80% power.
Patients will receive ECP from day -10 and day -8 before transplant and then from day of engraftment absolute neutrophil count (ANC>500) until day 90 after transplant. Patients who enter the study will receive a BMT or PBSC transplant from a donor who is matched unrelated (8/10 to 10/10 match). Rates of acute GvHD and chronic GvHD that occur in patients are 50-70% for the matched-unrelated donor transplant.
The choice of sample size is 21 patients. The analysis will determine if there are favorable trends for a treatment effect. Comparison on survival, and rates of acute and chronic GvHD will be made with historical controls who have undergone similar myeloablative transplant from an unrelated donor.
Study Design
Layout table for study information Study Type : Interventional
(Clinical Trial) Actual Enrollment : 22 participants Allocation: N/A Intervention Model: Single Group Assignment Masking: None (Open Label) Primary Purpose: Treatment Official Title: A Study of Extracorporeal Photopheresis With UVADEX® in the Setting of a Standard Myeloablative Conditioning Regimen in Related or Unrelated Donor Hematopoietic Stem Cell Transplantation for the Prevention of Graft Versus Host Disease Study Start Date : June 2010 Actual Primary Completion Date : August 2014 Actual Study Completion Date : August 2015
Resource links provided by the National Library of Medicine
Genetic and Rare Diseases Information Center resources: Lymphosarcoma Acute Lymphoblastic Leukemia Myeloid Leukemia Hodgkin Lymphoma Lymphoblastic Lymphoma Homologous Wasting Disease Myelodysplastic Syndromes
U.S. FDA Resources
Arms and Interventions
Arm Intervention/treatment Experimental: Extracorporeal Photopheresis Patients will receive 2 ECP treatments on day -10 and day -8 and then for two consecutive days every two weeks starting from post engraftment (ANC > 500) up to day 90 (total of 10 treatments). This may be given as an outpatient procedure. Drug: extracorporeal photopheresisPatients will receive 2 ECP treatments prior to the commencement of the high dose chemotherapy and then for two consecutive days every two weeks starting from post engraftment (ANC > 500) up to day 90 (total of 10 treatments). This may be given as an outpatient procedure.The dose of UVADEX® used to inoculate these cells will be calculated based on the treatment volume collected during the plasma/buffy coat collection process, using the following formula:Treatment Volume in mL X 0.017 of UVADEX® (20 mcg/ml) required for administration into the recirculation bag = Amount of UVADEX® (in mLs) required for administration into the recirculation bag.After the cells are inoculated with UVADEX®, the buffy coat/plasma suspension is irradiated with ultraviolet-A light and then re-infused back into the patient. Other Names: UVAR UVAR XTS
Outcome Measures
Primary Outcome Measures
:
Presence/absence of grade II-IV acute Graft versus Host Disease (aGVHD) [ Time Frame: 100 days after transplant ]
The primary efficacy variable is the presence/absence of grade II-IV acute GvHD within the first 100 days after transplantation
Secondary Outcome Measures
:
proportion of patients who develop chronic Graft versus Host Disease (cGVHD) and experience relapse of primary disease. [ Time Frame: 365 days after transplantation ]
These secondary efficacy variables for a patient are dichotomous:
the development of cGvHD during 365 days after transplantation (and which body sites are involved)
the relapse of primary disease (hematologic or lymphoproliferative malignancy)
the grade of aGvHD
the involved sites of cGvHD
Eligibility Criteria
Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information
Information from the National Library of Medicine
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
Layout table for eligibility information Ages Eligible for Study: 18 Years and older (Adult, Older Adult) Sexes Eligible for Study: All Accepts Healthy Volunteers: No
Criteria
Inclusion Criteria:
Patients are eligible if they have a diagnosis of one of the following hematologic or lymphoproliferative malignancies for which a treatment option would be an allogeneic BMT or PBSC transplant:
acute myelogenous leukemia
chronic myelogenous leukemia
acute lymphocytic/blastic leukemia
chronic lymphocytic leukemia
myelodysplastic syndrome
non-Hodgkin's lymphoma (expected survival > 60 days)
Hodgkin's disease (expected survival > 60 days)
Patients who are candidates for a standard allogeneic BMT or patients who are candidates for a standard allogeneic PBSC transplant.
Patients must have a suitable HLA- molecular matched (8/10 or more) related or unrelated donor.
Patients must be physically and psychologically capable of undergoing a BMT or PBSC transplant and the attendant period of strict isolation.
Patients must test negative for human immunodeficiency virus (HIV).
Patients must present no evidence of active ongoing infection.
Patients must have adequate renal, hepatic, pulmonary, and cardiac function to enable the patient to tolerate the extracorporeal volume shifts associated with ECP, as determined by the physician's clinical judgment.
Platelets ≥ 20,000/cmm.
Patients ≥ 18 years of age.
Weight ≥ 40 kg (88 lb).
Systolic Blood Pressure ≥ 90 mm Hg after the patient has been in a sitting position for five minutes.
Women of childbearing potential must agree to use a reliable method of birth control for the duration of the study.
Patients must be willing to comply with all study procedures.
Signed and dated informed consent must be obtained prior to conducting any study procedures. The parent or legal guardian of a minor must also provide written informed consent.
Exclusion Criteria
Patients who have received a prior allogeneic BMT or PBSC transplant.
Hypersensitivity or allergy to psoralen (methoxsalen).
Contraindication to radiation, cyclophosphamide, CSA, Busulphan or MTX.
Hypersensitivity or allergy to both heparin and citrate products. (If hypersensitive or allergic to only one of these two products, exclusion does not apply if the other product is strictly used for the patient.)
Patients whose treatment requires donor lymphocyte infusion up to day 100 post-transplant.
Participation in another clinical trial for prevention of GvHD within 7 days prior to patient enrollment or concurrent participation in any other clinical study.
Active gastrointestinal bleeding.
Females who are pregnant or lactating.
Previous treatment with ECP.
Contacts and Locations
Go to
Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01174940
Locations
Layout table for location information United States, Kansas University of Kansas Medical Center Kansas City, Kansas, United States, 66160
Sponsors and Collaborators
University of Kansas Medical Center
Mallinckrodt
Investigators
Layout table for investigator information Principal Investigator: Sunil Abhyankar, MD University of Kansas Medical Center
Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information
Layout table for additonal information Responsible Party: University of Kansas Medical Center ClinicalTrials.gov Identifier: NCT01174940 History of Changes Other Study ID Numbers: 12047 First Posted: August 4, 2010 Key Record Dates Last Update Posted: January 9, 2017 Last Verified: January 2017
Keywords provided by University of Kansas Medical Center:
myelogenous leukemia lymphocytic leukemia lymphoblastic leukemia myelodysplastic syndrome non-Hodgkin's lymphoma Hodgkin's disease
Additional relevant MeSH terms:
Layout table for MeSH terms Leukemia Graft vs Host Disease Neoplasms by Histologic Type Neoplasms Immune System Diseases
To Top
U.S. Department of Health and Human Services
| https://clinicaltrials.gov/ct2/show/NCT01174940 |
Stamp Duties (Conveyance Directions) (Remission) Rules 2015 - Singapore Statutes Online
Singapore Statutes Online is provided by the Legislation Division of the Singapore Attorney-General's Chambers
Stamp Duties (Conveyance Directions) (Remission) Rules 2015
Status:
Published in Subsidiary Legislation Supplement on 21 Dec 2015
—(1) Where — ( a ) a person (called in this rule the vendor) enters into a contract or agreement (called in this rule the contract) to transfer any immovable property to another person (called in this rule the initial purchaser); ( b ) the initial purchaser, before having obtained a conveyance of the immovable property, by direction in writing (called in this rule the conveyance direction), directs the vendor — (i) to convey or transfer that immovable property or any part of or share in that property to any person who is not a party to that contract (called in this rule the ultimate purchaser); or (ii) to convey or transfer the property to the initial purchaser (being more than one person) in shares other than as specified in the contract; ( c ) either — (i) in the case of sub-paragraph ( b )(i), the initial purchaser or, if the initial purchaser comprises more than one person, the initial purchasers (excluding one whose share in the property as specified in the contract, and in the conveyance direction, is the same), is or are related to the ultimate purchaser; or (ii) in the case of sub-paragraph ( b )(ii), the initial purchasers (excluding one whose share in the property as specified in the contract, and in the conveyance direction, is the same) are related to each other; and ( d ) the Commissioner is satisfied that — (i) no consideration with regard to that property is paid or agreed to be paid — (A) in the case of sub-paragraph ( b )(i), between the initial purchaser and the ultimate purchaser; or (B) in the case of sub-paragraph ( b )(ii), between the initial purchasers; (ii) duty had been duly paid upon the contract; (iii) in the case of sub-paragraph ( b )(i), either — (A) the initial purchaser; or (B) if the initial purchaser comprises more than one person, at least one of them, is also named in the conveyance direction as an ultimate purchaser; and (iv) the conveyance direction is made not more than 2 months after the date of the contract, there is to be remitted any unremitted duty chargeable on the conveyance direction under sections 22(4) and 22A of the Act, up to the limits specified in paragraphs (2) and (3).
(2) In the case of paragraph (1)( b )(i), the amount of ABSD remitted under this rule cannot be more than the amount derived by the following formula: where X is the amount of any unremitted ABSD chargeable on the contract to which the conveyance direction relates, and paid; Y is the amount of unremitted ABSD that (but for the operation of this rule) would have been chargeable on the conveyance direction; and Z is the amount of unremitted ABSD that would have been chargeable on the contract if all the ultimate purchasers named in the conveyance direction were purchasers under the contract.
(3) If the amount derived by the formula under paragraph (2) is zero or negative, then there is to be no remission under this rule of any ABSD chargeable on the conveyance direction in the case of paragraph (1)( b )(i).
(4) In paragraph (1)( c ), a person is related to another if he or she is the spouse, a parent, a child, or a sibling of the other.
(5) In paragraph (4), “child”, in relation to a person, means a legitimate child or stepchild of the person or a child adopted by the person in accordance with any written law relating to adoption.
| https://sso.agc.gov.sg/SL-Supp/S778-2015/Published?ProvIds=pr5- |
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G.14 Monthly Report of Assets and Liabilities of Large International Banking Facilities
G.14 U.S. Government Security Yields and Prices
G.15 Interdistrict Settlement Fund
G.16 Retail Furniture Report
G.16 Summary of Equity Security Transactions and Ownership of Directors, Officers, and Principal Stockholders of Member State Banks as Reported Pursuant to Section 16(a) of the Securities Exchange Act of 1934
G.17.2 Retail Instalment Credit at Furniture and Household Appliance Stores
G.17 Department Store Credit
G.17 Industrial Production and Capacity Utilization
G.17 Maturity Distribution of Euro-Dollar Deposits in Foreign Branches of U.S. Banks
G.18 Consumer Instalment Credit at Commercial Banks
G.19 Consumer Credit
G.20 Finance Companies
G.20 Sales Finance Companies
G.21 Commercial and Industrial Loan Commitments at Selected Large Commercial Banks
G.21 Consumer Loans Made Under Effective State Small Loan Laws
G.25 Automobile Loans by Major Finance Companies
G.26 Automobile Instalment Credit Developments
G.27 Commercial and Industrial Loans to U.S. Addresses, Excluding Bankers' Acceptances and Commercial Paper, by Industry
G.3 Capacity Utilization, Manufacturing, Mining, Utilities and Industrial Materials
G.4.5 Changes in Status of Banks and Branches
G.4 State Member Banks of the Federal Reserve System and Nonmember Banks that Maintain Clearing Accounts with Federal Reserve Banks and Corporations Doing Foreign Banking or Financing that Maintain Reserve Accounts with the Federal Reserve Banks
G.5a Foreign Exchange Rates
G.5 Foreign Exchange Rates
G.6 Bank Debits and Deposit Turnover
G.6 Debits and Deposit Turnover at Commercial Banks
G.7.1 Assets and Liabilities of All Member Banks by Districts
G.7.2 Monthly Department Store Sales, Selected Cities and Areas
G.7.3 Monthly Department Store Sales by Departments
G.7.4.1 Department Store Merchandising Data
G.7.4.2 Monthly Department Store Stocks
G.7 Loans and Securities at All Commercial Banks
G.8 Index Numbers of Wholesale Prices
G.9 Maturity Distribution of Outstanding Negotiable Time Certificates of Deposit at Large Commercial Banks
Gallery of Governors and Presidents of the Federal Reserve Bank of St. Louis
GAO Reports & Testimonies
Garn-St Germain Depository Institutions Act of 1982
The Gasoline and Fuel Oil Shortage : Hearings Before the Subcommittee on Consumer Economics of the Joint Economic Committee, Congress of the United States, Ninety-Third Congress, First Session, May 1, 2, and June 2, 1973
Gasoline Distribution : Hearings Before the Subcommittee on Consumer Economics of the Joint Economic Committee, Congress of the United States, Ninety-Third Congress, Second Session, March 12 and 14, 1974
Gasoline Shortages : Hearings Before the Subcommittee on Economic Stabilization of the Committee on Banking, Housing, and Urban Affairs, United States Senate, Ninety-Sixth Congress, First Session, May 22 and June 6, 1979
General Maximum Price Regulation : Bulletin of the United States Bureau of Labor Statistics, No. 879
General Records of the Department of Labor, Record Group 174
General Records of the Department of the Treasury, Record Group 56
Genworth Announces Filing for Savings and Loan Holding Company Status
Geographic Profile of Employment and Unemployment
George Leslie Harrison Papers on the Federal Reserve System, [ca. 1920]-1940
German Bank Inquiry of 1908 : Stenographic Reports
German Bank Inquiry of 1908 : Stenographic Reports
The German Great Banks and Their Concentration in Connection with the Economic Development of Germany
German Great Banks and Their Concentration in Connection with the Economic Development of Germany, Box 5, Item 8
German Imperial Banking Laws
Getting Ahead of the Curve : Assessing Card-Not-Present Fraud in the Mobile Payments Environment
Getting Started : Urban Youth in the Labor Market, Research Monograph XXVI
The Global Alphabet : A Method of Teaching English to the World, Box 1, Folder 5, Item 1
The Global Context and International Effects of the TARP : Congressional Oversight Panel August Oversight Report
The Global Financial Crisis : Analysis and Policy Implications
The Global Financial Crisis : Foreign and Trade Policy Effects
The Global Financial Crisis : Increasing IMF Resources and the Role of Congress
Glossary of Current Industrial Relations and Wage Terms : Bulletin of the United States Bureau of Labor Statistics, No. 1438
Glossary of Currently Used Wage Terms : Bulletin of the United States Bureau of Labor Statistics, No. 983
Glossary, Weekly Federal Reserve Statements
GMAC Financial Services and the Troubled Asset Relief Program : Hearing Before the Congressional Oversight Panel, One Hundred Eleventh Congress, Second Session, Hearing Held in Washington, DC, February 25, 2010
GM Agreement with U.S. Treasury and Canadian Governments Providing Fast Track to Competitive Future for 'New GM'
Going Places
Gold Regulations
Gold Regulations Prescribed by the Secretary of the Treasury Under the Executive Order of August 28, 1933 Relating to the Hoarding, Export, and Earmarking of Gold Coin, Bullion, or Currency and to Transactions in Foreign Exchange and the Executive Order of August 29, 1933 Relating to the Sale and Export of Gold Recovered from Natural Deposits
Gold Reserve Act of 1934
Gold Reserve Act of 1934 : Hearings Before the Committee on Banking and Currency, United States Senate, Seventy-Third Congress, Second Session, on S. 2366, January 19 to 23, 1934
Gold Reserve Act of 1934 : Hearings Before the Committee on Coinage, Weights and Measures, House of Representatives, Seventy-Third Congress, Second Session, on H.R. 6976, [January 15, 16, 18, 19, 20, 1934]
Gold, SDR's, and Central Bank Swaps : Report of the Subcommittee on International Exchange and Payments of the Joint Economic Committee, Congress of the United States
Gone to Texas : Immigration and the Transformation of the Texas Economy
Government Aid to Home Owning and Housing of Working People in Foreign Countries : Bulletin of the United States Bureau of Labor Statistics, No. 158
Government Ownership of the Twelve Federal Reserve Banks : Hearings Before the Committee on Banking and Currency, House of Representatives, Seventy-Fifth Congress, Third Session, on H.R. 7230, March 2, 3, 4, 14, 15, 16, 17, 21, 22, 23, 24, 28, 31, April 5, 6, 7, 12, 13, 19, 1938
Government Securities Market Performance in the Wake of Official Operations In Coupon Issues Day-To-Day Performance : Staff Study
Government Securities Market : Summary of Treasury-Federal Reserve Study
Government Securities Reform : Hearings Before the Subcommittee on Telecommunications and Finance of the Committee on Energy and Commerce, House of Representatives, One Hundred Third Congress, First Session, on H.R. 616 and H.R. 618, March 17 and 30, 1993
Grain Futures Act of 1922
A Graphic Summary of Agricultural Credit
The Great Inflation of the Seventies : What Really Happened?
Grievance and Arbitration Procedures in State and Local Agreements : Bulletin of the United States Bureau of Labor Statistics, No. 1833
Group Banking in the United States
Growth of Legal Aid Work in the United States: A Study of Our Administration of Justice Primarily as It Affects the Wage Earner and of the Agencies Designed to Improve His Position before the Law : Bulletin of the United States Bureau of Labor Statistics, No. 398
Growth of Legal-Aid Work in the United States: A Study of Our Administration of Justice Primarily as It Affects the Wage Earner and of the Agencies Designed to Improve His Position before the Law : Bulletin of the United States Bureau of Labor Statistics, No. 607
Guaranteed-Employment and Annual-Wage Provisions in Union Agreements Effective January 1945 : Bulletin of the United States Bureau of Labor Statistics, No. 828
Guaranteed Wage or Employment Plans : Bulletin of the United States Bureau of Labor Statistics, No. 906
Guaranteed Wage Plans in the United States : Bulletin of the United States Bureau of Labor Statistics, No. 925
Guarantees and Contingent Payments in TARP and Related Programs : Congressional Oversight Panel November Oversight Report
A Guide to Hiring Women with Disabilities
A Guide to Labour-Management Relations in the United States
A Guide to Seasonal Adjustment of Labor Force Data : Bulletin of the United States Bureau of Labor Statistics, No. 2114
Guide to the Flow of Funds Accounts, 1993
Guide to the Flow of Funds Accounts, 2000
G. William Miller Papers, 1977-1981
H
H.10 Foreign Exchange Rates
H.13 Selected Interest and Exchange Rates, Weekly Series of Charts
H.15 Selected Interest Rates
H.16 Capital Market Developments
H.2 Actions of the Board, Its Staff, and the Federal Reserve Banks; Applications and Reports Received
H.3 Aggregate Reserves of Depository Institutions and the Monetary Base
H.4.1 Factors Affecting Reserve Balances of Depository Institutions and Condition Statement of Federal Reserve Banks
H.4.2 Weekly Consolidated Condition Report of Large Commercial Banks in the United States
H.4.3 Condition of Weekly Reporting Member Banks in New York and Chicago
H.5 Selected Borrowings in Immediately Available Funds of Large Commercial Banks
H.6 Money Stock Measures
H.7 Deposits, Reserves and Borrowings of Member Banks
H.8 Assets and Liabilities of Commercial Banks in the United States
H.8 Assets and Liabilities of Insured Domestically Chartered and Foreign-Related Banking Institutions
H.8a Weekly Department Store Sales
H.8b Weekly Department Store Sales - Selected Cities and Areas
H.9 Weekly Summary of Reserves and Interest Rates
A Half Century of Federal Reserve Policymaking, 1914-1964
HAMP Activity by Metropolitan Statistical Area
HAMP Application Activity by Servicer
HAMP Performance Summary
Handbook of American Trade-Unions : Bulletin of the United States Bureau of Labor Statistics, No. 420
Handbook of American Trade-Unions : Bulletin of the United States Bureau of Labor Statistics, No. 506
Handbook of American Trade-Unions : Bulletin of the United States Bureau of Labor Statistics, No. 618
Handbook of Cyclical Indicators
Handbook of Facts on Women Workers : Bulletin (United States. Women's Bureau)
Handbook of Labor Statistics
Handbook on Women Workers : Bulletin (United States. Women's Bureau)
Handling of Rail Disputes Under the Railway Labor Act, 1950-69 : Bulletin of the United States Bureau of Labor Statistics, No. 1753
Harry S. Truman Papers
The Hartford Announces Agreement to Acquire Federal Trust Bank and Application to U.S. Treasury Capital Purchase Program
Hart-Scott-Rodino Antitrust Improvements Act of 1976
Health and Insurance Benefits and Pension Plans for Salaried Employees, Spring 1963 : Bulletin of the United States Bureau of Labor Statistics, No. 1405
Health and Insurance Plans Under Collective Bargaining: Accident and Sickness Benefits, Fall 1958 : Bulletin of the United States Bureau of Labor Statistics, No. 1250
Health and Insurance Plans Under Collective Bargaining : Hospital Benefits, Early 1959 : Bulletin of the United States Bureau of Labor Statistics, No. 1274
Health and Insurance Plans Under Collective Bargaining : Life Insurance and Accidental Death and Dismemberment Benefits, Early Summer 1960 : Bulletin of the United States Bureau of Labor Statistics, No. 1296
Health and Insurance Plans Under Collective Bargaining : Major Medical Expense Benefits, Fall 1960 : Bulletin of the United States Bureau of Labor Statistics, No. 1293
Health and Insurance Plans Under Collective Bargaining : Surgical and Medical Benefits, Late Summer 1959 : Bulletin of the United States Bureau of Labor Statistics, No. 1280
Health and Recreation Activities in Industrial Establishments, 1926 : Bulletin of the United States Bureau of Labor Statistics, No. 458
The Health and Safety of Women in Industry : Women's Bureau Bulletin, No. 136
Health-Benefit Programs Established Through Collective Bargaining, 1945 : Bulletin of the United States Bureau of Labor Statistics, No. 841
Health Care Costs and Their Effects on the Economy : Hearings Before the Joint Economic Committee, Congress of the United States, Ninety-Eighth Congress, Second Session, April 12 and August 29, 1984
Health, Insurance, and Pension Plans in Union Contracts : Bulletin of the United States Bureau of Labor Statistics, No. 1187
Health Problems of Women in Industry : Women's Bureau Bulletin, No. 18
Health Survey of the Printing Trades, 1922 to 1925 : Bulletin of the United States Bureau of Labor Statistics, No. 427
Hearing before the Federal Reserve Board on Behalf of the City of Louisville, Petitioning For a Branch Federal Reserve Bank of the St. Louis Reserve District, Washington, D.C., December 21, 1916
Hearing on Farm Credit : Congressional Oversight Panel, One Hundred Eleventh Congress, First Session, Hearing Held in Greeley, CO, June 7, 2009
Hearings Before the Committee on Banking and Currency, Fifty-Third Congress, First and Second Session (1893-1894)
Hearings before the Reserve Bank Organization Committee - Atlanta, Georgia
Hearings before the Reserve Bank Organization Committee - Austin, Texas
Hearings before the Reserve Bank Organization Committee - Boston, Massachusetts
Hearings before the Reserve Bank Organization Committee - Chicago, Illinois
Hearings before the Reserve Bank Organization Committee - Cincinnati, Ohio
Hearings before the Reserve Bank Organization Committee - Cleveland, Ohio
Hearings before the Reserve Bank Organization Committee - Denver, Colorado
Hearings before the Reserve Bank Organization Committee - El Paso, Texas
Hearings before the Reserve Bank Organization Committee - Kansas City, Missouri
Hearings before the Reserve Bank Organization Committee - Lincoln, Nebraska
Hearings before the Reserve Bank Organization Committee - Los Angeles, California
Hearings before the Reserve Bank Organization Committee - New Orleans, Louisiana
Hearings before the Reserve Bank Organization Committee - New York, New York
Hearings before the Reserve Bank Organization Committee - Portland, Oregon
Hearings before the Reserve Bank Organization Committee - Saint Louis, Missouri
Hearings before the Reserve Bank Organization Committee - San Francisco, California
Hearings before the Reserve Bank Organization Committee - Seattle, Washington
Hearings before the Reserve Bank Organization Committee - Washington, D.C.
Hearing with Herbert M. Allison, Jr., Assistant Secretary of the Treasury for Financial Stability : Hearing Before the Congressional Oversight Panel, One Hundred Eleventh Congress, First Session, October 22, 2009
Hearing with Secretary Timothy Geithner : Hearing Before the Congressional Oversight Panel, One Hundred Eleventh Congress, Second Session, Hearing Held in Washington, DC, June 22, 2010
Hearing with Treasury Secretary Geithner : Hearing Before the Congressional Oversight Panel, One Hundred Eleventh Congress, [Second] Session, Hearing Held in Washington, DC, December 16, 2010
Hearing with Treasury Secretary Steven T. Mnuchin - The Trump Administration's Response to the Economic Crisis : Hearing before the Select Subcommittee on the Coronavirus Crisis, One Hundred Sixteenth Congress, Second Session, September 1, 2020
Hearing with Treasury Secretary Timothy Geithner : Hearing, Congressional Oversight Panel, One Hundred Eleventh Congress, First Session, December 10, 2009
Hedge Funds and Systemic Risk: Perspectives of the President's Working Group on Financial Markets : Hearing Before the Committee on Financial Services, U.S. House of Representatives, One Hundred Tenth Congress, First Session, July 11, 2007
Hedge Funds and the Financial Market : Hearing Before the Committee on Oversight and Government Reform, United States House of Representatives, One Hundred Tenth Congress, Second Session, November 13, 2008
Helping Families Save Their Homes Act of 2009
Herb Allison, Assistant Secretary of the Treasury for Financial Stability : Hearing Before the Congressional Oversight Panel, One Hundred Eleventh Congress, First Session, Hearing Held in Washington, DC, June 24, 2009
Higher Interest Rates on Time Deposits of Foreign Governments : Report (To Accompany H.R. 12080)
Highlights, 1920-1960
Highlights of Women's Earnings in...
High-Wage Jobs in a Competitive Global Economy : Hearing Before the Joint Economic Committee, Congress of the United States, One Hundred Second Congress, Second Session, September 16, 1992
An Historical Analysis of the Economic Growth of St. Louis, 1840-1945
Historical and Projected Input-Output Tables of the Economic Growth Project : Bulletin of the United States Bureau of Labor Statistics, No. 2056
Historical Statistics of the United States : Colonial Times to 1957
Historical Statistics of the United States : Colonial Times to 1970
Historical Survey of International Action Affecting Labor : Bulletin of the United States Bureau of Labor Statistics, No. 268
Historical Tables, Budget of the United States Government
The History and Methods of the Paris Bourse
History and Methods of the Paris Bourse, Box 5, Item 7
The History of Banking in Canada
History of Banking in Canada, Box 5, Item 1
History of Crises Under the National Banking System
History of Crises Under the National Banking System, Box 5, Item 3
History of Labor Legislation for Women in Three States : Women's Bureau Bulletin, No. 66-I
A History of Modern Banks of Issue
A History of Savings Banks in the United States from Their Inception in 1816 Down to 1874 : With Discussions of Their Theory, Practical Workings and Incidents, Present Condition and Prospective Development
History of the Bank of England and Its Financial Services to the State
History of the Bank of England and Its Financial Services to the State, Box 6, Item 4
History of the Eighties : Lessons for the Future
A History of the Federal Reserve Bank of Atlanta, Sixth District
A History of the Federal Reserve Bank of Dallas
History of the Legal Tender Paper Money Issued During the Great Rebellion : Being a Loan Without Interest and a National Currency
History of the National-Bank Currency
History of the Shipbuilding Labor Adjustment Board, 1917 to 1919 : Bulletin of the United States Bureau of Labor Statistics, No. 283
History of Wages in the United States From Colonial Times to 1928 : Bulletin of the United States Bureau of Labor Statistics, No. 499
History of Wages in the United States From Colonial Times to 1928 : Bulletin of the United States Bureau of Labor Statistics, No. 604
Home Economics Occupations Series : Women's Bureau Bulletin, No. 234
Home Environment and Employment Opportunities of Women in Coal-Mine Workers' Families : Women's Bureau Bulletin, No. 45
Home Mortgage Disclosure Act
Homeowner Downpayment Assistance Programs and Related Issues : Hearing Before the Subcommittee on Housing and Community Opportunity of the Committee on Financial Services, U.S. House of Representatives, One Hundred Tenth Congress, First Session, June 22, 2007
Homeownership Preservation : Federal Efforts to Combat Foreclosure Rescue Schemes Are Under Way, But Improved Planning Elements Could Enhance Progress
Homeowners' Insurance Discrimination : Hearing Before the Committee on Banking, Housing, and Urban Affairs, United States Senate, One Hundred Third Congress, Second Session, May 11, 1994
Home Owners' Loan Act of 1933
Homes for Aged in the United States : Bulletin of the United States Bureau of Labor Statistics, No. 677
Home Work in Bridgeport Connecticut : Women's Bureau Bulletin, No. 9
HOPE NOW Alliance Created to Help Distressed Homeowners
Hourly Earnings Index, 1964-August 1975 : Bulletin of the United States Bureau of Labor Statistics, No. 1897
Hourly Earnings in ... Industries : Selected Wage Areas
Hourly Earnings in Private Ship-Repair Yards, Spring 1943 : Bulletin of the United States Bureau of Labor Statistics, No. 763
Hourly Earnings in Private Shipyards, 1942 : Bulletin of the United States Bureau of Labor Statistics, No. 727
Hourly Earnings in the Ammunition-Loading Industry, 1944 : Bulletin of the United States Bureau of Labor Statistics, No. 827
Hourly Entrance Rates of Common Laborers in Large Cities, Spring and Summer of 1943 : Bulletin of the United States Bureau of Labor Statistics, No. 775
Hourly Entrance Rates Paid to Common Laborers 1942 : Bulletin of the United States Bureau of Labor Statistics, No. 733
Hours and Conditions of Work for Women in Industry in Virginia : Women's Bureau Bulletin, No. 10
Hours and Earnings in Certain Men's-Wear Industries : Women's Bureau Bulletin, No. 163
Hours and Earnings in the Fertilizer Industry, January 1943 : Bulletin of the United States Bureau of Labor Statistics, No. 751
Hours and Earnings in the Leather-Glove Industry : Women's Bureau Bulletin, No. 119
Hours and Earnings in the United States, 1932-40: With Supplement for 1941 : Bulletin of the United States Bureau of Labor Statistics, No. 697
Hours and Earnings in Tobacco Stemmeries : Women's Bureau Bulletin, No. 127
Hours, Earnings, and Conditions of Labor of Women in Indiana Mercantile Establishments and Garment Factories : Bulletin of the United States Bureau of Labor Statistics, No. 160
Hours, Earnings, and Duration of Employment of Wage-Earning Women in Selected Industries in the District of Columbia : Bulletin of the United States Bureau of Labor Statistics, No. 116
Hours, Earnings, and Employment in Cotton Mills : Women's Bureau Bulletin, No. 111
Hours, Fatigue, and Health in British Munition Factories: Reprints of the Memoranda of the British Health of Munition Workers Committee : Bulletin of the United States Bureau of Labor Statistics, No. 221
Hours of Work and Output : Bulletin of the United States Bureau of Labor Statistics, No. 917
House Banking and Currency Bill : Comparative Print, H.R. 7837
Household Employment in Chicago : Women's Bureau Bulletin, No. 106
Household Employment in Philadelphia : Women's Bureau Bulletin, No. 93
Housing and Community Development Act of 1977 and Community Reinvestment Act of 1977
Housing and Community Development Act of 1977 : Hearings Before the Subcommittee on Housing and Community Development of the Committee on Banking, Finance and Urban Affairs, House of Representatives, Ninety-Fifth Congress, First Session
Housing and Community Development Act of 1992
Housing and Economic Recovery Act of 2008
Housing by Employers in the United States : Bulletin of the United States Bureau of Labor Statistics, No. 263
Housing Costs and Inflation : Hearings Before the Committee on the Budget, United States Senate, Ninety-Fifth Congress, Second Session, July 14, 1978
Housing Market Conditions
Housing Market Perspectives
Housing, Social Security, and Public Works
Houston Business : A Perspective on the Houston Economy
How Open is the U.S. Economy? : Papers Presented at the Federal Reserve Bank of St. Louis's Tenth Annual Economic Conference, October 12-13, 1985
How the Government Measures Unemployment
How to Pay for the War : A Radical Plan for the Chancellor of the Exchequer
How to Use Current Business Statistics
How Workers Get Their Training : Bulletin of the United States Bureau of Labor Statistics, No. 2226
H.R. 10280: A Bill to Amend the Act Approved December 23, 1913, Known as the Federal Reserve Act; to Define Certain Policies Toward Which the Powers of the Federal Reserve System Shall Be Directed; to Further Promote the Maintenance of a Stable Gold Standard; to Promote and Maintain, So Far as Such Purpose May Be Accomplished by Monetary and Credit Policy, a Stable Purchasing Power of the Dollar at Approximately the Wholesale Commodity Price Level of the Year 1926 ; to Direct the Governor of the Federal Reserve Board to Make Public Any Change in Its Policies; and for Other Purposes. : 72d Congress, 1st Session, Box 1, Folder 6, Item 3
H.R. 11, A Bill to Make the Federal Reserve System Responsive to the Best Interests of the People of the United States and to Improve the Coordination of Monetary, Fiscal, and Economic Policy : 89th Congress, 1st Session
H.R. 2316, A Bill to Amend the Federal Reserve Act, as Amended, to Provide That the Absorption of Exchange and Collection Charges Shall Not Be Deemed the Payment of Interest on Deposits : 80th Congress, 1st Session
H.R. 28; the Federal Reserve Accountability Act of 1993 : Hearing Before the Committee on Banking, Finance, and Urban Affairs, House of Representatives, One Hundred Third Congress, First Session, October 19, 1993
H.R. 28; the Federal Reserve Accountability Act of 1993 : Hearing Before the Committee on Banking, Finance, and Urban Affairs, House of Representatives, One Hundred Third Congress, First Session, October 27, 1993
H.R. 4145, A Bill to Provide for a More Equitable Distribution of the Earnings of Federal Reserve Banks : 68th Congress, 1st Session
H.R. 4332, The Financial Consumer Hotline Act of 2007: Providing Consumers with Easy Access to the Appropriate Banking Regulator : Hearing Before the Subcommittee on Financial Institutions and Consumer Credit of the Committee on Financial Services, U.S. House of Representatives, One Hundred Tenth Congress, First Session, December 12, 2007
H.R. 5661, A Bill to Provide for the Safer and More Effective Use of the Assets of Banks, to Regulate Interbank Control, to Prevent the Undue Diversion of Funds into Speculative Operations, and for Other Purposes : 73d Congress, 1st Session
Humanity in Government : Bulletin of the United States Bureau of Labor Statistics, No. 346
Hygiene of the Painters' Trade : Bulletin of the United States Bureau of Labor Statistics, No. 120
Hygiene of the Printing Trades : Bulletin of the United States Bureau of Labor Statistics, No. 209
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ICC Online Privacy Policy - ICC
ICC Online Privacy Policy
Introduction
The International Code Council, Inc., International Accreditation Service, Inc., ICC Evaluation Service, LLC, Solar Rating and Certification Corporation, S.K. Ghosh Associates, LLC, General Code, LLC, ICC Community Development Solutions, LLC, ICC NTA, LLC, Alliance for National & Community Resilience, Inc., ICC PEI, LLC, and their respective affiliates and subsidiaries (collectively, "ICC," “we,” “us,” or “our”) are strongly committed to respecting and protecting your privacy. Please carefully read the following Privacy Policy (“Policy”). Any person accessing, browsing or otherwise using any ICC Web site or online service or other service where this Policy is posted (collectively, the "Site") either manually or via an automated device or program, shall be considered a "User." This Policy explains the type of information that ICC collects from our Users of the Site and when you otherwise interact with us, what ICC does with that information, and with whom ICC shares this information. The data controllers for your information include all of the above listed ICC entities, who are located at 4051 Flossmoor Rd., Country Club Hills, IL 60478.
User Acknowledgment of ICC’s Privacy Practices
By accessing, browsing or using the Site, Users acknowledge that they have read, understand, and agree to the terms and conditions of the Policy. Users agree to the collection, use, and disclosure of User's personally identifiable information ("Personal Information"), including information collected from or about you or the device you use to access the Site (together “Information”) pursuant to the terms of this Policy. If you do not agree to these terms and conditions, please do not access, browse, or use this Site or otherwise provide Information to ICC.
The Information ICC Collects
Category of Personal Information Collected Source Purpose for Collection Categories of Recipients Contact information: such as name, address, and phone number. When you (a) submit an application for membership; (b) submit Information to become a volunteer; (c) submit Information at a seminar or other event; (d) register for an account; (e) purchase a product through the Site; (f) submit Information through our forums; (g) provide Information to ICC outside of the Site; (h) participates in a sweepstakes, contest, or survey; or (i) engages in any other activity through the Site in which Information is provided to ICC. To communicate with and respond to Users about the products and services we provide or about your account, including verification of identity or to meet legal obligations. We may share this information with select marketing, information technology, or other service providers and partners. Other identifiers: Such as your username, data of birth, gender, and age From our Users in the contexts described above. For the purposes described above. Our service providers Professional Information: Such as information about your professional expertise and experience, including your title, company name, industry, technical specialty, trade and/or organization(s)/associations(s) to which you belong From our Users in the contexts described above. Browsing information: This information may include (a) IP addresses, geo-location information, unique device identifiers and other information about your mobile phone or other mobile device(s), browser types, browser language, operating system, the state or country from which you accessed the Site; and (b) information related to the ways in which you interact with the Site, such as: referring and exit pages and URLs, platform type, the number of clicks, domain names, landing pages, pages and content viewed and the order of those pages, the amount of time spent on particular pages, the date and time you used the Site, the frequency of your use of the Site, error logs, and other similar information. CC and certain third parties that advertise or provide other services on the Site may automatically collect certain information about the computer or devices (including mobile devices) you use to access the Site when you use the Site or certain Site services, or click on advertisements on the Site or in ICC periodicals, such as the Building Safety Journal. ICC and its partners and service providers may collect and analyze the information about the devices that are used to access the Site. To evaluate usage of the Site and improve performance and Client Services; for advertising and marketing purposes; to protect the security and integrity of the Site and our business, such as preventing fraud, hacking, and other criminal activity or to meet legal obligations. Our marketing partners; service providers who help us with fraud protection and website analytics Payment information : name, card issuer and card type, credit or debit card number, expiration date, CVV code, and billing address From our clients and their payment card issuers Authorizing of credit card and other financial transactions for our clients and their customers Our service providers who process payments for us—they are prohibited from using personal information for any other purposes and are contractually required to comply with all applicable laws and requirements, which includes the Payment Card Industry Data Security standards Accident information: details about any accident or injury in our facilities, or health incident From you, witnesses, or observed about you To get you the help you need, deal with the emergency services, insurance and claims Law enforcement and other governmental authorities in accordance with applicable law, and our professional advisors Suspected crime information: details of your identity, image, name and address, suspected or alleged thefts, fraud, assault or other criminal behavior From crime and fraud prevention agencies, from you, witnesses, and from the police To protect customers, the public and our business against risks and crime Law enforcement and other governmental authorities in accordance with applicable law, and our professional advisors
Please note that some parts of our Site, such as message boards and advertising listings, allow you to post information that may be publicly viewable and can be collected and used by third parties without ICC’s knowledge.
Automatically-Collected Information
Browser Cookies:As explained above, ICC and its advertising partners may collect certain information automatically and passively through the use of certain electronic technologies, such as cookies, web beacons, pixels, clear GIFs, and similar technologies., ICC may use third-party analytics providers and technologies, including cookies and similar tools, to assist in collecting this information. As we adopt additional technologies, we may also gather additional information through other methods.
In particular, we and certain third-party advertising partners may use “cookies.” Cookies are small pieces of information that are stored by your browser on your device. These cookies may be used: (a) to improve or enhance your experience using the Site; (b) to deliver content, including advertising, specific to your interests; and (c) for other purposes, such as security and administrative functions. For example, cookies are used to store your preferences for certain types of information so that you do not have to input those preferences every time you use the Site. Most web browsers automatically accept cookies, though different browsers may address cookies differently. Your browser may enable you to set your device to accept all cookies, to notify you when a cookie is issued, or to not receive cookies at any time. If you set your browser to not accept cookies, it may result in certain personalized services or other features not being provided to you when you use that device.
Web Beacons, Pixels and Clear GIFs:We and our advertising partners may use web beacons, pixels and clear GIFs. These electronic technologies are transparent image files that, if used, allow us and our advertising partners to track Web site usage information, such as the number of times a given web page has been viewed and whether and when you have opened a HTML email, how many times the email was forwarded and which links in the email were clicked. Unlike cookies, these technologies do not place files on your device. We and our advertising partners use information collected through Web beacons, pixels, and clear GIFs to improve and enhance our Site and measure the effectiveness of these communications with you. These technologies may be used in association with cookies to understand how visitors interact with the Site or advertisements made by our advertising partners.
Information from Third Parties:ICC may obtain additional information about you from third parties such as marketers, partners, researchers, data brokers, clearinghouses, and others. We may combine Information that we collect from you with information that we obtain from such third parties and information derived from any other product or service we provide.
Aggregate or De-Identified Data:ICC may aggregate and/or de-identify information collected through the Site or via other means so that the data is not intended to identify you. Our use and disclosure of aggregated and/or de-identified data is not subject to any restrictions under this Policy, and we may disclose it to others without limitation for any purpose.
Manage Cookie Preferences
Legal Bases for Collection and Use of Your Information
In addition to the purposes of collection described in the chart above, the legal bases for using your information as set out in this Policy are as follows:
Where use of your information is necessary to perform our obligations under a contract with you or in order to take steps at your request subject prior to entering into a contract; (for example, to comply with: our website Terms of Use, which you accept by browsing the websites/registering; and/or our contract to provide our Site to you); or
Where use of your information is necessary for our legitimate interests or the legitimate interests of others (for example, to provide security for our website and applications; operate our business and our Site and its services; make and receive payments; customer service; marketing; analyze and improve our business; comply with legal requirements and defend our legal rights; prevent fraud and to know the customer to whom we are providing the Site and its services).
Where required by law, and in some other cases, we handle your information on the basis of consent.
How ICC Shares Your Information
ICC shares your information as described in the chart above. For more information, how ICC shares information collected in a particular situation will depend on factors including the nature of the information, the purpose and context of the collection, and applicable law. Subject to such factors, we may disclose information that we collect or receive for the purposes described below.
Consent/Action by Users: If ICC has a User’s consent to share any information, it may do so. For example, if a User agrees to have their information posted in the Members Only area of the Site, that User consents to ICC sharing their information with other ICC Members. Similarly, we may allow users to share content with others via email, blog posts or client success stories. We may also share a User’s information to provide that User with services or products that the User has requested.
Agents and Vendors: ICC may utilize other companies and individuals to perform functions on its behalf, such as marketing new or additional ICC products and services, sending postal and email to Users, transmitting text messages requested by Users, processing credit card payments, fulfilling orders, delivering products and services, and providing customer service. These third parties have access to Information needed to perform their functions, but may not use it for other purposes.
Sweepstakes and Contests: When you sign up to participate in a contest or sweepstakes, your information may also be provided to our sweepstakes or contest advertisers, operators, or sponsors and the use of that information may also be governed by those advertisers’, operators’, or sponsors’ privacy policies or practices.
Advertising and Analytics: As described in the section on Online Analytics and Tailored Advertising, ICC also may provide automatically collected information to third parties for purposes of delivering targeted advertisements and performing analytics.
Protection of ICC or Others: ICC may disclose your information to others if we have a good faith belief that we are required or permitted to do so by law or legal process, to respond to claims, to protect the rights, property or safety of ICC or others, or take action regarding illegal activities or suspected fraud.
Business Transfers: We may share your information in connection with any actual or proposed merger, reorganization, or sale of some or all ICC assets, or a financing or acquisition of all or a portion of our assets or business by another company.
Third Parties Providing Relevant and Valuable Products and Services: From time to time, ICC may share your information with other organizations that provide relevant and valuable products or services.
Online Analytics and Tailored Advertising
Online Analytics
We may use third-party web analytics services on our Site, such as those of Google Analytics. These service providers use the sort of technology described in Section 1.2 to help us analyze how users use the Site, including by noting the third-party Web site from which you arrive. The information (including your IP address) collected by the technology will be disclosed to or collected directly by these service providers, who use the information to evaluate your use of the Site. We also use Google Analytics for certain purposes related to advertising, as described in the following section. To prevent Google Analytics from using your information for analytics, you may install the Google Analytics Opt-out Browser Add-on by clicking here.
Tailored Advertising
Also, third parties whose products or services are accessible or advertised via the Site may also place cookies or other tracking technologies on your computer, mobile phone, or other device to collect information about your use of the Site in order to (i) inform, optimize, and serve ads based on past visits to our Web sites and other sites and (ii) report how our ad impressions, other uses of ad services, and interactions with these ad impressions and ad services are related to visits to our Web sites and use of our Site. We also allow other third parties (e.g., ad networks and ad servers such as Google Analytics, DoubleClick and others) to serve tailored ads to you on the Site, on other websites or social media platforms, like Facebook, and to access their own cookies or other tracking technologies on your computer, mobile phone, or other device you use to access the Site. We also may share with third-party advertisers a hashed (i.e., de-identified) version of your email address along with content that you share publicly when using the Site (e.g., user-generated content) for purposes of delivering tailored advertising. We neither have access to, nor does this Policy govern, the use of cookies or other tracking technologies that may be placed on your device by non-affiliated, third-party ad technology, ad servers, ad networks or any other non-affiliated third parties. Those parties that use these technologies may offer you a way to opt out of ad targeting as described below. You may receive tailored advertising on your computer through a web browser. If you are interested in more information about tailored browser advertising and how you can generally control cookies from being put on your computer to deliver tailored advertising, you may visit the Network Advertising Initiative’s Consumer Opt-Out Link, the Digital Advertising Alliance’s Consumer Opt-Out Link,the TRUSTe’s Advertising Choices Page, or Your Online Choicesif you live in the European Union to opt-out of receiving tailored advertising from companies that participate in those programs. You may also use the links available in advertisements that appear in the Site to learn more about advertising practices on our Site. We do not control any of the above opt-out links and are not responsible for any choices you make using these mechanisms or the continued availability or accuracy of these mechanisms.
Some ICC websites may also offer other tools to control what cookies are placed on your device when using the applicable ICC website. To manage cookies on the International Code Council website ( www.iccsafe.org), you may do so here: Manage Cookie Preferences on iccsafe.org
To opt out of Google Analytics for display advertising or customize Google display network ads, you can visit the Google Ad Settingspage. Please note that to the extent advertising technology is integrated into the Site, you may still receive advertisements even if you opt-out of tailored advertising, but those ads will not be tailored based on your online activities over time.
ICC may also offer mobile applications in connection with its provisions of services. When using a mobile application, you may also receive tailored in-application advertisements. Each operating system, iOS for Apple phones, Android for Android device
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Subsets and Splits