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Shamil Bank of Bahrain v Beximco Pharmaceuticals Ltd - Viewing document - ICLR
ICLR.4
Table of Contents |
Via caselaw.nationalarchives.gov.uk
Case No: A3/2003/1952
Neutral Citation No:[2004] EWCA Civ 19
IN THE SUPREME COURT OF JUDICATURE
COURT OF APPEAL (CIVIL DIVISION)
ON APPEAL FROM THE HIGH COURT OF JUSTICE
QUEEN’S BENCH DIVISION (MORISON J)
Royal Courts of Justice
Strand,
London, WC2A 2LL
Wednesday 28 thJanuary 2004
Before :
LORD JUSTICE POTTER
LORD JUSTICE LAWS
and
LADY JUSTICE ARDEN
Between :
(1) BEXIMCO PHARMACEUTICALS LTD(2) BANGLADESH EXPORT IMPORT CO LTD(3) MR AHMAD SOHAIL FASIUHUR RAHMAN(4) MR AHMED SALMAN FAZLUR RAHMAN(5) BEXIMCO (HOLDINGS) LTDAppellants- and -SHAMIL BANK OF BAHRAIN E.C.Respondent
(Transcript of the Handed Down Judgment of
Smith Bernal Wordwave Limited, 190 Fleet Street
London EC4A 2AG
Tel No: 020 7421 4040, Fax No: 020 7831 8838
Official Shorthand Writers to the Court)
Mr R Hacker QC and Mr M Arnold (instructed by Jaswal Johnston) for the Appellants
Mr B Doctor QC and Miss S Partington (instructed by Norton Rose) for the Respondent
Judgment
Lord Justice Potter:
Introduction
1.
This is an appeal from the judgment of Mr Justice Morison dated 1 August 2003 whereby he gave summary judgment in favour of the claimant Shamil Bank of Bahrain E.C. (“the Bank”) against the first and second defendants as principal debtors in respect of monies advanced to them by the Bank under various financing agreements and against the third, fourth and fifth defendants as guarantors of certain of those agreements. The total judgment sum awarded was some US $49.7million. The appellants were refused permission to appeal by Morison J, but permission was granted by Clarke LJ on 17 September 2003 in relation to a single issue relating to the construction and effect of the form of the governing law clause contained in the financing agreements. That clause reads as follows:
“Subject to the principles of the Glorious Sharia’a, this Agreement shall be governed by and construed in accordance with the laws of England.”
2.
It is not in dispute that “the principles of the Glorious Sharia’a” referred to are the principles described by the defendants’ expert, Mr Justice (retd) Khalil-Ur-Rehmam Khan as:
“the law laid down by the Qur’an, which is the holy book of Islam, and the Sunnah (the sayings, teachings and actions of Prophet Mohammad (pbuh) ). These are the principal sources of the Sharia. The Sunnah is the most important source of the Islamic faith after the Qur’an and refers essentially to the Prophet’s example as indicated by the practice of the faith. The only way to know the Sunnah is through the collection of Ahadith, which consists of reports about the sayings, deeds and reactions of the Prophet … ”
3.
One principle expressly stated in the Qur’an and Sunnah is that the charging of interest upon a loan, in whatever form, is “Riba” and is contrary to the Sharia. At Sura II, 275-79 of the Qur’an it is stated that:
“ … Allah has made buying and selling lawful and has made the taking of interest unlawful. Remember, therefore, that he who desists because of the admonition that has come to him from his Lord, may retain what he has received in the past; and his affair is committed to Allah. But those who revert to the practice, they are the inmates of the fire; therein shall they abide. … O Ye who believe, be mindful of your duty to Allah and relinquish your claim to what remains of interest, if you are truly believers. But if you do not, then beware of war from the side of Allah and his Messenger. If, however, you desist, you will still have your capital sums; thus you will commit no wrong, nor suffer any wrong yourself.”
Sura III 130 states that:
“O Ye who believe, devour not interest, for it goes on multiplying itself; and be mindful of your obligation to Allah that you may prosper.”: The Quran, translated by Muhammad Zafrulla Khan, Curzon Press, 1971.
The Factual Background
4.
The bank is incorporated under the laws of Bahrain and licensed to act as a bank by the Ministry of Commerce and Bahrain Monetary Agency. The Kingdom of Bahrain is a constitutional monarchy and 95% of its population are muslims. Nonetheless, while embracing and encouraging Islamic banking practice as a national policy, the principles of Islamic law, in particular the prohibition of Riba, have not been incorporated into the commercial law of Bahrain and there is an absence of any legal prescription as to what does and does not constitute “Islamic” banking or finance. In his survey of the commercial laws of the Arab Middle East, Professor Ballantyne states that:
“In our other jurisdictions, banking interest is, in practice, tolerated (Saudi Arabia) and even sanctioned by banking laws (Bahrain, Qatar and Oman), while any theoretical or hypothetical conflicts have been largely ignored.” W M Ballantyne: Commercial Law in the Arab Middle East: the Gulf States(1986) p.133
5.
The unchallenged position as far as the charging of interest in Bahrain is concerned is that stated in Unlawful Gain and Legitimate Profit in Islamic Law: Nabil Saleh(2nd ed) p.9:
“The matter of interest is regulated as far as commercial transactions are concerned by the provisions of Article 81 of the Commercial Code of 1987. The latest amendment of Article 81, affected by Law no.4 of 1992, gives the following instructions to courts: (1) interest on overdue payments of commercial debts becomes due by the mere occurrence of maturity dates unless otherwise provided for by law or agreement. (2) Under no circumstances, and with regard to debts whose settlement does not exceed a period of seven years, may the aggregate amount of interest paid to the creditor exceed the initial indebtedness. (3) The provisions of the preceding (2) do not apply to debts which were contracted in foreign currencies. (4) The creditor is entitled to claim complementary damages in addition to interest on overdue payments with no need to prove that the additional damage was caused by the debtor’s fraud or his serious fault.”
6.
Nonetheless, the Bank holds itself out as applying Islamic principles in the course of its business. The Bank’s full title is “Shamil Bank of Bahrain E.C. (Islamic Bankers)”. The main objects clause in its Memorandum of Association is in general terms:
“3.Notwithstanding the provisions of this Article, the company shall undertake at all times to comply with the Bahrain Monetary Agency Law and any circulars, rules or regulations issued by the BMA from time to time … According to the above, the company will carry on all banking, investment, financial activities, offshore units and all services relating thereto of various commercial, industrial, agricultural, real estate, tourism, housing and other services in the State of Bahrain and outside it.”
However, clause 34 of the Articles of Association provide for the Ordinary General Meeting to elect and appoint a Religious Supervisory Board “which shall comprise at least three persons who are recognised specialists and qualified in Islamic jurisprudence, religious provisions and Islamic economy”.
7.
Clauses 35 and 36 of the Articles provide:
“35.a.The Religious Supervisory Board shall ascertain that the Company’s investments and activities (and the activities of its subsidiary and affiliated companies) conform with the principles and provisions of Islamic Sharia’a. It shall, in particular, discuss with the members of the Board of Directors, managers of the Company or of any subsidiary or affiliated company under its control, such conformity and the business carried out by them and shall request any information it deems necessary. In particular, the Religious Supervisory Board shall adopt all the crucial decisions for applying the provisions of Islamic Sharia’a to ensure the realisation of the objects for which the company was incorporated. Also to ensure that the members of the Board of Directors, managers and employees are co-ordinating their activities according to such decisions which will be binding on all the shareholders. The Religious Supervisory Board shall within 6 months from the end of the Company’s financial year, submit a written report stating that it fulfilled the obligations indicated herein and ascertained that the Company’s investments and business activities (including its subsidiary companies) conform with the provisions of Islamic Sharia’a.
…
36.The Board of Directors shall take the necessary actions to ensure that all the investments and other business transactions have been referred to the Religious Supervisory Board for approval before carrying out any other business transactions by the Company or by any subsidiary or affiliate company under its control.”
8.
As made clear by the Bank’s expert witness, provisions of this kind are not unusual. In the absence of legal prescription as to what does and what does not constitute “Islamic” banking or finance, most Islamic banks create Religious or Sharia Supervisory Boards which review annually the operations of the bank and determine whether or not these have been carried out in accordance with Islamic law. They examine on a test basis each type of transaction entered into by the Bank and evidence to show that the transaction and dealings entered into by the Bank are in compliance with Sharia rules and principles, submitting an annual report to the shareholders in that respect. In this case the Bank’s own Religious Supervisory Board certified in respect of the years 1995 and 1996 that:
“The Board believes that all the bank’s business throughout the said year, including investment activities and banking services, were in full compliance with Glorious Islamic Sharia’a.”
9.
A certificate of compliance was also issued for that period by the Bank’s auditors, reviewing the Bank’s operation on the basis of the Financial Accounting Standards issued by the Accounting and Auditing Organisation for Islamic Financial Institutions.
10.
Until their defences were filed in this action, the appellants had never given any indication to the bank that they were dissatisfied on religious grounds with the arrangements agreed between the parties or that they sought to challenge them on the grounds that they did not comply with the principles of Sharia.
11.
The first two defendants are Bangladeshi companies (part of the Beximco group) involved in the manufacture, export and import of pharmaceuticals. The third and fourth defendants are directors of the first and second defendants and of the fifth defendant which is their parent company. I shall refer to the third, fourth and fifth defendants collectively as “the guarantors”.
12.
In 1995 the Beximco group wished to raise additional working capital to be used in its commercial activities. To this end, there were meetings between the Bank and, principally, Mr Chowdhury the Beximco Group Director of Finance and a director of the first and second defendants. The monies were advanced pursuant to the terms of two “Morabaha Financing Agreements” which, in form, related to the sale of goods.
13.
It is not in dispute that a Morabaha agreement is a sale contract recognised as valid by Islamic law whereby the seller (the financier institution) agrees to purchase goods desired by the buyer and to sell them to the buyer (the client) for a deferred price, the difference between the original purchase price to be paid by the financier and the deferred price payable by the client being a stated profit known to and agreed upon by both seller and buyer. In order to avoid the appearance or characteristics of a loan at interest and to provide for and preserve the features of a contract of sale, the financier purchases the goods in its own name, and the goods must come into its possession (actual or constructive), remaining at its risk until the commodity is sold to the client. However, for that purpose the financier may appoint the client as agent for the purchase on behalf of the financier and, once the client effects such purchase as the agent of the financier, the client may retain possession of the commodity on its own behalf. The detailed form and content of Morabaha agreements varies. There are no standard forms and, in practice, the detailed terms and conditions will be agreed by the bank and its customer around the essential characteristics I have mentioned. It is the function of an Islamic bank’s Religious Supervisory Board to ensure that the Morabaha agreement complies with Islamic law as interpreted by the Religious Supervisory Board.
14.
Following negotiations in which each side was advised, the Bank and the first and second defendants entered into a Morabaha Financing Agreement dated 28 December 1995 (“the 1995 Morabaha Agreement”) under which, pursuant to clauses 2.1, 2.2 and 4.2, the Bank agreed to purchase, through the second defendant acting as its agent, certain goods from specified sellers for immediate onward sale to the first defendant. In return, pursuant to clause 2.1, the first defendant agreed to pay to the Bank the Morabaha price, defined in the agreement as the aggregate of the purchase price of goods purchased plus the Profit Element, calculated by reference to clause 2 of a Market Rate Agreement also entered into between the parties. Pursuant to clause 4.5 of the Morabaha Agreement, the payments to be made were set out in a letter from the Bank to the defendants dated 28 December 1995 (“the 1995 Payment Schedule Letter”). Pursuant to clause 3 of the 1995 Market Rate Agreement, if any payment due remained unpaid for any period after its due date, compensation would be payable to the Bank.
15.
In accordance with clause 4.1 of the 1995 Morabaha Agreement, the Bank advanced to the second defendant US $15 million ostensibly for the purposes of purchasing the specified goods. Between 28 March 1996 and 28 September 1997, the first defendant made seven payments in accordance with the 1995 Payment Schedule Letter.
16.
In April 1996, following an approach by the second defendant seeking further funds, the Bank agreed to advance the second defendant a further sum of US $ 15 million. On 11 July 1996 the Bank and the first and second defendants entered into a further Morabaha Agreement (“the 1996 Morabaha Agreement”) and Market Rate Agreement in terms similar to those of the 1995 Agreements.
17.
In accordance with clause 4.1 of the 1996 Morabaha Agreement, on 15 July 1996, the Bank paid to the first defendant US $ 15 million ostensibly for the purpose of purchasing the specified goods. Between 15 October 1996 and 12 August 1997, the second defendant made four payments in accordance with the 1996 payment schedule letter.
18.
By December 1999 the first and second defendants had not paid the amounts due under the 1995 and 1996 Morabaha Agreements, although admitting and agreeing in writing that such sums were owed. Following negotiations, the Bank and the first and second defendants agreed to enter into new agreements to discharge the first and second defendants’ obligations in exchange for the first and second defendants undertaking alternative obligations to the Bank which the third, fourth and fifth defendants were to guarantee.
19.
On 14 September 1999 the Bank and the first and second defendants entered into two Exchange in Satisfaction and User Agreements, one relating to the 1995 Morabaha Agreement (“the First ESUA”) and the other relating to the 1996 Morabaha Agreement (“the Second ESUA”) which were each subsequently amended and restated by agreement on 4 February 2001 and 30 January 2002. The re-amended ESUAs became effective on 4 April 2002. Under clause 2.1 of the ESUAs the Bank agreed to discharge on the Effective Date the amount then outstanding under the 1995 and 1996 Morabaha Agreements in exchange for being granted the right to receive unencumbered title to certain assets. Pursuant to clauses 3.1 and 3.3, the Bank agreed to grant the first and second defendants the right to use those assets in the ordinary course of their respective businesses in consideration for payment by instalments of a user fee determined in accordance with clause 3.4. The first and second defendants were also obliged to make certain payments of accrued compensation. Under clause 4.1 of the ESUAs, it was a condition precedent that the third, fourth and fifth defendants guaranteed the first and second defendants’ obligations under the ESUAs.
20.
The form of the ESUAs, whereby the Bank, having acquired the ownership of the first and second defendants’ assets, permitted their retention and use in return for regular payment of the scheduled user fees was in principle a method of financing recognised as legitimate by the Sharia as “Ijarah”, the giving of something in rent. However, when that method of financing is adopted by a bank in place of a simple interest-bearing loan, the question of whether the transaction is legitimate according to the principles of Sharia depends upon an analysis of the particular terms and conditions of the agreement and may prove controversial.
21.
In this case, various defaults and “Termination Events” provided for under the ESUAs occurred and, as the Bank was entitled to do, it sent two default letters dated 18 August 2002 to the defendants under the terms of the first and second ESUAs in respect of the sums subsequently claimed in this action.
The Bank’s claims against the first and second defendants
22.
The Bank’s claims against the first and second defendants are made up as follows:
“(1)US $ 25,207,000 being the amount due under the first ESUA relating to the 1995 Morabaha Agreement;
(2)US $ 21,472,800 being the amount due under the second ESUA relating to the 1996 Morabaha Agreement;
(3)US $ 1,147,540.76 being accrued compensation due under clause 4.2.4 of the first ESUA;
(4)US $ 1,884,169.75 being accrued compensation due under clause 4.2.4 of the second ESUA.”
The Bank’s claims against the guarantors
23.
On 6 February 2001 the Bank and the third and fourth defendants entered into two personal guarantees, one relating to the first ESUA and one relating to the second ESUA (“the personal guarantees”). On the same date the Bank and the fifth defendant entered into two corporate guarantees, one relating to the first ESUA and one relating to the second ESUA (“the corporate guarantees”). The guarantees were all in materially similar terms. Each states that it is “governed by and shall be construed in accordance with English law”, with provision also for the jurisdiction of the English courts. There is no reference to the principles of Sharia.
24.
Each guarantee recites the relevant Morabaha financing agreement, the “Outstanding amount” pursuant thereto and the relevant ESUA Agreement as amended.
25.
The relevant provisions of the guarantee for the purposes of this appeal are as follows:
“2.1 Covenant to pay
In consideration of Shamil agreeing to discharge the Outstanding Amount in return for being granted the right to acquire title to the Assets and Shamil permitting Beximco and BEIC to use the Assets in return for the User Fee pursuant to the Exchange Agreement [i.e. the ESUA] the Guarantor hereby guarantees to Shamil Beximco and BEIC’s obligation to transfer title to the Assets to Shamil and guarantee to pay to Shamil, on demand by Shamil, the User Fee and all monies and discharge all obligations and liabilities now or hereafter due, owing or incurred by Beximco and BEIC (or either of them as the case may be) to Shamil under or pursuant to the Exchange Agreement and the other New Transaction Documents when the same become due for payment or discharge whether by acceleration or otherwise, and whether such monies, obligations or liabilities are express or implied, present, future or contingent, joint or several, incurred as principal or surety, originally owing to Shamil or purchased or otherwise acquired by it, denominated in Dollars or in any other currency, or incurred on a banking account or any other manner whatsoever …
2.2 Guarantor as principal debtor; indemnity
As a separate and independent stipulation, the Guarantor agrees that if any purported obligation or liability of Beximco and/or BEIC (as the case may be) which would have been the subject of this Guarantee had it been valid and enforceable is not or ceases to be valid or enforceable against Beximco and/or BEIC (as the case may be) on any ground whatsoever whether or not known to Shamil (including, without limitation, any irregular exercise or absence of any corporate power or lack of authority of, or breach of duty by, any person purporting to act on behalf of Beximco and/or BEIC (as the case may be) or any legal or other limitation … the Guarantor shall nevertheless be liable to Shamil in respect of that purported obligation or liability as if the same were fully valid and enforceable and the Guarantor were the principal debtor in respect thereof …”.
26.
The Bank claims against each of the guarantors the same sums as are claimed against the debtors as set out in paragraph 22 above.
The issues on this appeal
27.
A number of defences were advanced by the defendants before the judge below, certain of which were regarded by the judge as having the hallmarks of trumped-up defences designed to avoid or delay payment. However, the principal defence advanced was that, (a) on a true construction of the governing law clause quoted in paragraph 1 of this judgment, the Morabaha Agreements and the ESUAs were only enforceable insofar as they were valid and enforceable both (i) in accordance with the principles of the Sharia (i.e. the rules or laws of Islam) and (ii) in accordance with English law; (b) in fact, the agreements were unlawful, invalid and unenforceable under the principles of the Sharia in that, despite their form as Morabaha Agreements, in the case of the 1995 and 1996 Morabaha Agreements, and as Ijarah leases, in the case of the first and second ESUAs, (which would be enforceable if they were a true reflection of the underlying transaction) the transactions were in truth disguised loans at interest. As such they amounted to unlawful agreements to pay Riba and were thus void and/or unenforceable.
28.
In this connection it was stated in the witness statement of Mr Choudhury for the defendants that he made it clear that the monies sought from the Bank by the first and second defendants were required as working capital for the Beximco group and that it was the Bank which required that the transaction be structured in the forms adopted in order to comply with Sharia law. The fourth defendant, as a director of the first, second and fifth defendants’ and a personal guarantor of the ESUAs, stated that:
“ … it is not uncommon for banks, in their enthusiasm to make profitable loans, to use a Morabaha Agreement to disguise what is, as a matter of commercial reality, an interest-bearing loan. That is precisely what happened in the present case and both the Claimant and the Defendants were quite content that this should happen. Neither was under any illusion as to the commercial realities of the transactions, and the claimant was happy to dress the loan transactions up as Morabaha sales (or Ijarah leases), whilst taking no interest in whether the proper formalities of such a sale or lease were actually complied with.”
29.
The rival expert evidence as to the validity of the agreements under Islamic law was as follows. The Bank’s expert, Dr Lau, the former director of the Centre of Islamic and Middle Eastern Law, stated that the precise scope and content of Islamic law in general, and Islamic banking in particular, are marked by a degree of controversy within the Islamic world, best exemplified by the fact that the actual practice of Islamic banking differs widely within the Islamic world. Even within particular jurisdictions such as Pakistan, which are committed and constitutionally obliged to introduce Islamic financial systems, the issue is subject to on-going debate and a high degree of uncertainty. In the absence of any agreement on the boundaries of ‘Islamic banking’ or, indeed, on what ought to be the precise ingredients of a Morabaha agreement, it is in practice up to individual banks to determine the issue. In the absence of any legal prescription as to what does and what does not constitute Islamic banking or finance, most Islamic banks, including those in Bahrain, seek the advice of Islamic scholars who examine and approve particular agreements and forms of agreement, the role of the Religious Supervisory Committee being to formulate the bank’s interpretation of the Sharia.
30.
Strictly interpreted “ the Glorious Sharia’a” refers to the divine law as contained in the Qur’an and Sunnah. However, most of the classical Islamic law on financial transactions is not contained as ‘rules’ or ‘law’ in the Qur’an and Sunnah but is based on the often divergent views held by established schools of law formed in a period roughly between 700 and 850 CE. The particular form and content of Morabaha agreements varies. If a bank’s Religious Supervisory Board is satisfied that the bank’s activities are in accordance with Sharia law, that concludes the matter, there being no provision in Bahrain law, or Islamic law generally, for an appeal by a customer of the bank against the Board’s rulings and certifications. Finally, even if the relevant agreements amounted to agreements to pay Riba, the principal sums advanced could be validly claimed.
31.
Dr Lau’s conclusion was that the concern of the defendants that the sums advanced were not used to purchase the goods and/or equipment, the subject of the 1995 and 1996 Morabaha Agreements, but rather as part of the general working capital of the first and second defendants was of no relevance to the question whether or not the Morabaha agreements complied with Islamic law. He stated:
“In my opinion for the Morabaha Agreements to be in accordance with Islamic law all that is required is that they are certified as such by Shamil Bank’s Religious Supervisory Board and the principal amounts are dispensed in accordance with the terms of the 1995 and 1996 Morabaha Agreements.”
32.
The position of the defendants’ expert, Mr Justice Khan, former chairman of the Sharia Appellate Bench of the Supreme Court of Pakistan, shortly stated was as follows. He acknowledged that “wherever a question of interpretation of the principles contained in the Qur’an and Sunnah is involved, the application of the rules of Sharia’a has and will continue to give rise to disputes between different jurists”. He also did not contradict the assertion of Dr Lau that most of the classical Islamic law on financial transactions was not to be found in the Qur’an and Sunnah. However, he made clear (as Dr Lau did not dispute) that the injunction against the payment of Riba is contained in both those holy books and that it is uncontroversial that under Islamic law interest charged on loans by banks is Riba and prohibited. Equally, any agreement in which, in substance, interest is being charged upon a loan is unlawful, void and unenforceable.
33.
Mr Justice Khan acknowledged that the Sharia recognises two modes of financing as permissible, namely Morabaha and Ijarah agreements, but asserted that, for such transactions to be valid, the requirements prescribed and provided for in the agreement must be fulfilled, failing which the transaction as a whole will be void according to the principles and rules of Sharia. On the basis of the (uncontradicted) assertion of the defendants that the advances were never applied or intended to be applied in the purchase or lease of any property, the relevant agreements were void. The ESUAs were similarly void and unenforceable on the basis of a number of arguments advanced, the principal one of which was that, irrespective of their form as purported Ijarah leases of assets, the ESUAs simply constituted a rescheduling or roll-over of the 1995 and 1996 Morabaha Agreements, the bank charging interest or an additional amount over and above the sums due in consideration of the giving of time. This too was Riba and accordingly prohibited and void.
34.
Finally, so far as the position of the Bank’s Religious Supervisory Board was concerned, Mr Justice Khan stated that certification by the Board that the operations of the Bank were according to the Sharia would not be a decision binding on any court dealing with the dispute under the law of Sharia. The dispute would fall to be resolved by the court in the light of its own view of the position under Sharia law. In any event there was no evidence that the Board had had knowledge of, nor was it required to approve, the particular transaction in this case, its function being one of overall supervision and approval of the methods and procedures adopted by the bank in the course of its business.
35.
So far as the liability of the guarantors was concerned, two arguments were advanced before the judge which are of relevance to this appeal. The first was simply that, under the general law of guarantee, if the principal debtor was discharged from liability in respect of the obligations guaranteed, then the guarantors were similarly discharged.
36.
The second defence raised was that the guarantees had been entered into by the parties on the basis of a common mistake of a fundamental nature, namely that the first and second defendants were under enforceable obligations to the Bank under the Morabaha Agreements at the time when, and in respect of which, the ESUAs and guarantees were entered into.
The decision of Morison J
37.
The paragraph numbers referred to in this section reflect the numbered paragraphs of the judgment of Morison J.
38.
The judge held, and it is accepted by the Bank on this appeal, that if, on a proper construction of the applicable law clause, the court is obliged to concern itself with the application of Sharia law and its impact on the lawfulness of the agreements, it is arguable which of the two parties’ experts was right and that it would offend the principles underlying CPR Part 24 to seek to resolve the conflict between them before a trial. That is so not only in respect of the recoverability of sums which were effectively interest upon the capital sums advanced, but also of the capital sums themselves (paragraphs 45 and 46).
39.
However the judge concluded that, on the proper construction of the applicable law clause, he was not concerned with the principles of Sharia at all for the following reasons.
40.
First, it was common ground by concession that there could not be two separate systems of law governing the contract (paragraph 43). Yet, by contending that Sharia law and not English law would determine the enforceability of the agreement, the appellants were in substance contending that the agreements were governed both by English and Sharia law (paragraph 48). The judge declined to construe the wording of the clause as a choice of Sharia law as the governing law for the following reasons. First, Article 3.1 of the Rome Convention (which by s.2(1) of the Contracts (Applicable Law) Act1990 has the force of law in the United Kingdom) contemplates that a contract “shall be governed by thelaw chosen by the parties” and Article 1.1 of the Rome Convention makes it clear that the reference to the parties’ choice of the law to govern a contract is a reference to the law of a country. There is no provision for the choice or application of a non-national system of law such as Sharia law (paragraphs 39, 48 and 51). In any event, the principles of the Sharia are not simply principles of law but principles which apply to other aspects of life and behaviour (paragraph 53). Even treating the principles of Sharia as principles of law, the application of such principles in relation to matters of commerce and banking were plainly matters of controversy (paragraphs 49 and 53). In particular there is controversy as to the strictness with which principles of Sharia law will be interpreted or applied. In consequence it was highly improbable that the parties to the agreements intended an English court to determine any dispute as to the nature or application of such controversial religious principles which would involve it in the task of deciding between opposing points of view which themselves might be based on geopolitical and particular religious beliefs (paragraphs 49 – 54).
41.
The judge accepted the submission of the Bank that the words “subject to the principles of Glorious Sharia’a” were no more than a reference to the fact that the Bank purported to conduct all its affairs according to the principles of Sharia. However, in respect of what those principles were and their effect upon the contract, the judge concluded the relevant part of his judgment as follows:
“54.Whilst in one sense this court will answer any question posed to it, however difficult, it is improbable in the extreme, that the parties were truly asking this court to get into matters of Islamic religion and orthodoxy. This is especially so when the bank has its own religious Board to monitor the compliance of the bank with the Board’s own perception of Islamic principles of law in an international banking context.
55.So far as the bank was concerned, that is likely to have been sufficient for its own regulatory purposes but there is no suggestion that the defendants were in any way concerned about the principles of Sharia’a law either at the time the agreement was made or at any time before the proceedings were started. The Sharia’a law defence is, I think, a lawyer’s construct, but for the reasons I have given, in my view it does not work.”
The submissions of the appellants
42.
Before this court, Mr Hacker QC for the appellants has not resiled from his concession that there can only be one governing law of the agreements. He accepts, and indeed asserts that it was his case below, that the governing law is English law and English law alone. However, he submits that this does not preclude the possibility that the principles of Sharia have relevance. He submits that all the parties have done is to choose English law as the governing law but, at the same time to stipulate as a condition precedent that the contract is only to be enforceable insofar as it is consistent with the principles of Sharia, which principles amount to legal rules ascertainable and applicable by an English court. He submits that that is something different from an assertion that Sharia law governs the agreements.
43.
Mr Hacker accepts that the Rome Convention precludes the choice of Sharia, as a governing law, being concerned only with a potential choice between the laws of different countries. However, he submits that the construction of the governing law clause for which he contends produces a result no different from the incorporation by reference of a codified system of rules, such as the Hague Rules or the Warsaw Convention, into a contract governed by English law c.f. Nea Agrex SA v Baltic Shipping Co Ltd[1976] 1 QB 933 (CA) in which this court rejected the conclusion of Donaldson J at first instance that a paramount clause provision was to be treated as ineffective to incorporate the Hague Rules into a charterparty. He submits that such a construction is fully consistent with the bank’s self-proclaimed mode of business as an Islamic bank carrying on an Islamic banking business.
44.
Mr Hacker submits that, contrary to the view of the judge, it is neither unusual nor improbable that the parties to the contract should intend the English court to determine and apply the Sharia, nor, as he submits, is the English court ill-equipped to do so when assisted by expert evidence, in which respect he refers to the decision of Moore-Bick J in Glencore International AG v Metro Trading International Inc[2001] 1 Lloyds Law Rep 284 at paras 113-125 and that of Hart J in Al-Bassam v Al-Bassam[2002] EWHC 2281 (Ch).
45.
He further submits that the reasoning of the judge was influenced by an erroneous view that the principles of Sharia constituted a body of controversial religious (as opposed to legal) principles, which view he was wrong to form on the evidence before him. In this respect, Mr Hacker relies heavily upon the fact that the evidence of Mr Justice Khan was that the principles of Sharia raised in this casei.e. the proscription of Riba and the essentials of a valid Morabaha Agreement are not controversial. In this respect he referred us to the judgment of Tomlinson J in Islamic Investment Company of the Gulf (Bahamas) Ltd v Symphony Gems NV(unreported) 13 February 2002 in which, it is clear that, when giving expert evidence in that case, Dr Lau did not suggest that there was any difficulty in identifying the requirements for an effective Morabaha contract under Sharia law. He therefore submits that the judge’s conclusion that the principles of Sharia law relevant to this casewere controversial, so as to render it improbable that the parties would have chosen the English court to resolve a dispute as to the enforceability of the agreements, was incorrect or, at the very least, involved him in conducting a mini-trial in relation to the parties’ expert evidence contrary to the principles laid down in Swain v Hillman[2001] 1 All ER 91.
Discussion
The Governing Law Clause
46.
The central question in this appeal is one of construction in respect of the relevant ‘Governing Law’ clause, expressly so described and couched in the short form already quoted in paragraph 1 of this judgment. The task of construction is to ascertain the presumed intention of the parties bearing in mind that:
“In a commercial contract it is certainly right that the court should know the commercial purpose of the contract and this in turn presupposes knowledge of the genesis of the transaction, the background, the context, the market in which the parties are operating.” (per Lord Wilberforce in Reardon Smith Line Ltd v Yngvar Hansen-Tangen[1976] 1 WLR 989 at 996.)
47.
It is common ground in the context of the summary judgment application that, when the parties entered into the Morabaha Agreements and subsequently, neither side was under any illusion as to the commercial realities of the transactions, namely the provision by the Bank of working capital on terms providing for long term repayment, and both were content “to dress the loan transactions up as Morabaha sales (or Ijarah leases), whilst taking no interest in whether the proper formalities of such a sale or lease were actually complied with” (see paragraph 28 above). Nor, as Mr Hacker expressly accepted at the outset, was it ever intended in relation to any of the agreements made that they should be other than binding on the parties. In those circumstances, as it seems to me, the court, in approaching its task, should lean against a construction which would or might defeat the commercial purpose of the agreements. Accordingly, insofar as each of the clauses provides in clear terms that “this agreement shall be governed by and construed in accordance with the laws of England”, the proviso that such provision shall be “subject to the principles of the Glorious Sharia’a” should be approached on a basis which is reconcilable with the purpose evident from the words which follow, rather than operating to defeat such purpose.
48.
It is conceded by Mr Hacker that there cannot be two governing laws in respect of these agreements. He further concedes that the governing law is that of England. It seems to me that he is rightly driven to this concession. The wording of Article 1.1 of the Rome Convention (“the rules of this Convention shall apply to contractual obligations in any situation involving a choice between the laws of different countries.”) is not on the face of it applicable to a choice between the law of a country and a non-national system of law, such as the lex mercatoria, or “general principles of law”, or as in this case, the law of Sharia. Nevertheless, that wording, taken with Article 3.1 (“a contract shall be governed by thelaw chosen by the parties”) and the reference to choice of a “foreign law” in Article 3.3, make it clear that the Convention as a whole only contemplates and sanctions the choice of the law of a country: c.f. Dicey & Morrison The Conflict of Laws(13 thed) vol 2 at 32-079 (p.1223) and Briggs: The Conflict of Lawsat p.159.
49.
Mr Hacker thus opts for a construction that the wording is apt, and intended, to incorporate into English law for the purposes of its application to the contract, the “principles of … Sharia”. In this respect, and no doubt to avoid the difficulty that the principles of Sharia, generally stated, are of broad nature and application (indeed they are unexplored for the purposes of this litigation), Mr Hacker argues that the clause should be read as incorporating simply those specific rules of Sharia which relate to interest and to the nature of Morabaha and Ijarah contracts, thus qualifying the choice of English law as the governing law only to that extent.
50.
In that respect, he seeks to rely upon the passage in Dicey & Morris( supra) at paragraph 32-086, which expounds the distinction between reference to a foreign law as a choice of law to govern the contract (or part of a contract) on the one hand and incorporation of some provisions of a foreign law as a term or terms of the contract in question. While observing that it is sometimes difficult to draw the distinction in practice, it is there stated that:
“… it is open to the parties to an English contract to agree e.g. that the liability of an agent to his principal shall be determined in accordance with the relevant articles of the French Civil Code. In such a case the foreign law becomes a source of law upon which the governing law may draw. The effect is not to make French law the governing law of the contract but rather to incorporate the French articles as contractual terms into an English contract. This is a convenient ‘shorthand’ alternative to setting out the French articles verbatim. The court will then have to construe the English contract, ‘reading into it as if they were written into it the words’ of the French statute.
32-087It often happens that statutes governing the liability of a sea carrier, such as the former Harter Act in the United States, or statutes implementing the Hague Rules … are thus ‘incorporated’ in a contract governed by a law other than that of which the statute forms part. The statute then operates not as a statute but as a set of contractual terms agreed upon between the parties. The parties may make an express choice of one law (e.g. English law) and then incorporate the terms of a foreign statute. In such a case the incorporation of the foreign statute would only have effect as a matter of contract.”
51.
It does not seem to me that the passage cited or the authorities referred to in the notes thereto, assist the defendants. The doctrine of incorporation can only sensibly operate where the parties have by the terms of their contract sufficiently identified specific ‘black letter’ provisions of a foreign law or an international code or set of rules apt to be incorporated as terms of the relevant contractsuch as a particular article or articles of the French Civil Code or the Hague Rules. By that method, English law is applied as the governing law to a contract into which the foreign rules have been incorporated. In such a case, in construing and applying those rules, where there is ambiguity or doubt as to their ambit or effect, it may be appropriate for the court to have regard to evidence from experts in foreign law as to the way in which the provisions identified have been interpreted and applied in their ‘home’ jurisdiction. However, that is still only as an end to interpretation by the English court in the course of applying English law and rules of construction to the contract with which it is concerned. The authority of Nea Agrex v Baltic Shipping( supra) is no more than an illustration of this. The trial judge had held that a reference in the contract to the incorporation of a ‘Paramount Clause’ was ineffective for uncertainty, finding that he could not say whether the parties intended to incorporate the Hague Rules or part of the Hague Rules or, if so, which part. However, the Court of Appeal held that the clear meaning of ‘Paramount Clause’ was that:
“It brings the Hague Rules into the charterparty so as to render the voyage or voyages, subject to the Hague Rules, so far as applicable thereto; and it makes those rules prevail over any of the exceptions in the charterparty. The judge, however, took a different view. He said that there are many different paramount clauses and he could not say which of them was applicable …
I do not share the judge’s view. It seems to me that when the ‘Paramount clause’ is incorporated, without any words of qualification, it means that all the Hague Rules are incorporated. If the parties intend only to incorporate part of the Rules (for example Article IV), or only so far as compulsorily applicable, they say so. In the absence of any such qualification, it seems to me that a ‘Clause Paramount’ is a clause which incorporates all the Hague Rules.” (per Lord Denning MR at 943G – 944A)
52.
The general reference to principles of Sharia in this case affords no reference to, or identification of, those aspects of Sharia law which are intended to be incorporated into the contract, let alone the terms in which they are framed. It is plainly insufficient for the defendants to contend that the basic rules of the Sharia applicable in this caseare not controversial. Such ‘basic rules’ are neither referred to nor identified. Thus the reference to the “principles of … Sharia” stand unqualified as a reference to the body of Sharia law generally. As such, they are inevitably repugnant to the choice of English law as the law of the contract and render the clause self-contradictory and therefore meaningless.
53.
In these circumstances, having rightly conceded that English law is the governing law of the contract, Mr Hacker is left with little room for manoeuvre, save to assert that the court should accept his submission on the basis that otherwise the proviso to the governing law clause would be mere surplusage.
54.
I do not agree. It seems to me that there is an appropriate alternative construction, namely that favoured by the judge, i.e. that the words are intended simply to reflect the Islamic religious principles according to which the Bank holds itself out as doing business rather than a system of law intended to ‘trump’ the application of English law as the law to be applied in ascertaining the liability of the parties under the terms of the agreement. English law is a law commonly adopted internationally as the governing law for banking and commercial contracts, having a well-known and well developed jurisprudence in that respect which is not open to doubt or disputation on the basis of religious or philosophical principle. I share the judge’s view that, having chosen English law as the governing law, it would be both unusual and improbable for the parties to intend that the English court should proceed to determine and apply the Sharia in relation to the legality or enforceability of the obligations clearly set out in the contract. Reference to authority does not assist the defendants in this respect. In Glencore International v Metro Trading( supra) the judge was concerned with, and heard evidence in relation to, the meaning and scope of the word ‘ghasb’ (misappropriation) as a term used but undefined in Article 1326 of the Fujairah Civil Code which was the governing law in the case before him. As such he was obliged to interpret and apply the term in the dispute before him, with the assistance of rival experts in the law of Fujairah. The decision has no relevance to this case. As to the decision in Al-Bassam, ( supra) the court was concerned with Sharia law as being the law which the parties agreed was the law of succession applied in Saudi Arabia as the country of the deceased’s domicile at the date of his death. Again, it has no relevance to this case, other than demonstrating that, where it is clear that a particular system of law governs a dispute before the English court, the court is obliged to apply it, with the assistance of expert evidence. Neither case was concerned with the construction of a disputed choice of law clause.
55.
Finally, so far as the “principles of … Sharia” are concerned, it was the evidence of both experts that there are indeed areas of considerable controversy and difficulty arising not only from the need to translate into propositions of modern law texts which centuries ago were set out as religious and moral codes, but because of the existence of a variety of schools of thought with which the court may have to concern itself in any given case before reaching a conclusion upon the principle or rule in dispute. The fact that there may be general consensus upon the proscription of Riba and the essentials of a valid Morabaha agreement does no more than indicate that, if the Sharia law proviso weresufficient to incorporate the principles of Sharia law into the parties’ agreements, the defendants would have been likely to succeed. However, since I would hold that the proviso is plainly inadequate for that purpose, the validity of the contract and the defendants’ obligations thereunder fall to be decided according to English law. It is conceded in this appeal that, if that is so, the first and second defendants are liable to the Bank.
The Guarantors’ Liability
56.
It has necessarily been conceded that, if that is so, then the guarantors are similarly liable. The sole point relied on in this appeal to avoid their liability is the plea that the Bank and the guarantors entered into the guarantees on the basis of a mutual mistake, namely that the ESUAs constituted a binding obligation on the part of the Bank to discharge a pre-existing enforceable obligation, i.e. payment of the outstanding amounts as defined in the ESUAs. In this connection the guarantors rely upon the general law of guarantee and the fact that the opening line of the covenant to pay in clause 2.1 of the guarantees expressly made clear that they were given in consideration of the Bank agreeing to discharge the outstanding amount under the Morabaha agreements.
57.
Although it is not necessary so to decide, I consider that the judge was correct in his view that a common mistake as to the legal consequences of the Morabaha agreements in this case would not qualify as a mistake apt to give rise to a defence.
58.
Mr Hacker relies on recent authority to submit that, for the doctrine of mutual mistake to be operative at common law, it is no longer necessary for it to be a mistake of fact as opposed to a ‘mere’ mistake of law. He relies upon the decision of the House of Lords in Kleinwort Benson Ltd v Lincoln City Council[1999] 1 AC 153, in which the House of Lords held that there is no rule that only a mistake of fact would entitle a party to claim restitution on the grounds of mistake; also upon the statement of the position in Chitty on Contracts(28 thed) at paragraph 5-018 and the recent decision of Morland J in Brennan v Bolt Burden and others[2003] EWHC 2493 (QB) concerning the setting aside of a compromise agreement on the grounds of mistake of law when that agreement had been reached on the basis of a decision of the court of first instance which was subsequently overturned by the Court of Appeal. In coming to his decision that the agreement should be set aside, Morland J relied upon the speeches of Lord Goff and Lord Hoffmann in the Kleinwort Bensoncase at 379f and 398e-399 respectively and the paragraph in Chitty, as well as upon persuasive Commonwealth authority. Assuming, without deciding, that the decision of Morland J was correct, it was nonetheless reached upon the basis that the parties’ common mistaken assumption as to the law “was the fundamental basis for and a precondition of the compromise agreement, indeed its only springboard” (see paragraph 52 of the judgment).
59.
Before this court Mr Hacker has submitted that the mistake as to Sharia law was properly to be regarded as a mistake of fact by analogy with the position in respect of a mistake of foreignlaw: see Furness Withy (Australia) Pty Ltd v Metal Distributers (UK) Ltd (“The Amazonia”)per Dillon LJ at 250.
60.
If that analogy is correct, it is of course necessary for the guarantors to show that the mistake is such as to “render the subject matter of the contract essentially and radically different from the subject matter which the parties believed to exist” (per Lord Steyn in Associated Japanese Bank (International Ltd) v Crédit du Nord SA[1989] 1 WLR 255 at 268) or that it “renders the thing [contracted for] essentially different from the thing [that] it was believed to be” (per Lord Atkin in Bell v Lever Bros Ltd[1932] AC 161, as adopted and confirmed by this court in Great Peace Shipping Ltd v Tsavliris Salvage (International) Ltd[2002] EWCA Civ 1407 [2003] QB 679). Whether the mistake asserted should rightly be regarded as a mistake of fact or of law, it is plain to me that it is not a mistake based on a common assumption fundamental to the agreements in question. In that respect, the submissions of Mr Hacker inevitably founder upon the factual assertions of the defendants themselves, which demonstrate that their sole interest was to obtain advances of funds to be used as working capital and that they were indifferent to the form of the agreements required by the Bank or the impact of Sharia law upon their validity.
Conclusion
61.
In my view the judge was correct in the conclusion to which he came, broadly for the reasons which he gave. I would dismiss this appeal.
Lord Justice Laws:
62.
Lady Justice Arden:
63.
| https://www.iclr.co.uk/document/2001003387/2004ewcaciv19_TNA/html |
Lattice-induced modulators at terahertz frequencies (Journal Article) | OSTI.GOV
The U.S. Department of Energy's Office of Scientific and Technical Information
Title:
Lattice-induced modulators at terahertz frequencies
Full Record Other Related Research
Authors:
Naranjo, Guillermo A. ;
Search OSTI.GOV for author "Naranjo, Guillermo A." Search OSTI.GOV for ORCID "0000-0003-3257-5557" Search orcid.org for ORCID "0000-0003-3257-5557"
Peralta, Xomalin G.
Search OSTI.GOV for author "Peralta, Xomalin G." Search OSTI.GOV for ORCID "0000-0002-4034-3214" Search orcid.org for ORCID "0000-0002-4034-3214"
Publication Date:
2017-11-16
Sponsoring Org.:
USDOE
OSTI Identifier:
1409865
Alternate Identifier(s):
OSTI ID: 1409125
Grant/Contract Number:
AC52-06NA25396; NA-0003525
Resource Type:
Journal Article: Published Article
Journal Name:
Optics Letters
Additional Journal Information:
Journal Name: Optics Letters Journal Volume: 42 Journal Issue: 23; Journal ID: ISSN 0146-9592
Publisher:
Optical Society of America
Country of Publication:
United States
Language:
English
Citation Formats MLA APA Chicago BibTeX Naranjo, Guillermo A., and Peralta, Xomalin G. Lattice-induced modulators at terahertz frequencies . United States: N. p., 2017.
Web. doi:10.1364/OL.42.004780. Copy to clipboard Naranjo, Guillermo A., & Peralta, Xomalin G. Lattice-induced modulators at terahertz frequencies . United States. https://doi.org/10.1364/OL.42.004780 Copy to clipboard Naranjo, Guillermo A., and Peralta, Xomalin G. 2017.
"Lattice-induced modulators at terahertz frequencies". United States. https://doi.org/10.1364/OL.42.004780. Copy to clipboard @article{osti_1409865, title = {Lattice-induced modulators at terahertz frequencies}, author = {Naranjo, Guillermo A. and Peralta, Xomalin G.}, abstractNote = {}, doi = {10.1364/OL.42.004780}, url = {https://www.osti.gov/biblio/1409865},
journal = {Optics Letters}, issn = {0146-9592}, number = 23, volume = 42, place = {United States}, year = {2017}, month = {11} } Copy to clipboard
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Tokyo Airports most affected city by 787 grounding, losing 264 weekly flights | CAPA
Tokyo Airports most affected city by 787 grounding, losing 264 weekly flights
WithJapan's two leading airlines –All Nippon AirwaysandJapan Airlines– having about half of the world's787deliveries and being based in Tokyo,Japan's capital has become the most affected city by the grounding of theBoeing787Dreamliner. ANA andJALoperate out ofTokyo HanedaandTokyo Narita, and it isHanedaairport alone that has seen the widest impact as there are 229 weekly787frequencies, more than four times the next largest787airport,Delhi.Tokyo Naritasees the third most number of787services with 35 weekly flights.
YetJapan's carriers, and ANA especially, should be best equipped to mitigate the grounding. Schedules have slack and system load factors are low, at around 60-70%.
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ANA and JAL have different strategies for 787 network planning
Through 31-Dec-2012Boeinghad delivered 49 787s, about half to ANA andJAL, making the two the787's largest in-service customers so far. Hence the substantial impact onHanedain particular. But the two airlines have taken different approaches to deploying their 787s.
JALuses its787aircraft internationally, most notably to open a service toBoston. In Feb-2013JALis also due to open a new service toHelsinki.
Carrier Number Air India 5 ANA 17 Ethiopian 4 JAL 7 LAN 3 LOT 2 Qatar Airways 5 United 6
Source: CAPA – Centre for Aviation &Boeing
Airport Weekly frequencies Tokyo Haneda 229 Delhi 49 Tokyo Narita 35 Ube Yamaguchi 29 Houston 28 Okayama 27 Addis Ababa 26 Frankfurt 21 Takamatsu 21 Kumamoto 21 Matsuyama 20 Singapore 18 Osaka 18 Fukuoka 18 Los Angeles 17 Kagoshima 14 Chicago O’Hare 14 Beijing 14 Bangalore 14 Miyazaki 13 Sapporo Shin Chitose 12 Warsaw 7 Paris CDG 7 London Heathrow 7 Kolkata 7 Johannesburg 7 Hiroshima 7 Dubai 7 Doha 7 Denver 7 Chennai 7 Boston Logan 7 Washington Dulles 5 Seattle 5 San Jose 5 Harare - Lusaka 5 San Diego 4 Santiago 3 Moscow Domodedovo 3 Toronto Pearson 2 Naha 1 Lima Irregular Kuwait Irregular Hyderabad Irregular
Source: CAPA – Centre for Aviation & Innovata
Japanese airlines' low efficiency levels limit the consumer impact of 787 groundings
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| https://centreforaviation.com/analysis/reports/tokyo-airports-most-affected-city-by-787-grounding-losing-264-weekly-flights-94656 |
GtR
The Gateway to Research: UKRI portal onto publically funded research
The Virgo consortium for cosmological supercomputer simulations
Lead Research Organisation:
Durham University
Department Name: Physics
Abstract
The last twenty years have seen the emergence of a standard model for the geometry and material content of our Universe, as well as for the origin and evolution of all structure within it. According to this Lambda-CDM model, we live in a universe with a flat geometry where at least two thirds of all mass-energy is now in the form of a dark energy field which is causing the universe to expand at an ever increasing rate. About a quarter is dark matter, most probably a new weakly interacting elementary particle yet to be detected directly on Earth. Only about 5% is ordinary, or baryonic, matter of which only about a tenth is in stars today and the rest resides mostly in intergalactic gas. Structure was seeded by quantum fluctuations imprinted in the mass density of the universe at the very earliest instants of the Big Bang. These produced weak sound waves in the near-uniform primordial plasma that left observable imprints on the heat left over from the Big Bang, emitted when the universe was only 400,000 years old. These tiny ripples, mapped by imaging the cosmic microwave background radiation, eventually grew into the full richness of structure we see around us today. It is this transformation from a near-uniform primordial soup to a cosmic web of galaxies, clusters and larger structures that is the focus of this application. Gravity, mostly due to dark matter, amplifies the tiny primordial ripples, causing lumps of dark matter and gas to stop expanding with the universe and collapse to form today's cosmic structures. This process is complex, but it can be calculated using computer simulations. For a given a set of assumptions regarding the generation of inhomogeneities in the early universe, the identity of the dark matter, and the values of the cosmological parameters, simulations can now follow the formation history of cosmic structure, tracking the evolution of dark matter, gas and stars, in considerable detail. This application seeks computing resources for the Virgo consortium, a UK-led international collaboration engaged in supercomputer simulations of the formation of structure and generally recognized as the world leader in the subject. Over the past 25 years, the Virgo consortium and precursor collaborations have played a central role in defining the modern approach to physical cosmology and establishing Lambda-CDM as the standard model. Our programme can be divided into four broad, interrelated themes, each of which represents a 'Grand Challenge' in computational astrophysics. The themes are: (1) the dark matter universe; (2) the gaseous universe; (3) the first stars and galaxies; (4) the universe on gigaparsec scales. Our programme thus targets the first and fifth of the nine key science questions in the STFC roadmap: 'What is the universe made of and how does it evolve?', 'How do galaxies, stars and planets form and evolve?'' Our simulation programme has two specific aims. The first is to establish the physical processes that underlie the formation of cosmic structure and explore the LambdaCDM cosmological model in as yet untested regimes. The second goal is to provide a bridge between theory and observations. Simulations are the best, often the only, means to extract and test observable predictions from cosmological and astrophysical theory. Thus, our programme is closely integrated with observational initiatives in the UK and across Europe and seeks to maximize the return from the huge investments being made in space- and ground-based facilities such as Chandra, XMM-Newton, Spitzer, PLANCK, Herschel, Gemini, VLT, and ALMA.
Funded Value:
£1,581,238
Funded Period:
Nov 09
-
Jul 13
Funder:
STFC
Project Status:
Closed
Project Category:
Research Grant
Project Reference:
ST/H008519/1
Principal Investigator:
Carlos Frenk
Research Subject:
Astronomy - observation (80%)
Particle Astrophysics (20%)
Research Topic:
Cosmology (20%)
Extra-Galactic Astron.&Cosmol. (80%)
If populated the following is a graphic depicting where in the UK the given postcode is located.
Organisations
Durham University, United Kingdom (Lead Research Organisation)
University of Edinburgh, United Kingdom (Collaboration)
Institute of Zoology (Collaboration)
National Astronomical Observatories of China (Collaboration)
Planetary Science Institute, United States (Collaboration)
University of Sydney, Australia (Collaboration)
University of Massachusetts Lowell, United States (Collaboration)
Pontifical Catholic University of Chile (Collaboration)
Ohio State University, United States (Collaboration)
University of California, Santa Cruz, United States (Collaboration)
Harvard University (Collaboration)
Queen Mary, University of London, United Kingdom (Collaboration)
Seoul National University (Collaboration)
University of Cambridge (Collaboration)
Cardiff University, United Kingdom (Collaboration)
European Space Agency, France (Collaboration)
University of Nottingham (Collaboration)
University of Oxford, United Kingdom (Collaboration)
Washington University in St. Louis (Collaboration)
Max Planck Society (Collaboration)
Durham University, Durham (Collaboration)
Los Alamos National Laboratory, United States (Collaboration)
University of Leiden, Netherlands (Collaboration)
University of Hawaii (Collaboration)
Heidelberg Institute of Technology and Science (Collaboration)
University of Sussex, United Kingdom (Collaboration)
National Institute of Astrophysics INAF (Collaboration)
National Aeronautics and Space Administration (NASA) (Collaboration)
University of Manchester, Manchester, United Kingdom (Collaboration)
University of Canterbury (Collaboration)
Johns Hopkins University, United States (Collaboration)
<table><tbody><tr><td> People</td><td> ORCID iD</td></tr><tr><td> Carlos Frenk
(Principal Investigator)</td></tr><tr><td> Peter Thomas (Co-Investigator)</td><td><here is a image 28ebf4a7645b02cb-0191992e7eb9518a> http://orcid.org/0000-0001-6888-6483</td></tr><tr><td> Tom Theuns (Co-Investigator)</td></tr><tr><td> John Andrew Peacock (Co-Investigator)</td><td><here is a image 28ebf4a7645b02cb-0191992e7eb9518a> http://orcid.org/0000-0002-1168-8299</td></tr><tr><td> Adrian Jenkins (Co-Investigator)</td><td><here is a image 28ebf4a7645b02cb-0191992e7eb9518a> http://orcid.org/0000-0003-4389-2232</td></tr><tr><td> George Efstathiou (Co-Investigator)</td></tr><tr><td> Frazer Pearce (Co-Investigator)</td></tr><tr><td> Scott Thomas Kay (Co-Investigator)</td></tr></tbody></table>
Bose S
(2016) Reionization in sterile neutrino cosmologiesin Monthly Notices of the Royal Astronomical Society
Boselli A
(2014) The GALEX Ultraviolet Virgo Cluster Survey (GUViCS) IV. The role of the cluster environment on galaxy evolution???in Astronomy & Astrophysics
Bower R
(2010) The parameter space of galaxy formation The parameter space of galaxy formationin Monthly Notices of the Royal Astronomical Society
Bower R
(2011) Astronomy: Unlocking the secrets of the giant blobs.in Nature
Bower R
(2012) What shapes the galaxy mass function? Exploring the roles of supernova-driven winds and active galactic nuclei What shapes the galaxy mass function?in Monthly Notices of the Royal Astronomical Society
Bower R
(2017) The dark nemesis of galaxy formation: why hot haloes trigger black hole growth and bring star formation to an endin Monthly Notices of the Royal Astronomical Society
Boylan-Kolchin M
(2009) Resolving cosmic structure formation with the Millennium-II Simulationin Monthly Notices of the Royal Astronomical Society
Boylan-Kolchin M
(2010) There's no place like home? Statistics of Milky Way-mass dark matter haloes Statistics of Milky Way-mass haloesin Monthly Notices of the Royal Astronomical Society
Bozorgnia N
(2016) Simulated Milky Way analogues: implications for dark matter direct searchesin Journal of Cosmology and Astroparticle Physics
Brough S
(2011) Galaxy and Mass Assembly (GAMA): galaxies at the faint end of the Ha luminosity function GAMA: low-Ha-luminosity galaxiesin Monthly Notices of the Royal Astronomical Society
Bulla M
(2015) Polarization spectral synthesis for Type Ia supernova explosion modelsin Monthly Notices of the Royal Astronomical Society
Bœhm C
(2014) Using the Milky Way satellites to study interactions between cold dark matter and radiationin Monthly Notices of the Royal Astronomical Society: Letters
Cai Y
(2014) A POSSIBLE COLD IMPRINT OF VOIDS ON THE MICROWAVE BACKGROUND RADIATIONin The Astrophysical Journal
Cai Y
(2009) Mock galaxy redshift catalogues from simulations: implications for Pan-STARRS1in Monthly Notices of the Royal Astronomical Society
Cai Y
(2010) Full-sky map of the ISW and Rees-Sciama effect from Gpc simulations ISW ray-tracingin Monthly Notices of the Royal Astronomical Society
Cai Y
(2015) Testing gravity using cosmic voidsin Monthly Notices of the Royal Astronomical Society
Cai Y
(2017) Gravitational redshift and asymmetric redshift-space distortions for stacked clustersin Monthly Notices of the Royal Astronomical Society
Cai Y
(2009) Towards accurate modelling of the integrated Sachs-Wolfe effect: the non-linear contributionin Monthly Notices of the Royal Astronomical Society
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(2014) The integrated Sachs-Wolfe effect in f(R) gravityin Monthly Notices of the Royal Astronomical Society
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(2016) Cosmology with velocity dispersion counts: an alternative to measuring cluster halo massesin Monthly Notices of the Royal Astronomical Society
Callingham T
(2019) The mass of the Milky Way from satellite dynamicsin Monthly Notices of the Royal Astronomical Society
Callingham T
(2022) The chemo-dynamical groups of Galactic globular clustersin Monthly Notices of the Royal Astronomical Society
Calore F
(2015) Simulated Milky Way analogues: implications for dark matter indirect searchesin Journal of Cosmology and Astroparticle Physics
Calore F
(2016) The Fermi GeV excess: challenges for the dark matter interpretationin Journal of Physics: Conference Series
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| https://gtr.ukri.org/projects?fetchSize=25&pn=3&ref=ST%2FH008519%2F1&selectedSortOrder=ASC&selectedSortableField=firstAuthorName |
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SB996.DOC
Report Title:
Office of Hawaiian Affairs; Ceded Lands
Description:
Prohibits the disposition in fee simple of ceded lands.
<table><tbody><tr><td>THE SENATE</td><td rowspan=4>S.B. NO.</td><td>996</td></tr><tr><td>TWENTY-FIFTH LEGISLATURE, 2009</td><td></td></tr><tr><td>STATE OF HAWAII</td><td></td></tr><tr><td></td><td></td></tr><tr><td colspan=3></td></tr><tr><td colspan=3></td></tr></tbody></table>
A BILL FOR AN ACT
relating to lands controlled by the state.
BE IT ENACTED BY THE LEGISLATURE OF THE STATE OF HAWAII:
Section1. In 1978, the
Constitution of the State of Hawai`i was amended to include article XII,
sections 4, 5, and 6, which established the office of Hawaiian affairs and its
board of trustees.
Sections 4, 5, and 6 of the state constitution
provide:
SECTION 4. The lands granted to the State of
Hawaii by Section 5(b) of the Admission Act and pursuant to Article XVI,
Section 7, of the State Constitution, excluding therefrom lands defined as "available
lands" by Section 203 of the Hawaiian Homes Commission Act, 1920, as
amended, shall be held by the State as a public trust for native Hawaiians and
the general public.
SECTION 5. There is hereby established an Office
of Hawaiian Affairs. The Office of Hawaiian Affairs shall hold title to all
the real and personal property now or hereafter set aside or conveyed to it
which shall be held in trust for native Hawaiians and Hawaiians. There shall
be a board of trustees for the Office of Hawaiian Affairs elected by qualified
voters who are Hawaiians, as provided by law. The board members shall be
Hawaiians. There shall be not less than nine members of the board of trustees;
provided that each of the following Islands have one representative: Oahu,
Kauai, Maui, Molokai and Hawaii. The board shall select a chairperson from its
members.
SECTION 6. The board of trustees of the Office
of Hawaiian Affairs shall exercise power as provided by law: to manage and
administer the proceeds from the sale or other disposition of the lands,
natural resources, minerals and income derived from whatever sources for native
Hawaiians and Hawaiians, including all income and proceeds from that pro rata
portion of the trust referred to in section 4 of this article for native
Hawaiians; to formulate policy relating to affairs of native Hawaiians and
Hawaiians; and to exercise control over real and personal property set aside by
state, federal or private sources and transferred to the board for native Hawaiians
and Hawaiians. The board shall have the power to exercise control over the
Office of Hawaiian Affairs through its executive officer, the administrator of
the Office of Hawaiian Affairs, who shall be appointed by the board.
In Act 354, Session Laws of Hawaii 1993, the
legislature stated:
Until the
provisional government was recognized by John L. Stevens, the Kingdom of Hawaii was recognized as an independent nation by the United States, France, and Great Britain. Many native Hawaiians and others view the overthrow of 1893 and
subsequent actions by the United States, such as supporting establishment of
the provisional government and later the Republic of Hawaii, the designation of
the crown and government lands as public lands, annexation, and the ceding of
public lands to the federal government without the consent of native Hawaiians,
as illegal. Because the actions taken by the United States were viewed as
illegal and done without the consent of native Hawaiians, many native Hawaiians
feel there is a valid legal claim for reparations. Many native Hawaiians
believe that the lands taken without their consent should be returned and if
not, monetary reparations made, and that they should have the right to
sovereignty, or the right to self-determination and self-government as do other
native American peoples.
The legislature has also acknowledged that the actions
by the United States were illegal and immoral, and pledges its continued
support to the native Hawaiian community by taking steps to promote the
restoration of the rights and dignity of native Hawaiians.
In Act 359, Session Laws of Hawaii 1993, the
legislature stated:
(4) Throughout the 19th century and until 1893, the
United States:
. . . .
(6) In pursuit of that conspiracy, the United States
Minister and the naval representative of the United States caused armed forces
of the United States to invade the sovereign Hawaiian Nation in support of the
overthrow of the indigenous and lawful government, and the United States Minister
thereupon extended diplomatic recognition to a provisional government formed by
the conspirators without the consent of the native Hawaiian people or the
lawful Government of Hawaii in violation of treaties between the two nations
and of international law;
. . . .
(9) In 1898, Hawaii was annexed to the United States
through the Newlands Resolution without the consent of or compensation to the
indigenous people of Hawaii or their sovereign government. As a result, the
indigenous people of Hawaii were denied the mechanism for expression of their
inherent sovereignty through self-government and self-determination, their
lands and their ocean resources.
In 1993, Congress passed Public Law 103-150,
the Apology Resolution, which stated:
Whereas, from 1826 until 1893, the United States
recognized the independence of the Kingdom of Hawaii, extended full and
complete diplomatic recognition to the Hawaiian Government, and entered into
treaties and conventions with the Hawaiian monarchs to govern commerce and navigation
in 1826, 1842, 1849, 1875, and 1887;
Whereas, on July 4, 1894, the Provisional Government
declared itself to be the Republic of Hawaii;
Whereas, through the Newlands Resolution, the
self-declared Republic of Hawaii ceded sovereignty over the Hawaiian Islands to
the United States;
Whereas, the Republic of Hawaii also ceded 1,800,000
acres of crown, government and public lands of the Kingdom of Hawaii, without
the consent of or compensation to the Native Hawaiian people of Hawaii or their
sovereign government;
Whereas the Congress, through the Newlands Resolution,
ratified the cession, annexed Hawaii as part of the United States, and vested
title to the lands in Hawaii in the United States;
Whereas the indigenous Hawaiian people never directly
relinquished their claims to their inherent sovereignty as a people or over
their national lands to the United States, either through their monarchy or
through a plebiscite or referendum;
. . . .
SECTION 1.
ACKNOWLEDGMENT AND APOLOGY.
The Congress –
(1) On the occasion of the 100th anniversary of the
illegal overthrow of the Kingdom of Hawaii on January 17, 1893, acknowledges
the historical significance of this event which resulted in the suppression of
the inherent sovereignty of the Native Hawaiian people;
. . . .
(3) Apologizes to Native Hawaiians on behalf of the
people of the United States for the overthrow of the Kingdom of Hawaii on
January 17, 1893 with the participation of agents and citizens of the United
States, and the deprivation of the rights of Native Hawaiians to
self-determination;
(4) Expresses
its commitment to acknowledge the ramifications of the overthrow of the Kingdom
of Hawaii, in order to provide a proper foundation for reconciliation between
the United States and the Native Hawaiian people; and
(5) Urges
the President of the United States to also acknowledge the ramifications of the
overthrow of the Kingdom of Hawaii and to support reconciliation efforts
between the United States and the Native Hawaiian people.
In 1993, the legislature also adopted House
Concurrent Resolution No. 179 that included almost all of the parts of the
Apology Resolution including the finding that: "Whereas the indigenous
Hawaiian people never directly relinquished their claims to their inherent
sovereignty as a people or over their national lands to the United States, either through their monarchy or through a plebiscite or referendum".
In 1997, the legislature enacted Act 329, Session
Laws of Hawaii 1997, which stated:
The legislature finds that the events of history
relating to Hawaii and Native Hawaiians, including those set forth in [the
Apology Resolution] continue to contribute today to a deep sense of injustice
among many Native Hawaiians and others. The legislature recognizes that the
lasting reconciliation so desired by all people of Hawaii is possible only if
it fairly acknowledges the past while moving into Hawaii's future.
The legislature further finds that over the last few
decades, the people of Hawaii through amendments to their state constitution,
the acts of their legislature, and other means, have moved substantially toward
this permanent reconciliation. Foremost among these achievements have been the
creation of the [O]ffice of Hawaiian [A]ffairs and the allocation by
legislative action to the [O]ffice of Hawaiian [A]ffairs of substantial funds
out of a portion of the public land[s] trust established by section 5(f) of the
Admission Act. The overriding purpose of this Act is to continue this
momentum, through further executive and legislative action in conjunction with
the people of Hawaii, toward a comprehensive, just, and lasting resolution.
In 2001, S. 746, the federal legislation commonly
referred to as the "Akaka Bill" was passed out of the Senate
Committee on Indian Affairs. Senate Committee Report No. 107-66, on the Akaka
Bill explains that its purpose "is to authorize a process for the
reorganization of a Native Hawaiian government and to provide for the
recognition of the Native Hawaiian government by the United States for the purpose
of carrying on a government-to-government relationship." The Akaka Bill,
authorizes the federal government to negotiate with the State and the
reorganized native Hawaiian government for a transfer of land and resources to
a native Hawaiian government. The native Hawaiian government would thus have a
land base and resources and a status similar to that of other native peoples in
the United States. The Committee Report on the Akaka Bill explains that "it
is the Committee's intent that the references to 'land, resources, and assets
dedicated to [n]ative Hawaiian use' include, but not be limited to lands set
aside under the Hawaiian Homes Commission Act and ceded lands."
In 2007, H.R. 505, the latest version of the Akaka
Bill, passed the U.S. House of Representatives. Section 8 of H.R. 505 also
includes a provision authorizing the United States and State of Hawai‘i to "enter
into negotiations with the Native Hawaiian governing entity designed to lead to
an agreement addressing such matters as the transfer of lands, natural
resources, and other assets, and the protection of existing rights related to
such lands or resources[;]."
In January 2008, the Hawai`i supreme court in Office of Hawaiian Affairs v. Housing And Community
Development Corporation Of Hawai‘i , 117
Hawai'i 174, 177 P.3d 884 (2008) (OHA v. HCDCH), enjoined
the State from selling or otherwise transferring to third parties any ceded
lands from the public lands trust until the claims of the native Hawaiian
people to the ceded lands have been resolved.The plaintiffs in the OHA
v. HCDCH case and the legislature agree that based on the language of the OHA
v. HCDCH decision, the Hawaii supreme court intended that the injunction would
remain in place until the native Hawaiian claim to the ceded lands is resolved
unless, prior to any such resolution, the legislature no longer desires
reconciliation between the State and the native
Hawaiian people. In other words, if prior to any resolution, the legislature
no longer desired reconciliation, regardless of the Apology Resolution, the
injunction would no longer be appropriate.
In October 2008, the United States Supreme Court
granted the State’s petition for certiorari in the OHA v. HCDCH case.
The legislature supports this Act as a
means of preserving the status quo and ensuring that the public lands trust is
preserved in order to ensure a fair and just settlement leading to
reconciliation with the native Hawaiian people.
SECTION 2. Chapter 171,
Hawaii Revised Statutes, is amended by adding two new sections to be
appropriately designated and to read as follows:
"
§171-A Sale of lands in the public land trust.
Notwithstanding any
law to the contrary, no sale in fee simple shall be made of:
(1)
Lands ceded to the United States by the
Republic of Hawaii under the joint resolution of annexation, approved July 7,
1898 (30 Stat. 750), or acquired in exchange for lands so ceded, and granted to
the State of Hawaii by virtue of section 5(b) of the Admission Act of 1959; or
(2)
Lands retained by the United States
under section 5(c) and (d) of the Admission Act of 1959 and later conveyed to
the State under section 5(e) or under the Act of December 23, 1964 (Pub. Law
88-233, 77 Stat. 472).
§171-B Exchange of lands in the public land trust for private land.
(a)
Notwithstanding any law to the contrary, no exchange shall be made of:
(1)
Lands ceded to the United States by the
Republic of Hawaii under the joint resolution of annexation, approved July 7,
1898 (30 Stat. 750), or acquired in exchange for lands so ceded, and granted to
the State of Hawaii by virtue of section 5(b) of the Admission Act of 1959; or
(2)
Lands retained by the United States
under section 5(c) and (d) of the Admission Act of 1959 and later conveyed to
the State under section 5(e) or under the Act of December 23, 1964 (Pub. Law
88-233, 77 Stat. 472).
"
SECTION 3. Section
171-13, Hawaii Revised Statutes, is amended to read as follows:
" §171-13 Disposition of public lands.Except as otherwise provided by law and subject to other provisions of this
chapter, the board may:
(1) Dispose of public land in fee simple, by lease,
lease with option to purchase, license, or permit[
; and
]
, except
dispositions that result in or may result in alienation of the fee of lands:
(2) Grant easement by direct negotiation or otherwise
for particular purposes in perpetuity on such terms as may be set by the board,
subject to reverter to the State upon termination or abandonment of the
specific purpose for which it was granted, provided the sale price of such
easement shall be determined pursuant to section 171-17(b).
No person shall be eligible to purchase or lease
public lands, or to be granted a license, permit, or easement covering public
lands, who has had during the five years preceding the date of disposition a
previous sale, lease, license, permit, or easement covering public lands
cancelled for failure to satisfy the terms and conditions thereof."
SECTION
4. This Act does not affect the state practice of transferring remnants,
and issuing licenses, permits, easements and leases.
SECTION 5. This Act shall remain in
effect until the claims of the native Hawaiian people to the public land trust
lands have been resolved or until the legislature finds that the State no
longer supports reconciliation between the State and the native Hawaiian
people.
SECTION 6. In codifying the new sections added by section 2
of this Act, the revisor of statutes shall substitute appropriate section
numbers for the letters used in designating the new sections in this Act.
SECTION 7. Statutory material to be repealed is
bracketed and stricken. New statutory material is underscored.
SECTION 8. This Act shall take effect
upon its approval.
<table><tbody><tr><td>INTRODUCED BY:</td><td>_____________________________</td></tr><tr><td></td><td>By Request</td></tr></tbody></table>
| https://www.capitol.hawaii.gov/sessions/session2010/bills/SB996_.HTM |
Sustainability | Free Full-Text | Working Co-operatively for Sustainable and Just Food System Transformation
Co-operative ways of working can be understood as people-centred approaches. This article considers how co-operative ways of working have the potential to support the scaling-out of sustainable and just food systems in the context of Wales through people-centred change. Drawing upon a series of interviews with stakeholders involved in the sustainable and the co-operative food sector within Wales and international case studies, opportunities and challenges facing the scaling-out of sustainable and just food systems are considered. Findings demonstrate the potential of co-operative and community-based approaches to sustainable production, processing, distribution, and trading of healthy food that is affordable, culturally appropriate, and based upon an ethic of justice and care for land, workers, and animals. Community supported agriculture, incubator farms, food hubs, and platform co-operatives are identified as key mechanisms for sustainable and just food systems. Capacity building through education, information, and training are further critical foundations for co-operative and people-centred ways of working. In order to accelerate sustainable and just food futures, community-based participation, networks for training, access to resources and land, and transformative forms of governance, including legislative change, are key. We conclude by highlighting implications for future research into policy transfer and food system transformation.
Working Co-operatively for Sustainable and Just Food System Transformation
by Poppy Nicol * and Alice Taherzadeh
Sustainable Places Research Institute, Cardiff University, CF10 3BA, Cardiff, UK
*
Author to whom correspondence should be addressed.
Sustainability 2020 , 12 (7), 2816; https://doi.org/10.3390/su12072816
Received: 31 January 2020 / Revised: 26 February 2020 / Accepted: 4 March 2020 / Published: 2 April 2020
(This article belongs to the Special Issue People Centred Perspectives on the Sustainability of Food Systems )
Abstract
Co-operative ways of working can be understood as people-centred approaches. This article considers how co-operative ways of working have the potential to support the scaling-out of sustainable and just food systems in the context of Wales through people-centred change. Drawing upon a series of interviews with stakeholders involved in the sustainable and the co-operative food sector within Wales and international case studies, opportunities and challenges facing the scaling-out of sustainable and just food systems are considered. Findings demonstrate the potential of co-operative and community-based approaches to sustainable production, processing, distribution, and trading of healthy food that is affordable, culturally appropriate, and based upon an ethic of justice and care for land, workers, and animals. Community supported agriculture, incubator farms, food hubs, and platform co-operatives are identified as key mechanisms for sustainable and just food systems. Capacity building through education, information, and training are further critical foundations for co-operative and people-centred ways of working. In order to accelerate sustainable and just food futures, community-based participation, networks for training, access to resources and land, and transformative forms of governance, including legislative change, are key. We conclude by highlighting implications for future research into policy transfer and food system transformation.
Keywords:
food justice
;
sustainable food systems
;
co-operative
;
transformation
;
Wales
1. Introduction
This article investigates how co-operative ways of working, as people-centred approaches, can support the scaling-out of sustainable and just food systems. Based on fieldwork conducted within the Welsh food sector and a set of international case studies, the article considers the opportunities and challenges of sustainable and just food system transformation within Wales, and the potential role of co-operative approaches. It makes a contribution to the sustainable food systems literatures as a case study that considers the linkages between co-operative ways of working, people-centred approaches, and sustainable and just food system transformation.
Drawing upon sustainable and just food literatures, food systems are understood to include “the various processes and infrastructures involved in feeding a population, including growing and harvesting, processing, distribution, marketing, wholesaling, retailing, consumption and the disposal of waste” [ 1 ] (p. 319). Food systems are recognised as “an interactive, interdependent web of activities and relationships” [ 1 ] (p. 319). As indicated in the EAT Lancet Commission Report: “food systems have the potential to nurture human health and support environmental sustainability; however, they are currently threatening both” [ 2 ] (p. 447). There is growing understanding of the need to make large-scale shifts towards more sustainable and regenerative food systems [ 3 , 4 , 5 ]. Food systems currently have a major impact upon the water-food-energy nexus, recognised as central to sustainable futures [ 6 ]. Agriculture is the largest consumer of global freshwater resources and a major contributor of greenhouse gas emissions, whilst food production and supply accounts for one quarter of global energy use [ 6 ]. Meanwhile, the dual challenges of climate change and malnutrition play out in ways that affect most those who are most vulnerable [ 2 ]. According to Willett et al. [ 2 ], the ‘planetary healthy plate’ can provide both a sustainable and healthy diet for all. Derived from sustainable food production that operates within ‘safe operating spaces’ “for environmental systems and processes that contribute to the stability and resilience of the Earth system” [ 2 ] (p. 461), the proposed ‘planetary health plate’ “largely consists of vegetables, fruits, whole grains, legumes, nuts, and unsaturated oils, includes a low to moderate amount of seafood and poultry, and includes no or a low quantity of red meat, processed meat, added sugar, refined grains, and starchy vegetables” [ 2 ] (p. 447).
The ‘planetary health plate’ promotes an integrated understanding of the connections between planetary health and diet. However, food justice remains largely overlooked in this conceptualisation. Many would suggest that food justice is a critical dimension of sustainable food systems and sustainable healthy diets. Healthy food needs to be understood not only as fresh and nutritious, but also “affordable, culturally-appropriate and grown locally with care for the well-being of the land, workers and animals” [ 7 ]. From a rights-based approach, food justice is understood as “communities exercising their right to grow, sell and eat healthy food” [ 7 ]. Integrating these understandings of what constitutes a sustainable and just food system, we draw upon the concept of ‘just sustainabilities’, defined as “the need to ensure a better quality of life for all, now and into the future, in a just and equitable manner, whilst living within the limits of supporting ecosystems” [ 8 ] (p. 5). ‘Just sustainabilities’ highlights the need to consider the well-being of future generations in any understanding of sustainable food justice, attending not only to inter-generational justice, but also intra-generational justice. Within any conceptualisation of what counts as a ‘just food system’, epistemic and contributive justice as well as distributive justice need to be considered [ 9 , 10 ].
We further acknowledge the work of agri-food scholars who contest normative assumptions that local food systems, alternative food networks, or forms of direct exchange offer necessarily more sustainable, just, and equitable food systems. Born and Purcell [ 11 ] warn of the ‘local trap’, whilst DuPuis and Goodman [ 12 ] (pp. 360–361) warn that ‘local’ “is not an innocent term”, challenging the ‘unreflexive localism’ of many local food system narratives based upon the interests of a ‘sectionalist, authoritarian elite’. As DuPuis and Goodman highlight, ‘unreflexive localism’ does not necessarily create the radical new political processes that are envisaged [ 12 ]. Guthman [ 13 ] and Alkon [ 14 ] further challenge the tendency for colour-blindness and universalism of alternative food scholarship, which compromises the very social justice goals it claims to value and work towards. These critiques highlight the importance of an inter-sectional approach in attending to the investigation of sustainable and just food systems. We suggest people-centred approaches have the potential to create space for such work.
Scaling-out is identified as a pathway for food system change, alongside scaling-up and scaling-deep [ 15 , 16 ]. Pitt and Jones note the inconsistencies in distinctions between scaling-up and scaling-out, suggesting this “might be due to the reality that geographical expansion requires organizational growth” [ 15 ] (p. 4). Building upon Pitt and Jones, and Moore, Riddell, and Vocisano, we understand scaling-out as a form of horizontal and distributed scaling [ 15 , 16 ]. Scaling-out is based upon community-based capacity-building, including increasing the number of people or communities impacted or involved [ 16 ], whilst scaling-up is understood as “expanding institutional capacity” [ 15 ] and “changing institutions at the levels of policy, rules and laws” [ 16 ] (p. 75). Scaling-deep is understood as “changing relationships, cultural values and beliefs, ‘hearts and minds’” [ 16 ] (p. 75), centred upon acknowledgement that “culture plays a powerful role in shifting problem-domains, and change must be deeply rooted in people, relationships, communities and cultures” [ 16 ] (p. 77). Drawing upon these conceptualisations of scaling change, we highlight the need to attend to organisational and institutional structures as well as intersectionalities, suggesting scaling-up tends towards vertical integration and hierarchical forms of organisational structure, whilst scaling-out requires horizontal and distributed forms of organisational structure. Acknowledging the important role of scaling-up and scaling-deep within transformation processes and the need for further critical work on this, in this article we focus on the role of scaling-out to explore the question of people-centred change.
Whilst there is growing understanding and awareness around what constitutes a healthy and sustainable diet, achieving a sustainable and just healthy diet for all remains a global challenge. This paper focuses on the case of the nation of Wales, United Kingdom, in order to explore two research questions. First, what are the opportunities and challenges to scaling-out sustainable and just food systems within Wales? Second, can co-operative ways of working foster sustainable and just food systems through people-centred approaches? As Section 2 outlines, currently unsustainable and unjust food systems prevail within Wales. Section 3 presents the methodological approach. Drawing upon a series of interviews with stakeholders involved in the sustainable and the co-operative food sector within Wales and a set of indicative case studies, Section 4 presents an overview of barriers and opportunities to working co-operatively in Wales and the scaling-out of sustainable and just food systems. In Section 5 , we identify five foundations of people-centred approaches found synergistic with co-operative ethics, building upon Levkoe and Sheedy, Korten, and Samuels [ 1 , 17 , 18 ]. Findings demonstrate the opportunity of co-operative ways of working and community-based approaches to deliver sustainable production, processing, distribution, and trading of healthy food that is affordable, culturally appropriate, and based upon an ethic of justice and care for land, workers, and animals. We conclude by highlighting implications for future research into policy transfer and food system transformation. In order to accelerate towards sustainable and just food futures, transformative forms of governance, including legislative change, are recognised as key.
2. Context
2.1. Food Justice in Wales
Currently unsustainable and unjust food systems prevail within Wales. Marginal food security is common, particularly prevalent amongst young people [ 19 ]. Around one in four children are living in households for whom a healthy diet is increasingly unaffordable [ 20 ]. Low pay and poor quality employment mean that many working people remain in relative poverty and experience food insecurity [ 21 , 22 ]. The increase in food banks across Wales suggest growing levels of relative poverty and food insecurity, including amongst the working population [ 23 ]. Links between poor health and poverty are pronounced. There are further indications of health inequalities with regards to fresh fruit and vegetable consumption in Wales—less than one quarter of adults report to eat the recommended five-a-day portions of fruits and vegetables, whilst less than one-third of children report to eat at more than one portion of vegetables once a day or more [ 24 , 25 ]. Those living in more deprived communities are less likely to eat fruits and vegetables than those living in more affluent communities [ 24 ]. As the South Wales Food Poverty Alliance (SWFPA) note, achieving a healthy diet is complex. Key barriers to accessing healthy food include: Lack of finances; lack of nutrition knowledge and cooking skills; lack of access to affordable and healthy foods, and lack of cooking facilities or the ability to use them [ 26 ] (p. 10). Improving access to healthy food (including fresh vegetables, fruits, whole grains, legumes, nuts, and unsaturated fats) through addressing these barriers has the potential to enhance the long-term health and well-being of people living in Wales. One key step that could improve access is the scaling-out of food systems that support the production, distribution, and trading of healthy, nutritious, affordable, culturally-appropriate food. However, a people-centred approach further highlights the need for capacity-building within the current food system.
2.2. Sustainable Food Production in Wales
According to recent estimates, the amount of vegetables and fruits produced in Wales meets an estimated 5% of the recommended five a day requirement for the population of Wales [ 25 , 27 ]. Within the UK more generally, it is estimated that domestic production accounts for 57% of vegetable supply and 16% of fruit supply (2017 figures) [ 28 ]. Currently, the agricultural industry in Wales is dominated by livestock (49% sector output)—mainly cattle and sheep; and livestock products (37% sector output)—including milk/milk products and eggs [ 29 ]. Crops account for a small proportion of sector output (6.3%), around half of which are horticultural products—including fruits and vegetables; and half of which are split evenly between cereals and potatoes [ 29 ]. Arable farming in Wales accounts for 4.8% of total agricultural land use: Predominantly wheat (25.2%); barley (21.2%), and; crops for stock-feeding (18.7%), whilst horticulture accounts for 0.1% proportion of total agricultural land use: Predominantly commercial orchards, other orchards, and small fruits (55%); vegetable and salad growing in the open (22%), and; glasshouse (1.4%) [ 30 ]. Under-reporting of horticultural activity is likely, since many horticultural producers do not receive agricultural subsidy or are under the typical threshold for returning farm business data, hence they may not be included in national-level statistics [ 31 ]. That being said, arable and horticultural production still accounts for a very small proportion of crops consumed within Wales.
The current gap between the nation’s dietary requirement for fresh fruits and vegetables and what is being produced presents both challenge and opportunity for the scaling-out of sustainable and just food production. Within Wales and beyond, there are likely to be increasing pressures both from a public health perspective and environmental perspective for large-scale shifts towards more plant-based diets derived from sustainable food systems. Scaling-out sustainable arable and horticultural production in Wales could enable more people opportunity to both attain a sustainable and healthy diet and participate in sustainable food systems. Amidst growing awareness of the need for sustainable food systems, prospects for sustainable agriculture sector are good, particularly for the sustainable horticulture and arable sector. At present however, there are a number of obstacles preventing the scaling-out of sustainable production within Wales.
2.3. Scaling-out Sustainable Food Systems in Wales: Challenges
Currently, the area of land used for sustainable production is marginal, although promising. 4.9% of agricultural land within Wales is categorised as organic—higher than any other UK nation—England (3.1%), Scotland (1.6%), and Ireland (0.8%), and the global average (1.4%) [ 32 , 33 ]. Sustainable production is currently limited by three key factors: First, the challenge of competing with low-cost food based on economies of scale. Power within food supply chains has dramatically consolidated over time [ 34 , 35 ] (p. 6). Centralised systems prioritise suppliers that are vertically integrated, whilst minimising opportunities for individuals to influence management practices [ 26 , 34 , 35 ]. Second, the lack of infrastructure and processing facilities, particularly for small-scale sustainable meat, cereal, and horticulture products. Anecdotal evidence suggests many small-scale Welsh horticultural growers supplying multiple retailers have not been able to compete with larger scale farms that can offer the volumes and stringent qualities required by consolidating markets. Regional processing and distributing centres within Wales are in steady declined, replaced by national ‘mega-hubs’ [ 36 ]. Meanwhile, there are few facilities for small to medium-scale processing of cereals such as oats, wheat, and barley within Wales. Third, the ageing farming population. Currently, farmers in Wales are typically male and relatively old. Young farmers (under 40 years old) in the UK make up 5.3% of farm managers, compared with the EU average of 10.6% [ 37 ]. Whilst these statistics obscure farming demography, as they focus only upon farm managers, rendering trainees and other farm-workers invisible [ 38 ], sustainable farming remains a relatively unlikely career choice amongst young people living and working within Wales, particularly amongst those from non-farming families.
The scaling-out of sustainable production within Wales requires a new generation of sustainable farmers and growers. At present however, new entrant farmers and growers face a suite of challenges in Wales including: Limited opportunities for learning about sustainable agriculture; limited training provision in business and commercial skills, and access to land, capital, and markets [ 39 , 40 ]. Taherzadeh further identifies a ‘missing link’ in learning pathways for sustainable agriculture, with lack of mid-level farming opportunities which allow entrants to gain more experience after initial training and before heading their own farm business [ 38 ]. Land prices, particularly of smaller parcels of land; land retirement and farm consolidation; lack of tenure security; loss of farmland due to local development; and access to credit constitute significant challenges to accessing land in Wales [ 39 , 40 ].
Welsh agriculture currently accounts for 3.6% of regional employment and a total gross value added (GVA) to the Welsh economy of 0.6% [
41
]. Sustainable forms of agriculture are a key component in the scaling-out of sustainable food systems within Wales and have the potential to make significant contributions to the Welsh foundational economy through job creation and income generation [
42
]. Evidence suggests sustainable forms of agriculture create more jobs per farm and potentially more value. In the UK, it is estimated that organic farming provides 32% more jobs per farm than equivalent non-organic farm [
43
]. Local and regional food economies have also been found to have a ‘multiplier effect’—for example, income from an organic box scheme was found to generate about twice as much for the local economy as supermarkets [
44
].
However, at this juncture, there is a need to return to the critical agri-food literature warnings of the ‘local trap’, ‘unreflexive localism’, as well as colour-blindness and ‘universalism’ [
11
,
12
,
13
,
14
]. We argue that co-operative approaches have the potential to overcome a number of the challenges outlined above and support the scaling-out of inter-sectional, democratic, participatory, and empowering forms of sustainable production, processing, distributing, trading, and training within Wales, as well as job creation and income generation. As explored in the remainder of this paper, co-operative approaches foster people-centred approaches to producing, processing, distributing, and trading sustainable crops; support new entrant farmers and growers, and cultivate people-centred food systems.
2.4. Co-operatives: People-Centred Ways of Working?
Co-operatives have been described as “the only type of enterprises that have an internationally agreed ethical code of values” [
45
] (p. xi). In 1995, members of the International Co-operative Alliance (ICA) agreed and adopted
The Statement on the Co-operative Identity, Values and Principles
. Within the statement, a co-operative is defined as “an autonomous association of persons united voluntarily to meet their common economic, social, and cultural needs and aspirations through a jointly-owned and democratically-controlled enterprise” [
45
] (p. 34); co-operative values are defined as including “self-help, self-responsibility, democracy, equality, equity, and solidarity, as well as ethical values of honesty, openness, social responsibility and caring for others”; seven co-operative principles, as outlined below, are described as “guidelines by which co-operatives put their values into practice” [
45
] (p. i).
Voluntary and open membership
Democratic and member control
Member economic participation
Autonomy and independence
Education, training, and information
Co-operation among co-operatives
Concern for community
The ICA Statement has enabled recognition of co-operatives amongst international bodies, including the United Nations (UN) and International Labour Organisation (ILO) [ 46 , 47 ]. Whilst the definition, values, and principles of co-operatives constitute an internationally agreed and recognized set of guidelines, they are not legally binding. The ways in which they are applied depend upon the “economic, cultural, social, legal and regulatory context and particularities within which co-operative operates” [ 45 ] (p. xi). Although co-operative identity and values are ‘immutable’, principles can be ‘reformulated and restated’ [ 45 ] (p. 1). As Green states, co-operative economies are ‘diversified and pluralistic’ [ 45 ] (p. ix). The ways in which co-operatives operate on the ground can vary significantly. However, co-operatives as entities are underpinned by a globally agreed ethical code focused around people-centred approaches. Indeed, we suggest co-operative values and principles are closely aligned to five key foundations of people-centred approaches: Processes of democratisation; redistribution of power; strengthening participation; equality and justice, and transformative governance [ 1 , 17 , 18 ].
Cooperatives were established as a practical means of enabling working people to meet their everyday needs, and as a route to building a better society. At its simplest, co-operative action is about “people working together equitably as members of a formal and open body that exists to meet their economic and wider needs” [
48
] (p. 7). For the founders of the UK co-operative movement, the co-operative was not simply about finance (whether through credit or retailing), but about how the working and living conditions of people and the communities within which they lived could be improved [
49
] (p. 21). Within a people-centred business model, people are at the core, and any profit is seen as a means to serve the people. With a focus of inclusive and democratic participation; people over profit; co-operation over competition; capacity building through education, information, and training; and concern for community as core principles, co-operative ways of working could support with the scaling-out of more people-centred approaches. We suggest co-operative approaches provide opportunity to address some of the root challenges currently limiting sustainable and just food futures.
3. Materials and Methods
A series of interviews with key identified stakeholders were conducted to improve understanding of the opportunities and challenges to scaling-out of sustainable and just food systems in Wales, and how co-operative ways of working have the potential to foster sustainable and just transformation. Interviewees included representatives from a range of organisations and businesses operating within the food sector (including in the horticulture, dairy, meat, and processing sectors) that employed formal or informal co-operative ways of working. As well as those operating as co-operative societies, organisations and businesses oriented to sustainability and food justice that self-defined as co-operative were considered.
During initial stakeholder mapping, co-operatives in the meat and dairy sectors were found to be medium to large-scale co-operatives of between 20 to 7500 producer members, largely working to supply multiple retailers. Those in horticulture working formally or informally as co-operatives were more likely to be small-scale and community-based, tending to operate as single farm units. As outlined in
Figure 1
, twelve stakeholders representing nine co-operative businesses, two organisations working with co-operative principles informally, and a representative from the Wales Co-operative Centre were interviewed.
Figure 1. Sample of co-operatives by function, scale, and sector.
Small-scale includes single farms or small collectives of farms. Medium–scale co-operatives of between 20–500 producer members. Large-scale includes co-operatives of more than 500 producer members.
Research was conducted between May–September 2019. Five key topics were discussed in the interview [see Appendix A for more information]:
Investigating cooperative ways of working
Co-operative ways of working in Wales
Training and learning
Cooperative ways of working and sustainable food systems
Cooperative ways of working and the policy environment
An interview question guide was followed during interviews (see Appendix A ). Interviews were recorded, transcribed, and analysed thematically. Fieldwork was accompanied with desk-based research on international exemplars of co-operative approaches within the food sector. Research was underpinned by the BSA [ 50 ] and Cardiff University guidelines on research ethics and research integrity [ 51 ]. The research received ethical approval by Cardiff University Research Ethics Committee [SREC/3334].
4. Results
Drawing upon interviews, this section is presented in two parts. The first part presents key identified challenges and opportunities to producing co-operatively; distributing, processing, and trading co-operatively; and learning co-operatively in Wales. The second part presents key identified opportunities to scaling-out sustainable and just food systems, drawing upon a series of indicative case studies.
4.1. Working Co-Operatively in the Welsh Food System
4.1.1. Producing Co-operatively in Wales
Many producers interviewed voiced difficulty operating amidst a wider food system where the ‘real’ costs of food are often not translated. As one producer reflects:
“That’s the dilemma with food production. People expect it cheap. And to have it cheap you need economies of scale both from the farm side and the processing side and then that involves hauling the stuff half way around the country.”
For some producer-led, farmer-owned co-operatives, working together as a co-operative gives more collective bargaining power and guaranteed prices, regardless of farm size. This can be particularly beneficial for small-scale producers. According to one producer interviewed, an advantage of working co-operatively for small-scale producers is that they are able to work together to reach markets that could otherwise be inaccessible. Other forms of service-based agricultural co-operatives were identified whereby membership provides producers technical services that support compliance with quality accredited schemes and thus access to markets that would be otherwise difficult to reach.
Amongst small-scale horticultural producers interviewed, many identified opportunity in local and regional food economies. Several voiced difficulty of selling fresh produce to multiple retailers for prices that are not viable. According to one horticultural producer:
“The elephant in the room is that we are basically training people into an economically unviable career. But we need it to be economically viable if we want food to be produced locally and ecologically.”
Schemes with pricing structures that reflect the ‘real’ ecological and social costs of producing and distributing food were favoured amongst producers interviewed.
4.1.2. Distributing, Processing, and Trading Co-operatively in Wales
The lack of distributing and processing units within Wales, particularly within the organic dairy, meat, and cereal sectors was identified as a key challenge facing small-scale producers. The quote below highlights a key challenge currently facing small and medium-scale cereal growers within Wales:
“I have personally grown 140kg of milling quality oats this year as part of that network, but I cannot dehull them for human consumption. There are no de-hullers in Wales [...] We need funding for shared grain processing hubs, which will allow more small scale growers to grow grains and have them eaten by people in their communities.”
Transport costs were also identified as a significant sustainability challenge mentioned amongst stakeholders from the meat and dairy sector—particularly when it comes to transporting raw produce with a short lifespan, such as milk.
4.1.3. Learning Co-operatively in Wales
Education, training, and information were discussed with all stakeholders in this study, including both support for setting-up and managing co-operatives, as well as the broader training landscape for sustainable food systems. Long-term funding was identified as the main obstacle by stakeholders in terms of accessing high-quality training and relevant advice. Amongst stakeholders, there was a broad agreement that the food education and training landscape is “pretty sparse”, particularly in horticulture. Work-based apprenticeships and traineeships, formal training programmes to support new entrants, and qualifications and training centres for trainers were identified as initiatives that could support the scaling-out of sustainable food futures in Wales. Some stakeholders emphasised the importance of accreditation of training at recognised educational levels whilst others, particularly small-scale producers, saw themselves as key actors in expanding training opportunities through apprenticeship and mentoring networks. Improving training provision for sustainable production was identified as key. As one grower reflects, there is currently “not much training, but a lot of opportunity.” Many stakeholders also mentioned the importance of mentoring schemes at all stages.
A history of episodes of short-term funding has resulted in gaps in the food-sector training and mentoring landscape within Wales. Whilst many smaller-scale stakeholders connected sparse training opportunities with lack of funding, large-scale stakeholders were critical of the quality of government-funded training and expressed a preference for private consultancy or formal high- level qualifications. Training delivered by a broad range of actors on the basis of short-term government grants was considered potentially damaging to quality in comparison with core funding provided to experienced and trusted organisations. Scope for collaboration between organisations and educational institutions to provide accreditation was further recognised.
Despite increased recent efforts to support horticulture within Wales through programmes such as Tyfu Cymru [ 52 ], those interviewed highlighted the gap in horticultural training, and many were not aware of the full range of opportunities available to them. With constantly shifting training landscapes, stakeholders may fail to identify the appropriate training available to them.
4.2. Scaling-out Co-operative Ways of Working for Sustainable and Just Food Systems: Opportunities
4.2.1. Scaling-out Sustainable Agriculture
Community Supported Agriculture (CSA) emerges as an approach for small-scale growers that can support recognition of the ‘real’ costs of food and the scaling-out of sustainable agriculture through co-operative approaches to production, distribution, trading, and training. CSA is understood as “a partnership between farmers and consumers in which the responsibilities, risks and rewards of farming are shared” [
53
]. As a form of direct supply, it can facilitate more autonomous forms of sustainable production (including volumes, crops, and qualities sold) and more co-operative relations (including membership) [
54
].
Cae Tan [
55
] is one of the largest CSAs in Wales, operating in the Gower Peninsula, South-west Wales. As a grower-led CSA, decision-making is guided by the growers and supported by members, who pay for a share of the crop in the form of a weekly box of veg. Two growers manage farm operations, supported by an apprentice and volunteers. 120 members pick up their weekly veg box from a local hub. Through a one-year apprenticeship scheme, Cae Tan creates both training and employment opportunities for new entrant growers. Over the last four years, out of the four apprentices, two have secured employment in horticulture—one has become assistant grower at Cae Tan and one has set up a salad growing social enterprise on Cae Tan land, whilst another is in the process of setting up other CSAs in the Swansea area. Alongside the apprenticeship scheme, Cae Tan run a Sustainable Schools Programme, where primary school pupils from 5 local schools learn about sustainable farming.
4.2.2. Scaling-out Sustainable Distribution, Processing, and Trading
Findings suggest working together could or already does enable interviewees to overcome some of the challenges they face, including accessing capital to purchase equipment, reaching markets, and navigation of future challenges in Wales, particularly amidst a current context of climate emergency and political uncertainty. Informal and formal producer co-operatives enable collective approaches to: Processing; distribution (including transportation and sales); packaging, labelling, and promotion; organising of quality control; use of equipment and storage facilities; management of waste; and collective procurement of inputs [
56
] (p. 4). Working together particularly enables small-scale producers to overcome barriers—for example, sharing of resources and equipment avoids large capital costs, whilst processing hubs support more resource efficient approaches to processing.
Co-operatively-run processing food hubs are identified as another way of working co-operatively. Food hubs can support: Distributing collectively (including transportation and sales); sharing markets; purchasing and sharing infrastructure and equipment; and developing learning networks to address problems and share good practice [ 57 ]. They can include: Food distribution centres, online platforms, farmers’ markets, community kitchens, and certification programmes.
Co-operative approaches to online software and digital tools are further identified as a key means of addressing certain challenges facing the food sector—enabling technical assistance (for example, software that supports producers attain specific quality standards); distribution (for example, via online platforms); and network building (for example, via online social media platforms). This includes platform co-operatives—digital platforms “designed to provide a service or sell a product - that [is] collectively owned and governed by the people who depend on and participate in it” [ 58 ].
Open Food Network (OFN) [
59
] presents an innovative case of using technology to support local food economies. As a platform co-operative, open source software supports the distribution of food via food hubs. Via an online platform, producers can sell to food hubs as well as direct to consumers, wholesalers can manage buying groups and supply food hubs, and communities can set up food hubs enabling trade and distribution within the local community. Currently, over 1000 producers and around 50 community enterprises running local food hubs are registered on the OFN-UK. As a model of co-operatively managed software, all members (including food producers, food hubs, and shops) collectively own the software and data.
4.2.3. Scaling-out Learning for Sustainable and Just Food Futures
Amongst some stakeholders, education within co-operatives around co-operative ethics was noted as crucial to the continuation and sustainability of the co-operative and the co-operative movement more broadly. Many identifying with co-operative ethics had first encountered co-operative ways of working during training and work experience at other co-operatives, highlighting the necessary educational role of co-operatives in scaling-out. Some further noted the need for a “critical mass” in terms of numbers of co-operatives operating in Wales in order to scale-out co-operative ways of working within Wales. Whilst co-operatives have the potential to be more self-sustaining as co-operative economies grow, currently the opportunity for co-operative-to-co-operative exchange is limited by the relatively small number of co-operatives existing in the food sector in Wales. At present, there are an estimated 478 co-operatives in Wales (of which only 22 are within the agri-food sector) [
60
,
61
]. Stakeholders recognized a role for institutional support for new and fledgling co-operatives within the food sector in order to scale-out co-operative approaches within Wales and achieve the “critical mass” required.
Additionally, stakeholders identified need for networks of training that provide opportunities for new entrants, address identified gaps in the training landscape, and link different actors within the food system through knowledge exchange. Long-term core funding is required to establish and sustain such initiatives. Highlighted opportunities include the training and community educating roles of CSAs and incubator farms, as well as accredited training schemes operated via farm networks.
Mach Maethlon, a food co-operative and vegetable box scheme based in the Dyfi Valley, launched a pilot incubator farm scheme,
Pathways to Farming
, in 2018 [
62
]. The scheme aims to increase the number of sustainable horticultural food producers in the area and support the local food economy through training new entrants on micro-farm plots [
62
]. Participants are provided with training and support to develop innovative business models and access local markets through a 12-month programme. In the first year of the scheme, out of 12 trainees, 9 have gone on to grow produce for local sale, including 4 trainees who have joined together to create a veg box scheme [
63
]. Working with other local producers, they have developed a local food hub through the OFN network. However, they face a challenge in maintaining their active role in the broader Welsh training landscape if they are unable to access long-term institutional support and funding.
5. Discussion
Drawing upon interviews with stakeholders, key challenges and opportunities facing the scaling-out of sustainable and just food systems in Wales are identified. Accounting for the ‘real cost’ of food so that sustainable agriculture is economically viable; addressing gaps in distribution, processing, and trading infrastructure, particularly for small-scale producers; and improving sustainable food system and business training opportunities emerge as key. However, though fragmented, findings indicate a range of people-centred, community-based approaches to production, distribution, trade, and education. Case studies demonstrate a range of mechanisms addressing some of the systemic barriers within current unsustainable and unjust food systems. From sharing the risks, rewards, and responsibilities of farming via CSAs; scaling-out of training and opportunities for new entrant farmers through incubator farms; sharing equipment and other resources via producer co-operatives; and community-based mechanisms for processing, distributing, and trading food via platform co-operatives and food hubs. These approaches are focused upon placing people at the centre of food system transformation.
5.1. People-centred Approaches to Food Systems
As a capacity-building approach to development, people-centred approaches are about more than economic development and the re-distribution of financial and material resources—the purpose of a people-centred approach is to enhance people’s lives [
64
] (pp. 15-16). Within the context of sustainable and just food systems, a people-centred approach is not only about ensuring access to sustainable and healthy diets for all, it is also about building people’s capacity to participate and determine sustainable and healthy food systems. Drawing upon Levkoe and Sheedy, Korten, and Samuels [
1
,
17
,
18
], we identify five foundations of people-centred approaches that support the scaling-out of co-operative ways of working: 1. Processes of democratisation; 2. redistribution of power; 3. strengthening participation; 4. equity and justice; and 5. transformative governance. Co-operative approaches to the production, distribution, and trading of food demonstrate opportunity for embedding these foundations within sustainable and just food futures. The importance of transformative governance and a supportive legislative framework is noted as particularly critical in order for scaling-up and scaling-deep, as well as scaling-out.
First, processes of democratisation within sustainable food systems hinge upon a rights-based approaches to growing, trading, and eating sustainable and healthy food. Scaling-out community-based production, distribution, trade, and training increase opportunities for individuals to become food citizens and exercise democracy in terms of decision-making around food system approaches and practices. Such processes require education across different strands of society which provides exposure to, and training in co-operative values, people-centred economic and business models and participative modes of governance.
Second, redistribution of power within sustainable food systems requires people-centred change within the food system, as well as within society more broadly. Power has been dramatically consolidated within food supply chains [
1
,
23
]. Findings demonstrate co-operation as a means of reclaiming and redistributing power, providing opportunity for the emergence not only of distributive justice, but also epistemic and contributive forms of justice. A key channel for the redistribution of power is the exchange of experience and knowledge within co-operative networks to counter the current commodification of knowledge and education which maintains transformation as privilege.
Third, people-centred approaches are about strengthening people’s opportunities and abilities to participate meaningfully. The scaling-out of CSAs, incubator farms, and food hubs increases opportunities for participation in food system futures. Such mechanisms, as shown in the case studies in section four as well as those discussed below, can combine production of healthy, sustainable food whilst also supporting community-based reconnection with the land and food production, thus strengthening capacities for informed participation in the food system.
Fourth, equity and justice are critical foundations of a people-centred approach. As Levkoe and Sheedy [ 1 ] suggest, a people-centred approach needs to include undocumented and disenfranchised people as well as engaged citizens. This entails identifying the constraints to achieving a sustainable and just diet for all—including those marginalised within society, as well as identifying what is constraining people from participation in the cultivation of sustainable and just food systems, and what vehicles can strengthen their ability to participate.
The fifth and final foundation of a people-centred approach is transformative governance. According to Samuel, the ultimate goal of a people-centred approach is social transformation, rooted in a desire to “challenge and change unjust power relations at all levels” [
18
] (p. 617). Transformative governance hinges upon application of, and legislation for, the four foundations outlined above. Levkoe and Sheedy suggest that for any kind of food policy rooted in principles of equity and ecological sustainability to be effective it “requires meaningful engagement from civil society, and specifically, the people that produce, harvest, gather, process, distribute, and eat food” [
1
] (p. 321). A people-centred approach “is about mobilising the politics of the people to ensure that the politics of the state is accountable, transparent, ethical and democratic” [
18
].
Co-operative approaches to production, distribution, trading, and training demonstrate opportunity for embedding people-centred foundations within sustainable and just food futures. The importance of i. community-based participative approaches; ii. networks for training, access to resources and land; and iii. a supportive legislative framework, are noted as critical in order for scaling-up and scaling-deep, as well as scaling-out.
5.2. People-centred Approaches to Food System Transformation in Wales
5.2.1. Community-based Participative Approaches
Findings suggest producer and multi-stakeholder co-operatives, food hubs, and platform co-operatives enable more co-operative ways of working amongst producers, distributors, suppliers, traders, and consumers. However, for sustainable food system transformation to become embedded within places and communities, there is need for democratic, community-based participation. Drawing upon Blay-Palmer et al., we understand food hubs to comprise of “networks and intersections of grassroots, community-based organisations and individuals that work together to build increasingly socially just, economically robust and ecologically sound food systems that connect farmers with consumers as directly as possible” [
57
] (p. 524). As Blay-Palmer et al. [
57
] highlight, food hubs hinge upon community-based organisations and individuals working together. Between 2004–2015, around 300 community food co-operatives across Wales were created through the Community Food Co-operative programme funded by the Wales Rural Regeneration Unit [
65
]. Following the end of funding for this programme in 2015, a large number of the community food co-operatives have since ceased to exist. Food hubs may need initial institutional support in terms of capital costs and capacity building through training, mentoring, and network building. However, without sufficient community-based forms of democratic participation, there is a risk that such initiatives can become overly dependent upon institutional support and direction, and vulnerable if funding ceases.
The Stop Community Food Centre [
66
], located in a low income neighbourhood in Toronto, presents an example of how a community-based urban food hub can support food justice through supporting access to local, ecological produce, cultivating local food economies, and building community-based skills. Access to healthy, affordable food is supported through a community meal programme and market scheme, whilst community food training programs, peer advocacy, and support, community action training, social justice clubs, and volunteer programs support development of skills, knowledge, and confidence [
67
]. Taking a people-centred approach, The Stop prioritises capacity-building to address and sustain food justice and operate as a social enterprise.
5.2.2. Networks for Training, Access to Resources and Land
CSAs and incubator farms are identified as key mechanisms for scaling-out sustainable production, providing opportunities for new-entrant growers to gain access to land, training, tools and markets through a co-operative approach, as well as member education. Through improving access to sustainable, healthy food and supporting education, training, and learning around sustainable food systems, Cae Tan and Mach Maethlon demonstrate transformative potential. As exemplified by the case of The New Entry Sustainable Farming Project, incubator farms can also play a key role in addressing systemic inequalities within food systems.
The New Entry Sustainable Farming Project (Massachusetts, US) was launched in 1998 by Tufts University’s Friedman School of Nutrition Science and Policy with the aim of integrating recent immigrants and refugees with farming backgrounds into agriculture within Massachusetts [
68
]. Their mission is “to improve local and regional food systems by training the next generation of farmers to produce food that is sustainable, nutritious, and culturally-appropriate and making this food accessible to individuals regardless of age, mobility, ethnicity, or socio-economic status” [
68
]. The scheme provides farmer training, land access, and support for market entry. A CSA scheme generates income for new entrant farmers, whilst a Food Access programme further provides fresh produce to over 2000 food insecure individuals. Through the Food Access programme, donations, grants, and CSA membership close the gap between what food insecure consumers can afford and what farmers need to cover production costs and wage. As a result, food insecure individuals gain access to fresh, sustainably grown, culturally appropriate, affordable produce whilst new farmers benefit from income generated.
As demonstrated by the cases of Cae Tan, Mach Maethlon, and New Entry, CSAs and incubator farms could play an important role in sustainable and just food futures—cultivating openings for epistemic and contributive, as well as distributive, justice. At present, however, they represent a minority in terms of food supply in Wales. Currently, there are nine horticultural CSAs in Wales producing fruit and vegetable shares for approximately 410 share-holders [
69
], whilst there is one fledgling incubator farm in Wales, Mach Maethlon [
62
]. Institutions such as schools and universities, as well as legislative change, have the potential to play a key role in supporting the emergence of networks for training, as well as access to resources and land. We further identify opportunities for producer and multi-stakeholder co-operatives to facilitate the sharing of skills and expertise. As a multi-stakeholder co-operative of small-scale farmers, employees and agricultural development organisations, L’Atelier Paysan act as a learning network, sharing designs for tools, self-built machinery, and agricultural buildings adapted for small-scale organic farming, as well as creating space for farmer-to-farmer exchange [
70
].
5.2.3. Supportive Legislative Framework
Although the co-operative movement has emerged largely independent of legislation, Watkins notes “without an appropriate legislative framework, a co-operative movement in the form of a growing economic organism is not possible or even conceivable” [ 48 ] (p. 39). The economic, social and environmental role co-operatives play has been acknowledged by a number of international bodies including the UN and ILO [ 46 , 47 , 71 ]. National, regional, and local governments can play a key role in fostering co-operative values through implementing policies, rules, and laws that promote and encourage co-operative ways of working within society. Indeed, “it is no accident that co-operatives are more prolific in countries where policy has provided them with incentives and made their creation a priority” [ 72 ] (p. 17).
Currently within Wales, although the foundational economy highlights the importance of food, the policy environment is lacking in terms of legislating for sustainable and just food systems and co-operative ways of working. However, the Well-being of Future Generations (Wales) Act 2015 [ 73 ] presents opportunity for embedding co-operation within legislation and policy. In order to scale-out sustainable and just food systems, legislation needs to focus on enabling and promoting people-centred approaches capable of addressing sustainability and justice.
In Italy, support for co-operatives is enshrined in national law and economic policy [ 74 , 75 ]. Laws and policies strengthen the co-operative economy through supporting existing co-operatives and creating new ones [ 75 ]. DePasquale, Sarang, and Vena suggest Italian co-operative success reflects “broader values and politics” [ 74 ] (p. 940). Co-operative capital is considered not only the property of current members, but the legacy for future generations [ 74 ]. Whilst part of the strength of the Italian co-operative economy is the range of horizontal, vertical, and inter-connected networks [ 75 ], societal values have been fostered through long-term national and regional state investment in co-operation. Such support is reflected in the strength of the co-operative economy—4.5% of the Italian population are employed by cooperatives, and in some regions such as Emilia-Romagna, co-operatives produce around 30% of GDP, whilst two out of every three inhabitants are members of a co-operative [ 76 ]. Co-operative ways of working can also be fostered at a local and municipal level. In New York City, US, the city government is adopting regulations to assist co-operatives through prioritising co-operatives when they enter a contract for goods or services [ 74 ].
In the Welsh context, we identify a significant gap in terms of quality and availability of advice, training, and support for co-operation in the food sector. We further highlight broader need for public information campaigns, schools-based learning, and post-school learning to raise public awareness and understanding of co-operation. There is a need for long-term, core funding for infrastructures to be established to improve training, advice, support, and information around co-operation. Such investment would support greater public knowledge about co-operative values and co-operative food economies within Wales. There is also a key educating role amongst co-operatives both in terms of educating members and their wider community on co-operative ethics, as well as supporting other co-operatives through providing mentoring and advice on co-operative structure and sharing sectoral expertise. This internal and external form of co-operation is a key component of the co-operative economy within Wales and has the potential to scale-out co-operation for sustainable and just food futures, as well as increasing availability of sustainable food systems training. Drawing upon the people-centred foundation of processes of democratisation, there is recognised need for education which provides exposure to, and training in, co-operative values, people-centred economic and business models, and participative modes of governance.
6. Conclusions
In this article, our focus on co-operative ways of working as playing a potentially important role in people-centred food system change makes a contribution to the sustainable food systems literatures. Drawing upon fieldwork, findings demonstrate a number of key challenges and opportunities to scaling-out sustainable and just food systems in the context of Wales. As highlighted by the case studies, co-operative ways of working including CSAs, incubator farms, producer and multi-stakeholder co-operatives and food hubs are promising mechanisms for this transformation. Currently, however, co-operative economies remain marginal within Wales. Challenges include: Access to land, training, and resources; lack of distributing, processing, and trading facilities, particularly those that are community-based and community-led; and limited training opportunities in sustainable food systems and co-operative ethics.
We identify five foundations of people-centred approaches to food system change: 1. Processes of democratisation; 2. redistribution of power; 3. strengthening participation; 4. equity and justice; and 5. transformative governance. Integrating these foundations with our findings, we suggest three key mechanisms which have the potential to embed people-centred approaches in the scaling-out of sustainable and just food systems: i. Community-based participative approaches; ii. networks for training, access to resources and land; and iii. supportive legislative framework. Transformative governance is noted as particularly critical in order for scaling-up and scaling-deep, as well as scaling-out. The need for further work on scaling-deep co-operative, people-centred approaches is noted—which requires “investment in transformative learning, networks and communities of practice” [
16
] (p. 77). Such work could further explore the important role of contributive and epistemic, as well as distributive, justice in achieving people-centred food system change.
In Wales, the gap between the nation’s requirement for a sustainable and healthy diet and current domestic production presents significant opportunity for the scaling-out of sustainable and just food systems based upon co-operative, people-centred approaches.
Author Contributions
P.N. and A.T. jointly conceived, designed, and undertook the empirical research that underpins the article. P.N. led the conception, design, and literature review for the article; P.N. produced the first full draft of the article; A.T. revised the first draft; P.N. and A.T. collaborated to revise and produce the final draft. All authors have read and agreed to the published version of the manuscript.
Funding
This research was commissioned and funded by the National Assembly Wales Co-operative Group and the Wales Co-operative Party.
Acknowledgments
This paper is part of the output of the research project “Working Co-operatively for Sustainable and Just Food Systems in Wales.” The authors thank the funding bodies and Sustainable Places Research Institute, Cardiff University for supporting this work, and Prof. Terry Marsden for valuable comments on the work. The authors would also like to thank all of the stakeholders involved in the project, including those interviewed and those who participated in the National Assembly for Wales Senedd Roundtable event “Working Co-operatively for Sustainable and Just Food Systems in Wales” held in January 2020.
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 data; in the writing of the manuscript, or in the decision to publish the results.
Appendix A
Interview question guide
Investigating co-operative ways of working
Could you just briefly describe how your organisation works as a co-operative?
Why has your organisation decided to work as co-operative?
What do co-operative values mean to you?
For you, what distinguishes co-operative ways of working from other ways of working?
Co-operative ways of working in Wales
What has been your experience operating as a co-operative in Wales?
What do you consider to be the main opportunities of working as a co-operative in Wales?
What do you consider to be the main barriers of working as a co-operative in Wales?
Training and learning
How did you first encounter co-operative ways of working?
What is your view on training opportunities around co-operative ways of working in Wales and setting up co-operatives?
What about the current landscape of apprenticeships, trainings and mentoring?
Co-operative ways of working and sustainable food systems
What do you understand as a sustainable food system?
What do you consider to be key challenges to achieving a sustainable food system in Wales?
Do you think co-operative ways of working can help us achieve a sustainable food system in Wales?
Co-operative ways of working and the policy environment
Do you think the policy environment in Wales could change in any way to foster co-operative ways of working?
How do you think the policy environment could support the scaling-out of co-operative ways of working in Wales?
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Figure 1. Sample of co-operatives by function, scale, and sector.
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Nicol, P.; Taherzadeh, A. Working Co-operatively for Sustainable and Just Food System Transformation. Sustainability 2020, 12, 2816.
https://doi.org/10.3390/su12072816
AMA Style
Nicol P, Taherzadeh A. Working Co-operatively for Sustainable and Just Food System Transformation. Sustainability. 2020; 12(7):2816.
https://doi.org/10.3390/su12072816
Chicago/Turabian Style
Nicol, Poppy, and Alice Taherzadeh. 2020. "Working Co-operatively for Sustainable and Just Food System Transformation" Sustainability12, no. 7: 2816.
https://doi.org/10.3390/su12072816
| https://www.mdpi.com/2071-1050/12/7/2816/xml |
Cannabis‐based medicines for chronic neuropathic pain in adults - Mücke, M - 2018 | Cochrane Library
Analgesics, Non-Narcotic [adverse effects, *therapeutic use]; Analgesics, Opioid [therapeutic use]; Cannabidiol [adverse effects, therapeutic use]; Chronic Pain [*drug therapy]; Codeine [analogs & derivatives, therapeutic use]; Dronabinol [adverse effects, analogs & derivatives, therapeutic use]; Medical Marijuana [adverse effects, *therapeutic use]; Neuralgia [*drug therapy]; Numbers Needed To Treat; Randomized Controlled Trials as Topic
Cannabis‐based medicines for chronic neuropathic pain in adults
Martin Mücke
Tudor Phillips
Lukas Radbruch
Frank Petzke
Winfried Häuser
Authors' declarations of interest
Version published: 07 March 2018Version history
https://doi.org/10.1002/14651858.CD012182.pub2
Abstract
available in
Background
This review is one of a series on drugs used to treat chronic neuropathic pain. Estimates of the population prevalence of chronic pain with neuropathic components range between 6% and 10%. Current pharmacological treatment options for neuropathic pain afford substantial benefit for only a few people, often with adverse effects that outweigh the benefits. There is a need to explore other treatment options, with different mechanisms of action for treatment of conditions with chronic neuropathic pain. Cannabis has been used for millennia to reduce pain. Herbal cannabis is currently strongly promoted by some patients and their advocates to treat any type of chronic pain.
Objectives
To assess the efficacy, tolerability, and safety of cannabis‐based medicines (herbal, plant‐derived, synthetic) compared to placebo or conventional drugs for conditions with chronic neuropathic pain in adults.
Search methods
In November 2017 we searched CENTRAL, MEDLINE, Embase, and two trials registries for published and ongoing trials, and examined the reference lists of reviewed articles.
Selection criteria
We selected randomised, double‐blind controlled trials of medical cannabis, plant‐derived and synthetic cannabis‐based medicines against placebo or any other active treatment of conditions with chronic neuropathic pain in adults, with a treatment duration of at least two weeks and at least 10 participants per treatment arm.
Data collection and analysis
Three review authors independently extracted data of study characteristics and outcomes of efficacy, tolerability and safety, examined issues of study quality, and assessed risk of bias. We resolved discrepancies by discussion. For efficacy, we calculated the number needed to treat for an additional beneficial outcome (NNTB) for pain relief of 30% and 50% or greater, patient's global impression to be much or very much improved, dropout rates due to lack of efficacy, and the standardised mean differences for pain intensity, sleep problems, health‐related quality of life (HRQoL), and psychological distress. For tolerability, we calculated number needed to treat for an additional harmful outcome (NNTH) for withdrawal due to adverse events and specific adverse events, nervous system disorders and psychiatric disorders. For safety, we calculated NNTH for serious adverse events. Meta‐analysis was undertaken using a random‐effects model. We assessed the quality of evidence using GRADE and created a 'Summary of findings' table.
Main results
We included 16 studies with 1750 participants. The studies were 2 to 26 weeks long and compared an oromucosal spray with a plant‐derived combination of tetrahydrocannabinol (THC) and cannabidiol (CBD) (10 studies), a synthetic cannabinoid mimicking THC (nabilone) (two studies), inhaled herbal cannabis (two studies) and plant‐derived THC (dronabinol) (two studies) against placebo (15 studies) and an analgesic (dihydrocodeine) (one study). We used the Cochrane 'Risk of bias' tool to assess study quality. We defined studies with zero to two unclear or high risks of bias judgements to be high‐quality studies, with three to five unclear or high risks of bias to be moderate‐quality studies, and with six to eight unclear or high risks of bias to be low‐quality studies. Study quality was low in two studies, moderate in 12 studies and high in two studies. Nine studies were at high risk of bias for study size .We rated the quality of the evidence according to GRADE as very low to moderate.
Primary outcomes
Cannabis‐based medicines may increase the number of people achieving 50% or greater pain relief compared with placebo (21% versus 17%; risk difference (RD) 0.05 (95% confidence interval (CI) 0.00 to 0.09); NNTB 20 (95% CI 11 to 100); 1001 participants, eight studies, low‐quality evidence). We rated the evidence for improvement in Patient Global Impression of Change (PGIC) with cannabis to be of very low quality (26% versus 21%;RD 0.09 (95% CI 0.01 to 0.17); NNTB 11 (95% CI 6 to 100); 1092 participants, six studies). More participants withdrew from the studies due to adverse events with cannabis‐based medicines (10% of participants) than with placebo (5% of participants) (RD 0.04 (95% CI 0.02 to 0.07); NNTH 25 (95% CI 16 to 50); 1848 participants, 13 studies, moderate‐quality evidence). We did not have enough evidence to determine if cannabis‐based medicines increase the frequency of serious adverse events compared with placebo (RD 0.01 (95% CI ‐0.01 to 0.03); 1876 participants, 13 studies, low‐quality evidence).
Secondary outcomes
Cannabis‐based medicines probably increase the number of people achieving pain relief of 30% or greater compared with placebo (39% versus 33%; RD 0.09 (95% CI 0.03 to 0.15); NNTB 11 (95% CI 7 to 33); 1586 participants, 10 studies, moderate quality evidence). Cannabis‐based medicines may increase nervous system adverse events compared with placebo (61% versus 29%; RD 0.38 (95% CI 0.18 to 0.58); NNTH 3 (95% CI 2 to 6); 1304 participants, nine studies, low‐quality evidence). Psychiatric disorders occurred in 17% of participants using cannabis‐based medicines and in 5% using placebo (RD 0.10 (95% CI 0.06 to 0.15); NNTH 10 (95% CI 7 to 16); 1314 participants, nine studies, low‐quality evidence).
We found no information about long‐term risks in the studies analysed.
Subgroup analyses
We are uncertain whether herbal cannabis reduces mean pain intensity (very low‐quality evidence). Herbal cannabis and placebo did not differ in tolerability (very low‐quality evidence).
Authors' conclusions
The potential benefits of cannabis‐based medicine (herbal cannabis, plant‐derived or synthetic THC, THC/CBD oromucosal spray) in chronic neuropathic pain might be outweighed by their potential harms. The quality of evidence for pain relief outcomes reflects the exclusion of participants with a history of substance abuse and other significant comorbidities from the studies, together with their small sample sizes.
PICOs
The PICO model is widely used and taught in evidence-based health care as a strategy for formulating questions and search strategies and for characterizing clinical studies or meta-analyses. PICO stands for four different potential components of a clinical question: Patient, Population or Problem; Intervention; Comparison; Outcome.
Plain language summary
available in
Cannabis products for adults with chronic neuropathic pain
Bottom line
There is a lack of good evidence that any cannabis‐derived product works for any chronic neuropathic pain.
Background
Neuropathic pain is pain coming from damaged nerves. It is different from pain messages that are carried along healthy nerves from damaged tissue (for example, a fall, or cut, or arthritic knee). Neuropathic pain is treated by different medicines to those used for pain from damaged tissue.
Several products based on the cannabis plant have been suggested as treatment for pain, including neuropathic pain. These products include inhaled herbal cannabis, and various sprays or tablets containing active cannabis ingredients obtained from the plant, or made synthetically.
Some people with neuropathic pain claim that cannabis‐based products are effective for them, and that is often highlighted in the media. Study characteristics
In November 2017 we searched for clinical trials that used cannabis products to treat conditions with chronic neuropathic pain in adults. We found 16 studies involving 1750 people. Studies lasted 2 to 26 weeks. Studies compared different cannabis‐based medicines. Ten studies compared an oromucosal (mouth) spray with a plant‐derived combination of tetrahydrocannabinol (THC), the principal psychoactive constituent of cannabis, and cannabidiol (CBD), an anti‐inflammatory ingredient of cannabis, against a fake medication (placebo). Two studies each compared inhaled herbal cannabis and cannabis plant‐derived THC with placebo, and one study compared a man‐made cannabinoid mimicking the effects of THC (nabilone) with placebo. One study compared nabilone with a pain killer (dihydrocodeine).
Key results and quality of the evidence
We rated the quality of the evidence from studies using four levels: very low, low, moderate, or high. Very low‐quality evidence means that we are very uncertain about the results. High‐quality evidence means that we are very confident in the results.
There was no high‐quality evidence.
All cannabis‐based medicines pooled together were better than placebo for the outcomes substantial and moderate pain relief and global improvement. All cannabis‐based medicines pooled together were better than placebo in reducing pain intensity, sleep problems and psychological distress (very low‐ to moderate‐quality evidence).
There was no difference between all cannabis‐based medicines pooled together and placebo in improving health‐related quality of life, stopping the medication because it was not effective, and in the frequency of serious side effects (low‐quality evidence).
More people reported sleepiness, dizziness and mental problems (e.g. confusion) with all cannabis‐based medicines pooled together than with placebo (low‐quality evidence). There was moderate‐quality evidence that more people dropped out due to side effects with cannabis‐based medicines than with placebo.
Herbal cannabis was not different from placebo in reducing pain and the number of people who dropped out due to side effects (very low‐quality evidence).
Visual summary
Authors' conclusions
Implications for practice
For people with chronic neuropathic pain
There is no high‐quality evidence for the efficacy of any cannabis‐based product including herbal cannabis (marijuana) in any condition with chronic neuropathic pain. Some adverse events (particularly somnolence or sedation, confusion, psychosis) may limit the clinical usefulness of cannabis‐based medicines. It might be expected that, at best, a few people with neuropathic pain will benefit from long‐term use of cannabis‐based medicines.
Some current clinical guidelines and systematic reviews consider cannabis‐based medicines as third‐ or fourth‐line therapy for chronic neuropathic pain syndromes if established therapies (e.g. anticonvulsants, antidepressants) have failed (Moulin 2014;Petzke 2016).
For physicians
There is no high‐quality evidence for the efficacy of any cannabis‐based medicine (herbal cannabis, plant‐derived THC (dronabinol), synthetic THC (nabilone), plant‐derived THC/CBD combination) in any condition with chronic neuropathic pain. Some adverse events (particularly somnolence or sedation, confusion, psychosis) may limit the clinical usefulness of cannabis‐based medicines. It might be expected that, at best, a few people with neuropathic pain will benefit from long‐term use of cannabis‐based medicines. Since relatively few participants achieve a worthwhile response with cannabis‐based medicines, decisions to use these medicines may require stopping rules to avoid the unnecessary exposure to harms in the absence of benefit. .
The Canadian Pain Society recommended cannabis‐based medicines as third‐line therapy for chronic neuropathic pain syndromes if established therapies (e.g. anticonvulsants, antidepressants) had failed (Moulin 2014). The Special Interest Group on Neuropathic Pain (NeuPSIG) for the pharmacotherapy of neuropathic pain gave a weak recommendation against the use of cannabis‐based medicines (Finnerup 2015).
The status of approval of cannabis‐based medicines and reimbursement by health insurance companies for chronic pain differs from country to country (Ablin 2016;Krcevski‐Skvarc 2018).
For policy‐makers
There is no high‐quality evidence suggesting that cannabis‐based medicines (herbal cannabis plant‐derived THC (dronabinol), synthetic THC (nabilone), plant‐derived THC/CBD combination) are of value in treating people with chronic neuropathic pain. This needs to be explained to people requesting this treatment in jurisdictions where it is allowed, e.g. Canada, Germany and Israel.
The license of cannabis‐based medicines including herbal cannabis for people with chronic (neuropathic) pain is scheduled for some countries. A patient register to document the efficacy and risks of cannabis‐based medicines financed by public funds is preferable.
In the absence of high‐quality evidence of benefit, the use of cannabis‐based medicines at the discretion of a pain specialist with particular expertise in use of cannabis‐based medicines is desirable. Cannabis‐based medicines are no first‐line treatment of any condition with chronic neuropathic pain.
For funders
Since no single treatment is effective in a majority of individuals with chronic neuropathic pain, this relatively small number of people with neuropathic pain who benefit from cannabis‐based medicines may be considered worthwhile, particularly if switching rules are in place. The treatment should be supervised by a pain specialist.
Implications for research
General
There may be differences in effect of different cannabis‐based medicines in different types of neuropathic pain. The optimal ratio of THC/CBD still needs to be determined. In addition, pure CBD products or the development of peripherally acting cannabinoid agonists may reduce central nervous system and psychiatric adverse events. To be certain of a result in terms of both direction and magnitude of effect would require very large clinical trials. These trials would need to have important design features.
Chronic neuropathic pain conditions that have not been included in previous trials, such as post‐stroke pain, need to be studied.
Study duration with a minimum of three months is recommended.
In those clinical conditions for which there is an established treatment option, a three‐arm study (study drug – standard drug treatment‐ placebo) is desirable, in order to allow the assessment of comparative efficacy and safety.
Outcomes of clinical utility, such as moderate and substantial benefit using neuropathic pain scales and Patient Global Impression of Change scale (PGIC), are recommended.
Imputation method are to be abandoned, as the outcome desired is that of adequate pain relief in the longer term, and for that people have to continue on therapy. Withdrawal for any reason has to be classified as treatment failure.
It is preferable that the study protocol defines that treating people with cannabis‐based medicines who do not have pain relief is unacceptable, so that there would be built‐in stopping rules linked to pain relief after an adequate trial of therapy.
It is valuable to design and analyse studies whether there are any predisposing features linked with treatment success or failure.
Study data have to be made available for review authors for individual participant data analyses.
Reporting the details of the assessment of adverse events (spontaneous reports, open questions, symptom questionnaires) is mandatory because the type and frequency of adverse events is influenced by the modes of assessment (Häuser 2012). Adverse events have to be reported using the International Conference on Harmonization guidelines, and coded within organ classes using the Medical Dictionary for Regulatory Activities (International Council for Harmonisation 2016). It is desirable that regulatory agencies standardise the assessment strategies of adverse events in randomised controlled trials.
Design
The key question is whether there are any people with neuropathic pain who do well on cannabis‐based medicines in the long term; that is, with a substantial reduction in pain and/or improvement of daily functioning maintained and tolerable adverse events. An alternative to clinical trials might be the use of registry studies.
Measurement (endpoints)
Reporting of average pain changes is inadequate, and the use of responder analyses (pain relief of 50% or greater or participants experiencing mild or no pain) is preferred.
The contextual details (e.g. type of pain (average, worst, least, current), time period to be rated, location of pain) of their administration are typically not standardised, nor well‐reported in the literature, resulting in trial results that are challenging to interpret. In an effort to standardise pain intensity assessment. The Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public‐private partnership has developed a training system for participants in clinical trials using a zero to 10 numerical rating scale (NRS) to rate pain intensity (Smith 2016).
The use of validated neuropathic pain scales and the reports of the effects of cannabis‐based medicines on all items of the neuropathic pain scale are recommended. In addition, a subgrouping of participants with neuropathic syndromes based on sensory profiles is possible and may be useful in clinical trial design to enrich the study population for treatment responders (Baron 2017).
Long‐term studies aiming to capture data on misuse and abuse of cannabis‐based medicines and cannabis‐induced mental disorders are valuable.
Summary of findings
Summary of findings 1. Cannabis‐based medicines compared with placebo for chronic neuropathic pain
Cannabis‐based medicines compared with placebo for chronic neuropathic pain
Patient or population: adults with chronic neuropathic pain Settings: outpatient study centres and hospitals in Europe and North America Intervention: cannabis‐based medicines (smoked cannabis; oral plant‐based (dronabinol) or synthetic tetrahydrocannabinol (THC) (nabilone); oromucosal spray of THC and cannabidiol (CBD)) Comparison: placebo
Outcomes Probable outcome with intervention 95% CI Probable outcome with placebo Relative effect Risk difference (95% CI) No. of participants (studies) Quality of the evidence (GRADE) Comments
Participant‐reported pain relief of 50% or greater209 per 1000(196 to 222)173 per 10000.05 (0.00 to 0.09)1001 (8 studies)⊕⊕⊝⊝ low 1,2NNTB 20 (11 to 100)
Patient Global Impression of Change much or very much improved261 per 1000(246 to 276)211 per 10000.09 (0.01 to 0.17)1092 (6 studies)⊕⊝⊝⊝ very low 1,3,4NNTB 11 (6 to 100)
Withdrawals due to adverse events104 per 1000(99 to 107)47 per 10000.04 (0.02 to 0.07)1848 (13 studies)⊕⊕⊕⊝ moderate 1NNTH 25 (16 to 50)
Serious adverse events66 per 1000(63 to 69)52 per 10000.01 (‐0.01 to 0.03)1876 (13 studies)⊕⊕⊝⊝ low 1,2NNTH not calculated
Participant‐reported pain relief of 30% or greater377 per 1000(358 to 396)304 per 10000.09 (0.03 to 0.15)1586 (10 studies)⊕⊕⊕⊝ moderate 1NNTB 11 (7 to 33)
Specific adverse events: nervous system disorder611 per 1000(576 to 644)287 per 10000.38 (0.18 to 0.58)1304 (9 studies)⊕⊕⊝⊝ low 1,3NNTH 3 (2 to 6)
Specific adverse events: psychiatric disorders165 per 1000(156 to 174)49 per 10000.10 (0.06 to 0.15)1314 (9 studies)⊕⊕⊝⊝ low 1,3NNTH 10 (7 to 16)
Abbreviations: CI: Confidence interval; NNTB: number needed to treat for an additional beneficial outcome; NNTH: number needed to treat for an additional harmful outcome; RD: risk difference
GRADE Working Group grades of evidence High quality: we are very confident that the true effect lies close to that of the estimate of the effect; Moderate quality: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different; Low quality: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect; Very low quality: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.
1Downgraded once: indirectness. People with current or historical substance abuse, or both, and major medical diseases excluded. 2Downgraded once: imprecision. CI included zero. 3Downgraded once: inconsistency. I²>50%. 4Downgraded once: Publication bias. All studies funded by the manufacturer of the drug.
Background
The protocol for this review was based on a template for reviews of drugs used to relieve neuropathic pain. The aim is for all reviews to use the same methods, based on new criteria for what constitutes reliable evidence in chronic pain (Moore 2010a;Moore 2012;Appendix 1).
Description of the condition
The 2011 International Association for the Study of Pain definition of neuropathic pain is "pain caused by a lesion or disease of the somatosensory system" (Jensen 2011), and based on a definition agreed at an earlier consensus meeting (Treede 2008). Neuropathic pain is a consequence of a pathological maladaptive response of the nervous system to 'damage' from a wide variety of potential causes. It is characterised by pain in the absence of a noxious stimulus and may be spontaneous (continuous or paroxysmal) in its temporal characteristics or be evoked by sensory stimuli (dynamic mechanical allodynia where pain is evoked by light touch of the skin). Neuropathic pain is associated with a variety of sensory loss (numbness) and sensory gain (allodynia) clinical phenomena, the exact pattern of which vary between people and disease, perhaps reflecting different pain mechanisms operating in an individual person and, therefore, potentially predictive of response to treatment (Demant 2014;Helfert 2015;von Hehn 2012). Pre‐clinical research hypothesises a bewildering array of possible pain mechanisms that may operate in people with neuropathic pain, which largely reflect pathophysiological responses in both the central and peripheral nervous systems, including neuronal interactions with immune cells (Baron 2012;Calvo 2012;von Hehn 2012). Overall, the treatment gains in neuropathic pain, to even the most effective of available drugs, are modest (Finnerup 2015;Moore 2013a), and a robust classification of neuropathic pain is not yet available (Finnerup 2013).
Neuropathic pain is usually divided according to the cause of nerve injury. There may be many causes, but some common causes of neuropathic pain include diabetes (painful diabetic neuropathy (PDN)), shingles (postherpetic neuralgia), amputation (stump and phantom limb pain), neuropathic pain after surgery or trauma, stroke or spinal cord injury, trigeminal neuralgia, and HIV infection. Sometimes the cause is unknown.
Many people with neuropathic pain conditions are significantly disabled with moderate or severe pain for many years. Chronic pain conditions comprised five of the 11 top‐ranking conditions for years lived with disability in 2010 (Vos 2012), and are responsible for considerable loss of quality of life and employment, and increased healthcare costs (Moore 2014a). A study in the USA found that healthcare costs were three‐fold higher for people with neuropathic pain than matched control participants (Berger 2004). A UK study and a German study showed a two‐ to three‐fold higher level of use of healthcare services in people with neuropathic pain than those without (Berger 2009;Berger 2012). For postherpetic neuralgia, for example, studies demonstrate a large loss of quality of life and substantial costs (Scott 2006;Van Hoek 2009).
In systematic reviews, the overall prevalence of neuropathic pain in the general population is reported to be between 7% and 10% (Van Hecke 2014), and about 7% in a systematic review of studies published since 2000 (Moore 2014a). In individual countries, prevalence rates have been reported as 3.3% in Austria (Gustorff 2008), 6.9% in France (Bouhassira 2008), and up to 8% in the UK (Torrance 2006). Some forms of neuropathic pain, such as PDN and post‐surgical chronic pain (which is often neuropathic in origin), are increasing (Hall 2008).
Estimates of incidence vary between individual studies for particular origins of neuropathic pain, often because of small numbers of cases. In primary care in the UK, between 2002 and 2005, the incidences (per 100,000 person‐years' observation) were 28 (95% confidence interval (CI), 27 to 30) for PHN, 27 (95% CI, 26 to 29) for trigeminal neuralgia, 0.8 (95% CI, 0.6 to 1.1) for phantom limb pain, and 21 (95% CI, 20 to 22) for PDN (Hall 2008). Other studies have estimated an incidence of 4 in 100,000 per year for trigeminal neuralgia (Katusic 1991;Rappaport 1994), and 12.6 per 100,000 person‐years for trigeminal neuralgia and 3.9 per 100,000 person‐years for PHN in a study of facial pain in the Netherlands (Koopman 2009). One systematic review of chronic pain demonstrated that some neuropathic pain conditions, such as PDN, can be more common than other neuropathic pain conditions, with prevalence rates up to 400 per 100,000 person‐years (McQuay 2007).
Neuropathic pain is difficult to treat effectively, with only a minority of people experiencing a clinically relevant benefit from any one intervention (Kalso 2013;Moore 2013b). A multidisciplinary approach is now advocated, combining pharmacological interventions with physical or cognitive (or both) interventions. The evidence for interventional management is very weak, or non‐existent (Dworkin 2013). Conventional analgesics such as paracetamol and nonsteroidal anti‐inflammatory drugs (NSAIDs) are not thought to be effective, but without evidence to support or refute that view (Moore 2015a). Some people may derive some benefit from a topical lidocaine patch or low‐concentration topical capsaicin, although evidence about benefits is uncertain (Derry 2012;Derry 2014). High‐concentration topical capsaicin may benefit some people with PHN (Derry 2017). Treatment is often by so‐called pain modulators such as antidepressants (duloxetine and amitriptyline;Lunn 2014;Moore 2017;Moore 2015b;Sultan 2008), or antiepileptics (gabapentin or pregabalin;Moore 2009;Moore 2014b;Wiffen 2013). Evidence for efficacy of opioids is unconvincing (Gaskell 2016;Sommer 2015;Stannard 2016).
The proportion of people who achieve worthwhile pain relief (typically at least 50% pain intensity reduction;Moore 2013a) is small, generally only 10% to 25% more than with placebo, with numbers needed to treat for an additional beneficial outcome (NNTB) usually between 4 and 10 (Kalso 2013;Moore 2013b). Neuropathic pain is not particularly different from other chronic pain conditions in that only a small proportion of trial participants have a good response to treatment (Moore 2013b).
The current National Institute for Health and Care Excellence (NICE) guidance for the pharmacological management of neuropathic pain suggests offering a choice of amitriptyline, duloxetine, gabapentin, or pregabalin as initial treatment for neuropathic pain (with the exception of trigeminal neuralgia), with switching if the first, second, or third drugs tried are not effective or not tolerated (NICE 2013). This concurs with other recent guidelines (Finnerup 2015).
There is a need to explore other treatment options, with different mechanisms of action and from different drug categories, for treatment of neuropathic pain syndromes. Medical cannabis has been promoted by some patient organisations and advocates for the treatment of chronic pain refractory to conventional treatment and is available for pain management in some countries of the world, e.g. Canada and Israel (Ablin 2016). However, the use of cannabis for medical reasons is highly contested because of the adverse health effects of long‐term cannabis use for recreational purposes (Volkow 2014).
Description of the intervention
The cannabinoid system is ubiquitous in the animal kingdom, with multiple functions that move the organism back to equilibrium. A large body of evidence currently supports the presence of cannabinoid (CB) receptors and ligands in the peripheral and central nervous system, but also in other tissues such as bone and in the immune system (Owens 2015).
The endocannabinoid system has three broad and overlapping functions in mammals. The first is a stress recovery role, operating in a feedback loop in which endocannabinoid signalling is activated by stress and functions to return endocrine, nervous, and behavioural systems to homeostatic balance. The second is to control energy balance through regulation of the intake, storage, and utilisation of food. The third involves immune regulation; endocannabinoid signalling is activated by tissue injury and modulates immune and inflammatory responses (Hillard 2012). Thus, the endocannabinoid neuromodulatory system appears to be involved in multiple physiological functions, such as anti‐nociception, cognition and memory, endocrine function, nausea and vomiting, inflammation, and immune recognition (De Vries 2014;Hillard 2012). Cannabisis a genus of the flowering plant in the family Cannabaceae. The number of species within the genus is disputed. Three species may be recognized, Cannabis sativa, Cannabis indicaand Cannabis ruderalis. These plants, commonly known as marijuana, have been used for pain relief for millennia, and have additional effects on appetite, sleep, and mood (Kalant 2001). Data from clinical trials with synthetic and plant‐based cannabis‐based medicines suggest a promising approach for the management of chronic neuropathic pain of different origins (De Vries 2014;Jensen 2015).
How the intervention might work
Cannabiscontains over 450 compounds, with at least 70 classified as phytocannabinoids. Two are of particular medical interest. Delta 9‐tetrahydrocannabinol (delta 9‐THC) is the main active constituent, with psychoactive (e.g. reduction of anxiety and stress) and pain‐relieving properties. The second molecule of interest is cannabidiol (CBD), which has lower affinity for the cannabinoid (CB) receptors and the potential to counteract the negative effects of THC on memory, mood, and cognition, but also has an effect on pain modulation by anti‐inflammatory properties. The specific roles of currently identified endocannabis‐based medicines that act as ligands at CB receptors within the nervous system (primarily but not exclusively CB 1 receptors) and in the periphery (primarily but not exclusively CB 2 receptors) are only partially elucidated, but there are abundant pre‐clinical data to support their influence on nociception (Owens 2015).
It is also hypothesised that cannabis reduces alterations in cognitive and autonomic processing in chronic pain states (Guindon 2009). The frontal‐limbic distribution of CB receptors in the brain suggests that cannabis may preferentially target the affective qualities of pain (Lee 2013). In addition, cannabis may attenuate low‐grade inflammation, another postulate for the pathogenesis of neuropathic pain (Zhang 2015).
The content of THC and CBD in medical cannabis is highly variable and ranges from 1% to 22% THC and 0.05% to 9% CBD. In contrast the THC/CBD concentration in THC/CBD (nabiximols) oromucosal spray and the THC content in plant‐derived and synthetic THC are standardised (Häuser 2017).
Taking into consideration the poorly understood pathogenesis of chronic neuropathic pain syndromes, the complexity of symptom expression, and the absence of an ideal treatment, the potential for manipulation of the cannabinoid system as a therapeutic modality is attractive.
Why it is important to do this review
While recent guidance tends to be generally in agreement about the role of antidepressants and anticonvulsants in the management of chronic neuropathic pain (Finnerup 2015;NICE 2013), the role of opioids (Sommer 2015) and of cannabis‐based medicines (Häuser 2017,Häuser 2018) is under debate. Recent systematic reviews on the use of cannabis‐based medicines to treat chronic pain came to different conclusions on their importance in chronic neuropathic pain (Boychuk 2015;Finnerup 2015;Petzke 2016;Whiting 2015). This was probably due to the inclusion of different trials, different standards to evaluate the quality of evidence, and different weighting of the outcomes of efficacy, tolerability, and safety. Due to the conflicting conclusions of recent systematic reviews on the importance of cannabis‐based medicines in treating chronic neuropathic pain, as well as the public debate on the medical use of herbal cannabis for chronic pain (Ablin 2016;Fitzcharles 2014), we saw the need for a Cochrane Review applying the standards of Cochrane Pain, Palliative and Supportive Care (PaPaS).
Objectives
To assess the efficacy, tolerability, and safety of cannabis‐based medicines (herbal, plant‐based, synthetic) compared to placebo or conventional drugs for conditions with chronic neuropathic pain in adults.
Methods
Criteria for considering studies for this review
Types of studies
We included studies if they were randomised, double‐blind, controlled trials (RCTs) of at least two weeks' duration (drug titration and maintenance or withdrawal). We included studies with a parallel, cross‐over, and enriched enrolment randomised withdrawal (EERW) design with at least 10 participants per treatment arm. We required full journal publication, with the exception of online clinical trial results summaries of otherwise unpublished clinical trials, and abstracts with sufficient data for analysis. We did not include short abstracts. We excluded studies that were not randomised, studies of experimental pain, case reports, and clinical observations. We included studies that reported at least one outcome of efficacy and one of safety as defined below.
Types of participants
Studies included adults aged 18 years and above with one or more chronic (three months and more) neuropathic pain condition including (but not limited to):
cancer‐related neuropathy;
central neuropathic pain (e.g. multiple sclerosis);
complex regional pain syndrome (CRPS) Type II;
HIV neuropathy;
painful diabetic neuropathy;
peripheral polyneuropathy of other aetiologies, for example toxic (alcohol, drugs);
phantom limb pain;
postherpetic neuralgia;
postoperative or traumatic peripheral nerve lesions;
spinal cord injury;
nerve plexus injury;
trigeminal neuralgia.
Where included studies had participants with more than one type of neuropathic pain, we analysed results according to the primary condition. Studies had to state explicitly that they included people with neuropathic pain (by title). We excluded studies that assessed pain in people with neurological diseases without specifying that the pain assessed was of neuropathic nature. We excluded studies with fibromyalgia because the nature of fibromyalgia (neuropathic or not) is under debate (Clauw 2015); cannabis‐based medicines in fibromyalgia are the subject of another Cochrane Review (Häuser 2016). We excluded studies with 'mixed pain' (Baron 2004), because the concept is neither internationally accepted nor sufficiently validated and the focus of this review is only neuropathic pain.
Types of interventions
Cannabis‐based medicines, either herbal cannabis (hashish, marihuana), plant‐based cannabinoids (dronabinol: nabiximols), or pharmacological (synthetic) cannabinoids (e.g. levonantradol, nabilone), at any dose, by any route, administered for the relief of neuropathic pain and compared to placebo or any active comparator. We did not include studies with drugs under development that manipulate the endocannabinoid system by inhibiting enzymes that hydrolyse endocannabninoids and thereby boost the levels of the endogenous molecules (e.g. blockade of the catabolic enzyme fatty acid amide hydrolase (FAAH)) (Long 2009).
Types of outcome measures
The standards used to assess evidence in chronic pain trials have changed substantially in recent years, with particular attention being paid to trial duration, withdrawals, and statistical imputation following withdrawal, all of which can substantially alter estimates of efficacy. The most important change is the move from using mean pain scores, or mean change in pain scores, to the number of people who have a large decrease in pain (by at least 50%) and who continue in treatment, ideally in trials of eight to 12 weeks' duration or longer. These standards are set out in the PaPaS Author and Referee Guidancefor pain studies of Cochrane Pain, Palliative and Supportive Care (Cochrane PaPaS 2012). This Cochrane Review assessed evidence using methods that make both statistical and clinical sense, and will use criteria for what constitutes reliable evidence in chronic pain (Moore 2010a).
We anticipated that studies would use a variety of outcome measures, with most studies using standard subjective scales (numerical rating scale (NRS) or visual analogue scale (VAS) for pain intensity or pain relief, or both). We were particularly interested in Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) definitions for moderate and substantial benefit in chronic pain studies (Dworkin 2008).
Primary outcomes
Participant‐reported pain relief of 50% or greater. We preferred composite neuropathic pain scores over single‐scale generic pain scores if both measures were used by studies;
PGIC (Patient Global Impression of Change) much or very much improved;
Withdrawals due to adverse events (tolerability);
Serious adverse events (safety). Serious adverse events typically include any untoward medical occurrence or effect that at any dose results in death, is life‐threatening, requires hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, is a congenital anomaly or birth defect, is an 'important medical event' that may jeopardise the person, or may require an intervention to prevent one of the above characteristics/consequences.
Secondary outcomes
Participant‐reported pain relief of 30% or greater. We preferred composite neuropathic pain scores over single‐scale generic pain scores if both measures were used by studies;
Mean pain intensity. We preferred composite neuropathic pain scores over single‐scale generic pain scores if both measures were used by studies;
Health‐related quality of life;
Sleep problems;
Fatigue;
Psychological distress;
Withdrawals due to lack of efficacy;
Any adverse event;
Specific adverse events, particularly nervous system (e.g. dizziness, somnolence, headache) and psychiatric disorders (e.g. confusion state; paranoia, psychosis, substance dependence) according to the Medical Dictionary for Regulatory Activities (MedDRA) (International Council for Harmonisation 2016).
Search methods for identification of studies
Electronic searches
We searched the following databases, without language restrictions:
The Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online (CRSO) (searched 7 November 2017);
MEDLINE (via Ovid) (1946 to 7 November 2017);
Embase (via Ovid) (1974 to 7 November 2017).
Appendix 2shows the search strategies.
Searching other resources
We reviewed the bibliographies of any RCTs identified and review articles, and searched the following clinical trials databases: US National Institutes of Health clinical trial register (www.ClinicalTrials.gov), European Union Clinical Trials Register (www.clinicaltrialsregister.eu), World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (apps.who.int/trialsearch/), and International Association for Cannabinoid Medicines (IACM) databank (www.cannabis-med.org/studies/study.php) to identify additional published or unpublished data. We contacted trial investigators to request missing data.
Data collection and analysis
We performed separate analyses according to particular neuropathic pain conditions. We combined different neuropathic pain conditions in analyses for exploratory purposes only.
Selection of studies
Two review authors (WH, FP) determined eligibility by reading the abstract of each study identified by the search. We eliminated studies that clearly did not satisfy the inclusion criteria, and obtained full copies of the remaining studies. Two review authors (WH, FP) independently read these studies and reached agreement by discussion. We did not anonymise the studies before assessment. We created a PRISMA flow chart (Moher 2009).
Data extraction and management
Two review authors (WH, FP) extracted data independently using a standard form and checked for agreement before entering data into Review Manager 5 (RevMan 2014). Two review authors (WH, MM) extracted independently data calculated by imputation. We included information about the pain condition and number of participants treated, study setting, inclusion and exclusion criteria, demographic and clinical characteristics of the study samples (age, gender, race, pain baseline), prior recreational cannabis use, drug and dosing regimen, co‐therapies allowed, rescue medication, study design (placebo or active control), study duration and follow‐up, analgesic outcome measures and results, withdrawals, and adverse events (participants experiencing any adverse event or serious adverse event).
Assessment of risk of bias in included studies
Two review authors (WH, FP) independently assessed risk of bias for each study, using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions(Higgins 2011a), and adapted from those used by Cochrane Musculoskeletal for recent reviews on drug therapy in fibromyalgia, with any disagreements resolved by discussion. We assessed the following for each study.
Random sequence generation (checking for possible selection bias). We assessed the method used to generate the allocation sequence as: low risk of bias (i.e. any truly random process, e.g. random number table; computer random number generator); unclear risk of bias (when the method used to generate the sequence was not clearly stated). We excluded studies at a high risk of bias that used a non‐random process (e.g. odd or even date of birth; hospital or clinic record number).
Allocation concealment (checking for possible selection bias). The method used to conceal allocation to interventions prior to assignment determines whether intervention allocation could have been foreseen in advance of, or during, recruitment, or changed after assignment. We assessed the methods as: low risk of bias (e.g. telephone or central randomisation; consecutively numbered, sealed, opaque envelopes); unclear risk of bias (when method was not clearly stated). We excluded studies that did not conceal allocation and were therefore at a high risk of bias (e.g. open list).
Blinding of participants and personnel/treatment providers (systematic performance bias). We assessed the methods used to blind participants and personnel/treatment providers from knowledge of which intervention a participant received. We assessed the methods as: low risk of bias (study stated that it was blinded and described the method used to achieve blinding, e.g. identical tablets; matched in appearance and smell); unclear risk of bias (study stated that it was blinded but did not provide an adequate description of how it was achieved); high risk of bias (blinding of participants was not ensured, e.g. tablets different in form or taste).
Blinding of outcome assessment (checking for possible detection bias). We assessed the methods used to blind study outcome assessors from knowledge of which intervention a participant received. We assessed the methods as: low risk of bias (study stated that outcome assessors were blinded to the intervention or exposure status of participants); unclear risk of bias (study stated that the outcome assessors were blinded but did not provide an adequate description of how it was achieved); high risk of bias (outcome assessors knew the intervention or exposure status of participants).
Incomplete outcome data (checking for possible attrition bias due to the amount, nature, and handling of incomplete outcome data). We assessed the methods used to deal with incomplete data as: low risk of bias (i.e. less than 10% of participants did not complete the study or used 'baseline observation carried forward' (BOCF) analysis, or both); unclear risk of bias (used 'last observation carried forward' analysis); or high risk of bias (used 'completer' analysis).
Reporting bias due to selective outcome reporting (reporting bias). We checked if an a priori study protocol was available and if all outcomes of the study protocol were reported in the publications of the study. There is low risk of reporting bias if the study protocol is available and all of the study's pre‐specified (primary and secondary) outcomes that are of interest in the review are reported in the pre‐specified way, or if the study protocol is not available but it is clear that the published reports include all expected outcomes, including those that are pre‐specified (convincing text of this nature may be uncommon). There is a high risk of reporting bias if not all of the study's pre‐specified primary outcomes are reported; one or more primary outcomes is reported using measurements, analysis methods or subsets of the data (e.g. subscales) that are not pre‐specified; one or more reported primary outcomes are not pre‐specified (unless clear justification for their reporting is provided, such as an unexpected adverse effect); one or more outcomes of interest in the review are reported incompletely so that they cannot be entered in a meta‐analysis; the study report did not include results for a key outcome that would be expected to have been reported for such a study. There is unclear risk of bias if insufficient information is available to permit judgement of ‘Low risk’ or ‘High risk’.
Group similarity at baseline (selection bias). We assessed similarity of the study groups at baseline for the most important prognostic clinical and demographic indicators. There is low risk of bias if groups are similar at baseline for demographic factors, value of main outcome measure(s), and important prognostic factors. There is an unclear risk of bias if important prognostic clinical and demographic indicators are not reported. There is high risk of bias if groups are not similar at baseline for demographic factors, value of main outcome measure(s), and important prognostic factors.
Size of study (checking for possible biases confounded by small size). We assessed studies as being at low risk of bias (200 participants or more per treatment arm); unclear risk of bias (50 to 199 participants per treatment arm); or high risk of bias (fewer than 50 participants per treatment arm).
Two review authors (WH, FP) assessed the included studies using the Cochrane 'Risk of bias' tool. We defined studies with zero to two unclear or high risks of bias to be high‐quality studies, with three to five unclear or high risks of bias to be moderate‐quality studies, and with six to eight unclear or high risks of bias to be low‐quality studies (Schaefert 2015).
Measures of treatment effect
We calculated numbers needed to treat for an additional beneficial outcome (NNTB) as the reciprocal of the absolute risk reduction (ARR;McQuay 1998). For unwanted effects, the NNTB becomes the number needed to treat for an additional harmful outcome (NNTH) and is calculated in the same manner. We used dichotomous data to calculate risk differences (RD) with 95% CIs using a fixed‐effect model unless we found significant statistical or clinical heterogeneity (see below). We set the threshold for a clinically relevant benefit or a clinically relevant harm for categorical variables by an NNTB or NNTH less than 10 (Moore 2008).
We calculated standardised mean differences (SMD) with 95% CIs for continuous variables using a fixed‐effect model unless we found significant statistical or clinical heterogeneity. We used Cohen's categories to evaluate the magnitude of the effect size, calculated by SMD, with Hedges' g value of 0.2 = small, 0.5 = medium, and 0.8 = large (Cohen 1988). We labelled a g value less than 0.2 to be a 'not substantial' effect size. We assumed a minimally important difference if the Hedges' g value was 0.2 or greater (Fayers 2014).
Unit of analysis issues
We split the control treatment arm between active treatment arms in a single study if the active treatment arms were not combined for analysis.
We included studies with a cross‐over design where separate data from the two periods were reported, data were presented that excluded a statistically significant carry‐over effect, or statistical adjustments were carried out in case of a significant carry‐over effect.
Dealing with missing data
We used intention‐to‐treat (ITT) analysis where the ITT population consisted of participants who were randomised, took at least one dose of the assigned study medication, and provided at least one post‐baseline assessment.
Where means or standard deviations (SDs) were missing, we attempted to obtain these data through contacting trial authors. Where SDs were not available from trial authors, we calculated them from t values, P values, CIs, or standard errors, where reported by the studies (Higgins 2011b). Where rates of pain relief of 30% and of 50% or greater were not reported or provided on request, we calculated them from means and SDs using a validated imputation method (Furukawa 2005).
Assessment of heterogeneity
We dealt with clinical heterogeneity by combining studies that examined similar conditions. We assessed statistical heterogeneity visually (L'Abbé 1987), and using the I 2statistic (Higgins 2003). When the I 2value was greater than 50%, we considered possible reasons for this.
Assessment of reporting biases
We assessed publication bias using a method designed to detect the amount of unpublished data with a null effect required to make any result clinically irrelevant (usually taken to mean an NNTB of 10 or higher;Moore 2008).
Data synthesis
We intended to use a fixed‐effect model for meta‐analysis. We used a random‐effects model using the inverse variance method in Review Manager 5 for meta‐analysis (RevMan 2014) because there was significant clinical heterogeneity due to the different types of neuropathic pain conditions included.
Quality of the evidence
Two review authors (WH, FP) independently rated the quality of the outcomes. We used the GRADE system to rank the quality of the evidence using the GRADEpro Guideline Development Tool software (GRADEpro GDT 2015), and the guidelines provided in Chapter 12.2 of the Cochrane Handbook for Systematic Reviews of Interventions(Schünemann 2011).
The GRADE approach uses five considerations (study limitations, consistency of effect, imprecision, indirectness and publication bias) to assess the quality of the body of evidence for each outcome. The GRADE system uses the following criteria for assigning grade of evidence:
high: we are very confident that the true effect lies close to that of the estimate of the effect;
moderate: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different;
low: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect;
very low: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.
We decreased the grade rating by one (‐ 1) or two (‐ 2) if we identified:
serious (‐ 1) or very serious (‐ 2) limitation to study quality;
important inconsistency (‐ 1);
some (‐ 1) or major (‐ 2) uncertainty about directness;
imprecise or sparse data (‐ 1);
high probability of reporting bias (‐ 1).
In addition, there may be circumstances where the overall rating for a particular outcome needs to be adjusted as recommended by GRADE guidelines (Guyatt 2013a). For example, if there are so few data that the results are highly susceptible to the random play of chance, or if a study uses last observation carried forward (LOCF) imputation in circumstances where there are substantial differences in adverse event withdrawals, one would have no confidence in the result, and would need to downgrade the quality of the evidence by three levels, to very low quality. In circumstances where there were no data reported for an outcome, we planned to report the level of evidence as very low quality (Guyatt 2013b).
See alsoAppendix 3: GRADE: criteria for assigning grade of evidence.
'Summary of findings' table
We included one 'Summary of findings' table to present the main findings in a transparent and simple tabular format. In particular, we included key information concerning the quality of evidence, the magnitude of effect of the interventions examined, and the sum of available data on the outcomes. The 'Summary of findings' table includes the primary outcomes and the secondary outcomes of participant‐reported pain relief of 30% or greater, and nervous system disorders and psychiatric disorders as specific adverse events.
Subgroup analysis and investigation of heterogeneity
We performed subgroup analyses according to individual neuropathic pain syndromes because placebo response rates for the same outcome can vary between conditions, as can the drug‐specific effects (Moore 2013b). We performed subgroup analyses (different cannabis‐based medicines; very short‐term (less than four weeks), short‐term (four to 12 weeks), intermediate‐term (13 to 26 weeks), and long‐term (more than 26 weeks) study duration) where there were at least two studies available. We post‐hoc decided to perform subgroup analyses of studies with and without publication in peer‐reviewed journals. We performed subgroup analyses if at least two studies for a subgroup were available.
Sensitivity analysis
We planned no sensitivity analysis because the evidence base is known to be too small to allow reliable analysis.
Results
Description of studies
SeeCharacteristics of included studies;Characteristics of excluded studies;Characteristics of studies awaiting classification.
Results of the search
Appendix 2shows the search strategies and hits retrieved for these databases. The searches (performed 7 November 2017) produced 1446 records after duplicates were removed. We identified 264 potentially relevant studies in CENTRAL, 949 in MEDLINE, 494 in Embase, three in the European Union Clinical Trials Register, 27 in the US National Institutes of Health clinical trials register, 116 in the WHO clinical trial register and 28 in the International Association for Cannabinoid Medicines (IACM) databank. After removing duplicates and reading the full reports, we included 16 studies involving 1750 participants into the qualitative and quantitative analysis (Bermann 2004;Ellis 2009;Frank 2008;Langford 2013;Lynch 2014;NCT00710424;NCT01606176;NCT01606202;Nurmikko 2007;Rog 2005;Schimrigk 2017;Selvarajah 2010;Serpell 2014;Schimrigk 2017Svendsen 2004;Toth 2012;Ware 2010) (seeFigure 1). We excluded 15 studies. Of note, three studies from the database of the US National Institutes of Health have been not published in peer‐reviewed journals, and are awaiting classification. The results of three studies have not been published so far in the database of the US National Institutes of Health (NCT00710424;NCT01606176;NCT01606202).
Figure 1
Study flow diagram
Included studies
Characteristics of the studies
Study design
Six studies used a cross‐over design (Bermann 2004;Ellis 2009;Frank 2008;Lynch 2014;Svendsen 2004;Ware 2010), nine a parallel design (Langford 2013;NCT00710424;NCT01606176;NCT01606202;Nurmikko 2007;Rog 2005;Schimrigk 2017;Selvarajah 2010;Serpell 2014) and two an enriched enrolment randomised withdrawal (EERW) design (Langford 2013;Toth 2012).
Study duration
Three studies were very short‐term studies (two to four weeks) (NCT01606176;NCT01606202;Ware 2010), eight were short‐term studies (four to 12 weeks) (Bermann 2004;Ellis 2009;Frank 2008;Lynch 2014;Nurmikko 2007;Rog 2005;Selvarajah 2010;Toth 2012), and five were intermediate‐term studies (12 to 26 weeks) (Langford 2013;NCT00710424;Schimrigk 2017;Serpell 2014;Svendsen 2004).
Study setting
Five studies were conducted in the UK (Bermann 2004;Frank 2008;NCT01606176;Rog 2005;Selvarajah 2010), three studies in Canada (Lynch 2014;Toth 2012;Ware 2010), three studies in multiple European countries (Langford 2013;NCT00710424;Nurmikko 2007), and one study in multiple countries of different continents (Serpell 2014), one study in USA (Ellis 2009), one study in Romania (NCT01606202), one study in Germany (Schimrigk 2017) and one study in Denmark (Svendsen 2004). Nine studies were single centre (Bermann 2004;Ellis 2009;Lynch 2014;Rog 2005;Schimrigk 2017;Selvarajah 2010;Svendsen 2004;Toth 2012;Ware 2010), and seven were multicentre (Frank 2008;Langford 2013;NCT00710424;NCT01606176;NCT01606202;Nurmikko 2007;Serpell 2014).
Sample sizes
The sample sizes ranged between 20 and 339.
Study periods
Study period was between 2000 and 2010 in seven studies (Bermann 2004;Frank 2008;Langford 2013;Schimrigk 2017;Serpell 2014;Svendsen 2004;Ware 2010). The remaining studies did not report the study period.
Study funding
Three studies were funded by public funds (Ellis 2009;Selvarajah 2010;Ware 2010), one study reported that there was no external funding (Lynch 2014), and the remaining studies were funded by the manufacturer of the drug. Four authors declared that they had no conflict of interest (Ellis 2009;Lynch 2014;Selvarajah 2010;Ware 2010). Six studies did not report on conflicts of interest (Bermann 2004;NCT00710424;NCT01606176;NCT01606202;Nurmikko 2007;Svendsen 2004). Six authors reported potential conflicts of interest by honoraria and/or funding received by the manufacturer of the drug studied (Frank 2008;Langford 2013;Rog 2005;Schimrigk 2017;Serpell 2014;Toth 2012).
Characteristics of the participants
Types of neuropathic pain
Five studies included participants with neuropathic pain associated with multiple sclerosis (Langford 2013;NCT01606176;Rog 2005;Schimrigk 2017;Svendsen 2004), three studies with mixed peripheral pain of various aetiologies (Nurmikko 2007;Serpell 2014;Ware 2010), three studies with diabetic polyneuropathy (NCT00710424;Selvarajah 2010;Toth 2012), and one study with plexus injury (Bermann 2004), one study with spinal cord injury (NCT01606202), one study with HIV‐neuropathy (Ellis 2009), one study with chemotherapy‐induced polyneuropathy (Lynch 2014), and one study with mixed central or peripheral pain of various aetiologies (Frank 2008).
Demographics
The mean age of the participants ranged between 34 and 61 years. The youngest mean age was in the studies with medical cannabis (Ellis 2009;Ware 2010). The percentage of men ranged between 17% and 100%.
Inclusion criteria
Nine studies required a pain score of 4 or above on a zero to 10 scale at baseline for inclusion (Bermann 2004;Ellis 2009;Frank 2008;Langford 2013;Lynch 2014;NCT00710424;Nurmikko 2007;Rog 2005;Schimrigk 2017). The remaining studies did not report on an inclusion criterion of a defined pain intensity. Five studies required for inclusion that the pain was refractory to previous analgesics without specifying the type and dosage of previous unsuccessful analgesic therapy (Ellis 2009;Langford 2013;NCT00710424;NCT01606176;Ware 2010).
Exclusion criteria
All studies excluded people with major medical diseases (heart, liver, kidney, seizures). Ten studies mentioned explicitly that they excluded people with a history of substance abuse (Bermann 2004;Ellis 2009;Frank 2008;Langford 2013;Lynch 2014;NCT00710424;NCT01606176;Nurmikko 2007;Rog 2005;Schimrigk 2017).
Previous experience of participants with herbal cannabis
Nine studies reported previous herbal cannabis experience of participants for medical and/or recreational use (Bermann 2004;Ellis 2009;Langford 2013;Lynch 2014;Nurmikko 2007;Rog 2005;Selvarajah 2010;Serpell 2014;Ware 2010). The percentage of participants with previous herbal cannabis experience ranged from 7% to 91%. Of note, the rates of previous herbal cannabis experience were the highest in the two studies with inhaled cannabis, with 91% inEllis 2009and 81% inWare 2010. One study excluded people who had used marijuana in the month before study entry (Schimrigk 2017).
Characteristics of the treatment delivered
Types of cannabis‐based medicines
All studies used THC/CBD oromucosal spray except two studies that used oral synthetic THC (nabilone) (Frank 2008;Toth 2012), two studies that used plant‐based THC (dronabinol) (Schimrigk 2017;Svendsen 2004Schimrigk 2017and two studies that used inhaled (by pipe or cigarette) herbal cannabis (Ellis 2009;Ware 2010). All studies compared to placebo except one study that compared to dihydrocodeine (DHC) (Frank 2008).
Rescue and Co‐medication
Two studies (Bermann 2004;Nurmikko 2007) did not allow rescue medication. Five studies used paracetamol (Frank 2008;Langford 2013;NCT01606202;Serpell 2014;Svendsen 2004) and one study tramadol (Schimrigk 2017). The remaining studies did not report details on rescue medication (Ellis 2009;Lynch 2014;NCT00710424;NCT01606176;Rog 2005;Selvarajah 2010;Toth 2012;Ware 2010). Four studies did not report if co‐medications were allowed (NCT00710424;NCT01606176;Selvarajah 2010;Toth 2012). The remaining studies allowed stable dosage of analgesic co‐medications.
Excluded studies
We excluded 15 studies for the following reasons: five studies because no definite statement was given that the pain was of neuropathic nature (Corey‐Bloom 2012;Novotna 2011;Wade 2004;Wissel 2006;Zajicek 2012); five studies because the study duration was less than two weeks (Abrams 2007;Karst 2003;Wallace 2015;Wilsey 2013;Wilsey 2008). one because the reports of the outcomes of efficacy did not meet the predefined inclusion criteria for efficacy (Zajicek 2003), two studies because there were fewer than 10 participants per treatment arm (Rintala 2010;Turcotte 2015), and one study each because participants with non‐neuropathic pain were included (Notcutt 2011) and participants without pain were included (Wade 2003).
Studies awaiting assessment
We found three studies with unpublished results or unknown status of which we received no information from the contacted authors. All three studies were conducted with nabilone by Canadian universities (NCT00699634;NCT01035281;NCT01222468). One of these studies was sponsored by the manufacturer of the drug (NCT00699634); the remaining two studies were funded by the university (NCT01035281;NCT01222468).
Risk of bias in included studies
The risk of bias of most domains was unclear in all studies: seeFigure 2andFigure 3for a ’Risk of bias’ summary and graph andCharacteristics of included studiesfor detailed information regarding 'Risk of bias' assessments of each study. The overall study quality according to the predefined criteria of the Cochrane 'Risk of bias' tool was low quality in two studies (Selvarajah 2010;Ware 2010), moderate quality in 12 studies (Bermann 2004;Ellis 2009;Frank 2008;Langford 2013;Lynch 2014;NCT00710424;NCT01606176;NCT01606202;Schimrigk 2017;Serpell 2014;Svendsen 2004;Toth 2012) and high quality in two studies (Nurmikko 2007;Rog 2005).
Figure 2
'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies
Figure 3
'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study
Allocation
Random sequence generation
Random sequence generation was adequately described and therefore of low risk of bias in all studies exceptNCT00710424;NCT01606176;NCT01606202;Selvarajah 2010;Ware 2010, which did not adequately describe it (unclear risk of bias).
Allocation concealment
Allocation concealment was adequately described and therefore of low risk of bias in all studies exceptNCT00710424;NCT01606176;NCT01606202;Schimrigk 2017;Selvarajah 2010;Ware 2010, which did not adequately describe it (unclear risk of bias).
Blinding
Blinding of participants and personnel
Blinding of participants and personnel was adequately described and therefore of low risk of bias in all studies exceptBermann 2004;Ellis 2009;Langford 2013;Lynch 2014;Schimrigk 2017;Selvarajah 2010;Ware 2010, which did not adequately describe it (unclear risk of bias).
Blinding of outcome assessor
Blinding of outcome assessment for adverse events was only adequately described byNurmikko 2007andRog 2005. The remaining studies did not adequately describe it (unclear risk of bias).
Incomplete outcome data
Only one study performed intention‐to‐treat (ITT) analysis by baseline observation carried forward (BOCF) method (Svendsen 2004). Three studies performed completer analysis (Frank 2008;Selvarajah 2010;Ware 2010) (high risk of bias). The remaining studies performed ITT by last observation carried forward (LOCF) method and were therefore of unclear risk of bias.
Selective reporting
Two studies were of high risk of bias because they did not report all predefined outcomes (Ellis 2009;Selvarajah 2010). Four studies did not report on a study protocol and were therefore of unclear risk of bias (Bermann 2004;Lynch 2014;Svendsen 2004;Toth 2012). The remaining studies reported the outcomes as defined in a study protocol.
Other potential sources of bias
Group similarity at baseline
All studies had a low risk of bias because there were no significant differences in demographic and clinical variables at baseline except one study with a high risk of bias (Toth 2012).
Sample size
Sample size was of unclear risk of bias in seven studies (Frank 2008;Langford 2013;NCT00710424;NCT01606202;Nurmikko 2007;Schimrigk 2017;Serpell 2014), and of high risk of bias in nine studies (Bermann 2004;Ellis 2009;Lynch 2014;NCT01606176;Rog 2005;Selvarajah 2010;Svendsen 2004;Toth 2012;Ware 2010).
Effects of interventions
See: Summary of findings 1Cannabis‐based medicines compared with placebo for chronic neuropathic pain
All cannabis‐based medicines versus placebo ‐ studies with a cross‐over and parallel design
Seesummary of findings Table 1.
Primary outcomes
The quailty of evidence was downgraded by one level due to indirectness (people with current or historical substance abuse, or both, and major medical diseases excluded) for all outcomes.
Participant‐reported pain relief of 50% or greater
We analysed eight studies with 1001 participants. One hundred and 10 of 526 (20.9%) participants in the cannabis‐based medicines and 82 of 475 (17.3%) participants in the placebo group reported pain relief of 50% or greater (risk difference (RD) 0.05, 95% CI 0.00 to 0.09); P value 0.04; I² = 29%). NNTB was 20 (11 to 100). According to the predefined categories, there was no clinically relevant benefit of cannabis‐based medicines (seeAnalysis 1.1). The quality of evidence was low, downgraded due to indirectness and imprecision (CI included zero).
Patient Global Impression of Change much or very much improved
We analysed six studies with 1092 participants. One hundred and fifty‐six of 548 (28.4%) participants in the cannabis‐based medicines and 112 of 544 (22.1%) participants in the placebo group reported to be much or very much improved (RD 0.09 (95% CI 0.01 to 0.17; P value 0.02; I² = 58%). The NNTB was 11 (6 to 100). According to the predefined categories, there was no clinically relevant benefit of cannabis‐based medicines (seeAnalysis 1.2). The quality of evidence was very low, downgraded due to indirectness, inconsistency (I²>50%) and publication bias (all studies funded by the manufacturer of the drug).
Withdrawals due to adverse events
We analysed 13 studies with 1848 participants. One hundred and three of 989 (10.4%) participants in the cannabis‐based medicines and 40 of 859 (4.7%) participants in the placebo group withdrew due to adverse events (RD 0.04, 95% CI 0.02 to 0.07; P value 0.0009; I² = 25%). The NNTH was 25 (16 to 50). According to the predefined categories there was no clinically relevant harm by cannabis‐based medicines (seeAnalysis 1.3). The quality of evidence was moderate, downgraded due to indirectness.
Serious adverse events
We analysed 13 studies with 1876 participants. Sity‐six of 989 (6.7%) participants in the cannabis‐based medicines and 46 of 887 (5.2%) participants in the placebo group reported serious adverse events (RD 0.01, 95% CI ‐0.01 to 0.03; P value 0.29; I² = 0%) (seeAnalysis 1.4). The quality of evidence was low, downgraded due to indirectness and imprecision (CI included zero; low number of events).
Secondary outcomes
Participant‐reported pain relief of 30% or greater
We analysed 10 studies with 1586 participants. Three hundred and twenty‐three of 819 (39.4%) participants in the cannabis‐based medicines and 251 of 767 (32.7%) participants in the placebo group reported pain relief of 30% or greater (RD 0.09, 95% CI 0.03 to 0.15; P value 0.004; I² = 34%). NNTB was 11 (7 to 33). According to the predefined categories, there was no clinically relevant benefit by cannabis‐based medicines (seeAnalysis 1.5). The quality of evidence was moderate, downgraded due to indirectness.
Mean pain intensity
We analysed 14 studies with 1837 participants. Cannabis‐based medicines were superior to placebo in the reduction of mean pain intensity (standardised mean difference (SMD) ‐0.35, 95% CI ‐0.60 to ‐0.09; P value 0.008; I² = 84%). According to Cohen’s categories, there was a small effect size indicating a minimal clinically important improvement (seeAnalysis 1.6). The quality of evidence was low, downgraded due to indirectness and inconsistency (I²>50%).
Health‐related quality of life
We analysed nine studies with 1284 participants. Cannabis‐based medicines were not superior to placebo in the improvement of health‐related quality of life (HRQoL) (SMD 0.02, 95% CI ‐0.10 to 0.13; P value 0.79; I² = 0%) (seeAnalysis 1.7). The quality of evidence was low, downgraded due to indirectness and inconsistency (CI included zero).
Sleep problems
We analysed eight studies with 1386 participants. Cannabis‐based medicines were superior to placebo in the reduction of sleep problems (SMD ‐0.47, 95% CI ‐0.90 to ‐0.04; P value 0.03; I² = 92%). According to Cohen’s categories, there was a small effect size indicating a minimal clinically important improvement (seeAnalysis 1.8). The quality of evidence was low, downgraded due to indirectness and inconsistency (I²>50%).
Fatigue
The analysis was not possible because fatigue was assessed only by one study (Langford 2013).
Psychological distress
We analysed seven studies with 779 participants. Cannabis‐based medicines were statistically significantly superior to placebo in the reduction of psychological distress (SMD ‐0.32, 95% CI ‐0.61 to ‐0.02; P value 0.04; I² = 66%). According to Cohen’s categories, there was a small effect size indicating a minimal clinically important improvement (seeAnalysis 1.9). The quality of evidence was low, downgraded due to indirectness and inconsistency (I²>50%).
Withdrawals due to lack of efficacy
We analysed nine studies with 1576 participants. There was no difference in the frequency of withdrawals due to lack of efficacy between cannabis‐based medicines and placebo. Twenty‐two of 818 (2.7%) participants in the cannabis‐based medicines and 31 of 758 (4.1%) participants in the placebo group withdrew due to lack of efficacy (RD ‐0.00, 95% CI ‐0.02 to 0.01; P value 0.79; I² = 0%) (seeAnalysis 1.10). The quality of evidence was low, downgraded due to indirectness and imprecision (CI included zero).
Any adverse event
We analysed seven studies with 1356 participants. Five hundred and sixty‐two of 684 (80.2%) participants in the cannabis‐based medicines and 441 of 672 (65.6%) participants in the placebo group reported adverse events (RD 0.19, 95% CI 0.12 to 0.27; P value < 0.0001; I² = 64%). NNTH was 5 (4 to 8). According to the predefined categories, there was a clinically relevant harm by cannabis‐based medicines (seeAnalysis 1.11). The quality of evidence was low, downgraded due to indirectness and inconsistency (I²>50%).
Specific adverse events
Nervous system disorders
We analysed nine studies with 1304 participants. Four hundred and fourteen of 677 (61.1%) participants in the cannabis‐based medicines and 180 of 627 (28.7%) participants in the placebo group reported adverse events of the nervous system (RD 0.38, 95% CI 0.18 to 0.58; P value 0.0003; I² = 94%). NNTH was 3 (2 to 6). According to the predefined categories, there was a clinically relevant harm by cannabis‐based medicines (seeAnalysis 1.12). The quality of evidence was low, downgraded due to indirectness and inconsistency (I²>50%).
Psychiatric disorders
We analysed nine studies with 1314 participants. One hundred and twelve of 677 (16.5%) participants in the cannabis‐based medicines and 31 of 637 (4.9%) participants in the placebo group reported psychiatric adverse events (RD 0.10, 95% CI 0.06 to 0.15; P value < 0.0001; I² = 54%). NNTH was 10 (7 to 16). According to the predefined categories, there was no clinically relevant harm by cannabis‐based medicines (seeAnalysis 1.13). The quality of evidence was low, downgraded due to indirectness and inconsistency (I²>50%).
Cannabis‐based medicines versus placebo ‐ studies with an enriched enrolment randomised withdrawal design (results of double‐blind phase)
We present a qualitative analysis of the study results (Langford 2013;Toth 2012) because the data were not suited for quantitative analysis. The quality of evidence for each outcome was very low, downgraded because of indirectness (people with current or historical substance abuse, or both, and major medical diseases excluded), imprecision (low number of events) and publication bias (all studies funded by manufacturer of the drug).
Primary outcomes
Participant‐reported pain relief of 50% or greater
We analysed one study with 26 participants. There was no difference between nabilone and placebo in the number of participants with a 50% pain relief or greater (31% versus 8%; P value 0.12).
We analysed one study with 42 participants. There was a difference between THC/CBD and placebo in the number of participants with a treatment failure (24% versus 57%; P value 0.04).
Patient Global Impression of Change much or very much improved
We analysed one study with 26 participants. Six of 13 participants in the nabilone and one of 13 participants in the placebo group reported to be much or very much improved (P value 0.04).
Withdrawals due to adverse events
We analysed two studies with 68 participants. There was no difference between cannabis‐based medicines and placebo. None of the 21 participants dropped out of the THC/CBD spray group and one of 21 dropped out of the placebo group. None dropped out in the nabilone (13 participants) or placebo (13 participants) groups.
Serious adverse events
We analysed two studies with 68 participants. There was no difference between cannabis‐based medicines and placebo. Three of 21 participants experienced a serious adverse event in the THC/CBD spray and one of 21 in the placebo group. None experienced a serious adverse event in the nabilone (13 participants) or placebo (13 participants) group.
Secondary outcomes
Participant‐reported pain relief of 30% or greater
We analysed one study with 26 participants. There was a difference between nabilone and placebo in the number of participants with pain relief of 30% or greater (85% versus 38%; P value 0.006).
Mean pain intensity
We analysed two studies with 68 participants. The estimated treatment difference between THC/CBD spray and placebo was ‐0.79 (P value 0.03). The average pain intensity was 3.5 ± 1.3 in the nabilone and 5.4 ± 1.7 in the placebo group (P value 0.005) (higher scores indicate more pain).
Health‐related quality of life
We analysed two studies with 68 participants. The estimated treatment difference between THC/CBD spray and placebo was 1.94 (P value 0.18) in one study. The HRQoL score was 0.74 ± 0.03 in the nabilone and 0.60 ± 0.8 in the placebo group (P value < 0.05) in one study (higher scores indicating a better HRQoL).
Sleep problems
We analysed two studies with 68 participants. The estimated treatment difference between THC/CBD spray and placebo was ‐0.99 (P value 0.02). The sleep problems score was 27.1 ± 2.1 in the nabilone and 33.0 ± 2.6 in the placebo group (P value < 0.05) (higher scores indicate more sleep problems).
Fatigue
Neither of these studies assessed this outcome.
Psychological distress
We analysed one study with 42 participants. The estimated treatment difference between THC/CBD spray and placebo was ‐0.56 (P value 0.73).
Withdrawals due to lack of efficacy
We analysed one study with 42 participants. None of the participants in the THC/CBD study dropped out due to lack of efficacy.
Any adverse event
We analysed two studies with 68 participants. Ten per cent of participants with THC/CBD spray and 24% of participants with placebo reported an adverse event. Fifty‐four per cent of the participants receiving nabilone and 46% of the participants receiving placebo reported at least one adverse event (P value 1.0).
Specific adverse events
Nervous system disorders
We analysed one study with 42 participants. None of the participants in the THC/CBD group reported adverse events of the nervous system.
Psychiatric disorders
We analysed one study with 42 participants. Five per cent of participants in both groups reported a psychiatric adverse event.
Cannabis‐based medicines versus any active other drug
Only one study compared nabilone with dihydrocodeine (DHC) in 73 participants (Frank 2008). We therefore present a qualitative analysis of the study results. The quality of evidence for each outcome was very low, downgraded because of indirectness (people with current or historical substance abuse, and major medical diseases excluded), imprecision (low number of events) and publication bias (all studies funded by manufacturer of the drug).
Primary outcomes
Participant‐reported pain relief of 50% or greater
Frank 2008assessed this outcome, however the study authors reported only the mean pain intensity.
Patient Global Impression of Change much or very much improved
Frank 2008did not assess this outcome.
Withdrawals due to adverse events
There was no difference between nabilone and DHC. Four of 96 participants dropped out in the nabilone group and 8/96 in the DHC group (P value 0.23).
Serious adverse events
No major adverse events occurred when participants took either drug.
Secondary outcomes
Participant‐reported pain relief of 30% or greater
Frank 2008assessed this outcome, however the study authors reported only the mean pain intensity.
Mean pain intensity
There was no difference between nabilone (59.93 ± 24.42) and DHC (58.58 ± 24.08) (P value not reported).
Health‐related quality of life
There was no difference between nabilone and DHC with a treatment difference of 8.9 (P value 0.48).
Sleep problems
There was no difference between nabilone and DHC with a treatment difference of 0.2 (P value 0.28).
Fatigue
Frank 2008did not assess this outcome.
Psychological distress
There was no difference between nabilone and DHC with a treatment difference of 2.5 (P value 0.35).
Withdrawals due to lack of efficacy
Frank 2008did not assess this outcome.
Any adverse event
There were 334 adverse events reported in the nabilone and 305 in the DHC group (no difference).
Specific adverse events
Nervous system disorders
This outcome was not assessed.
Psychiatric disorders
This outcome was not assessed.
Assessment of publication bias
The planned assessment of publication bias was not possible because the NNTB of all cannabis‐based medicines pooled together versus placebo for all dichotomous primary and secondary outcomes surpassed the pre‐set level of an NNTB of 10 or less.
Subgroup analysis and investigation of heterogeneity
We post‐hoc decided to restrict subgroup analyses to the outcomes pain relief of 50% or greater, PGIC (Patient Global Impression of Change) much or very much improved, withdrawals due to adverse events, serious adverse events and mean pain intensity. A subgroup analysis was only performed with at least two studies available.
Different types of neuropathic pain syndromes
We excluded studies with mixed samples of central and/or peripheral neuropathic pain from subgroup analysis because we wanted to assess the effects of cannabis‐based medicines on distinctive neuropathic pain syndromes. We found no subgroup difference between different types of neuropathic pain syndromes in the outcomes pain relief of 50% or greater (P value 0.20), withdrawals due to adverse events (P value 0.13), serious adverse events (P value 0.97), and mean pain intensity (P value 0.46). There was a subgroup difference between different types of neuropathic pain syndromes in the outcome PGIC (P value 0.02).
Different types of cannabis‐based medicines
Participant‐reported pain relief of 50% or greater
THC/CBD oromucosal spray was not different to placebo. RD was 0.05 (95% CI ‐0.00 to 0.11) (P value 0.07) (seven studies with 737 participants. Dronabinol (two studies with 264 participants) was not different to placebo. RD was 0.05 (95% CI ‐0.05 to 0.15) (P value 0.31) This outcome could not be analysed for herbal cannabis.
Patient Global Impression of Change much or very much improved
THC/CBD oromucosal spray (six studies with 1092 participants) was superior to placebo. RD was 0.09 (95% CI 0.01 to 0.17) (P value 0.02). The trials with dronabinol and herbal cannabis did not report this outcome.
Withdrawals due to adverse events
THC/CBD oromucosal spray (nine studies with 1408 participants) was superior to placebo. RD was 0.05 (95% CI 0.01 to 0.08) (P value 0.007). Dronabinol (two studies with 264 participants) was not different to placebo. RD was 0.05 (95% CI ‐0.04 to 0.13) (P value 0.27). Herbal cannabis (two studies with 152 participants) was not different to placebo. RD was 0.00 (95% CI ‐0.08 to 0.08) (P value 0.71).
Serious adverse events
THC/CBD oromucosal spray (eight studies with 1436 participants) was not different to placebo. RD was 0.01 (95% CI ‐0.01 to 0.02) (P value 0.52). Dronabinol (two studies with 264 participants) was not different to placebo. RD was 0.04 (95% CI ‐0.02 to 0.11) (P value 0.16). Herbal cannabis (two studies with 152 participants) was not different to placebo. RD was 0.01 (95% CI ‐0.05 to 0.06) (P value 0.74).
Mean pain intensity
THC/CBD oromucosal spray (nine studies with 1433 participants) was superior to placebo. SMD was ‐0.40 (95% CI ‐0.75 to ‐0.05) (P value 0.03). Dronabinol (two studies with 264 participants) was not superior to placebo. SMD was ‐0.09 (95% CI ‐0.33 to 0.15) (P value 0.45). Herbal cannabis (two studies with 152 participants) was not superior to placebo. SMD was ‐0.28 (95% CI ‐0.64 to 0.08) (P value 0.13).
Very short‐term, short‐term and intermediate‐term duration studies
Participant‐reported pain relief of 50% or greater
Cannabis‐based medicines in short‐term studies were not superior to placebo (three studies with 840 participants). RD was 0.06 (95% CI ‐0.01 to 0.13) (P value 0.05). Cannabis‐based medicines in intermediate‐term studies were not superior to placebo (three studies with 603 participants). RD was 0.04 (95% CI ‐0.03 to 0.11) (P value 0.24).
Patient Global Impression of Change much or very much improved
Cannabis‐based medicines in very short‐term studies were not superior to placebo (two studies with 186 participants). RD was 0.17 (95% CI ‐0.18 to 0.51) (P value 0.34). Cannabis‐based medicines in intermediate‐term studies were not superior to placebo (three studies with 840 participants). RD was 0.05 (95% CI ‐0.00 to 0.11) (P value 0.05).
Withdrawals due to adverse events
Cannabis‐based medicines in very short‐term studies were not superior to placebo (three studies with 270 participants). RD was 0.03 (95% CI ‐0.03 to 0.09) (P value 0.34). Cannabis‐based medicines in short‐term studies were not superior to placebo (four studies with 478 participants). RD was 0.01 (95% CI ‐0.02 to 0.04) (P value 0.80). Cannabis‐based medicines in intermediate‐term studies were superior to placebo (five studies with 1120 participants). RD was 0.07 (95% CI 0.03 to 0.12) (P value 0.002).
Serious adverse events
Cannabis‐based medicines in very short‐term studies were not superior to placebo (three studies with 270 participants). RD was ‐0.01 (95% CI ‐0.05 to 0.34) (P value 0.59). Cannabis‐based medicines in short‐term studies were not superior to placebo (five studies with 435 participants). RD was 0.00 (95% CI ‐0.02 to 0.02) (P value 1.0). Cannabis‐based medicines in intermediate‐term studies were superior to placebo (five studies with 1120 participants). RD was 0.03 (95% CI 0.00 to 0.06) (P value 0.05).
Mean pain intensity
Cannabis‐based medicines in very short‐term studies were not superior to placebo (three studies with 268 participants). SMD was ‐0.13 (95% CI ‐0.38 to 0.12) (P value 0.31). Cannabis‐based medicines in short‐term studies were not superior to placebo (six studies with 453 participants). SMD was ‐0.63 (95% CI ‐1.31 to 0.05) (P value 0.07). Cannabis‐based medicines in intermediate‐term studies were not superior to placebo (five studies with 1109 participants). SMD was ‐0.09 (95% CI ‐0.20 to 0.03) (P value 0.31).
Published and unpublished trials with THC/CBD oromucosal spray
Participant‐reported pain relief of 50% or greater
An analysis was not possible because the outcome was not reported by the unpublished trials.
Patient Global Impression of Change much or very much improved
THC/CBD spray was superior to placebo in published trials (three studies with 655 participants). RD was 0.07 (95% CI 0.01 to 0.13) (P value 0.03). THC/CBD spray was not superior to placebo in unpublished trials (three studies with 437 participants). RD was 0.12 (95% CI ‐0.10 to 0.33) (P value 0.29).
Withdrawals due to adverse events
There was a difference between THC/CBD spray and placebo in published trials (six studies with 935 participants). RD was 0.03 (95% CI 0.00 to 0.07) (P value 0.03). There was no difference between THC/CBD spray and placebo in unpublished trials (three studies with 437 participants). RD was 0.06 (95% CI ‐0.03 to 0.15) (P value 0.17).
Serious adverse events
There was no difference between THC/CBD spray and placebo in published trials (six studies with 935 participants). RD was 0.01 (95% CI ‐0.01 to 0.03) (P value 0.48). There was no difference between THC/CBD spray and placebo in unpublished trials (three studies with 437 participants). RD was ‐0.00 (95% CI ‐0.04 to 0.04) (P value 1.0).
Mean pain intensity
THC/CBD spray was superior to placebo in published trials (eight studies with 1069 participants). SMD was ‐0.46 (95% CI ‐0.42 to ‐0.01) (P value 0.05). THC/CBD spray was not superior to placebo in unpublished trials (three studies with 437 participants). SMD was ‐0.08 (95% CI ‐0.26 to 0.10) (P value 0.39).
Studies with high and unclear risk of bias due to sample size
Five of the 10 studies that reported the outcome 30% or more pain relief had treatment group sizes below 50 participants and we considered them at high risk of bias. Analysis of these five studies with 328 participants (24% of the total) showed an RD for pain relief of 30% or greater of 0.17 (95% CI 0.06 to 0.27); 40% of participants reported this outcome with cannabis‐based medicines and 26% with placebo.
Five of the 10 studies that reported the outcome 30% or more pain relief had treatment group sizes above 50 but below 200 participants and we considered them at unclear risk of bias. Analysis of these four studies with 1018 participants (76% of the total) showed an RD for pain relief of 30% or greater of 0.05 (95% CI ‐0.00 to 0.11); 41% of participants reported this outcome with cannabis‐based medicines and 37% with placebo.
Heterogeneity
I² was less than 50% except for Patient Global Impression of Change (I² = 58%), mean pain intensity (I² = 55%), sleep problems (I² = 92%), psychological distress (I² = 66%), any adverse event (I² = 64%), nervous system disorders as adverse event (I² = 94%) and psychiatric disorders as adverse event (I² = 54%). We did not find clinical explanations for heterogeneity.
Discussion
Summary of main results
We included 16 studies, 2 to 26 weeks long, with 1750 participants. All studies compared cannabis‐based medicines with placebo except one study that compared synthetic THC with dihydrocodeine (DHC). Studies compared an oromucosal spray with a plant‐derived combination of THC and CBD (10 studies), inhaled herbal cannabis (two studies), synthetic THC (nabilone) (two studies) and plant‐derived THC (dronabinol) (two studies).
All cannabis‐based medicines (at any dose) pooled together were superior to placebo for substantial (50% and more) (low‐ quality evidence) and moderate (30% and more) pain relief (moderate‐quality evidence), for global improvement (very low‐quality evidence), and in reduction of mean pain intensity (low‐quality evidence), sleep problems (low‐quality evidence), and psychological distress (low‐quality evidence). The effect sizes of mean pain intensity, sleep problems and psychological distress were clinically relevant. There was moderate‐quality evidence that more people dropped out due to adverse events with cannabis‐based medicines compared to placebo. There was low‐quality evidence that more people reported any adverse event and adverse events of the central nervous system and psychiatric disorders with all cannabis‐based medicines pooled together than with placebo. The effect size of adverse events of the nervous system disorders was clinically relevant. There was no difference between all cannabis‐based medicines pooled together and placebo in the frequency of serious adverse events (low‐quality evidence), for improvement of health‐related quality of life (low‐quality evidence) and dropouts due to lack of efficacy (moderate‐quality evidence).
There was no high‐quality evidence suggesting that any cannabis‐based medicine (herbal cannabis, THC/CBD oromucosal spray, synthetic or plant‐based THC) was of value in treating people with chronic neuropathic pain.
Overall completeness and applicability of evidence
The overall completeness and applicability of the evidence were poor. The usefulness of the available evidence was limited because reporting quality was poor by current standards (Moore 2010a). The reliability of the pooled results in general and of findings on nabilone in particular was limited because the results of three studies with nabilone have not been published and the results were not provided by the study authors on request (NCT00699634;NCT01035281;NCT01222468). The applicability of the evidence to routine clinical care was limited because all the included studies excluded people with current or historical substance abuse, or both, and major medical diseases.
Quality of the evidence
We found the evidence for most outcomes to be low quality because of indirectness (people with major medical disorders excluded) and inconsistent results. Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. In addition, we found signs of publication bias. We found three industry‐sponsored studies of THC/CBD spray with negative results, which have not been fully published yet. We also found three studies of nabilone but the results were unknown; the study authors did not respond to our requests. Despite growing requirements for trial registration, full access to clinical trial data remains elusive (Mintzes 2015).
Six studies reviewed used a cross‐over design with a study duration between one to two weeks for each period, and cross‐over designs have methodological issues that could lead to bias (Elbourne 2002). The short study duration limits their applicability. In addition, there are issues about the time needed (if any) for washout between treatment periods. Poor reporting limits their use in meta‐analysis, possibly with some biases (Moore 2013b).
A large number of participants (7% to 91%) in the studies were former cannabis users. No subgroup comparisons (former cannabis users versus cannabis‐naive participants) were conducted by any study. A prospective observational study found that the rate of non‐serious adverse events among current cannabis users was lower than that among ex‐cannabis users or naive users (Ware 2015).Therefore we do not know if the study results on efficacy and safety of the RCTs reviewed are valid for cannabis‐naive participants.
People with chronic neuropathic pain exhibit a variety of pain‐related sensory symptoms and findings (Baron 2017). They use different descriptors for their pain (e.g. burning, tugging, pricking, cramping). None of the neuropathic pain scales available cover all potential descriptors of neuropathic pain (Thyson 2014). Eight of the studies reviewed used a neuropathic pain scale. However, none of the studies reported the effects of cannabis‐based medicines on the single dimensions of the neuropathic pain scales used. A recent study with botulinum toxin in peripheral neuropathic pain demonstrated a statistically significant effect on paroxysmal pain, but not on burning and deep pain (Attal 2016). Therefore we do not know the efficacy of cannabis‐based medicines for specific qualities of neuropathic pain.
Perhaps the biggest issue is that of the relatively small size of the studies. Nine of the 16 studies were at high risk of bias because of small size. There are issues over both random chance effects with small amounts of data, and potential bias in small studies, especially in pain (Dechartes 2013;Dechartres 2014;Moore 1998;Nüesch 2010;Thorlund 2011). Cochrane Reviews have been criticised for perhaps over‐emphasising results of underpowered studies or analyses (AlBalawi 2013;Turner 2013). On the other hand, it may be unethical to ignore potentially important information from small studies or to randomise more participants if a meta‐analysis including small, existing studies provided conclusive evidence. In this review, we chose to limit analyses to studies with a minimum of 10 participants per treatment group. Small studies may have influenced positive results in this review. For example, for moderate pain relief (at least 30% pain relief), the overall result was positive with an RD of 0.09 (0.03 to 0.15) in an analysis of 10 studies with 1566 participants, but the difference between cannabis‐based medicines and placebo was much larger in small studies. We had not initially planned this analysis, but examination of the forest plots demonstrated that for this and other outcomes, the elimination of small studies eliminated statistical significance. In view of the accumulating evidence regarding potential bias in small studies, the quality of the evidence for cannabis‐based medicines for treating neuropathic pain cannot be relied upon.
Potential biases in the review process
The absence of publication bias (unpublished trials showing no benefit of cannabis‐based medicines over placebo) can never be proved. We carried out a broad search for studies and feel it is unlikely that significant amounts of relevant data remain unknown to us.
We might have overestimated the risk of bias of some studies that did not report some details of methodology (e.g. randomisation and blinding procedures).
Most studies selected statistical methods (last observation carried forward, completer analysis) that bias results towards exaggerating the efficacy of drugs (Moore 2013b).
The influence of allowed co‐interventions (e.g. rescue medication) on positive effects and adverse events was unclear because type and dosage of co‐interventions were not clearly reported or controlled for.
This systematic review included 1750 participants. To capture rare and potentially severe adverse events a larger data set would have been necessary. For example, to capture an adverse event with a frequency of 1:100,000, 300,000 participants' observations would have been necessary (Andersohn 2008).
Agreements and disagreements with other studies or reviews
We cannot share the optimistic conclusions of some reviews that cannabis‐based medicines are effective, well‐tolerated and safe in the treatment of chronic neuropathic pain (Andreae 2015;Boychuk 2015;Lynch 2011).Lynch 2011performed a qualitative systematic review on cannabis‐based medicines in chronic non‐cancer pain with 11 studies in chronic neuropathic pain and concluded that cannabis‐based medicines are "modestly" effective in neuropathic pain and did not lead to withdrawal from the study.Boychuk 2015performed a qualitative analysis of 13 studies of cannabis‐based medicines in 771 participants with chronic neuropathic pain and concluded that cannabis‐based medicines should be considered as an alternative treatment for neuropathic pain. The authors made no definitive statement on tolerability and safety.Andreae 2015performed an individual participant data analysis of 178 participants from five studies of inhaled cannabis. They calculated an NNTB of 6 (95% CI 3 to 14) for a more than 30% reduction in pain scores compared to placebo. Withdrawals due to adverse events were found to be rare. The differences to our rather cautious conclusions on the efficacy, tolerability and safety of cannabis‐based medicines in chronic neuropathic pain can be explained as follows.
We performed a quantitative analysis, which included unpublished studies with negative results. The authors of the above‐mentioned reviews did not include the data of studies that are only available in databases.
We excluded studies of very short‐term duration.Andreae 2015;Boychuk 2015andLynch 2011included two, one‐day studies (Wilsey 2013;Wilsey 2008), which we excluded because of short study duration. The European Medicines Agency requires that study duration for chronic neuropathic pain trials should be at least 12 weeks after a stable dose is achieved in order to exclude a transient effect (European Medicines Agency 2007).
We excluded studies that did not explicitly state that the pain was of neuropathic nature. This exclusion criterion was applied to some large studies in people with multiple sclerosis with spasticity as a major outcome. There is moderate‐quality evidence for the efficacy of cannabis‐based medicines to reduce spasticity symptoms (Whiting 2015;Zettl 2016). However, spasticity‐associated pain should not be mixed with central neuropathic pain (Koppel 2014).
We performed a detailed analysis of adverse events and withdrawals due to adverse events.
On the other hand, our analyses do not support the conclusions of the Special Interest Group on Neuropathic Pain (NeuPSIG) of the International Association for the Study of Pain that cannabis‐based medicines are not effective in chronic neuropathic pain (Finnerup 2015). Our result that the use of cannabis‐based medicines is associated with an increased risk of short‐term adverse events, especially of the central nervous system, is in accordance with a systematic review ofWhiting 2015who analysed eight trials of cannabis‐based medicines in chronic neuropathic pain.
We did not find a long‐term RCT with cannabis‐based medicines answering the question of long‐term efficacy and safety. One study with dronabinol included in the review added a 32‐week, open‐label extension period to the randomised controlled period. The study authors reported that, during long‐term follow‐up, pain intensities remained at a low level (range 2.5 to 3.8 of a 0 to 10 scale). The number of adverse events and dropouts due to adverse events was lower in the long‐term than in the randomised‐controlled period. "Mild signs" of drug dependency were documented for one participant (Schimrigk 2017). THC/CBD oromucosal spray was investigated in a 38‐week, open‐label extension study. Three hundred and eighty participants with polyneuropathy associated with diabetes or allodynia entered this study from two previous RCTs. Participants received THC/CBD spray for a further 38 weeks in addition to their current analgesic therapy. The proportion of participants who reported at least a clinically relevant 30% improvement in pain continued to increase with time (up to nine months); at least half of all participants reported a 30% improvement at all time points. Improvements were observed for all secondary efficacy outcomes, including sleep quality, Patient Global Impression of Change and HRQoL. THC/CBD spray was well tolerated for the study duration and participants did not seek to increase their dose with time, with no new safety concerns arising from long‐term use (Hoggart 2015).
| https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD012182.pub2/full/hr |
(PDF) More than just Frequency? Demasking Unsupervised Hypernymy Prediction Methods
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More than just Frequency? Demasking Unsupervised Hypernymy Prediction Methods
Abstract and Figures
This paper presents a comparison of unsupervised methods of hypernymy prediction (i.e., to predict which word in a pair of words such as fish-cod is the hypernym and which the hyponym). Most importantly, we demonstrate across datasets for English and for German that the predictions of three methods (WeedsPrec, invCL, SLQS Row) strongly overlap and are highly correlated with frequency-based predictions. In contrast, the second-order method SLQS shows an overall lower accuracy but makes correct predictions where the others go wrong. Our study once more confirms the general need to check the frequency bias of a computational method in order to identify frequency-(un)related effects.
Prediction results for WordNet (above) and GermaNet (below) non-compound pairs across equally-sized subsets of target pairs sorted by difference in hypernym frequency and hyponym frequency. …
Proportions of pairs predicted wrongly by word frequency but correctly by the given method. …
Figures - available via license: Creative Commons Attribution 4.0 International
Content may be subject to copyright.
More than just Frequency?
Demasking Unsupervised Hypernymy Prediction Methods
Thomas Bott, Dominik Schlechtweg and Sabine Schulte im W alde
Institute for Natural Language Processing, University of Stuttgart, Germany
{ bottts,schlecdk,schulte } @ims.uni-stuttgart.de
Abstract
This paper presents a comparison of unsuper-
vised methods of hypernymy prediction (i.e.,
to predict which word in a pair of words such
as fish–cod is the hypernym and which the hy-
ponym). Most importantly, we demonstrate
across datasets for English and for German
that the predictions of three methods (W eeds-
Prec, invCL, SLQS Row) strongly ov erlap and
are highly correlated with frequency-based
predictions. In contrast, the second-order
method SLQS shows an overall lo wer accu-
racy but makes correct predictions where the
others go wrong. Our study once more con-
firms the general need to check the frequency
bias of a computational method in order to
identify frequency-(un)related effects.
1 Introduction
Hypernymy represents a major paradigmatic se-
mantic relation between two concepts, a hypernym
(superordinate) and a hyponym (subordinate), as in
tree–oak and fish–cod , where the hyponym implies
the hypernym, but not vice versa. From a cognitive
perspective hypernymy is central to the or ganisa-
tion of the mental lexicon ( Deese , 1965 ; Miller and
Fellbaum , 1991 ; Murphy , 2003 ), next to further
semantic relations such as synonymy , antonymy,
etc. From a computational perspective hypernymy
is central to solving a number of Natural Language
Processing (NLP) tasks such as taxonomy creation
( Hearst , 1998 ; Cimiano et al. , 2004 ; Snow et al. ,
2006 ; Navigli and Ponzetto , 2012 ), textual entail-
ment ( Dagan et al. , 2006 ; Clark et al. , 2007 ) and
text generation ( Biran and McKeown , 2013 ).
Accordingly, the field has witnessed acti ve re-
search on two subtasks involv ed in computational
models of hypernymy (see Shwartz et al. ( 2017 ) for
an extensive o verview): hypernymy detection (i.e.,
distinguishing hypernymy from other semantic rela-
tions) and hypernymy prediction (i.e., determining
which word in a pair of words is the hypernym
and which is the hyponym). The target subtask
of the current study is hypernymy prediction: we
perform a comparative analysis of a class of ap-
proaches commonly refered to as unsupervised hy-
pernymy methods ( W eeds et al. , 2004 ; Kotlerman
et al. , 2010 ; Clarke , 2012 ; Lenci and Benotto , 2012 ;
Santus et al. , 2014 ). These methods all rely on the
distributional hypothesis ( Harris , 1954 ; Firth , 1957 )
that words which are similar in meaning also occur
in similar linguistic distributions. In this vein, they
exploit asymmetries in distributional vector space
representations, in order to contrast hypernym and
hyponym vectors.
While these unsupervised hypernymy prediction
methods have been explored and compared exten-
sively on a number of benchmark datasets ( Shwartz
et al. , 2017 ), this study takes a novel perspectiv e
and performs a detailed analysis of whether and
where the methods make similar or different deci-
sions. Our prediction experiments on simplex and
complex nouns in English and German W ordNets
and evaluation benchmarks sho w that most of the
methods we investigate o verlap in their specific pre-
dictions to a surprisingly high degree, and that the
predictions strongly correlate with those based on
raw frequencies. Our study therefore emphasises
the general need to check the frequency bias of a
computational method and to distinguish between
frequency-related and frequency-unrelated effects.
2 Data and Methods
In the following we describe our gold standard
datasets (Section 2.1 ), our corpora and vector
spaces (Section 2.2 ) and our hypernymy predic-
tion methods (Section 2.3 ). The code and links
to the gold standards are available from
https:
//github.com/Thommy96/hyp-freq- comp .
arXiv:2106.00055v1 [cs.CL] 31 May 2021
2.1 Gold Standard Datasets
Our study focuses on hypernymy between nouns
and uses two types of gold standard resources for
hypernymy relations. On the one hand, we rely
on W ordNets as classical large-scale taxonomies
where hypernymy represents one of the core seman-
tic relations for organisation: the English Wor dNet
1
( Miller et al. , 1990 ; Fellbaum , 1998 ), version 3,
and the German GermaNet
2
( Hamp and Feldweg ,
1997 ; Kunze and W agner , 1999 ; Lemnitzer and
Kunze , 2007 ), version 11. From both W ordNets,
we extracted all noun–noun pairs with a hypernymy
relation and removed duplicates, autohyponyms
and space-separated multiword expressions. W e
also distinguish between compounds (which fre-
quently represent hyponyms of their constituent
heads, as in dog–lapdog ) and non-compounds by
applying a simple heuristic, i.e., categorising all
hypernym–hyponym pairs as compounds if one is
a substring of the other. W e expected this subset to
exhibit idiosynchratic behaviour in our prediction
experiments.
On the other hand, we rely on a number of bench-
mark datasets for hypernymy evaluation: BLESS
( Baroni and Lenci , 2011 ) provides related concepts
for 200 English concrete nouns connected through
a semantic relation (hypernymy , co-hyponymy,
meronymy , attribute, ev ent) or a null-relation. The
dataset by Lenci and Benotto ( 2012 ) contains a sub-
set of BLESS relation pairs, as created for previ-
ous comparisons of hypernymy detection methods.
A dataset similar to BLESS, EVALution , was in-
duced from ConceptNet and W ordNet ( Santus et al. ,
2015 ). Its semantic relations include hypernymy,
synonymy , antonymy and meronymy . For quality
reasons, the pairs were filtered by automatic meth-
ods and crowd-sourcing to improve consistenc y
and to determine prototypical pairs. Finally , we use
the W eeds dataset ( W eeds et al. , 2004 ; W eeds and
W eir , 2005 ) which contains word pairs related by
hypernymy and co-hyponymy across word classes.
From all four benchmark datasets we extracted all
noun–noun pairs related by hypernymy .
The first row in T able 1 shows the numbers of
hypernymy pairs in the W ordNets and in the bench-
mark datasets.
1 https://wordnet.princeton.edu
2 https://uni-tuebingen.de/en/142806
2.2 Corpora and V ector Spaces
W e created our distributional vector spaces based
on the W aCky
3
corpora ( Baroni et al. , 2009 ) for En-
glish and for German. The English PukW aC corpus
is the syntax-annotated version of ukW aC ( Ferraresi
et al. , 2008 ) and contains
≈
1.9 billion words; the
German SdeW aC corpus ( Faaß and Eckart , 2013 )
is a cleaned version of the W aCky corpus deW aC
and contains
≈
880 million words; both corpora are
pos-tagged with the Tr eeT agg er ( Schmid , 1994 ).
For each corpus we created a traditional count
vector space
4
based on a co-occurrence window of
±
10 words within sentences (because sentences in
the SdeW aC are shuffled, so going beyond sentence
border is meaningless). W e used a bag-of-words ap-
proach only taking into account lemmatised nouns,
2.3 Hypernymy Methods and Baselines
W e selected four unsupervised hypernymy methods
and defined two baselines. The methods were cho-
sen from different families with regard to ho w they
exploit the distributional hypothesis for hypernymy
detection: W eedsPrec and In vCL rely on the Distri-
butional Inclusion Hypothesis , according to which
a significant number of distributional features of a
word x is included in the distributional features of
a word
y
, if
x
is semantically more specific than
y
.
SLQS Row and SLQS Sec
5
rely on the Distribu-
tional Informativeness Hypothesis using first- and
second-order variants of word entropy , respectiv ely .
f
in the two word vectors
~ x
and ~ y for a word pair h x, y i .
W eedsPrec
: An asymmetric precision method sug-
gested by W eeds et al. ( 2004 ) that quantifies the
weighted inclusion of the features of word
x
in
the features of word
y
. If
W eedsP rec ( x, y ) >
W eedsP rec ( y, x )
, then
x
is predicted as the hy-
ponym and y as the hypernym, and vice versa.
W eedsP rec ( x, y ) = P f ∈ ( − →
x ∩ − →
y ) x f
x x f
3 http://wacky.sslmit.unibo.it/
4
Note that not all of the selected methods are applicable to
embeddings, and it also not our goal to identify the optimal
vector spaces, rather than analysing their predictions; this is
why our analyses rely on standard count dimensions.
5
Originally, this method is called SLQS, b ut to distinguish
it from SLQS Row we refer to it as SLQS Sec.
W ordNet GermaNet BLESS EV ALution LB Weeds
¬ comp comp ¬ comp comp
sizes: 106,397 3,366 102,714 35,963 1,337 606 1,747 1,117
W ord Length 47.26 94.65 56.14 99.41 23.19 34.86 52.42 44.76
W ord Frequency 73.19 92.81 73.66 98.78 62.30 68.96 76.48 76.63
WeedsPr ec 72.22 92.93 74.01 98.87 57.52 64.22 77.02 74.22
InvCL 72.97 92.84 73.92 98.78 63.05 68.86 76.48 76.45
SLQS Row 71.82 93.02 74.40 98.79 58.56 55.91 71.27 72.43
SLQS Sec 65.05 74.66 70.38 90.15 71.80 59.63 62.66 65.71
T able 1: Sizes of datasets and overall prediction results across datasets.
InvCL
: An asymmetric precision method suggested
inclusion as well as feature non-inclusion (origi-
nally suggested as ClarkDE (cde) by Clarke ( 2012 ))
into account. If
invC L ( x, y ) > inv CL ( y , x )
,
then
x
is predicted as the hyponym and
y
as the
hypernym, and vice versa.
cde ( x, y ) = P f ∈ ( − →
x ∩ − →
y ) min ( x f , y f )
P f ∈ − →
x x f
invC L ( x, y ) = p cde ( x, y ) · (1 − cde ( y, x ))
SLQS Row
: An asymmetric method suggested
by Shwartz et al. ( 2016 ) which relies on the
word entropy
H ( w )
for a word
w
, taking all
context words as features into account:
w f
. If
SLQS Row ( x, y ) > 0
, then
x
is predicted as the
hyponym and y as the hypernym, and vice versa.
SLQS Row ( x, y )=1 − H ( x )
H ( y )
H ( w ) = − X
w f
p ( w f | w ) · log 2 ( p ( w f | w ))
SLQS Sec
: An asymmetric method suggested by
Santus et al. ( 2014 ) which relies on second-order
word entropy
E ( w )
and is calculated as the median
entropy
M ed
of a word’s most strongly associated
context words
w f
. W e use the 50 strongest contexts
in our vector spaces, as determined by weighted
co-occurrence scores using positive local mutual
information ( Evert , 2005 ). If
SLQS S ec ( x, y ) > 0
,
then
x
is predicted as the hyponym and
y
as the
hypernym, and vice versa.
SLQS S ec ( x, y ) = 1 − E ( x )
E ( y )
E ( w ) = M ed w f H ( w f )
Baselines:
In comparison to the hypernymy meth-
ods we applied two baselines, cf. Zipf ’s principles
of least effort ( Zipf , 1949 ):
• W ord Length
: Given that hyponyms refer to
more specific concepts than their hypernyms,
and assuming that more specific concepts tend
to have a longer word length, this baseline
predicts the longer word in a word pair (as
measured by the number of characters) as the
hyponym.
• W ord Frequency
: Given that hyponyms refer
to more specific concepts than their hyper-
nyms and assuming that more specific con-
cepts appear less often in a corpus, this base-
line predicts the less frequent word in a word
pair (as measured by corpus frequency) as the
hyponym.
3 Prediction Results and Comparisons
3.1 Overall results
T able 1 shows the overall accurac y results of the
predictions across methods and datasets (best re-
sults in bold fonts). Accuracy is defined by the pro-
portion of correct predictions given that we know
which word in a word pair is the hypernym and
which is the hyponym.
For each W ordNet we list two results, one for
the non-compound pairs (in blue, as the benchmark
results) and one for the compound pairs (in grey).
For compound pairs word length is an almost per-
fect predictor,
6
as expected, and all unsupervised
methods are also above 90%, with SLQS Sec as
an exception. In all other columns we can see that
word length is generally a poor baseline. W ord
6
The prediction does not reach 100% because our heuristic
included non-compound pairs, such as selection–election .
Figure 1: SMC correlations between methods for WordNet (above) and GermaNet (below) non-compound pairs.
frequency , however , is a very powerful baseline;
across datasets it keeps up or even outperforms
the respective best methods, which are SLQS Sec
on BLESS; InvCL on EV ALution and W eeds; and
W eedsPrec on LB. Across datasets, the best re-
sults vary between 68.96% and 77.02% for non-
compounds; compounds obviously represent “easy”
cases of hypernymy .
T o explore similarities in predictions across meth-
ods, we applied the Simple Matching Coefficient
(SMC) ( Sokal , 1958 ) to determine for each two
methods to which degree their decisions overlap,
by comparing the number of matching decisions
(i.e., where both methods predicted the same noun
in a noun pair as the hypernym) against the number
of decisions (i.e., the total number of noun pairs).
The heatmaps in Figure 1 show the results for the
non-compounds in the English W ordNet (left) and
in GermaNet (right). They clearly demonstrate that
word length makes very different decisions to w ord
frequency and the unsupervised methods, and that
word frequency and all unsupervised methods but
SLQS Sec highly correlate in their predictions.
3.3 Role of frequency
W e go one step further to explore the role of fre-
quency . Figure 2 presents the prediction results
on 10 equally-sized subsets of the non-compound
pairs in the W ordNets after the target pairs were
sorted by decreasing difference in hypernym cor-
pus frequency minus hyponym corpus frequency .
x
-axis we see
the results on the subset with largest differences in
hypernym–hyponym frequencies.
W e can clearly see that up to subset 7 (up to
which the hyponym frequencies are all below the
hypernym frequencies), decisions based on word
frequency , W eedsPrec, invCL and SLQS Ro w pre-
dict the hypernym almost perfectly; for subset 8
(where the hyponym frequencies start to become
larger than the hypernym frequencies) their predic-
tions are becoming worse; and for subsets 9–10 the
predictions are mostly wrong. Results by relying
on word length and SLQS Sec are clearly worse
for the first seven subsets but also better for the
last two subsets, thus confirming that they make
different predictions.
3.4 Correctness of predictions
While SMC in Section 3.2 informed us about over-
lap in decisions, it did not tell us whether one of the
methods is qualitatively superior , so we analysed
whether some methods are simply worse than oth-
or whether the methods all have their own strengths.
W e calculated for each pair of methods which pro-
portion of wrongly predicted pairs of one method
was predicted correctly by the other method. Fig-
ure 3 illustrates for the English W ordNet how many
pairs wrongly predicted by word frequency are pre-
dicted correctly by another method (see x -axis).
As we can see, while word length and SLQS Sec
are often worse in performance than frequency , they
still manage to make correct predictions when fre-
quency fails, which is much less the case for the
frequency-alike methods W eedsPrec, invCL and
SLQS Row . In particular, invCL seems to make al-
most identical predictions as frequency , which was
already indicated by their almost perfectly overlap-
ping lines in Figure 2 .
Figure 2: Prediction results for WordNet (above) and GermaNet (below) non-compound pairs across equally-sized
subsets of target pairs sorted by difference in hypernym frequenc y and hyponym frequency .
Figure 3: Proportions of pairs predicted wrongly by
word frequency but correctly by the giv en method.
4 Conclusion
This study performed a series of hypernymy predic-
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ubingen, Ger-
many .
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ing Hypernyms in Distributional Semantic Spaces.
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eal, Canada.
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baum, Derek Gross, and Katherine J. Miller. 1990.
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mantic Networks of English. Cognition , 41:197–
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M. Lynne Murphy . 2003. Semantic Relations and the
Lexicon . Cambridge University Press.
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Net: The Automatic Construction, Evaluation and
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250.
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Schulte im W alde. 2014. Chasing Hypernyms in
V ector Spaces with Entropy . In Proceedings of the
14th Conference of the Eur opean Chapter of the As-
sociation for Computational Linguistics , pages 38–
42, Gothenburg, Sweden.
Enrico Santus, Frances Y ung, Alessandro Lenci, and
Chu-Ren Huang. 2015. EV ALution 1.0: an Evolv-
ing Semantic Dataset for Training and Evaluation
of Distributional Semantic Models. In Proceedings
of the 4th W orkshop on Linked Data in Linguistics ,
pages 64–69, Beijing, China.
Helmut Schmid. 1994. Probabilistic Part-of-Speech
T agging using Decision Trees. In Proceedings of
the 1st International Conference on New Methods in
Language Processing .
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Improving Hypernymy Detection with an Integrated
Path-based and Distributional Method. In Proceed-
ings of the 54th Annual Meeting of the Association
for Computational Linguistics , pages 2389–2398,
V ered Shwartz, Enrico Santus, and Dominik
Schlechtweg. 2017. Hypernyms under Siege:
Linguistically-motivated Artillery for Hypernymy
Detection. In Proceedings of the 15th Conference
of the European Chapter of the Association for
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Spain.
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Robert R. Sokal. 1958. A Statistical Method for
Evaluating Systematic Relationships. University of
Kansas Science Bulletin , 38:1409–1438.
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work for Lexical Distributional Similarity . Compu-
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Julie W eeds, David W eir, and Diana McCarthy . 2004.
Characterising Measures of Lexical Distributional
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ciple of Least-Effort . Addison-W esley , Cambridge.
EVALution 1.0: an Evolving Semantic Dataset for Training and Evaluation of Distributional Semantic Models
Conference Paper
Full-text available
Jul 2015
Enrico Santus
Frances Yung
Alessandro Lenci
Chu-Ren Huang
In this paper, we introduce EVALution
1.0, a dataset designed for the training and
the evaluation of Distributional Semantic
Models (DSMs). This version consists of
almost 7.5K tuples, instantiating several
semantic relations between word pairs (including
hypernymy, synonymy, antonymy,
meronymy). The dataset is enriched with
a large amount of additional information
(i.e. relation domain, word frequency,
word POS, word semantic field, etc.) that
can be used for either filtering the pairs
or performing an in-depth analysis of the
results. The tuples were extracted from a
combination of ConceptNet 5.0 andWordNet
4.0, and subsequently filtered through
automatic methods and crowdsourcing in
order to ensure their quality. The dataset
is freely downloadable. An extension in
RDF format, including also scripts for data
processing, is under development.
Chasing Hypernyms in Vector Spaces with Entropy
Conference Paper
Full-text available
Apr 2014
Enrico Santus
Alessandro Lenci
Qin Lu
| https://www.researchgate.net/publication/352054349_More_than_just_Frequency_Demasking_Unsupervised_Hypernymy_Prediction_Methods |
Matthew 4 | pao Bíblia | YouVersion
Soo Te Naa Besa Pooha ka Te Pabe'e sukwe oona numu-wanatoo taya oo nanesootuhi tuunguna. Soo Suta'yoo yise suda oo too'e nemadunaga'a. Watsu mano (40) tooi petuga nanesootuhina gi hemma tukana. Ka saa
Matthew 4
1 Soo Te Naa Besa Pooha ka Te Pabe'e sukwe oona numu-wanatoo taya oo nanesootuhi tuunguna. 2 Soo Suta'yoo yise suda oo too'e nemadunaga'a. Watsu mano (40) tooi petuga nanesootuhina gi hemma tukana. 3 Ka saa'a yise soo Suta'yoo ka Te Pabe'e meeoo too'e netamma, “U sakwa nasootza'me ka Numu Manumudoopu Tooa'ana. U sakwa ka eka tupe tukaba mayugwese ka tsuayina a tuka.” Soo Te Pabe'e gi oo soonakabetseana, meeoo oo sukwe netamma, 4 “Soo E Naa meeoo unnepu, ‘Soo tukapu suu'mu nadukana gi numu magwetzoi-wa'ne'yoo. Ka Te Naa unnepu suu'mu nakabetseana mu numu namagwetzoikwu.’ ”
5 Soo Suta'yoo yise ka Te Pabe'e oona Jerusalem-witoo pabow nobe, pukwi mu numu nanesootuhi-kwitoo bikea. Pa'atse'e ka pabow nanesootuhi nobe-kooba oo bi petugase
6 yise meeoo oo netamma, “U sakwa nanasookwugi manena ma-kooba'yoona nadawunihoo u ka Numu Manumudoopu Naa Dooa mee unnena. U gi namaniyaha-wa'ne'yoo ka u Naa u-kooba tueya'e. ‘Soo U Naa ume pumme tummatzidu toha kakasa-gakoo u-kooba tueya'e tuungukwu, umu pa'akoosoo u-gwuuhookwu.’ ”
7 Soo Te Pabe'e yise meeoo oo netamma, “Nu gi ume unnena nakabetsea-wa'ne'yoo, soo Te Naa mooasoo meeoo unnepu, ‘Tamme sakwa gi ka Te Naa tooe hownnekoo tooe mapoonnepana, ha'oo sakwa oosoo mani mee sokwamadu-kwa'ne.’ ”
8-9 Soo Suta'yoo yise tuwazoo oo bi ka oona pa'a kiba-matoo petugase, mu no'obatusoo nana'atakoosoo numu ka teepu-koobatu oo tzapoonnekute. Soo Suta'yoo yise meeoo tuwazoo ka Te Pabe'e netamma, “O'nosoo nuka mu numu yaa teepu-koobatu moohe tuungu, umu yise no'yoona e nakabetseakwu. U ka nu-matoo nanesootuhina, nu ume mu nakabetsea tuungukwu.” 10 Soo Te Pabe'e ka sutakoo meeoo netamma, “Nu gi u-matoo nanesootuhi-wa'ne'yoo. Soo Te Naa mee mooasoo tubotugupu, ‘Tamme sakwa ka Te Naa-matoo suu'mu nanesootuhi. Tamme sakwa ookow suu'mu nakabetsea.’ ”
11 Soo Suta'yoo yise ka Te Pabe'e too'e nepetukuse oo soomabanase, oo-baa'yoo meahoo. Yise Te Naa tutummatziwabe, mu toha kakasa-ga'yoo oo-baa wupetuhoose, ka Te Pabe'e tummatzi.
12-16 Soo Te Pabe'e ka John nakwutamase oo nakase, ka teepu Galilee-witoo kodyuka. Ka Nazareth-wi nobe-ga pana ka Capernaum mee naneadu-witoo nowu'a. O'nosoo soo Te Naa yadooawabe Isaiah mee naneadu ka Te Pabe'e manekwuna mee botugupu. “Mu numu ka Capernaum-wi # 4:12-16 4 Soo Capernaum umu teepu Zebulan noko Naphtali mee nananeadu tasegayi, ka paba hooodu Jordan mee naneadu noko ka banunadu-tamme po habetu-kumaba. nonobe-ga'yoo uga gi Te Naa unnepu nakasopedakwatoodu. Wunametoo gi ka Te Naa unnepu naka pana meno'o yise umu Te Naa unnepu nakasopedakwadoose Te Pabe'e-wi tunaka'oedyukute.”
17 Yaa manakwana soo Te Pabe'e yise mu numu ka Te Naa-witu nanesootuhi tunedyooekooha, mee yise mu netamma, “Mu sakwa ka sutakoo gi nakabetseapana, ka besa'hoo podo meadabe, o'no soo Te Naa no'oko pumme naka'oedyukudu sootuhikwu.”
18 Waha'yoo nawanga'a pakwegana, mu Andrew-no Simon Peter mee nananeadu. Umu ka puma tu tuukwina ka banunadu-witoo wukwazuyakwe, soo Te Pabe'e ka pakumi meana mu poonnese meeoo mu netamma,
19 “Mu sakwa nu-no memease e tummatzimo. Nu mu tunedyooena mu e nakatzimokwu, o'no mu numu nu-kwitu naka'oedyukukwu.”
20 Umu nawanga'a yise ka puma tu tuukwina ma'wuoogase yaa manakwana ka Te Pabe'e nakatzimodu manegakwu.
21 Umu-tzage'e waha'yoo nawanga'a James-no John ka tu naa Zebedee mee naneadu-no punno'o oona sake-wi'yoona ka puma tu tuukwina mabetsabedyakwe. Soo Te Pabe'e ka banunadu kumi meadabena mu poonnegase mu nawanga'a bi.
22 Umu yise ka tu sake noko tu naa ma'wukase ka Te Pabe'e-no memeahoo.
23 Soo Te Pabe'e yise no'oko ka teepu Galilee mee naneadu-kooba'yoona no'oko mu tuoegoedu mabesakumena, yise mu nanesootuhi-wi'yoona tuwow mu numu tunedyooemena mee mu netamma, “Mu sakwa ka Te Naa naka'oedyuku, pudusoo soo Te Naa puusoo besa mu sootuhikwu.”
24 Mana tooe hano tooe numu ka Te Pabe'e-witu naka, ka teepu Syria mee naneadu-witoo tooe. Mu numu tuoegoedu hane petudyakwe, tsoapayidu, ya'ehookayidu, gi yuyutsunga manepu numu tuwazoo. Soo Te Pabe'e yise mu mabesakuyakwe.
25 Ewa'yoo numu yise oo nakatzipetu. Mana ka teepu Galilee-witu yise tuwazoo mana teepu Sumu Mano Nogadu-witu, Judea mee naneadu, yise ka Jerusalem mee naneadu-kwitu, ka hooodu Jordan mee naneadu ooenapatu numu tuwazoo ka Te Pabe'e-baa petudyakwe.
| https://www.bible.com/pt/bible/658/MAT.4.PAO |
Banks Are Passing the Buck in Cost Cutting | INSEAD Knowledge
Misaligned incentives still reign in the banking industry, turning cost cutting into a hot potato passed around divisions.
Banks Are Passing the Buck in Cost Cutting
Misaligned incentives still reign in the banking industry, turning cost cutting into a hot potato passed around divisions.
As we wrote in our last piece, there is a certain mindset in the banking industry that still runs contrary to value creation. We promised a follow-up on how value is destroyed in relation to disposals and acquisitions. But before that, we want to dive deeper into how banks currently conduct cost cutting, which will provide a decent backdrop for exploring how value is lost in disposals and acquisitions.
Large financial institutions are typically divided into front office and service providers. Front office consists of functions such as retail banking, corporate banking and global markets. Service providers are numerous and typically include departments such as human resources, IT, operations, control, legal, compliance, risk and audit, to name a few.
The front office functions run their own P&L but the service providers do not. So when HR works with a business unit, it incurs costs and allocates them to the product line. Because of this process, the product division typically incurs more than 60 percent of its overall costs through internal allocations from service providers and less than 40 percent through direct costs (or costs which it can influence directly) such as headcount, floor space, computers and external consultants. The exact split varies from location to location, and department to department.
Cut or challenge
When the CEO and the board decide to embark on a cost reduction, targets are typically set by the board at the product level where the organisational profitability resides. Managers in the product divisions have three main areas where they can cut costs: 1) the internal direct costs in their divisions incurred by their staff and their direct expenses such as salaries, benefits, travel and entertainment; 2) the external direct costs in their divisions incurred through third parties such as vendors or market data providers; and 3) and, by far the largest bulk, the indirect costs allocated to them through service providers. The largest of these indirect cost allocations is no doubt from IT and operations but given the increase in regulatory requirements, service providers such as finance, compliance, legal and risk have gained substantially in importance and hence in costs. In fact, during the last 20 years, large financial institutions actually have seen their direct front office costs drop while overall costs increased – a reflection of the increasing complexity of the control functions and service providers.
Product divisions very quickly learn that cost reduction initiatives in the first two areas are highly undesirable and hard to achieve. They reduce front office staff motivation, and frequently require an upfront cost investment to redesign a process. Cost reduction initiatives could result in lower quality product offerings to their clients and hence perhaps long-term negative repercussions to their business.
Take a division such as retail banking. Front-office cost reduction in the first category – internal direct costs – can be achieved through branch closure or staff reductions in the remaining branches. The former having a negative impact on long-term client coverage, the latter on overall client services and both on front-office staff morale. A cost reduction in the second category – external direct costs – can be achieved through renegotiation with and/or cancellation of business consultants supporting the division or reduction of available data terminals such as Reuters and Bloomberg terminals. Both have a negative impact on client services.
The most desirable area to look at is the third area – the allocated costs from service providers. Here two general options open up to the division. Either tackle the overall costs of the service provider or challenge how much has been allocated to the product line. The former is difficult as it typically results in a fierce discussion between the front office and the service provider about who is responsible for deciding on the appropriate level of resourcing of the service providers. Naturally, the service provider will have an information advantage of its own cost base and tends to block most front-office suggestions for cost reductions in their areas of expertise. This is extremely tricky in control areas which monitor the legal and regulatory behaviour of the front office such as compliance, audit or finance. Here the business division faces a conflict of interest. On the one side, it wants these functions to be cost effective but, at the same time, it does not want to be perceived as wanting to reduce the oversight of its division. So the front office tends to find that the easiest and most effective way to reduce their respective costs is by challenging and making changes to the highly complex cost allocation matrix, i.e. the percentile cost allocation it receives.
Squeezing the sausage
Naturally, the overall costs for the firm are not reduced at all in these battles but are merely shifted from one area to anotherwithout creating any additional value to the organisation. This is akin to squeezing a sausage on one end just to shift some of the meat to the other. The size of the sausage (i.e. costs) remains exactly the same. Given that the cost allocation keys are such a crucial factor in the overall divisional costs – each division is well advised in this process to appoint cost experts to analyse the key cost allocation factors to arm themselves with the best arguments to change the relevant cost allocation keys. The divisions are facing a typical prisoners’ dilemmawith the overall result being a “cost allocation expertise” arms race. So the net result of these cost reduction programmes is frequently additional costs within divisions. This can be seen by the mushrooming in the last decade of functions such as Business Managers, Chief Operating Officers within divisions, numerous locations and ever-increasing support staff.
The discussion about cost allocation is far removed from value or value creation and yet financial institutions are investing good time and effort in the misplaced hope that somehow squeezing that sausage will make it smaller.
Cutting the sausage
Fixing this state of affairs is easier said than done, but it starts with a culture change on two fronts. First, by focusing on cost allocations, the product lines essentially get out of looking for ways to create value in their front office functions and asking whether their service providers could be giving more value. The management should have front offices focus on optimising their business to minimise costs, as opposed to challenging internal cost allocations.
Second, a mindset shift is also necessary among the service providers. With no P&L responsibility, there is no incentive to run operations in a cost efficient way, because work can be allocated to the product lines. Costs in the financial industry have gone up over the years despite optimising front office functions due to increased compliance and regulatory costs. , Therefore, financial institutions will have to find more ways of optimising their front offices and squeezing more value from their external providers. Otherwise, the squeezing of the sausage is likely to continue.
Boris Liedtke is a Distinguished Executive Fellow in the INSEAD Emerging Markets Institute.
S. David Young is a Professor of Accounting & Control at INSEAD. He is a co-author of The Blue Line Imperative .
This article needs more in-depth and elaboration of details, specific to the contexts and its applicability, please..!
Cost cutting is a matter of commitment from the top management. In view of the depression in oil market, costs have been cut by most E&P companies and related services providers to levels no one would have imagined before. The costs cut are mainly in the form of CAPEX, headcount reduction, further IT expansion, and yes it has hit P&L effectively. But this has also led to a leaner structure as firms focus on their core business. Any firm should have visibility over it's fixed and variable costs, with a further classification as touchable or untouchable cost. For example support services cost like HR should have a threshold for bare minimum to ensure effective service provision to the operations. Below threshold it should be untouchable but above the line it could be rationalized and cut. However, any cost cutting exercise should not be limited to internal service providers. Analyzing the current structure of operations team is essential as it should vary to quite an extent with the revenues generated in order to ensure a certain margin. Retaliation would be at its highest as operations lead would argue of business efficacy with current structure, but leaders should consider that why did they start cost cutting in first place. It was because current costs are too high, which is due to current structure. So essentially current structure has to be reviewed and renewed to address current challenges and to effectively reduce costs. Without undermining results of cost cutting, greater focus should on bringing in new products and increasing revenue as current offerings would be most likely the same as competitors are offering and hence no competitive advantage is available to the firm and no premium pricing can be done. So to conclude, cost cutting should be viewed as rationalization of structure rather than freeze on spending.
| https://knowledge.insead.edu/economics-finance/banks-are-passing-buck-cost-cutting?elqTrack=true |
Polymers | Free Full-Text | Preparation and Electrochemical Properties of Porous Carbon Nanofiber Electrodes Derived from New Precursor Polymer: 6FDA-TFMB
Porous carbon nanofibers (CNFs) with high energy storage performance were fabricated with a single precursor polymer, 6FDA-TFMB, without the use of any pore-generating materials. 6FDA-TFMB was synthesized, electrospun, and thermally treated to produce binder-free CNF electrodes for electrochemical double-layer capacitors (EDLCs). Highly porous CNFs with a surface area of 2213 m2 g−1 were prepared by steam-activation. CNFs derived from 6FDA-TFMB showed rectangular cyclic voltammograms with a specific capacitance of 292.3 F g−1 at 10 mV s−1. It was also seen that CNFs exhibit a maximum energy density of 13.1 Wh kg−1 at 0.5 A g−1 and power density of 1.7 kW kg−1 at 5 A g−1, which is significantly higher than those from the common precursor polymer, polyacrylonitrile (PAN).
Preparation and Electrochemical Properties of Porous Carbon Nanofiber Electrodes Derived from New Precursor Polymer: 6FDA-TFMB
Taehwa Ha 2 ,
Dong Yun Lee 3 ,
Myung-Seok Choi 4 ,
Seung Woo Lee 2,* and
Kyung-Hye Jung 1,*
School of Advanced Materials and Chemical Engineering, Daegu Catholic University, Gyeongsan 38430, Korea
Department of Polymer Science and Engineering, Kyungpook National University, Daegu 41566, Korea
4
Division of Chemical Engineering, Konkuk University, Seoul 143701, Korea
*
Authors to whom correspondence should be addressed.
Polymers 2020 , 12 (8), 1851; https://doi.org/10.3390/polym12081851
Received: 21 July 2020 / Revised: 13 August 2020 / Accepted: 13 August 2020 / Published: 18 August 2020
(This article belongs to the Special Issue Polymer-Based Electrodes )
Abstract
Porous carbon nanofibers (CNFs) with high energy storage performance were fabricated with a single precursor polymer, 6FDA-TFMB, without the use of any pore-generating materials. 6FDA-TFMB was synthesized, electrospun, and thermally treated to produce binder-free CNF electrodes for electrochemical double-layer capacitors (EDLCs). Highly porous CNFs with a surface area of 2213 m 2 g −1 were prepared by steam-activation. CNFs derived from 6FDA-TFMB showed rectangular cyclic voltammograms with a specific capacitance of 292.3 F g −1 at 10 mV s −1 . It was also seen that CNFs exhibit a maximum energy density of 13.1 Wh kg −1 at 0.5 A g −1 and power density of 1.7 kW kg −1 at 5 A g −1 , which is significantly higher than those from the common precursor polymer, polyacrylonitrile (PAN).
Keywords:
carbon nanofiber electrodes
;
EDLCs
;
6FDA-TFMB
;
electrospinning
;
porous carbon
Graphical Abstract
1. Introduction
Electrochemical double-layer capacitors (EDLCs) store charge using ion adsorption at the electrode surface without redox reactions, and thus have high power and long cyclability. The development of nanostructured carbon electrode materials such as carbon nanotubes (CNTs) or graphene enables high EDLC performance due to a large number of active sites on their surface [ 1 , 2 ].
Carbon nanofibers (CNFs) are a good candidate for EDLC electrode materials due to their large surface area-to-volume ratio, reliable electrical conductivity, and well-controlled nanostructures. They are generally fabricated by thermal treatment of electrospun precursor nanofibers such as polyacrylonitrile (PAN), polybenzimidazole (PBI) [ 3 ], lignin [ 4 ], and cellulose [ 5 ]. Among precursors, aromatic polyimides are good precursor candidates due to their high thermal stability and well-defined molecular structure, and they have been mainly investigated as carbon molecular sieve membranes for gas separation [ 6 , 7 , 8 , 9 , 10 , 11 ]. The molecular structure of polyimides can be controlled by the selection of dianhydride and diamine, which is crucial to determine carbonization behavior. Additionally, they can be converted to porous carbon due to the release of nitrogen caused by the decomposition of imide rings during carbonization (around 800 °C) [ 12 ].
Polyimides containing hexafluoroisopropylidene diphthalic anhydride (6FDA) moiety show high thermal stability and free volume, which makes them outstanding candidates for CNF precursors [ 13 , 14 , 15 ]. Among them, a polyimide consisting of 6FDA and 2-2′-bis(trifluoromethyl)benzidine (TFMB) contains four trifluoromethyl (CF 3 –) groups in the repeating unit, and the decomposition of CF 3 – groups can additionally generate pores during pyrolysis [ 16 ]. In addition, high free volume caused by CF 3 – groups is favorable for polymer chain rearrangement during thermal treatment. It has also been reported that porous CNFs can be prepared when the precursor polymers have high free volume [ 17 , 18 , 19 ]. Therefore, 6FDA-TFMB seems likely to produce porous CNFs without using pore-generating materials.
Here we report synthesis of CNFs via pyrolysis of electrospun 6FDA-TFMB nanofibers, which serve as binderless electrodes in EDLCs. The surface area and porosity of CNFs were investigated by nitrogen adsorption/desorption measurements while the carbon microstructures were investigated by Raman spectroscopy. The electrochemical properties were studied by assembling coin cells with an aqueous electrolyte.
2. Materials and Methods
The synthesis of 6FDA-TFMB was carried out according to literature procedures [ 20 , 21 ]. The solution of an equivalent mol of 6FDA-TFMB in isoquinoline and 1-methyl-2-pyrrolidinone (NMP) was heated at 70 °C for 2 h, refluxed for 5 h, and then precipitated in methanol. The number average molecular weight ( M n ) of 6FDA-TFMB was 54,000 with a polydispersity index (PDI) of 1.43 from a gel permeation chromatography (GPC) system using a PL-GPC 210 (Polymer laboratories, Church Stretton, UK).
6FDA-TFMB dissolved in NMP with concentrations of 30–33 wt % was electrospun under applied voltages of 9–15 kV, stabilized at 300 °C under air flow for 3 h, and carbonized at 800 °C under N
2
for 30 min. To enhance the surface properties, carbonized 6FDA-TFMB was subsequently steam-activated at 700 °C for 30 min with the feed rate of 0.05 mL h
−1
, and annealed at 800 °C for 30 min to remove undesired oxygen-containing functional groups induced by the steam treatment. The CNFs derived from PAN were also prepared for comparison.
Fourier-transform infrared (FTIR) spectroscopy was recorded using a Nicolet 6700 (Thermo Scientific, Waltham, MA, USA) at a 4 cm
−1
resolution using a liquid-nitrogen-cooled mercury cadmium telluride (MCT) detector. Thermogravimetric analysis (TGA) was carried out with a TGA7 (Perkin-Elmer, Waltham, MA, USA) by heating the 6FDA-TFMB up to 800 °C at a heating rate of 10 °C min
−1
under nitrogen. Scanning electron microscopy (SEM, SU8220, Hitachi, Japan) was measured to investigate the surface morphology of the precursor and carbon nanofibers. Carbon microstructures were observed with a Raman spectrometer (inVia reflex, Renishaw, Wotton-under-Edge, UK) with a 780 nm laser. The surface and pore properties of the activated CNFs were characterized using N
2
adsorption/desorption isotherms measured on a Quantachrome (Autosorb-iQ and Quadrasorb SI, Quantachrome, Boynton Beach, FL, USA).
The activated CNFs were directly used as electrodes in the symmetric coin-type cells with two electrodes. Glass fiber separators and 6.0 M of potassium hydroxide were employed as a separator and an electrolyte, respectively. The electrochemical properties were investigated using a WBCS3000S (Wonatech, Seoul, South Korea). From cyclic voltammetry (CV), the specific capacitance (
C
sp
, F g
−1
) for symmetric cells was calculated using Equation (1) as follows:
C sp = 4 m I v
(1)
where
m
is the mass of both electrodes (g),
I
the discharge current (A), and
ν
the scan rate (V s
−1
). CV measurements were conducted in the voltage range of −0.5 to 0.5 V with the scan rate range of 10 to 100 mV/s. Cyclic performance was studied by measuring capacitance retention after 5000 cycles under the voltage range of −0.5 to 0.5 V and a scan rate of 100 mV/s.
The galvanostatic charge–discharge test was carried out with a voltage range of 1.0 to 0 V and a discharge current density range of 0.5 to 5 A/g. From the discharge curves, energy density (
E
, Wh kg
−1
) and power density (
P
, W kg
−1
) were calculated using Equations (2) and (3) as follows:
E = I d t d V 2 m
(2)
P = t d E
(3)
respectively, where
I
d
is the discharge current (A),
t
d
the discharge time (s), and
V
the voltage window (V). Electrochemical impedance spectra (EIS) were evaluated over the frequency range of 100 kHz and 0.1 Hz using a 0.01 V amplitude on a PEC-L01, Peccek, Japan.
3. Results and Discussion
The chemical structures of synthesized 6FDA-TFMB were observed using FTIR spectroscopy, as shown in Figure 1 . It shows distinctive bands at 1727 and 1787 cm −1 for C=O symmetric and asymmetric stretch, and 1362 cm −1 for C–N stretch of imide. A peak at 1211 cm −1 for C–F stretch is also found.
Figure 1. FTIR spectrum of synthesized 6FDA-TFMB.
The thermal stability of synthesized 6FDA-TFMB was studied by measuring TGA, as shown in Figure 2 , and 6FDA-TFMB seems thermally stable up to 500 °C. It was reported that a breakage of carbonyl groups in the imide ring takes place around 500 °C while benzene ring cleavage was barely found during the pyrolysis of polyimides [ 12 , 22 , 23 ]. It is also seen that weight loss is less than 50% up to 800 °C.
Figure 2. Thermogravimetric analysis of 6FDA-TFMB.
6FDA-TFMB was dissolved in NMP and electrospun to produce precursor nanofibers, and their surface image was shown in Figure 3 a. The fiber diameter of the 6FDA-TFMB nanofibers is in the range of 660 ± 40 nm. After the pyrolysis process of stabilization at 300 °C and carbonization at 800 °C, the nanofibrous structure successfully remains with a reduced diameter of 630 ± 30 nm, as shown in Figure 3 b.
Figure 3. Surface images of ( a ) electrospun and ( b ) carbonized 6FDA-TFMB nanofibers.
The microstructures of carbon derived from 6FDA-TFMB were investigated via Raman spectroscopy. In Figure 4 , two sharp peaks appear near 1595 and 1310 cm −1 , associated with E 2 g 2 graphitic crystallites (G-band) and structure defects and disordered carbon (D-band), respectively. It is also seen that the ratio of peak intensities, I D / I G is 1.8, indicating the conversion of 6FDA-TFMB to predominantly disordered carbon via pyrolysis with a typical degree of graphitization for carbon derived from precursor polymers.
Figure 4. Raman spectroscopy of carbon nanofibers (CNFs) derived from 6FDA-TFMB.
CNFs have been mainly produced via either catalytic chemical vapor deposition (CVD) growth or electrospinning followed by thermal treatment [ 24 , 25 ]. Compared to CVD grown ones, CNFs prepared via electrospinning have relatively high contents of amorphous carbon, which may cause lower electrical conductivity. Still, it is advantageous to use electrospun nanofibers for CNF synthesis since they can be readily fabricated, and they have large surface area and porosity.
When a voltage is applied in EDLCs, potential-driven accumulation of ions takes place to counterbalance the surface charge of electrodes, which is the double layers formed at the electrode/electrolyte interface [ 26 ]. Due to the energy storage mechanism of EDLCs, many research studies focus on improving the surface porosity of CNFs using sacrificial porogens [ 27 , 28 ].
The CNFs were steam-activated to achieve high surface properties, and the specific surface area and pore sizes were calculated using the Brunauer–Emmett–Teller (BET) method and density functional theory (DFT), respectively. Table 1 shows the summarized nitrogen sorption/desorption data, based on Figure 5 . The activated CNFs derived from 6FDA-TFMB show a high surface area of 2210 m 2 g −1 without using porogens. In addition, it is seen that 28% of the pores are meso-sized, which can facilitate the accessibility of electrolyte ions.
Figure 5. Nitrogen adsorption/desorption isotherms ( a ) and pore size distribution ( b ) of CNFs derived from 6FDA-TFMB.
Table 1. Surface properties of CNFs derived from 6FDA-TFMB.
6FDA-based polyimides show high thermal stability due to the benzene rings in their backbone and high flexibility due to the bulky fluorinated substituents, which is important for carbon precursors. Polymer chain flexibility is critical for carbon precursors as the high mobility of polymer chains is favorable for polymer chain rearrangement during the stabilization process, and high free volume can be translated to high porosity in carbon [ 17 , 18 , 19 ]. Previously, 6FDA-durene (2,3,5,6-tetramethyl-1,4-phenylenediamine) was employed as a single CNF precursor, and highly porous CNFs with a surface area of 1210 m 2 g −1 and pore volume of 0.580 cm 3 g −1 were successfully prepared [ 17 ]. 6FDA-TFMB exhibits a lower glass transition temperature (335 °C) as it contains four CF 3 – groups than 6FDA-durene (424 °C) containing two CF 3 – groups [ 29 , 30 ].
Additionally, Ohta et al. reported that carbon films prepared by carbonization of 6FDA-TFMB above 600 °C show higher surface area and pore volume than those from polyimides containing less CF 3 – groups as a result of the additional pore generation caused by the evolution of gaseous fluorine compounds such as CF 3 , CF, CH 2 F 2 and COF 2 [ 16 ]. Therefore, it can be concluded that high free volume and CF 3 – groups of 6FDA-TFMB enables the production of highly porous carbon.
For electrochemical testing, symmetric coin cells were assembled with two identical electrodes of activated CNFs and an aqueous electrolyte, KOH. EDLC performances were studied via CV and galvanostatic charge–discharge testing. The electrochemical properties of CNFs derived from 6FDA-TFMB and PAN are summarized in Table 2 .
Table 2. Electrochemical performances of CNF electrodes derived from 6FDA-TFMB and polyacrylonitrile (PAN).
In Figure 6 , CNF electrodes derived from 6FDA-TFMB show rectangular CVs without faradaic peaks with a high specific capacitance of 292.3 F g −1 at 10 mV s −1 . As the scan rate increases from 10 to 100 mV s −1 , the specific capacitance is decreased from 292.3 to 246.1 F g −1 due to the limited interaction between the electrolyte ions and the electrode surface.
Figure 6. Cyclic voltammograms (CVs) of CNF electrodes derived from 6FDA-TFMB.
To evaluate cycling stability, CVs were measured for 5000 cycles and the specific capacitance at 100 mV s −1 for every 100 cycles is shown in Figure 7 . CNF electrodes derived from 6FDA-TFMB exhibit a capacitance retention of 89.2% after 5000 cycles, which is comparable to those from PAN.
Figure 7. Cyclic performance of CNF electrodes derived from 6FDA-TFMB.
The energy and power densities in Table 2 were calculated from galvanostatic discharge times and ohmic drops in discharge curves over a discharge current density range of 0.5 to 5 A g −1 , as shown in Figure 8 . The activated CNFs derived from 6FDA-TFMB show a significantly higher energy density of 13.1 Wh kg −1 at 0.5 A g −1 than those from PAN due to the long discharge time resulting from high surface area and porosity.
Figure 8. Discharge curves of CNF electrodes derived from 6FDA-TFMB.
The breakdown voltage for supercapacitors is mainly determined by the type of electrolyte. For example, the maximum voltage for supercapacitors with aqueous electrolytes, such as KOH, in this study is 1.1 V. For electrode materials, the surface properties are critical to widen the operating of the electrolyte. CNF electrodes derived from 6FDA-TFMB exhibit high surface area and porosity, and cause low IR drops and high energy densities, as shown in Figure 8 .
Electrochemical properties of CNFs have been typically improved by adding pore-generating materials to precursor polymers such as PAN. Recently, poly(acrylic acid) (PAA), poly(ethylene glycol) (PEG), and poly(methyl methacrylate) (PMMA) have been utilized as porogens to produce porous CNFs, and energy storage performances were successfully improved compared to CNFs derived from PAN only [ 31 , 32 , 33 ]. Porous CNF electrodes derived from a single precursor such as 6FDA-durene were also reported [ 17 , 34 ]. The higher surface area and porosity of CNFs derived from 6FDA-TFMB result in higher electrochemical properties compared to those from 6FDA-durene.
The EIS measurement was carried out as shown in
Figure 9
. The intercept between the semicircle and the real axis in the high frequency region represents the sum of the resistance of the electrolyte, the intrinsic resistance of the electrode, and the interfacial resistance at electrode/current collectors. The charge-transfer resistance (Rct) of the electrodes, the half of the value of the real semicircle in the high frequency region, is 2.95 Ω cm
−1
, which is drastically lower than those from PAN (8.50 Ω cm
−1
). The resistance of electrode materials determines the size of the semicircle at high frequency while electrochemical double-layer formation at the electrode surface determines the slope of the plots at low frequency [
35
]. Highly porous CNF electrodes enable fast electrolyte ion accumulation and diffusion onto the electrode surface, resulting in low resistance. It also causes significantly higher energy storage performances compared to CNFs derived from PAN or other precursors.
Figure 9. Electrochemical impedance spectra (EIS) of CNF electrodes derived from CNF electrodes derived from 6FDA-TFMB.
Compared to PAN, the cost of 6FDA-TFMB might be high. However, PAN has high crystallinity caused by high interaction between nitrile groups, which causes poor processability, and PAN-based CNFs have low electrochemical performances for electrode materials. To solve this, copolymerization or blends of PAN have been used, which can increase the production cost and cause lower mechanical stability. Regarding the electrochemical performance, we have not found any drawbacks of using 6FDA-TFMB so far. We agree that more studies are required to determine the possible drawbacks of using 6FDA-TFMB as electrode materials for supercapacitors.
Recently, carbon composite electrodes using transition metal oxides or conducting polymers have been widely investigated to improve electrochemical properties such as energy density caused by pseudocapacitance [ 36 , 37 ]. It has been reported that pseudocapacitor electrodes were prepared by applying a surface coating of MnO 2 onto the CNFs, which resulted in high energy storage performances [ 38 , 39 ]. Additionally, CNF electrodes have been prepared by thermal treatment of PAN and polyvinylpyrrolidone (PVP) to increase nitrogen content for high electrochemical properties [ 40 , 41 ]. It seems reasonable that these strategies can be applied to CNFs derived from 6FDA-TFMB to obtain even better energy storage performances by providing highly porous carbon support.
4. Conclusions
Porous CNF electrodes were prepared by pyrolysis of 6FDA-TFMB without the addition of porogens due to four CF 3 – groups and high free volume of the precursor polymer. Successful conversion of 6FDA-TFMB to carbon was confirmed via Raman spectroscopy with an I D / I G of 1.8. Surface properties were further improved by activating CNFs with steam, and the resultant CNF electrodes exhibited a high surface area of 2210 m 2 g −1 and pore volume of 1.055 cm 3 g −1 with 28% of meso-sized pores. Symmetric coin cells were assembled with binder-free CNF electrodes and a specific capacitance of 292.3 F g −1 (at 10 mV s −1 ), maximum energy density of 13.1 Wh kg −1 (at 0.5 A g −1 ) and power density of 1.7 kW kg −1 (at 5 A g −1 ) were obtained, which is significantly higher than those from PAN. It can be concluded that the high surface area and porosity of CNFs derived from 6FDA-TFMB enables exceptional EDLC performance.
Author Contributions
K.-H.J. and S.W.L. designed the experiments, analyzed the data, and wrote the manuscript; B.J. and T.H. performed the fabrication and characterization of materials; D.Y.L. and M.-S.C. analyzed the data. All authors have read and agreed to the published version of the manuscript.
Funding
This research was funded by Basic Science Research Program of the National Research Foundation of Korea (NRF-2019R1H1A2079746) and Human Resources Program in Energy Technology (No. 20194010201760) of the Korea Institute of Energy Technology Evaluation and Planning (KETEP), Ministry of Trade, Industry and Energy, Republic of Korea.
Conflicts of Interest
The authors declare no conflict of interest.
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Figure 1. FTIR spectrum of synthesized 6FDA-TFMB.
Figure 2. Thermogravimetric analysis of 6FDA-TFMB.
Figure 3. Surface images of ( a ) electrospun and ( b ) carbonized 6FDA-TFMB nanofibers.
Figure 4. Raman spectroscopy of carbon nanofibers (CNFs) derived from 6FDA-TFMB.
Figure 5. Nitrogen adsorption/desorption isotherms ( a ) and pore size distribution ( b ) of CNFs derived from 6FDA-TFMB.
Figure 6. Cyclic voltammograms (CVs) of CNF electrodes derived from 6FDA-TFMB.
Figure 7. Cyclic performance of CNF electrodes derived from 6FDA-TFMB.
Figure 8. Discharge curves of CNF electrodes derived from 6FDA-TFMB.
Figure 9. Electrochemical impedance spectra (EIS) of CNF electrodes derived from CNF electrodes derived from 6FDA-TFMB.
Table 1. Surface properties of CNFs derived from 6FDA-TFMB.
1 SSA: specific surface area. 2 TPV: total pore volume. 3 V micro : micro-pore (<2 nm) volume. 4 V meso : meso-pore (2–50 nm) volume.
Table 2. Electrochemical performances of CNF electrodes derived from 6FDA-TFMB and polyacrylonitrile (PAN).
Precursor 6FDA-TFMB PAN Specific capacitance (F g −1 ) at 10 mV s −1 292.3 210.7 Energy density (Wh kg −1 ) at 0.5 A g −1 13.1 8.0 Power density (kW kg −1 ) at 5 A g −1 1.7 1.7
| https://www.mdpi.com/2073-4360/12/8/1851/htm |
Canada Gazette, Part 2, Volume 155, Number 14: Regulations Amending the Special Economic Measures (Belarus) Regulations
July 7, 2021, Part 2, Volume 155, Number 14, Canada Gazette
Regulations Amending the Special Economic Measures (Belarus) Regulations: SOR/2021-154
Canada Gazette, Part II, Volume 155, Number 14
RegistrationSOR/2021-154 June 17, 2021
SPECIAL ECONOMIC MEASURES ACT
P.C. 2021-610 June 17, 2021
Whereas the Administrator in Council is of the opinion that gross and systematic human rights violations have been committed in Belarus;
Therefore, His Excellency the Administrator of the Government of Canada in Council, on the recommendation of the Minister of Foreign Affairs, pursuant to subsections 4(1)
footnote a
, (1.1)
footnote b
, (2) and (3) of the
Special Economic Measures Act
footnote c
, makes the annexed
Regulations Amending the Special Economic Measures (Belarus) Regulations
.
Regulations Amending the Special Economic Measures (Belarus) Regulations
Amendments
1 The schedule to the Special Economic Measures (Belarus) Regulations footnote 1is amended by adding the following after the heading “Persons”:
PART 1
Individuals
2 The schedule to the Regulations is amended by adding the following after item 55:
56 Aleksey Oleksin
57 Aleksey Nikolayevich Avramenko
58 Leonid Nikolayevich Churo
59 Oleg Sergeyevich Gaidukevich
60 Igor Vladimirovich Golub
61 Andrey Nikolayevich Gurtsevich
62 Valeriy Valeryevich Ivankovich
63 Nikolay Nikolayevich Karpenkov
64 Viktor Gennadyevich Khrenin
65 Igor Vladimirovich Lutsky
66 Maxim Vladimirovich Ryzhenkov
67 Andrey Ivanovich Shved
68 Artem Igorevich Sikorsky
69 Nikolay Nikolayevich Vorobei
70 Aleksandr Vladimirovich Vasiliuk
71 Aleksandr Nikolayevich Zaitsev
72 Oleg Nikolayevich Belyakov
PART 2
Entities
1 Belaeronavigatsia Republican Unitary Air Navigation Services Enterprise
2 Belarusski Avtomobilnyi Zavod BelAZ (Belarusian Automobile Plant)
3 Bremino Group
4 Novaya Neftenaya Kompaniya (New Oil Company)
5 Minski Avtomobilnyi Zavod MAZ (Minsk Automobile Plant)
Application Before Publication
3 For the purpose of paragraph 11(2)(a) of the Statutory Instruments Act, these Regulations apply according to their terms before they are published in the Canada Gazette.
Coming into Force
4 These Regulations come into force on the day on which they are registered.
REGULATORY IMPACT ANALYSIS STATEMENT
( This statement is not part of the Regulations.)
Issues
In August 2020, following a fraudulent presidential election marred by significant irregularities, ensuing public protests in Belarus against the national government were brutally suppressed by government security forces resulting in gross and systematic human rights violations. Since then, the Belarusian authorities have continued to employ aggressive rhetoric towards the opposition, refused to engage in dialogue, and rejected calls for the holding of new presidential elections. Human rights violations continue and there has been no accountability for past or current violations. In recent months, actions targeting opposition voices and the media have become more brazen. On May 23, the Government of Belarus orchestrated the forced diversion of a civilian aircraft, Ryanair flight FR4978, flying from Athens, Greece, to Vilnius, Lithuania. The flight was ordered to land in Minsk under the pretext of a bomb threat. Upon landing, Belarusian journalist, Roman Protasevich, and his companion, Russian national Sofia Sapega, were arrested. Canada and its like-minded international partners have repeatedly condemned the actions of the Belarusian authorities and their treatment of opposition voices.
Background
On August 9, 2020, the Republic of Belarus held presidential elections marred by widespread irregularities. Under the direction of Alexander Lukashenko, the Government of Belarus led a systematic campaign of repression during the lead up to the vote and through the conduct of the election itself, and used state-sponsored violence against the people of Belarus in an effort to suppress anti-government protests. Human Rights Watch, Amnesty International, the Office of the United Nations Human Rights Commissioner, Viasna Human Rights Centre, along with the Organization for Security and Co-operation in Europe, all reported numerous human rights violations.
The Government of Belarus has continued to commit gross and systematic human rights violations. These include prolonged arbitrary detentions, brutality, intimidation, and the excessive use of force against peaceful protesters. Arbitrary arrests continue. In addition, there are undue restrictions on the rights to freedom of expression, peaceful assembly, and freedom of association. Human rights observers identified an escalation in the scale of repression against independent journalists in late 2020/early 2021, including arbitrary detention, the imposition of fines and prison sentences, loss of media credentials and police raids. A number of legislative measures have been taken to restrict civil rights, including labelling a broad range of activities as “extremist,” and removing accountability measures for security forces using violent means to silence protesters. There have been more than 35 000 detained since August 2020, and more than 377 political prisoners as of late May 2021.
On May 23, the Government of Belarus orchestrated an event that was a significant and dangerous escalation in its attacks on opposition voices. Ryanair flight 4978, flying between Athens, Greece, and Vilnius, Lithuania, was diverted to Minsk National Airport at the behest of the Belarusian aviation authorities. The diversion was requested on the premise of a possible bomb threat on board, which turned out to be unsubstantiated. Upon landing in Minsk, two passengers, Belarus journalist and activist Roman Protasevich and his Russian companion Sofia Sapega, were removed from the flight. A subsequent public appearance by Mr. Protasevich, during which he “confessed” to “organizing mass disorder” has led observers to believe he is being ill-treated in detention, and that his statements may have been coerced.
There is no indication that the Government of Belarus is genuinely committed to finding a negotiated solution with opposition groups, or in ensuring accountability for those responsible for gross and systematic human rights violations. Appropriate steps to restore democratic rights or to address ongoing human rights violations have also not been taken.
Canada has been strongly engaged in the situation in Belarus, directly with the Government of Belarus and with international partners, as well as in multilateral forums such as at the Organization for Security and Co-operation in Europe, Media Freedom Coalition and Freedom Online Coalition. On September 29, 2020, Canada, in coordination with the United Kingdom, announced sanctions against 11 Belarusian officials via the
Special Economic Measures (Belarus) Regulations
(the Regulations). On October 15, 2020, Canada, in coordination with the European Union, announced further sanctions against an additional 31 Belarusian officials via the Regulations. On November 6, additional sanctions were announced against another 13 Belarusian officials also in alignment with the European Union. To date, Canada has sanctioned 55 Belarusian officials under the
Special Economic Measures Act
.
The Regulations prohibit persons (individuals and entities) in Canada and Canadians outside Canada from conducting the following activities with listed individuals:
(a) deal in any property, wherever situated, that is owned, held or controlled by a listed person or by a person acting on behalf of a listed person;
(b) enter into or facilitate any transaction related to a dealing referred to in paragraph (a);
(c) provide any financial or related services in respect of a dealing referred to in paragraph (a);
(d) make available any goods, wherever situated, to a listed person or to a person acting on behalf of a listed person; or
(e) provide any financial or related services to or for the benefit of a listed person.
Consequential to being listed in the Regulations, and pursuant to the application of paragraph 35(1)(d) of the
Immigration and Refugee Protection Act
, the listed individuals are inadmissible to Canada.
The
Special Economic Measures (Belarus) Permit Authorization Order
(the Order) was also made to authorize the Minister of Foreign Affairs to issue to any individual or entity in Canada and any Canadian outside Canada a permit to carry out a specified activity or transaction, or any class of activity or transaction that is otherwise restricted or prohibited pursuant to the Regulations.
Objective
To put pressure on the Government of Belarus to change its behaviour;
To communicate a clear message to the Government of Belarus that Canada will not accept that gross and systematic human rights violations continue to take place at the hands of the State with impunity; and
To align with actions taken by our like-minded partners.
Description
The
Regulations Amending the Special Economic Measures (Belarus) Regulations
(the amendments) add 17 individuals and 5 entities to the schedule of the Regulations.
Regulatory development
Consultation
Global Affairs Canada engages regularly with relevant stakeholders including civil society organizations and cultural communities and other like-minded governments regarding Canada's approach to sanctions implementation.
With respect to the amendments, public consultation would not have been appropriate, as publicizing the names of the listed persons targeted by sanctions would have likely resulted in asset flight prior to the coming into force of the amendments.
Modern treaty obligations and Indigenous engagement and consultation
An initial assessment of the geographical scope of the initiative was conducted and did not identify any modern treaty obligations, as the amendments do not take effect in a modern treaty area.
Instrument choice
Regulations are the sole method to enact sanctions in Canada. No other instrument could be considered.
Regulatory analysis
Benefits and costs
Application of sanctions will serve to put pressure on the Government of Belarus to change its behaviour. The sanctions communicate a clear message that Canada will not accept that gross and systematic human rights violations continue to take place in Belarus at the hands of the State with impunity. As efforts to date have not convinced the Government of Belarus to accept accountability for human rights violations or to fully implement agreements stemming from the negotiation process with opposition groups, sanctions send an important message from Canada and encourage progress with the negotiations.
Canadian banks and financial institutions are required to comply with the sanctions. They will do so by adding the new prohibitions to their existing monitoring systems, which may result in a minor compliance cost.
The amendments will create additional compliance costs for businesses seeking permits that would authorize them to carry out specified activities or transactions that are otherwise prohibited. However, costs will likely be low, as it is unlikely that Canadian businesses have dealings with the newly listed persons.
Small business lens
As it is unlikely that Canadian businesses have dealings with the newly listed persons, no significant loss of opportunities for small businesses is expected as a result of the amendments.
To facilitate compliance by small businesses, Global Affairs Canada is in the process of conducting enhanced outreach with stakeholders to better inform them of changes to the Regulations. This includes updates to the sanctions website as well as the creation of the sanctions hotline. In addition, the Trade Commissioner Service is engaged in implementing Canada's Trade Diversification Strategy, which will support Canadian companies seeking to find alternative export markets.
One-for-one rule
The one-for-one rule does not apply to the amendments, as they do not impose an incremental administrative burden on businesses.
Regulatory cooperation and alignment
While the amendments are not related to a work plan or commitment under a formal regulatory cooperation forum, they align with actions taken by like-minded partners.
Strategic environmental assessment
The amendments are unlikely to result in important environmental effects. In accordance with the
Cabinet Directive on the Environmental Assessment of Policy, Plan and Program Proposals
, a preliminary scan concluded that a strategic environmental assessment is not required.
Gender-based analysis plus (GBA+)
The focus of the amendments is on specific individuals who are members of the Government of Belarus and/or persons engaged in activities that contribute to human rights violations in Belarus, rather than on Belarus as a whole. This results in minimizing collateral effects to people dependent on those individuals.
Exceptions are included in the Regulations, including, among others, to allow for the delivery of humanitarian assistance to provide some mitigation of the impact of sanctions on vulnerable groups. The Minister of Foreign Affairs can also issue permits pursuant to the Order. As such, these new sanctions are likely to have limited impact on the citizens of Belarus.
Implementation, compliance and enforcement, and service standards
Canada's sanctions regulations are enforced by the Royal Canadian Mounted Police and the Canada Border Services Agency. In accordance with section 8 of the
Special Economic Measures Act
, every person who willfully contravenes the
Special Economic Measures (Belarus) Regulations
is liable upon summary conviction to a fine of not more than $25,000 or to imprisonment for a term of not more than one year or to both, or upon conviction on indictment, to imprisonment for a term or not more than five years.
Contact
Alison Grant
Director
Eastern Europe and Eurasia Relations Division
Telephone: 343‑203‑3603
Email:
[email protected]
Footnotes
Footnote a
S.C. 2017, c. 21, s. 17(1)
Footnote b
S.C. 2017, c. 21, s. 17(2)
Footnote c
S.C. 1992, c. 17
Footnote 1
SOR/2020-214
| https://www.gazette.gc.ca/rp-pr/p2/2021/2021-07-07/html/sor-dors154-eng.html |
Biomolecules | Free Full-Text | The Antitumor Agent Ansamitocin P-3 Binds to Cell Division Protein FtsZ in Actinosynnema pretiosum
Ansamitocin P-3 (AP-3) is an important antitumor agent. The antitumor activity of AP-3 is a result of its affinity towards & beta;-tubulin in eukaryotic cells. In this study, in order to improve AP-3 production, the reason for severe growth inhibition of the AP-3 producing strain Actinosynnema pretiosum WXR-24 under high concentrations of exogenous AP-3 was investigated. The cell division protein FtsZ, which is the analogue of & beta;-tubulin in bacteria, was discovered to be the AP-3 target through structural comparison followed by a SPR biosensor assay. AP-3 was trapped into a less hydrophilic groove near the GTPase pocket on FtsZ by hydrogen bounding and hydrophobic interactions, as revealed by docking analysis. After overexpression of the APASM_5716 gene coding for FtsZ in WXR-30, the resistance to AP-3 was significantly improved. Moreover, AP-3 yield was increased from 250.66 mg/L to 327.37 mg/L. After increasing the concentration of supplemented yeast extract, the final yield of AP-3 reached 371.16 mg/L. In summary, we demonstrate that the cell division protein FtsZ is newly identified as the bacterial target of AP-3, and improving resistance is an effective strategy to enhance AP-3 production.
The Antitumor Agent Ansamitocin P-3 Binds to Cell Division Protein FtsZ in Actinosynnema pretiosum
by Xinran Wang 1,2 , Rufan Wang 1 , Qianjin Kang 1,2 and Linquan Bai 1,2,*
1
State Key Laboratory of Microbial Metabolism, School of Life Sciences & Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China
2
Joint International Research Laboratory of Metabolic & Developmental Sciences, Shanghai Jiao Tong University, Shanghai 200240, China
Author to whom correspondence should be addressed.
Biomolecules 2020 , 10 (5), 699; https://doi.org/10.3390/biom10050699
Received: 27 March 2020 / Revised: 25 April 2020 / Accepted: 28 April 2020 / Published: 30 April 2020
Abstract
Ansamitocin P-3 (AP-3) is an important antitumor agent. The antitumor activity of AP-3 is a result of its affinity towards β-tubulin in eukaryotic cells. In this study, in order to improve AP-3 production, the reason for severe growth inhibition of the AP-3 producing strain
Actinosynnema pretiosum
WXR-24 under high concentrations of exogenous AP-3 was investigated. The cell division protein FtsZ, which is the analogue of β-tubulin in bacteria, was discovered to be the AP-3 target through structural comparison followed by a SPR biosensor assay. AP-3 was trapped into a less hydrophilic groove near the GTPase pocket on FtsZ by hydrogen bounding and hydrophobic interactions, as revealed by docking analysis. After overexpression of the
APASM_5716
gene coding for FtsZ in WXR-30, the resistance to AP-3 was significantly improved. Moreover, AP-3 yield was increased from 250.66 mg/L to 327.37 mg/L. After increasing the concentration of supplemented yeast extract, the final yield of AP-3 reached 371.16 mg/L. In summary, we demonstrate that the cell division protein FtsZ is newly identified as the bacterial target of AP-3, and improving resistance is an effective strategy to enhance AP-3 production.
Keywords:
ansamitocin P-3
;
FtsZ
;
tubulin
;
toxicity
;
resistance
1. Introduction
Ansamitocin P-3 (AP-3) is an important antitumor agent with potent activity against various cancer cell lines [ 1 , 2 ]. Since 2012, AP-3 has been used as the ‘warhead’ molecule of the currently commercialized antibody-conjugated (ADC) drug trastuzumab emtansine (T-DM1) for the treatment of breast cancer [ 3 ]. T-DM1 is also under clinical trials for the treatment of HER2-positive lung cancer [ 4 ].
In eukaryotic cells, binding of AP-3 on β-tubulin inhibits microtubule assembly and chromosome segregation during the interphase and mitotic phase resulting in cell apoptosis [
5
]. AP-3 has a strong interaction with β-tubulin with a dissociation constant (
K
D
) of 1.3 ± 0.7 µM [
5
]. In a high-resolution crystal structure of tubulin in complex with maytansine, an AP-3 analogue [
6
], it was found that binding of maytansine interferes the interaction of longitudinal tubulin in microtubule assembly. The identified maytansine-binding site is distinct from the vinblastine-binding site, and is also shown as the common binding site of a rhizoxin variant and PM060184 [
6
].
Since tubulin is not present in bacterial cells, the intracellular targets of AP-3 in bacteria are still unknown. The cell division protein FtsZ has been shown to have similar function and architecture with tubulin [ 7 , 8 , 9 ]. Both FtsZ and tubulin work as cytoskeletons and form filaments with GTP hydrolysis [ 10 , 11 ]. Several compounds, such as curcumin, taxanes and plumbagin, are found to inhibit the function of tubulin as well as FtsZ [ 9 ]. Whether AP-3 is also an inhibitor of FtsZ remained to be studied.
As an important drug precursor, various strategies have been applied to improve AP-3 yield [ 12 , 13 , 14 , 15 , 16 , 17 ]. Previously in our lab, a high-yield AP-3 producing strain Actinosynnema pretiosum NXJ-24 was constructed by engineering the post-modification steps, which resulted in a 5-fold increase in AP-3 yield to 246 mg/L [ 14 ]. However, the AP-3 yield could not be further improved despite several attempts, suggesting a cell inhibition or toxicity effect caused by high concentrations of AP-3.
In this study, the cell toxicity of AP-3 against its producing strain was observed and investigated. The interaction of AP-3 with FtsZ was validated by SPR biosensor analysis, in vitro assembly assay and docking analysis. Further overexpression of FtsZ improved the resistance of the resulting strain and the yield of AP-3 as well.
2. Materials and Methods
2.1. Strains, Plasmids and Media
A. pretiosum
strains were cultured on YMG plates (0.4% yeast extract, 1% malt extract, 0.4% glucose and 1.5% agar). For fermentation, strains were initially cultured on YMG plates at 30 °C for 48 h and then inoculated into S1 medium (0.5% yeast extract, 3% tryptone soya broth and 10.3% sucrose) to grow at 30 °C, 220 rpm for 24 h. S1 culture was subsequently transferred at 3.3% (
v
/
v
) into S2 medium (0.8% yeast extract, 3% tryptone soya broth, 10.3% sucrose, isobutanol 500 μL/L and isopropanol 500 μL/L, pH 7.5) and cultivated for another 24 h. S2 was transferred at 10% (
v
/
v
) into the fermentation medium (1.6% yeast extract, 1% malt extract, 10.3% sucrose, isopropanol 12 mL/L, isobutanol 5 mL/L, MgCl
2
2 mM and L-valine 40 mM, pH 7.5) and cultivated at 25 °C, 220 rpm for 10 days. The composition of the optimized fermentation medium is: 2.4% yeast extract, 1% malt extract, 10.3% sucrose, isopropanol 12 mL/L, isobutanol 5 mL/L, MgCl
2
2 mM and L-valine 40 mM, pH 7.5. For
E. coli
strains, Luria-Bertani (LB) broth was used. The information of strains, plasmids and primers used in this study are listed in
Table S1
.
2.2. Growth Determination of Actinosynnema pretiosum Using Microplate Reader
Growth of A. pretiosum was determined using a microplate reader. During fermentation, 100 μL of culture was collected each day and mixed with 900 μL 10.3% sucrose. Then 50 μL of the mixture was transferred into a well of a 96-well plate. The fermentation medium without inoculation was used as a negative control. For each well, the absorbance was calculated by averaging the readings from 21 different positions of the well at 600 nm.
2.3. AP-3 Resistance Evaluation
Resistance evaluation on solid medium was performed with petri dishes (d = 3.5 cm). Before resistance evaluation, glycerol stocks of WXR-24 (high-yield AP-3 producer of
A. pretiosum)
and WXR-30 (
ftsZ
-overexpressing mutant of
A. pretiosum
) were diluted with 20% glycerol to have around 100 colony forming units (CFU) per 1 μL. For resistance evaluation, each Petri dish was filled with 4 mL YMG solid medium containing different concentrations of AP-3. Then 20 μL diluted stock of WXR-24 or WXR-30 were spread on the dishes. The dishes were incubated at 30 °C for 72 h and taken out for pictures and colony counting.
To evaluate strain resistance in liquid medium, WXR-24 and WXR-30 were initially cultivated on YMG plates for two days, followed by consecutive cultivation in S1 and S2 media. Then 150 μL of S2 was transferred into a well of 24-deep-well plate, in which 1.5 mL fermentation medium containing different concentrations of AP-3 was added. For growth comparison of WXR-24 and WXR-30, the S2 cultures of the two strains were diluted to obtain similar CFUs before inoculation. Strain resistance was evaluated by growth determination from day 1 to day 5 using a microplate reader.
For AP-3 supplementation, AP-3 was dissolved in DMSO, and the solution was added to the solid or liquid media before inoculation. Media supplied with same amount of DMSO was used as a control. The final concentration of DMSO was 1.5% (
v
/
v
).
2.4. Colony Counting and Average Colony Size
The numbers of colonies (CFU) were counted by the scientific image analysis software IMAGE J 1.52a (NIH, Bethesda, MD, USA). For each Petri dish, the 2-mm edge was removed to avoid light interruption. For average colony size analysis, particles with sizes from 5 to 500 pixel 2 were considered to obtain an average colony size (pixel 2 ) of each dish, with SD. The true colony size was calculated by converting the pixel 2 into the actual size with a ratio of pixel-to-mm, obtained from the ‘scale’ function.
2.5. Homologous Modeling and Structure Comparison
The 3D structure of FtsZ in A. pretiosum NXJ-24 was built according to the structure of Mycobacterium tuberculosis (Protein Data Bank (PDB) entry 5v68) by homologous modeling with Discovery Studio 3.5 (Accelrys, San Diego, CA, USA). The structure of β-tubulin was obtained from Protein Data Bank (PDB) entry 4TV8, chain D. The structures of FtsZ and β-tubulin were compared using the FATCAT server [ 18 ]. A flexible alignment model was chosen for structure comparison.
2.6. Protein Expression and Purification
Gene
APASM_5716
, coding for the cell division protein FtsZ in
A. pretiosum
WXR-24, was amplified by PCR using primers 5716-28a-FP and 5716-28a-RP (
Table S1
), sequenced and inserted into the
Nde
I/
Eco
RI sites of the vector pET28a. The resulted plasmid was introduced into
E. coli
BL21(DE3) for protein expression. The resulting strain was cultivated at 37 °C to OD
600nm
of 0.6–0.8, then induced with 0.1 mM IPTG and cultivated at 30 °C for another 12 h. Cells were then harvested by centrifugation and re-suspended in 10 mM PBS (pH 7.5). After sonication, cell debris were removed by centrifugation at 11,000 rpm for 30 min on a Thermo Sorvall ST 16R centrifuge (ThermoFisher, Waltham, MA, USA). FtsZ was purified by nickel-NTA affinity chromatography after elution with PBS containing 50 mM–250 mM imidazole. The 250 mM imidazole eluent was ultra-filtrated into a volume of 500 μL, and then 10 mL corresponding buffer for the following assays was added, followed by ultra-filtration again into 500 μL. For SPR molecule interaction determination, the eluent after nickel-NTA purification was ultra-filtrated and directly injected into fast protein liquid chromatography (FPLC) equipped with a Superdex 200 gel filtration column (GE Healthcare Life Sciences, Marlborough, MA, USA) for further purification [
19
]. The purified proteins were used for analysis or stored at −80 °C for future use.
2.7. Surface Plasmon Resonance (SPR) Biosensor Analysis
The interaction and dissociation constants between FtsZ and AP-3 were determined by surface plasmon resonance biosensor analysis using Biacore TM 8K biosensor (GE Healthcare) at 25 °C. For molecule interaction determination, the purified FtsZ was bound to the Series S sensor chip CM5. In detail, 20 μg/mL FtsZ in 10 mM NaAc (pH 4.0) was coupled to the CM5 chip at 6000 RU, then AP-3 solutions of 0–100 μM were flew through the chip, and signal responses were recorded. The signal of solution without AP-3 was used as a blank control, and the value was subtracted from other values during data processing.
2.8. Light Scattering and GTPase Activity Assays
In vitro assembly of FtsZ was monitored on a F-7000 fluorescence spectrometer (Hitachi, Tokyo, Japan). Purified FtsZ was ultra-filtrated into J buffer (50 mM KCl, 50 mM MES, pH 6.5, 10 mM CaCl 2 , 5 mM MgCl 2 ). 15 μM FtsZ was used for light scattering assay. The reaction was performed at room temperature and initiated upon the addition of 1 mM GTP. The emission and excitation wavelengths were set at 350 nm, and the slit width was 5 nm. Scatter signals were recorded every 2 min.
GTPase activity was determined using Malachite Green Phosphate Assay Kit (BioAssay Systems, Hayward, CA, USA) following the manufacturer’s instructions. To test if the supplementation of AP-3 affected FtsZ assembly and GTPase activity, 500 μM AP-3 was used, and same amount of DMSO was added as control.
2.9. Gene Overexpression
APASM_5716 was amplified by PCR using primers 5716-646-FP and 5716-646-RP ( Table S1 ) and inserted into the Nde I/ Eco RI sites of a pSET152-derived shuttle vector pLQ646 using Multi One Step Cloning Kit (Yeasen, Shanghai, China) ( Figure S1 ) [ 20 ]. The resulted plasmid was sequenced and transformed to E. coli ET12567(pUZ8002) [ 19 ]. Then it was introduced into A. pretiosum WXR-24 by conjugation according to protocol described elsewhere [ 21 ].
2.10. AP-3 Yield Determination
For yield determination, two volumes of methanol was added to the final culture after fermentation. The mixture was sonicated for 30 min. Then 1 mL of the mixture was collected and centrifuged, and the supernatant was filtered through a 0.22-μm filter and subjected to HPLC analysis. The yields of AP-3 were analyzed according to the standard curve ( Figure S2 ).
For HPLC determination, samples were analyzed on an Agilent series 1260 HPLC system (Agilent Technologies, Santa Clara, CA, USA) equipped with an Agilent Eclipse Plus C 18 column (4.6 × 250 mm, 5 µm), eluted with 45% A (H 2 O with 0.5% formic acid):55% B (acetonitrile) for 10 min and detected at 254 nm.
2.11. Docking Analysis
Molecule docking was performed using Discovery Studio 3.5 (Accelrys). AP-3 structure was obtained by modification of a maytansine structure from the co-structure of tubulin and maytansine from PDB entry 4TV8. Before docking, the ligands were prepared using the “prepare ligand” module. The ligands were primarily positioned in the binding site using LibDock, which is a high-throughput docking algorithm that positions catalyst-generated ligand conformations in the protein active site based on polar interaction sites (hotspots) [
22
]. Other algorithms such as GOLD and CDOCKER generated random conformations using CHARMm-based molecular dynamics. FtsZ was enclosed in a sphere grid with a radius of 15 Å. The Lamarckian genetic algorithm was used. Total of 15 runs were performed, and 32 output conformations were obtained. A cutoff RMSD of 2.14 Å was employed to cluster all conformations, and clusters having lowest docking energy were considered. The residues in the interphase of two FtsZ monomers were identified by sequence alignment with the model of
Methanocaldococcus jannaschii
(PDB number 1w5a).
2.12. Microscopy Analysis
The morphology of mycelia was observed using a Revolve-100-G microscope (ECHO, San Diego, CA, USA). For sampling, 1 mL culture of WXR-24 or WXR-30 was collected, washed twice and resuspended in 10 mM PBS (pH 7.5). Ten μL of the mycelial suspension was mixed with 50 μL H 2 O on a standard glass slide (25 × 75 mm). After immobilization, the sample was dyed with crystal violet staining solution. The images were captured using digital camera with 20- or 60-fold magnification under the optical microscope mode.
2.13. qRT-PCR Analysis
RNA was extracted with the Redzol reagent (SBS Genetech, Beijing, China) and converted to cDNA using the RevertAid TM H Minus First Strand cDNA Synthesis Kit (ThermoFisher), according to the manufacture’s instruction. RT-PCR was performed on a QuantStudio TM 3 Real-Time PCR Instrument (Applied Biosystems, Carlsbad, CA, USA) using TB Green Premix Ex Taq TM GC enzyme (Takara, Shiga, Japan). The gene transcription was calculated using 2 - △△ CT method, and the sigma factor gene hrdB was set as the internal control.
3. Results
3.1. Growth Inhibition of Actinosynnema pretiosum WXR-24 Under Exogenous AP-3 Supplementation
The previously constructed high-yield strain NXJ-24 has an integrated copy of the pSET152-based plasmid (pLQ586) in the genome [ 14 ]. For stable fermentation and convenience of further engineering, an alternative strain WXR-24 was constructed by introducing the overexpressing cassette ( kasOp*-asm10 ) from pLQ586 to the chromosome by double crossover recombination ( Table S1 ). To test whether WXR-24 has the potential to be a high-yield AP-3 producer, its tolerance to high concentrations of AP-3 was evaluated. The growth of WXR-24 was determined on YMG plates containing 0, 100, 200, 300 and 400 mg/L AP-3. After 3 days, no decrease in survival rate was observed under supplementation of 100 mg/L AP-3. However, when the AP-3 concentration increased to 200 mg/L, the survival rate decreased to 72%. No growth occurred on plates with 300 mg/L and 400 mg/L AP-3 ( Figure 1 a,b and Table S2 ). After 16 days of incubation, slow growth was observed on plates containing 300 mg/L and 400 mg/L AP-3, with 150 and 11 CFUs, respectively ( Figure S3 ). In addition, the average colony size of WXR-24 decreased 38.4% with supplementation of 100 mg/L AP-3, and a further decrease of 66.0% was observed with 200 mg/L AP-3 ( Table S3 ), suggesting growth inhibition of WXR-24 by AP-3 on YMG plates.
Figure 1.
Resistance and growth of
A. pretiosum
WXR-24 under different concentrations of AP-3. (
a
) Growth of
A. pretiosum
WXR-24 on YMG plates containing 0, 100, 200, 300 or 400 mg/L AP-3. The photos were taken on day 3 after inoculation. (
b
) Survive rate (%) of WXR-24 on YMG plates containing 0, 100, 200, 300 or 400 mg/L AP-3. The survive rate of the plates supplemented without AP-3 was set as 100%, and the values on other plates were accordingly calculated. Mean values of three independent experiments are shown with SD indicated by error bars. (
c
) Growth of
A. pretiosum
WXR-24 in fermentation broths containing 0, 100, 200, 300 or 400 mg/L AP-3. Mean values of three independent experiments are shown with SD indicated by error bars. (
d
) The cultures of
A. pretiosum
WXR-24 on day 5 after inoculation. Less mycelia are observed in fermentation broths containing 200–400 mg/L AP-3.
Cell growth in liquid medium was also studied. In the medium without AP-3 supplementation, OD 600 of WXR-24 increased rapidly from 0.05 to 0.25 during cultivation. While the initial OD 600 was unchanged, the final OD 600 decreased from 0.25 to 0.22, 0.20, 0.11 and 0.08 in media supplemented with 100, 200, 300 and 400 mg/L AP-3, respectively ( Figure 1 c,d). These results indicate that the growth of WXR-24 is also inhibited in liquid culture by AP-3 supplementation.
3.2. Cell Division Protein FtsZ is Predicted as a Target of AP-3
Since the growth of WXR-24 was inhibited by AP-3 supplementation, in order to understand the mechanism, it is necessary to identify the intracellular targets of AP-3. In eukaryotic cells, AP-3 binds to β-tubulin and consequently inhibits microtubule assembly and cell division [ 7 ]. Because tubulins are not present in A. pretiosum , it was therefore inferred that FtsZ, as a structural homolog to tubulin [ 23 ], is likely to be the intracellular target of AP-3. To confirm the hypothesis above, the two structures were compared.
The structure of FtsZ in WXR-24 was simulated by homologous modeling based on the structure of FtsZ from Mycobacterium tuberculosis (Protein Data Bank (PDB) entry 5v68). The structure of β-tubulin was obtained from the maytansine-tubulin complex (PDB entry 4TV8, chain D). Both proteins consist of twelve α-helices spaced by ten β-sheets. The N-terminal and C-terminal domains of the two proteins are divided by the featured α-helix 7 located horizontally in the middle of the proteins ( Figure 2 a,b).
Figure 2.
Structure comparison of FtsZ and β-tubulin. (
a
) The architecture of FtsZ from
A. pretiosum
WXR-24, built by homologous modeling. The featured α-helix 7 is labeled in red, connecting the yellow-labeled N-terminal domain and orange-labeled C-terminal domain. (
b
) The architecture of β-tubulin from
Bos taurus
retrieved from PDB database. The featured α-helix 7 is labeled in red, connecting the yellow-labeled N-terminal domain and orange-labeled C-terminal domain. (
c
) The graph of flexible structure alignment of FtsZ and β-tubulin. Three large structurally conserved blocks are shown in red, yellow or pink, and 2 twists are indicated by black arrows. (
d
) Sequence-based structural alignment of FtsZ and β-tubulin. FtsZ is highlighted in grey, and structurally conserved blocks in β-tubulin are highlighted in red, yellow or pink. The key amino acids of β-tubulin interacting with maytansine are indicated by red dots. (
e
) Superposition of the 3D structures of FtsZ and β-tubulin. FtsZ is colored in grey, and structurally conserved blocks in β-tubulin are in red, yellow or pink. The GDP-binding pockets of FtsZ and β-tubulin are labeled in blue, and the maytansine-binding pocket on β-tubulin is labeled in orange. May, maytansine.
These two structures were further compared according to the flexible structure alignment algorithm [ 18 ]. The result showed that they are significantly similar with a p -value of 2.56 × 10 −7 (raw score is 483.77). The two structures have 333 equivalent positions with an RMSD of 3.02, and 2 positions could not be completely aligned. Three large conserved blocks made up of the 333 equivalent positions are formed (colored in red, yellow or pink), which are separated by the two non-homologous positions ( Figure 2 c). In detail, structures from S1 to S10 (red, corresponding to amino acid residues 31–331 of FtsZ and 1–381 of β-tubulin), H11 (yellow, residues 347–357 of FtsZ and 382–400 of β-tubulin) and H12 (pink, residues 401–420 of FtsZ and 415–438 of β-tubulin) are highly similar between the two proteins, but structure between S10 and H11 and that between H11 and H12 could not be aligned ( Figure 2 d,e). In the superposition of FtsZ and β-tubulin, GDP pockets are located in similar positions of the two proteins ( Figure 2 e). Although most key amino acid residues in β-tubulin interacting with maytansine are absent in FtsZ ( Figure 2 d), similar structure of the maytansine-binding pocket still exists in FtsZ ( Figure 2 e). Based on these comparison, FtsZ was considered to be the intracellular target of AP-3.
3.3. In Vitro Interaction of FtsZ and AP-3
To test if AP-3 could bind to FtsZ, FtsZ protein from
A. pretiosum
WXR-24 was heterologously expressed in
E. coli
and purified. The interaction of FtsZ with AP-3 was determined by surface plasmon resonance (SPR) biosensor analysis. Before analysis, 6000 RU of FtsZ was immobilized on a CM5 chip, then AP-3 solutions with concentrations of 6.25, 12.5, 25, 50 and 100 μM successively flew over the FtsZ conjugated surface. The injection of 6.25–100 μM AP-3 induced a gradually increased response of the FtsZ-bound surface, indicating a stable binding between FtsZ and AP-3 (
Figure 3
a). The binding ratio of FtsZ and AP-3 was 1:1, and the association rate and dissociation rate constants
K
a and
Kd
were 2.36 × 10
3
M
−1
s
−1
and 0.794 s
-1
, respectively. The equilibrium dissociation constant
K
D
was 3.36 × 10
-4
M (
Table S4
). Since the
K
D
of AP-3 and β-tubulin is 1.3 ± 0.7 × 10
-6
M [
5
], the binding of AP-3 to FtsZ was thought to be much weaker than the binding of AP-3 to β-tubulin.
Figure 3. The in vitro interaction of FtsZ with AP-3. ( a ) The interaction of FtsZ with AP-3, determined by Biacore biosensor assay. 6.25, 12.5, 25, 50 or 100 μM AP-3 flowed over a CM5 chip pre-immobilized with FtsZ. The response signals were recorded. ( b ) The inhibition of FtsZ assembly by the supplementation of AP-3, as detected by the real-time light scattering assay. Fluorescence signals of the reactions with (red line) or without (black line) 500 μM AP-3 were recorded every 2 min. ( c ) The impact of AP-3 (500 μM) on the GTPase activity of FtsZ, as detected by the Malachite Green Phosphate Assay Kit. Black line, without AP-3; Red line, with AP-3.
To study whether the supplementation of AP-3 affects FtsZ assembly, light scattering experiment was performed to monitor the real-time FtsZ assembly process. The supplementation of AP-3 had an obvious negative impact on in vitro FtsZ assembly ( Figure 3 b). GTPase activity of FtsZ was also studied under AP-3 supplementation. The GTPase activity of FtsZ was slightly decreased upon AP-3 addition ( Figure 3 c), suggesting that FtsZ assembly is inhibited by AP-3 binding in a GTPase-independent manner.
3.4. Docking Analysis of AP-3 on FtsZ
Since AP-3 was confirmed to bind to FtsZ and inhibit FtsZ assembly, it is necessary to explore the interaction between AP-3 and FtsZ at the molecular level. For this purpose, docking analysis was performed around the putative maytansine-binding structure on FtsZ obtained from the structure comparison in Section 3.2 . Fifteen independent runs were performed, generating 32 output conformations. Simulated conformation with the lowest energy of -19.47 kcal/mol was selected.
AP-3 binding site is located near the N-terminal of α-helix 3, α-helix 4 and α-helix 5, and not far from the GDP pocket (
Figure 4
a). As shown in
Figure 4
b, the AP-3 binding site is at the edge of the junction region between two FtsZ monomers, which explains the inhibition of FtsZ assembly by AP-3 supplementation and the unaffected GTPase activity of FtsZ. Whereas the surface of FtsZ is highly hydrophilic, the AP-3 binding pocket is comprised of less hydrophilic amino acids (
Figure 4
c). The macrolactam ring of AP-3 is inserted into the hydrophobic pocket, and key amino acid residues of FtsZ interacting with AP-3 are identified as Pro92, His96, Gly129, Gln169 and Asn173. In detail, the carbinolamide ring of AP-3 is attached to the amine groups of Gln169 and Asn173 with hydrogen bonds, and the nearby oxygen atom on C-10 of AP-3 forms hydrogen bond with the amine group on His96. The other side of the macrolactam ring attaches to the pocket via hydrophobic interactions between the carbon skeleton of C14-C15 and Pro92 and Gly129 (
Figure 4
d).
Figure 4.
Interaction of FtsZ and AP-3 revealed by docking analysis. (
a
) The binding site of AP-3 on FtsZ is apart from the GDP binding site, from side view. The surface of FtsZ is displayed by hydrophobicity. Orange and blue indicate high and low hydrophobicity, respectively. The junction interphase between two FtsZ monomers is colored in green. (
b
) The binding site of AP-3 on FtsZ, from top view. (
c
) Close-up view of the AP-3 binding groove on FtsZ. The colors on the groove indicate that this part is more hydrophobic than the surrounding area. (
d
) The key amino acid residues interacting with AP-3. The interactions between key amino acids and AP-3 are displayed by dashed lines. Red dashed lines represent hydrogen bonds, and grey dashed lines represent hydrophobic interactions. The bond lengths (Å) are indicated by the numbers beside the dotted lines.
3.5. Introducing an Extra Copy of ftsZ Improved AP-3 Resistance and Production
Since FtsZ was identified as the target of AP-3, we hypothesized that its overexpression might be able to alleviate the toxicity of AP-3 to the growth of WXR-24. To test this,
APASM_5716
, coding for FtsZ in
A. pretiosum
, was overexpressed under the strong promoter
kasOp*
on the integrative plasmid pLQ646 (
Figure S1
). The resulting plasmid pLQ1913 was introduced into WXR-24 by conjugation, and the resulting strain was named as WXR-30. The transcriptional level of
ftsZ
had a 202% increase in WXR-30 (
Figure S4
). As shown in
Figure S5
, WXR-30 exhibited superior growth than WXR-24 during cultivation. Microscopic observation showed that, with the overexpression of
ftsZ
, the mycelial morphology of
A. pretiosum
was changed, the branches became shorter and the long hyphae intertwined with each other to form clumps (
Figure S6
).
The resistance of WXR-30 was evaluated after 3 days of incubation, and the cell survive rate was 100% under supplementation of 100 mg/L AP-3. (
Figure 5
a,b and
Table S2
). With supplemented 200 mg/L AP-3, the survive rate of WXR-30 showed a slight decrease to 95%, which was obviously higher than that of WXR-24 under the same conditions (72%). Moreover, 14 and 8 colonies appeared on plates supplemented with 300 mg/L and 400 mg/L AP-3, respectively. After 16-day incubation, 1080 and 1302 colonies appeared on plates supplemented with 300 mg/L and 400 mg/L AP-3, respectively (
Figure S3
), which was 7-fold and 118-fold those of WXR-24 under the same conditions. In addition, the average colony sizes of WXR-30 decreased by 31% and 38% when supplemented with 100 and 200 mg/L of AP-3, respectively (
Table S3
), substantially lower than those of WXR-24 (38% and 66%), suggesting a better growth of WXR-30 under AP-3 supplementation conditions.
Figure 5.
Effects of FtsZ overexpression on the resistance, growth and AP-3 yield of
A. pretiosum
WXR-30. (
a
) Growth of WXR-30 on YMG plates containing 0, 100, 200, 300 or 400 mg/L AP-3. The photos were taken on day 3 after inoculation. (
b
) Survive rate (%) of WXR-24 and WXR-30 on YMG plates containing 0, 100, 200, 300 or 400 mg/L AP-3. The survive rate on the plates supplemented without AP-3 was set as 100%, and the survive rates on other plates were accordingly calculated. Mean values of three independent experiments are shown with SD indicated by error bars. (
c
) Growth of
A. pretiosum
WXR-24 and WXR-30 in the fermentation broth containing 300 mg/L AP-3. Mean values of three independent experiments with SD are indicated by error bars. (
d
) AP-3 yields of WXR-24 and WXR-30 cultivated with 16 g/L yeast extract, and WXR-30 cultivated with 24 g/L yeast extract. Mean values of three independent experiments with SD are indicated by error bars. ***
p
< 0.001.
Cell growth of WXR-30 in liquid medium was also studied. The initial OD 600 of WXR-24 and WXR-30 were both 0.05. Whereas the final OD 600 of WXR-24 was 0.11, the final OD 600 of WXR-30 reached 0.21, showing a significantly improved growth of WXR-30 in liquid culture ( Figure 5 c).
The effect of FtsZ overexpression on AP-3 production was also evaluated with WXR-30. Compared with the starting strain WXR-24, the yield of AP-3 for WXR-30 was increased by 31%, from 250.66 mg/L to 327.37 mg/L ( Figure 5 d). In addition, the concentrations of supplemented yeast extract were optimized with WXR-30. When 24 g/L yeast extract was used in the fermentation medium, the AP-3 yield of WXR-30 was further improved to 371.16 mg/L ( Figure 5 d and Figure S7 ), i.e., 48% higher than that of WXR-24.
4. Discussion
In this study, FtsZ was identified as the intracellular target of AP-3 in A. pretiosum. It was initially believed that AP-3 is not toxic to bacteria, because tubulin does not exist in bacteria. However, since the bacterial cell division protein FtsZ was reported to have a similar structure to tubulin, it was inferred that FtsZ might be a target of AP-3 [ 7 , 8 , 9 ]. In this study, structures of FtsZ from A. pretiosum and β-tubulin from Bos taurus were compared and shown to be structurally similar to each other [ 18 ]. In a subsequent in vitro interaction test, it was validated that AP-3 could bind to FtsZ and inhibit FtsZ assembly. This is the first time that the bacterial target of AP-3 has been identified. Our further experiments found that AP-3 could also inhibit the assembly of FtsZ from Bacillus subtilis and Streptomyces coelicolor ( Figure S8 ), indicating that the inhibition of AP-3 on FtsZ is not limited in Actinosynnema but broadly applicable among bacteria.
Some antitumor antibiotics also showed cell toxicities towards their bacterial producers [ 24 , 25 , 26 ]. During the production of antitumor tiancimycin A, for example, its accumulation was extremely toxic to its producer Streptomyces sp. CB03234, and the yield was only 0.2 mg/L [ 27 ]. In this study, it was observed that exogenous AP-3 at a concentration higher than 300 mg/L caused severe inhibition on the growth of WXR-24 ( Figure 1 c and Table S2 ). Improving strain resistance has been widely used to enhance the yields of various antibiotics, such as oxytetracycline [ 28 ], doxorubicin [ 29 ], rimocidin [ 30 ], daptomycin [ 31 ] and toyocamycin [ 32 ]. However, these strategies mainly focus on overexpressing efflux genes or engineering resistance genes. As another option, overexpressing the drug targets has also been long used to alleviate cell toxicities and improve resistance [ 33 ]. For example, the overexpression of embAB genes, coding for the targets of the antimycobacterial compound ethambutol (Emb), resulted in Emb resistance [ 34 ]. The overexpression of FDP synthase, target of aminobisphosphonate (aBP) drugs, improved resistance of aBP drugs in Dictyostelium amoebas [ 35 ]. In our study, overexpression of the AP-3 target FtsZ improved both strain resistance and AP-3 production, showing again that the overexpression of target proteins is an effective way to enhance antibiotic production.
FtsZ plays a fundamental role in cell division of bacteria. Before cell division, a ring-like structure is formed in the middle of the dividing cell by FtsZ polymerization, which then recruits other related proteins to start the dividing program [ 9 ]. Increased expression of ftsZ often results in change of cell morphology. For example, in B. subtilis and E. coli , ftsZ overexpression will cause asymmetric cell division [ 36 , 37 ], while in C. glutamicum an increase in cell diameter is observed [ 38 ]. Improved expression of ftsZ in S. coelicolor and S. lividans inhibited aerial mycelia and spore formation, and antibiotic production was increased [ 39 ]. In our study, it was found the length of the branching hyphae in the ftsZ -overexpressing mutant WXR-30 was much shorter than the control strain ( Figure S6 ). The result is in accordance with the work in S. venezuelae , in which highly branched mycelia were found in the ftsZ mutant [ 40 ]. The relationship between mycelial morphology and AP-3 resistance or production needs further investigation.
The cell toxicity of AP-3 on its producer
A. pretiosum
was less pronounced than on eukaryotic cells. In fact, the IC
50
of AP-3 on MCF-7 cells is 20 ± 3 pmol/L, which is much lower than that on
A. pretiosum
(315.0–472.4 μmol/L). The binding force of AP-3 with FtsZ (
K
D
= 3.36 × 10
−4
M) (
Table S4
) is also obviously weaker than that with β-tubulin (
K
D
= 1.3 × 10
−6
M). As shown in
Figure 4
d, three hydrogen bonds are formed between AP-3 and Gly129, Asn173 and Gln169 on FtsZ, with bond lengths of 3.1, 5.9 and 3.9 Å, respectively. In comparison, five hydrogen bonds are formed between maytansine and Gly100, Asn102, Lys105, Asn101 and Val181 on β-tubulin, with bond lengths of 3.1, 3.2, 2.5, 3.3 and 2.9 Å, respectively. As hydrogen bonding is relatively strong among intermolecular interactions [
41
], the interaction between AP-3 and β-tubulin is therefore much stronger than that with FtsZ, which explains the toxicity of AP-3 towards
A. pretiosum
only at high concentrations.
Although the resistance of WXR-30 was substantially improved ( Figure 4 a), the strain was still sensitive to 300 mg/L and 400 mg/L AP-3, which implies that FtsZ overexpression could not fully confer resistance to AP-3. From our docking analysis, five key amino acid residues, namely Pro92, His96, Gly129, Gln169 and Asn173, were proposed to interact with AP-3 ( Figure 4 d). Therefore, these key residues, especially Gly129, Gln169 and Asn173 forming hydrogen bonds with AP-3, will be considered for future mutagenesis to further alleviate or even abolish the interactions and consequent cell toxicity.
5. Conclusions
AP-3 toxicity was found to be a rate-limiting factor for high AP-3 production in A. pretiosum WXR-24. For the first time, FtsZ was identified as the target of AP-3 in bacteria. Over-expression of the FtsZ coding gene resulted in AP-3 resistance and overproduction. Our study suggests that toxicity is one of crucial factors limiting antibiotic production, especially in high-yield industrial strains, and resistance improvement is an effective way to further enhance antibiotic yields.
Supplementary Materials
The following information are available online at
https://www.mdpi.com/2218-273X/10/5/699/s1
. Table S1: Strains, plasmids and primers used in this study; Table S2: CFUs and cell survive rates (%) of WXR-24 and WXR-30 on YMG plates containing different concentrations of AP-3; Table S3: Average colony sizes (× 10
−2
mm
2
) of WXR-24 and WXR-30 on YMG plates containing different concentrations of AP-3; Table S4: Binding constants of FtsZ with AP-3; Figure S1: Schematic representation of
APASM_5716
overexpression; Figure S2: HPLC standard curve of AP-3; Figure S3: Growth of
A. pretiosum
WXR-24 (a) and WXR-30 (b) on YMG plates containing 300 mg/L or 400 mg/L AP-3. The photos were taken on day 16 after inoculation; Figure S4: Transcription level of
ftsZ
in WXR-24 and WXR-30; Figure S5: Growth of
A. pretiosum
WXR-24 and WXR-30 in the fermentation broth; Figure S6: Mycelial morphology of WXR-24 (a and c) and WXR-30 (b and d) on the first day of fermentation, observed by optical microscope under 20x objective (a and b) and 60x objective lenses (c and d); Figure S7: AP-3 yields of WXR-30 in fermentation media supplemented with 16 g/L, 24 g/L or 32 g/L yeast extract; Figure S8: The inhibition of FtsZ assembly by AP-3 with FtsZ from
Streptomyces coelicolor
(a) and
Bacillus subtilis
(b).
Author Contributions
L.B. and Q.K. designed and supervised the experiments, and contributed to the funding. X.W. and R.W. conducted experiments, collected data, and performed data analysis. X.W., R.W., and L.B. drafted the manuscript and contributed to data interpretation. All authors have read and agreed to the published version of the manuscript
Funding
X.R.W. was funded by National Natural Science Foundation of China (31800023), and L.B. was funded by National Key R&D Program of China (2019YFA0905400) and National Natural Science Foundation of China (31830104, 21661140002).
Acknowledgments
We are grateful to Yu Tang and the Instrumental Analysis Centre of Shanghai Jiao Tong University, for the Biacore TM 8K biosensor analysis. We thank Prof. Tao Dong for revising the manuscript.
Conflicts of Interest
The authors declare no conflict of interest.
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Figure 1. Resistance and growth of A. pretiosum WXR-24 under different concentrations of AP-3. ( a ) Growth of A. pretiosum WXR-24 on YMG plates containing 0, 100, 200, 300 or 400 mg/L AP-3. The photos were taken on day 3 after inoculation. ( b ) Survive rate (%) of WXR-24 on YMG plates containing 0, 100, 200, 300 or 400 mg/L AP-3. The survive rate of the plates supplemented without AP-3 was set as 100%, and the values on other plates were accordingly calculated. Mean values of three independent experiments are shown with SD indicated by error bars. ( c ) Growth of A. pretiosum WXR-24 in fermentation broths containing 0, 100, 200, 300 or 400 mg/L AP-3. Mean values of three independent experiments are shown with SD indicated by error bars. ( d ) The cultures of A. pretiosum WXR-24 on day 5 after inoculation. Less mycelia are observed in fermentation broths containing 200–400 mg/L AP-3.
Figure 2. Structure comparison of FtsZ and β-tubulin. ( a ) The architecture of FtsZ from A. pretiosum WXR-24, built by homologous modeling. The featured α-helix 7 is labeled in red, connecting the yellow-labeled N-terminal domain and orange-labeled C-terminal domain. ( b ) The architecture of β-tubulin from Bos taurus retrieved from PDB database. The featured α-helix 7 is labeled in red, connecting the yellow-labeled N-terminal domain and orange-labeled C-terminal domain. ( c ) The graph of flexible structure alignment of FtsZ and β-tubulin. Three large structurally conserved blocks are shown in red, yellow or pink, and 2 twists are indicated by black arrows. ( d ) Sequence-based structural alignment of FtsZ and β-tubulin. FtsZ is highlighted in grey, and structurally conserved blocks in β-tubulin are highlighted in red, yellow or pink. The key amino acids of β-tubulin interacting with maytansine are indicated by red dots. ( e ) Superposition of the 3D structures of FtsZ and β-tubulin. FtsZ is colored in grey, and structurally conserved blocks in β-tubulin are in red, yellow or pink. The GDP-binding pockets of FtsZ and β-tubulin are labeled in blue, and the maytansine-binding pocket on β-tubulin is labeled in orange. May, maytansine.
Figure 3. The in vitro interaction of FtsZ with AP-3. ( a ) The interaction of FtsZ with AP-3, determined by Biacore biosensor assay. 6.25, 12.5, 25, 50 or 100 μM AP-3 flowed over a CM5 chip pre-immobilized with FtsZ. The response signals were recorded. ( b ) The inhibition of FtsZ assembly by the supplementation of AP-3, as detected by the real-time light scattering assay. Fluorescence signals of the reactions with (red line) or without (black line) 500 μM AP-3 were recorded every 2 min. ( c ) The impact of AP-3 (500 μM) on the GTPase activity of FtsZ, as detected by the Malachite Green Phosphate Assay Kit. Black line, without AP-3; Red line, with AP-3.
Figure 4. Interaction of FtsZ and AP-3 revealed by docking analysis. ( a ) The binding site of AP-3 on FtsZ is apart from the GDP binding site, from side view. The surface of FtsZ is displayed by hydrophobicity. Orange and blue indicate high and low hydrophobicity, respectively. The junction interphase between two FtsZ monomers is colored in green. ( b ) The binding site of AP-3 on FtsZ, from top view. ( c ) Close-up view of the AP-3 binding groove on FtsZ. The colors on the groove indicate that this part is more hydrophobic than the surrounding area. ( d ) The key amino acid residues interacting with AP-3. The interactions between key amino acids and AP-3 are displayed by dashed lines. Red dashed lines represent hydrogen bonds, and grey dashed lines represent hydrophobic interactions. The bond lengths (Å) are indicated by the numbers beside the dotted lines.
Figure 5. Effects of FtsZ overexpression on the resistance, growth and AP-3 yield of A. pretiosum WXR-30. ( a ) Growth of WXR-30 on YMG plates containing 0, 100, 200, 300 or 400 mg/L AP-3. The photos were taken on day 3 after inoculation. ( b ) Survive rate (%) of WXR-24 and WXR-30 on YMG plates containing 0, 100, 200, 300 or 400 mg/L AP-3. The survive rate on the plates supplemented without AP-3 was set as 100%, and the survive rates on other plates were accordingly calculated. Mean values of three independent experiments are shown with SD indicated by error bars. ( c ) Growth of A. pretiosum WXR-24 and WXR-30 in the fermentation broth containing 300 mg/L AP-3. Mean values of three independent experiments with SD are indicated by error bars. ( d ) AP-3 yields of WXR-24 and WXR-30 cultivated with 16 g/L yeast extract, and WXR-30 cultivated with 24 g/L yeast extract. Mean values of three independent experiments with SD are indicated by error bars. *** p < 0.001.
Wang, X.; Wang, R.; Kang, Q.; Bai, L. The Antitumor Agent Ansamitocin P-3 Binds to Cell Division Protein FtsZ in Actinosynnema pretiosum. Biomolecules 2020, 10, 699.
https://doi.org/10.3390/biom10050699
AMA Style
Wang X, Wang R, Kang Q, Bai L. The Antitumor Agent Ansamitocin P-3 Binds to Cell Division Protein FtsZ in Actinosynnema pretiosum. Biomolecules. 2020; 10(5):699.
https://doi.org/10.3390/biom10050699
Chicago/Turabian Style
Wang, Xinran, Rufan Wang, Qianjin Kang, and Linquan Bai. 2020. "The Antitumor Agent Ansamitocin P-3 Binds to Cell Division Protein FtsZ in Actinosynnema pretiosum" Biomolecules10, no. 5: 699.
https://doi.org/10.3390/biom10050699
| https://www.mdpi.com/2218-273X/10/5/699 |
COVID-19 and the courts: April 7 update | Canadian Lawyer
Today’s update for courthouses across Canada
COVID-19 and the courts: April 7 update
Today’s update for courthouses across Canada
The Court of Appeal for Ontario in Toronto.
Courts across Canada are taking extraordinary measures to control the spread of the new coronavirus COVID-19. Below is a roundup of actions courts are taking across the country.
Alberta
Provincial Court of Alberta
Notice to self-represented litigants in family law mattersGiven that the Intake and Caseflow Management Regulation states that self-represented individuals wishing to file an application should meet with a Family Court Counsellor, these counsellors may be reached via the phone numbers listed in the notice. Payors involved in support matters and registered with the Maintenance Enforcement Program should contact the program before reaching out to a Family Court Counsellor, to know whether alternate payment schemes can be arranged. With regard to files that are using the Caseflow Conference program, in Calgary, Edmonton and Red Deer, all scheduled Caseflow Conference matters are automatically adjourned for 10 weeks to the same time as the scheduled Caseflow Conference date, while Grande Prairie is maintaining the delivery of services by telephone as scheduled.
Warrant protocolAs regards warrants and other judicial authorization applications in Edmonton and Calgary, the court has developed a certain protocol and has released three documents relating to this matter: a warrant protocol, a notice to law enforcement agencies and a warrant checklist.
Ontario
Court of Appeal for Ontario
Practice Direction Regarding the Electronic Conduct of Matters During the Covid-19 EmergencyUntil further notice, the court has adopted certain guidelines concerning the electronic processes utilized by the court. All matters will proceed by remote appearance or in writing, in lieu of in-person hearings. The requirements governing hard-copy document filings and oral hearings will be dispensed with. Instead, documents should be filed in an electronic format in accordance with the guidelines for filing electronic documents, subject to certain amendments, which have been listed. Documents which must be filed under seal should be password-protected. The court encourages parties to hyperlink their key factums to online judgment databases and to hyperlink the key documents referred to in their factums. At the present time, the court is not requiring counsel to gown for remote appearances.
Northwest Territories
Supreme Court of the Northwest Territories
COVID 19 Response: changes to Supreme Court proceedings and schedulingThe court has introduced changes to their directive issued on Mar. 24. As regards criminal matters, sittings outside of Yellowknife scheduled to proceed between now and June 5 have been cancelled. In Yellowknife, jury trials, judge alone trials, voir dires, which are scheduled to proceed between now and June 5 have been cancelled, while other scheduled hearings will proceed, with the accused appearing by videoconference and counsel appearing by phone, as long as the parties have agreed to this. The Supreme Court list scheduling set for May 8 will be postponed until June 5. As for civil and family matters, family hearings where witnesses are to be called and which are scheduled to proceed between now and June 5 have been cancelled. Special chambers hearings scheduled to proceed between now and June 5 which do not involve the calling of evidence may push through as long as counsel are ready to appear by phone. Judicial settlement conferences scheduled between now and June 5 have been cancelled, except if these can proceed by phone.
Court of Appeal for the Northwest Territories
COVID 19 Response: changes to Supreme Court proceedings and schedulingThe list of pending cases in the appeal court will be called on May 8. Counsel and parties will appear by telephone.
| https://www.canadianlawyermag.com/practice-areas/litigation/covid-19-and-the-courts-april-7-update/328435 |
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Zip code 49836 Michigan Healthcare data and hospitals 49840 and 49820
Zip code 49836 Michigan Healthcare industry data and local research 49840 and 49820
ZIP code 49836 Health Insurance Charts
This section of charts shows ZIP code 49836 Michigan healthcare data based on the most recent 2022 data from the Census Bureau which was released in November of 2022 and tracks healthcare in the United States.
Figure 1
shows the percentage of people who acquired some form of health coverage insurance during open enrollment.
49836
shows it has a With Coverage of 91.0% which is in the mid point range of other zip codes in the area. The zip code with the highest health insurance coverage in the area is
49820
which shows an insured of 100.0% (9.9% larger). The next chart (
Figure 2
) shows the change in the percent of people covered from 2020 to 2021 (latest year available) in the percentage of people in the greater ZIP code 49836 area who had some form of health insurance coverage. ZIP code 49836 shows it has a Change in Coverage of -3.0% which is less than most other zip codes in the metro area. The zip code with the highest change in health insurance coverage in the area is
49820
which shows a change in insured of 4.3% (42.8% larger).
Figure 3
the relative proportions of different types of health insurance coverage benefits are shown (broken down by major categories of public versus private.) Not public insurance includes affordable care act/Obamacare, Medicare, and Medicaid. ZIP code 49836 has the percentage of private health insurance in the middle range of other zip codes in the local area at 58.7% of the total.
Figure 4
shows the proportion of ZIP code 49836 Michigan residents who are covered by more than one health insurance carrier. This occurs when, for instance a person might have Medicare as well as a private health plan. ZIP code 49836 has the percentage of people with one health care insurance policy in the mid range of other zip codes in the metro area at 38% of the total.
The next chart shows a more detailed view of the types of health insurance held by people in the area including employer provided, direct purchased, Medicare, and public healthcare options (e.g. Medicaid.)
Figure 5
, has the percentage of medicare less than most other zip codes in the greater region at 20% of the total. Second, it has one of the largest proportions of medicaid or public coverage at 16% of the total and is ranked #3. Only #2
49840
(18%), and #1
49883
(27%) are larger.
The next two charts show the percentage of men and women with coverage. First,
Figure 6
shows men and it has a With Healthcare Coverage-Men of 90% which is in the mid range of other zip codes in the area. The zip code with the highest men with health care insurance coverage in the area is
49820
which depicts an insurance coverage of 100% (11.7% larger). In the next chart women are shown for the percentage that are covered by health insurance.
Figure 7
shows it has a With Healthcare Coverage-Women of 93% which is in the center range of other zip codes in the local area. The zip code with the highest women with health care insurance coverage in the area is
49820
which depicts an insurance coverage of 100% (8.0% larger).
The next two charts show the percentage of people who do not have health care insurance. Both charts show the data broken out by household income with
Figure 8
showing the percent covered by income group. ZIP code 49836 shows it has the hightest change in the percentage of people not covered with insurance of 20.0% for the $75k to $100k classification.
Figure 9
shows the change in the percentage of people who have no insurance from 2020 to 2021. ZIP code 49836 depicts it has the hightest change in the percentage of people not covered with insurance of 281.5% for the under $25k-change aggregate.
Figure 10
shows a breakdown of the people in the area who do not have health insurance. Of the people who DO NOT HAVE healthcare coverage, what is the breakdown by race. ZIP code 49836 has the largest proportion of asians without coverage at 20% of the total and is ranked #1. The next chart shows the percentage of children (17 years of age and younger) who do not have health insurance. In
Figure 11
, it has a Children without Health Insurance of 5.8% which is the third most children without health insurance of all other zip codes in the greater ZIP code 49836 region. The zip code with the highest children without health insurance in the area is
49840
which shows a children without insurance of 18.0% (approximately 3.1 times bigger).
ZIP code 49836 Area Hospital Info Charts
Figure 14
shows a listing of hospitals in the area which provide a variety of health services/treatment including: primary care, urgent care, hospice, ICU, orthopedic, family medicine, clinic, home health care and other health coverage to the community. Data from Medicare and Medicaid Services (CMS) and not the Michigan Department of Health. Some of the Area Hospital Info are: Helen Newberry Joy Hospital, Munising Memorial Hospital, Schoolcraft Memorial Hospital, Mackinac Straits Hospital And Health Center, and St Francis Hospital. In
Figure 15
, the number of patients discharged from each hospital is shown. Looking at Discharges for Area Hospital Info we find that Mclaren - Northern Michigan ranks the largest with a value of 4,409 discharges. The next largest values are for: Helen Newberry Joy Hospital (0), Munising Memorial Hospital (0), Schoolcraft Memorial Hospital (0), and Mackinac Straits Hospital And Health Center (0). The difference between the highest value (Mclaren - Northern Michigan) and the next highest (Helen Newberry Joy Hospital) is that the discharges is about substantially bigger. The next
Figure 16
shows the average level of illness of an average patient treated at each hospital using the Medicare Case Mix Index (CMI). This indicator is considered an important healthcare industry metric for a hospital and shows the average severity level of procedures performed by a physician at the location. Looking at CMI for Area Hospital Info we find that Mclaren - Northern Michigan ranks the largest with a value of 1.85 cmi. The next largest values are for: Helen Newberry Joy Hospital (0.00), Munising Memorial Hospital (0.00), Schoolcraft Memorial Hospital (0.00), and Mackinac Straits Hospital And Health Center (0.00). The difference between the highest value (Mclaren - Northern Michigan) and the next highest (Helen Newberry Joy Hospital) is that the cmi is about about twice as large.
ZIP code 49836 Patient Experience Charts
The next set of charts are based on a national survey of patient experience in hospitals and covers a range of caregiver staff (doctor, primary care, medical assistant, behavioral health, pain management, and other provider.) These metrics provide overall and important quality of care metrics for the hospitals in the community and how comfortable your child or loved ones will be at the facility.
Figure 17
shows the percent of patients surveyed who said their hospital room and bathroom were always clean. Looking at Room and bathroom Always clean for Patient Experience we find that Munising Memorial Hospital ranks the largest with a value of 89.0% room and bathroom always clean. The next largest values are for: Schoolcraft Memorial Hospital (88.0%), Mackinac Straits Hospital And Health Center (88.0%), Helen Newberry Joy Hospital (82.0%), and Charlevoix Area Hospital (80.0%). The difference between the highest value (Munising Memorial Hospital) and the next highest (Schoolcraft Memorial Hospital) is that the room and bathroom always clean is about only slightly larger.
Figure 18
shows the percent of patient residents surveyed who said the area around the hospital room was always quiet. Looking at Always quiet at night for Patient Experience we find that Munising Memorial Hospital ranks the largest with a value of 90.0% always quiet at night. The next largest values are for: Schoolcraft Memorial Hospital (75.0%), Mackinac Straits Hospital And Health Center (71.0%), Charlevoix Area Hospital (71.0%), and St Francis Hospital (57.0%). The difference between the highest value (Munising Memorial Hospital) and the next highest (Schoolcraft Memorial Hospital) is that the always quiet at night is about 20.0% larger.
In
Figure 19
, the percent of patients who said that they always received help when they need it. Looking at Always received help when needed for Patient Experience we find that Munising Memorial Hospital ranks the largest with a value of 88.0% always received help when needed. The next largest values are for: Schoolcraft Memorial Hospital (87.0%), Helen Newberry Joy Hospital (84.0%), Charlevoix Area Hospital (82.0%), and St Francis Hospital (79.0%). The difference between the highest value (Munising Memorial Hospital) and the next highest (Schoolcraft Memorial Hospital) is that the always received help when needed is about only slightly larger.
Figure 20
provides a pain management analysis using the percent of patient residents who reported that their pain was always well controlled for all the hospitals in the community. Looking at Pain Always Well Controlled for Patient Experience we find that Munising Memorial Hospital ranks the largest with a value of 79.0% pain always well controlled. The next largest values are for: Schoolcraft Memorial Hospital (79.0%), Mackinac Straits Hospital And Health Center (79.0%), St Francis Hospital (77.0%), and Charlevoix Area Hospital (77.0%). The difference between the highest value (Munising Memorial Hospital) and the next highest (Schoolcraft Memorial Hospital) is that the pain always well controlled is about about the same size.
The next chart,
Figure 21
, is the percent of patients who said that the nurses always communicated well with them. Looking at Nurses Always Communicated Well for Patient Experience we find that Munising Memorial Hospital ranks the largest with a value of 86.0% nurses always communicated well. The next largest values are for: Schoolcraft Memorial Hospital (86.0%), Mackinac Straits Hospital And Health Center (83.0%), Charlevoix Area Hospital (83.0%), and St Francis Hospital (81.0%). The difference between the highest value (Munising Memorial Hospital) and the next highest (Schoolcraft Memorial Hospital) is that the nurses always communicated well is about about the same size.
Figure 22
, shows the percent of patients who said that the doctors always communicated well with them. Looking at Doctors Always Communicated Well for Patient Experience we find that Munising Memorial Hospital ranks the largest with a value of 92.0% doctors always communicated well. The next largest values are for: Schoolcraft Memorial Hospital (87.0%), Helen Newberry Joy Hospital (86.0%), Charlevoix Area Hospital (85.0%), and St Francis Hospital (81.0%). The difference between the highest value (Munising Memorial Hospital) and the next highest (Schoolcraft Memorial Hospital) is that the doctors always communicated well is about only about 5.7% larger.
In
Figure 23
, each hospital in the community is rated based on a scale from 1 to 10 (where 10 is the best) and provides a high level metric of favorable wellness from treatment. Looking at Hospital Rating for Patient Experience we find that Schoolcraft Memorial Hospital ranks the largest with a value of 82.0% hospital rating. The next largest values are for: Mackinac Straits Hospital And Health Center (78.0%), Charlevoix Area Hospital (78.0%), Mclaren - Northern Michigan (71.0%), and Helen Newberry Joy Hospital (70.0%). The difference between the highest value (Schoolcraft Memorial Hospital) and the next highest (Mackinac Straits Hospital And Health Center) is that the hospital rating is about only about 5.1% larger.
The final chart (
Figure 24
) provides comparative data for ZIP code 49836 community hospitals looking at overall patient experience. This section specifically shows the percent of patients who would definitely recommend this adult specialty hospital to other people in the community. Looking at Would Recommend Hospital for Patient Experience we find that Mackinac Straits Hospital And Health Center ranks the largest with a value of 85.0% would recommend hospital. The next largest values are for: Charlevoix Area Hospital (84.0%), Schoolcraft Memorial Hospital (80.0%), Munising Memorial Hospital (78.0%), and Mclaren - Northern Michigan (76.0%). The difference between the highest value (Mackinac Straits Hospital And Health Center) and the next highest (Charlevoix Area Hospital) is that the would recommend hospital is about only slightly larger.
Zip code 49836, Michigan Healthcare Data
Demographics
Housing
Economy
Education
Healthcare
Health Insurance
Area Hospital Info
Patient Experience
Figure 1: Percent of People with Health Insurance Figure 2: Change in People with Health Coverage (2019 to 2020) 0% 50% 100% 49883 49840 49827 49836 United States 49838 Michigan Appleton-Oshkosh- Neenah 49853 49820 Place With Coverage 49883 83.3% 49840 87.3% 49827 88.1% 49836 91% United States 91.2% 49838 93.9% Michigan 94.7% Appleton-Oshkosh-Neenah 95.5% 49853 97.8% 49820 100% Neenah -20% 0% 20% 49883 49840 49836 49838 United States Michigan 49853 Appleton-Oshkosh- Neenah 49827 49820 Place Change in Coverage 49883 -15.3% 49840 -6.6% 49836 -3% 49838 -1.9% United States -0% Michigan 0% 49853 0.3% Appleton-Oshkosh-Neenah 3.9% 49827 4.1% 49820 4.3% Neenah
Figure 3: Type of Health Insurance Figure 4: Amount of Health Insurance Coverage Private he… Public heal… No health i… 49836 0% 50% 100% Place Private health insurance Public health insurance No health insurance 49836 64.6% 58.7% 9% No health in… One Coverage T… 1/3 0% 100% 200% 49836 49840 49820 49853 49838 49827 49883 United States Michigan Appleton-Oshkosh- Neenah Place One Coverage Type Two Coverage Types No Healthcare Coverage 49836 53% 38% 9% 49840 55% 33% 13% 49820 60% 40% 0% 49853 58% 40% 2% 49838 52% 42% 6% 49827 66% 22% 12% 49883 63% 20% 17% United States 75% 17% 9% Michigan 75% 20% 5% Appleton-Oshkosh-Neenah 81% 15% 5% No Healthcare Co…
Figure 5: Detailed Types of Health Insurance Coverage in 49836, MI Employer-Based He… Direct-Purchase He… Medicare Medicaid or Public… No Coverage 49836 49840 49820 49853 49838 49827 49883 United States Michigan Appleton-Oshkosh-Neenah 0% 50% 100% 150% Place Employer-Based Health Insurance Direct-Purchase Health Insurance Medicare Medicaid or Public Coverage No Coverage 49836 49% 15% 10% 20% 16% 49840 48% 14% 5% 17% 18% 49820 25% 12% 18% 53% 0% 49853 53% 21% 7% 10% 5% 49838 65% 7% 7% 22% 12% 49827 43% 2% 12% 42% 14% 49883 35% 4% 18% 39% 27% United States 63% 11% 4% 15% 12% Michigan 66% 10% 5% 19% 8% Appleton-Oshkosh-Neenah 76% 10% 3% 10% 6% Medicaid or Public C…
Figure 6: Men with Health Insurance Coverage Figure 7: Women with Health Insurance Coverage 0% 50% 100% 49827 49883 49840 49836 United States Michigan 49838 Appleton-Oshkosh- Neenah 49853 49820 Place With Healthcare Coverage-Men 49827 86% 49883 86% 49840 87% 49836 90% United States 90% Michigan 94% 49838 95% Appleton-Oshkosh-Neenah 95% 49853 98% 49820 100% Neenah 0% 50% 100% 49883 49840 49827 United States 49836 49838 Michigan Appleton-Oshkosh- Neenah 49853 49820 Place With Healthcare Coverage-Women 49883 79% 49840 88% 49827 91% United States 92% 49836 93% 49838 93% Michigan 96% Appleton-Oshkosh-Neenah 96% 49853 97% 49820 100% Neenah
Figure 8: Percent of People with No Insurance by Income Group Figure 9: Change in Percent of People with No Insurance from 2019 to 2020 Under $25k $25k to $… 1/3 49836 0% 10% 20% Place Under $25k $25k to $50k $50k to $75k $75k to $100k Over $100k 49836 11.1% 9.2% 5.1% 20% 3.8% $75k to $1… Under… $25k t… 1/3 -5 0 5 49836 Place Under $25k-change $25k to $50k-change $50k to $75k-change $75k to $100k-change Over $100k-change 49836 281.5% 0% -36.4% 194.5% -55.1% $75k to…
Figure 10: People without Health Insurance Coverage by Race White Black Hispanic Asian Native American 49836 49840 49853 49838 49827 49883 United States Michigan Appleton-Oshkosh-Neenah 0% 50% 100% Place White Black Hispanic Asian Native American 49836 81% 0% 0% 0% 20% 49840 94% 0% 0% 0% 6% 49853 100% 0% 0% 0% 0% 49838 100% 0% 0% 0% 0% 49827 100% 0% 0% 0% 0% 49883 78% 22% 0% 0% 0% United States 50% 12% 32% 4% 2% Michigan 69% 16% 11% 3% 1% Appleton-Oshkosh-Neenah 74% 3% 14% 5% 4% Native American
Figure 11: Children without Health Insurance Figure 12: Advertisement 0% 10% 20% Michigan Appleton-Oshkosh- Neenah United States 49836 49827 49840 Place Children without Health Insurance Michigan 3.1% Appleton-Oshkosh-Neenah 3.6% United States 5.3% 49836 5.8% 49827 17.7% 49840 18% Neenah
Figure 13: Insurance Coverage Broken Down by Age and Detailed Type Insurance All Under 18 18 to 64 65+ Direct Purchase 30.1% 2.6% 15.1% 65.2% Employer Paid 37.9% 16.8% 48.6% 30.8% Medicare 38.9% 1.9% 10.1% 99.4% Military 5.3% 0% 3.7% 10.0% No Insurance 9% 5.8% 15.8% 0% Public 23.4% 77.4% 19.6% 5.4% Two or More Types 38.2% 4.5% 11.5% 93.7%
Figure 14: Hospitals in the 49836, MI Area and Key Information Hospital Name City Hospital Type Hospital Ownership Emergency Services St Francis Hospital Escanaba Critical Access Hospitals Voluntary non-profit - Church Yes Schoolcraft Memorial Hospital Manistique Critical Access Hospitals Government - Local Yes Munising Memorial Hospital Munising Critical Access Hospitals Voluntary non-profit - Private Yes Mclaren - Northern Michigan Petoskey Acute Care Hospitals Voluntary non-profit - Other Yes Mackinac Straits Hospital And Health Center Saint Ignace Critical Access Hospitals Voluntary non-profit - Private Yes Helen Newberry Joy Hospital Newberry Critical Access Hospitals Government - Local Yes Charlevoix Area Hospital Charlevoix Critical Access Hospitals Voluntary non-profit - Other Yes
Figure 15: Patients Discharged Figure 16: Level of Illness Measured by Case Mix Index 0 2,500 5,000 Mclaren - Northern Michigan Hospital Name Discharges Mclaren - Northern Michigan 4,409 Michigan 0 1 2 Mclaren - Northern Michigan Hospital Name CMI Mclaren - Northern Michigan 1.85 Michigan
Figure 17: Patients Room and Bathroom Always clean Figure 18: Patients Room Always Quiet at Night 0% 50% 100% Mclaren - Northern Michigan St Francis Hospital Charlevoix Area Hospital Helen Newberry Joy Hospital Schoolcraft Memorial Hospital Mackinac Straits Hospital And Health Center Munising Memorial Hospital Hospital Name Room and bathroom Always clean Mclaren - Northern Michigan 71% St Francis Hospital 77% Charlevoix Area Hospital 80% Helen Newberry Joy Hospital 82% Schoolcraft Memorial Hospital 88% Mackinac Straits Hospital And Health Center 88% Munising Memorial Hospital 89% Munising Memorial 0% 50% 100% Helen Newberry Joy Hospital Mclaren - Northern Michigan St Francis Hospital Mackinac Straits Hospital And Health Center Charlevoix Area Hospital Schoolcraft Memorial Hospital Munising Memorial Hospital Hospital Name Always quiet at night Helen Newberry Joy Hospital 48% Mclaren - Northern Michigan 49% St Francis Hospital 57% Mackinac Straits Hospital And Health Center 71% Charlevoix Area Hospital 71% Schoolcraft Memorial Hospital 75% Munising Memorial Hospital 90% Munising Memorial
Figure 19: Patients Always Received Help When Needed Figure 20: Patients Pain Always Well Controlled 0% 50% 100% Mclaren - Northern Michigan Mackinac Straits Hospital And Health Center St Francis Hospital Charlevoix Area Hospital Helen Newberry Joy Hospital Schoolcraft Memorial Hospital Munising Memorial Hospital Hospital Name Always received help when needed Mclaren - Northern Michigan 71% Mackinac Straits Hospital And Health Center 74% St Francis Hospital 79% Charlevoix Area Hospital 82% Helen Newberry Joy Hospital 84% Schoolcraft Memorial Hospital 87% Munising Memorial Hospital 88% Munising Memorial 0% 50% 100% Helen Newberry Joy Hospital Mclaren - Northern Michigan St Francis Hospital Charlevoix Area Hospital Munising Memorial Hospital Schoolcraft Memorial Hospital Mackinac Straits Hospital And Health Center Hospital Name Pain Always Well Controlled Helen Newberry Joy Hospital 57% Mclaren - Northern Michigan 71% St Francis Hospital 77% Charlevoix Area Hospital 77% Munising Memorial Hospital 79% Schoolcraft Memorial Hospital 79% Mackinac Straits Hospital And Health Center 79% And Health Center
Figure 21: Nurses Always Communicated Well Figure 22: Doctors Always Communicated Well 0% 50% 100% Mclaren - Northern Michigan Helen Newberry Joy Hospital St Francis Hospital Mackinac Straits Hospital And Health Center Charlevoix Area Hospital Munising Memorial Hospital Schoolcraft Memorial Hospital Hospital Name Nurses Always Communicated Well Mclaren - Northern Michigan 79% Helen Newberry Joy Hospital 80% St Francis Hospital 81% Mackinac Straits Hospital And Health Center 83% Charlevoix Area Hospital 83% Munising Memorial Hospital 86% Schoolcraft Memorial Hospital 86% Schoolcraft Memorial 0% 50% 100% Mackinac Straits Hospital And Health Center Mclaren - Northern Michigan St Francis Hospital Charlevoix Area Hospital Helen Newberry Joy Hospital Schoolcraft Memorial Hospital Munising Memorial Hospital Hospital Name Doctors Always Communicated Well Mackinac Straits Hospital And Health Center 78% Mclaren - Northern Michigan 79% St Francis Hospital 81% Charlevoix Area Hospital 85% Helen Newberry Joy Hospital 86% Schoolcraft Memorial Hospital 87% Munising Memorial Hospital 92% Munising Memorial
Figure 23: Overall Hospital Rating of 9 or 10 by Patients Figure 24: Would Definitely Recommend Hospital 0% 50% 100% Munising Memorial Hospital St Francis Hospital Helen Newberry Joy Hospital Mclaren - Northern Michigan Mackinac Straits Hospital And Health Center Charlevoix Area Hospital Schoolcraft Memorial Hospital Hospital Name Hospital Rating Munising Memorial Hospital 67% St Francis Hospital 69% Helen Newberry Joy Hospital 70% Mclaren - Northern Michigan 71% Mackinac Straits Hospital And Health Center 78% Charlevoix Area Hospital 78% Schoolcraft Memorial Hospital 82% Schoolcraft Memorial 0% 50% 100% Helen Newberry Joy Hospital St Francis Hospital Mclaren - Northern Michigan Munising Memorial Hospital Schoolcraft Memorial Hospital Charlevoix Area Hospital Mackinac Straits Hospital And Health Center Hospital Name Would Recommend Hospital Helen Newberry Joy Hospital 60% St Francis Hospital 65% Mclaren - Northern Michigan 76% Munising Memorial Hospital 78% Schoolcraft Memorial Hospital 80% Charlevoix Area Hospital 84% Mackinac Straits Hospital And Health Center 85% And Health Center
Cities marked with an asterisk ("*") should resemble a city or town but do not have their own government (i.e. Mayor, City Council, etc.) These places should be recognizable by the local community but their boundaries have no legal status. Technically these include both Census Designated Places (CDP) and Census County Divisions (CCD) which are defined by the Census Bureau along with local authorities. (For more information, see: Census Designated Place or "CDP") and Census County Division "CCD".) For comparison purposes, the US national average and the state average value are provided. Additionally, the "Combined Statistical Area" or CSA is shown that is closest to the city, county, or zip code shown. A CSA is a large grouping of adjacent metropolitan areas that identified by the Census Bureau based on social and economic ties. (See: Combined Statistical Area ) Data sources - Mouse over icon in upper right corner of each chart for information.
| https://www.towncharts.com/Michigan/Healthcare/49836-Zipcode-MI-Healthcare-data.html |
Weaning problems. - September 2021 Birth Club - BabyCenter Australia
Weaning problems. : Has anyone had trouble weaning their little one off the boob? I am trying to wean my girl off the boob and onto formula atm but it is proving to be so much more difficult than I ever imagined. Bub went through a bottle aversion a few backs, flat out refused to take one for around month for unknown reasons. She is back taking one now but it’s still hit and miss. ...
Weaning problems.
Has anyone had trouble weaning their little one off the boob? I am trying to wean my girl off the boob and onto formula atm but it is proving to be so much more difficult than I ever imagined. Bub went through a bottle aversion a few backs, flat out refused to take one for around month for unknown reasons. She is back taking one now but it’s still hit and miss. Like today wouldn’t have a bar of the bottle but took the boob straight away so she was obvs hungry. I’ve only been mixing a tiny bit of formula in with expressed breast milk too so the whole process is just taking too long. And with bub refusing the bottle sometimes it’s taking longer again. I am starting to get super frustrated and just don’t know what to do. Can anyone offer any advice if they have been through something similar? Bub is 5.5 months. Please help, it’s beginning to stress me out heaps. 😔
I have just come out of the other end of the tunnel with this! I had been offering a bottle of formula or sometimes expressed milk for the last 8 weeks or so (bub almost 6 months) and he would NOT take it, I tried everything, every bottle and everyone. I went and saw a child health nurse who said he will eventually take it once he gets desperate! Which is obviously super hard as you just want to feed your hungry crying child!
I was getting very stressed about it then on Thursday just decided today was the day to go hard so I breastfed him in the morning then didn’t offer it all day and kept offering the bottle. It helped that we had a busy day with my toddler so I was more distracted and we were in the car/pram where he was able to sleep more easily. He only drank 15mls from the bottle all day!! So I breastfed him to bed to make sure he was full. He only woke once overnight which I breastfed again then did the same thing the next day but started with the bottle. That day he took a bit more. Flash forward 2 more days to today and he absolutely smashed 3 bottles of 120-180mls!!! I never thought I’d see the day but the nurse was right.. they get desperate then take to it. I tried lots of bottles but went with the Pigeon Wide neck which I had read was most like a breast than other bottles.
I think what helped me most was not sitting around the house forcing the bottle all day, it winds you both up and you end up just breastfeeding out of exhaustion! I’d try start on a day where you have something on and pack all of the bottles and you might be surprised how long bub will last. Good luck xx
In reply to Tracey_magnolia
I have just come out of the other end of the tunnel with this! I had been offering a bottle of formula or sometimes expressed milk for the last 8 weeks or so (bub almost 6 months) and he would NOT take it, I tried everything, every bottle and everyone. I went and saw a child health nurse who said he will eventually take it once he gets desperate! Which is obviously super hard as you just want to feed your hungry crying child!
I was getting very stressed about it then on Thursday just decided today was the day to go hard so I breastfed him in the morning then didn’t offer it all day and kept offering the bottle. It helped that we had a busy day with my toddler so I was more distracted and we were in the car/pram where he was able to sleep more easily. He only drank 15mls from the bottle all day!! So I breastfed him to bed to make sure he was full. He only woke once overnight which I breastfed again then did the same thing the next day but started with the bottle. That day he took a bit more. Flash forward 2 more days to today and he absolutely smashed 3 bottles of 120-180mls!!! I never thought I’d see the day but the nurse was right.. they get desperate then take to it. I tried lots of bottles but went with the Pigeon Wide neck which I had read was most like a breast than other bottles.
I think what helped me most was not sitting around the house forcing the bottle all day, it winds you both up and you end up just breastfeeding out of exhaustion! I’d try start on a day where you have something on and pack all of the bottles and you might be surprised how long bub will last. Good luck xx
That looks like a great trick.Were you also offering your bub solid during this transition?
My bub was the same . I had to cut out breast completely and just offer bottle … he then took to the bottle after about two days of taking small amounts
In reply to Jigna1509
That looks like a great trick.Were you also offering your bub solid during this transition?
Not much, only a teaspoon or so at lunch time, we haven’t really started yet!
In reply to Tracey_magnolia
I have just come out of the other end of the tunnel with this! I had been offering a bottle of formula or sometimes expressed milk for the last 8 weeks or so (bub almost 6 months) and he would NOT take it, I tried everything, every bottle and everyone. I went and saw a child health nurse who said he will eventually take it once he gets desperate! Which is obviously super hard as you just want to feed your hungry crying child!
I was getting very stressed about it then on Thursday just decided today was the day to go hard so I breastfed him in the morning then didn’t offer it all day and kept offering the bottle. It helped that we had a busy day with my toddler so I was more distracted and we were in the car/pram where he was able to sleep more easily. He only drank 15mls from the bottle all day!! So I breastfed him to bed to make sure he was full. He only woke once overnight which I breastfed again then did the same thing the next day but started with the bottle. That day he took a bit more. Flash forward 2 more days to today and he absolutely smashed 3 bottles of 120-180mls!!! I never thought I’d see the day but the nurse was right.. they get desperate then take to it. I tried lots of bottles but went with the Pigeon Wide neck which I had read was most like a breast than other bottles.
I think what helped me most was not sitting around the house forcing the bottle all day, it winds you both up and you end up just breastfeeding out of exhaustion! I’d try start on a day where you have something on and pack all of the bottles and you might be surprised how long bub will last. Good luck xx
Thanks so much for the tips! Have you been giving formula or have you been pumping and giving expressed milk? If you’re using formula which one did you go with?
In reply to Sarah_13
My bub was the same . I had to cut out breast completely and just offer bottle … he then took to the bottle after about two days of taking small amounts
Did you offer formula when you cut out breast or were you pumping? If formula which one did you go with?
So I did both but found breast milk was more easily taken too. I then moved completely into formula . I use A2. My first bub liked A2 also
In reply to Lil_Mumma0101
Did you offer formula when you cut out breast or were you pumping? If formula which one did you go with?
I was only offering formula, I had tried offering expressed breast milk a few weeks ago and he still wasn’t taking it so I realised it wasn’t the taste that was an issue it was just that he wanted boobie! The first few days I expressed some milk and stored in the freezer just in case it didn’t work out or if he would only take breastmilk but once he started taking the formula I stopped pumping and have just hand expressed to relieve the pressure. I can happily report I’m on day 5
today and he had bottles all day and even one at bedtime which I had always breastfed to sleep!! So it’s really good now :) He usually wakes once overnight for a feed so I think I’ll just breastfeed that one for now as he seems to be ok taking both now 🤞
In reply to Lil_Mumma0101
Did you offer formula when you cut out breast or were you pumping? If formula which one did you go with?
Also I went with the bellamys formula :)
| https://www.babycenter.com.au/thread/5230392/weaning-problems- |
(PDF) Life is Water Electric
PDF | New evidence suggests that the L-field is generated by, and embodied in, the quantum-coherent liquid crystalline water that makes up to 70–90% of... | Find, read and cite all the research you need on ResearchGate
Article
PDF Available
Life is Water Electric
Authors:
<here is a image 26a4bf19fd20f0d7-327f5300d1f5e97b>
Mae-Wan Ho
The Institute of Science in Society
Abstract and Figures
New evidence suggests that the L-field is generated by, and embodied in, the quantum-coherent liquid crystalline water that makes up to 70–90% of organisms and cells, and is essential for life. Water forms quantum coherent domains at ordinary temperatures and pressures. Within organisms, coherent domains become stabilized as liquid crystalline water on the vast amount of membrane and macromolecular surfaces, effectively aligning the entire body electrically to form a single uniaxial crystal. This liquid crystalline water makes life possible by enabling proteins and nucleic acids to act as quantum molecular machines that transform and transfer energy at close to 100% efficiency. It provides excitation energy to split water in photosynthesis, releasing oxygen for the teaming millions of air-breathing species that colonize the earth, at the same time generating electricity for intercommunication and the redox chemistry that powers the entire biosphere. Living water is the means, medium, and message of life. Life, the Universe, and everything In his book Science and the Modern World 1 first published in 1926, Alfred North Whitehead (1861–1947) showed how the mechanical laws that describe objects with 'simple location in space and time' utterly fail to represent natural processes, and argued it is only possible to know and understand nature as an organism. He wrote (p. 100): " The concrete enduring entities are organisms, so that the plan of the whole influences the very characters of the various subordinate organisms which enter into it. In the case of an animal, the mental states enter into the plan of the total organism and thus modify the plans of the successive subordinate organisms until the ultimate smallest organisms, such as electrons, are reached " [italics mine]. Whitehead's organisms include everything in nature, from the universe to galaxies, stars, planets, plants, animals, human beings, bacteria, right down to fundamental particles; they are bundles of electromagnetic activities— " vibratory organisms " —endowed with a kind of primal consciousness that experience their environment in acts of " prehensile unification, " and most important of all, evolve as the result of the experience. Whitehead was remarkably prescient, as evidence has been accumulating since the latter half of the twentieth century that our Universe is 99.999% electric plasma. Gigantic plasma currents and their magnetic fields are constantly engaged in creating super-galaxy clusters, galaxies, and stars, in direct contradiction to the conventional Big Bang theory based solely on gravity and Einstein's theory of general relativity. 2 I have taken Whitehead's philosophy to heart. Not only is nature an all-encompassing electromagnetic super-organism, but the knower is also an electromagnetic organism maximally sensitive and responsive, fully engaged in mind and body, intellect and feeling to other organisms, ultimately to all nature. the eLectrodynamic organism attUned to the cosmos There is substantial evidence that living things are fundamentally organized by electric fields and electromagnetic activities. Whitehead's concept of a " plan of the body " that modifies the motion of electrons within it anticipates
<here is a image bea2f46a5c08557b-59bc1c6619ba41fc>
<here is a image 4ef8a8f298e71b24-e73f2e135cec6958>
Structured water confined in narrow nanotube (right) compared with ordinary water in wide nanotube (left). (Rearranged from Ye H, Naguib N, Gogotsi Y. JEOL News 2004;39:2–7.) …
<here is a image 88c6b30b23a426d7-2a97b37ebd0d3e1e>
Action potentials at successive later time segments at nuclear migration stage (43-53 min from start of development). (From Ho MW et al. J Sci Expl 1992;6:59-77.) …
<here is a image ea8775f2151b3577-8901e1d57e7dbc4d>
The new setting stumbled upon that is especially good for biological liquid crystals. …
93
New evidence suggests that the L-eld is generated by, and
embodied in, the quantum-coherent liquid crystalline water
that makes up to 70–90% of organisms and cells, and is
essential for life.
Water forms quantum coherent domains at ordinary tem-
peratures and pressures. Within organisms, coherent domains
become stabilized as liquid crystalline water on the vast
amount of membrane and macromolecular surfaces, effec-
tively aligning the entire body electrically to form a single
uniaxial crystal. This liquid crystalline water makes life pos-
sible by enabling proteins and nucleic acids to act as quantum
molecular machines that transform and transfer energy at
close to 100% efciency. It provides excitation energy to split
water in photosynthesis, releasing oxygen for the teaming
millions of air-breathing species that colonize the earth, at
the same time generating electricity for intercommunication
and the redox chemistry that powers the entire biosphere.
Living water is the means, medium, and message of life.
Life, the Universe, and everything
In his book Science and the Modern World 1rst published in
1926, Alfred North Whitehead (1861–1947) showed how the
mechanical laws that describe objects with ‘simple location
in space and time’ utterly fail to represent natural processes,
and argued it is only possible to know and understand nature
as an organism. He wrote (p. 100): “The concrete enduring
entities are organisms, so that the plan of the whole inu-
ences the very characters of the various subordinate organ-
isms which enter into it. In the case of an animal, the mental
states enter into the plan of the total organism and thus
modify the plans of the successive subordinate organisms
until the ultimate smallest organisms, such as electrons, are
reached ” [italics mine].
Whitehead’s organisms include everythingin nature, from
the universe to galaxies, stars, planets, plants, animals, human
beings, bacteria, right down to fundamental particles; they
are bundles of electromagnetic activities—“vibratory organ -
isms”—endowed with a kind of primal consciousness that
experience their environment in acts of “prehensile unication,”
and most important of all, evolve as the result of the experience.
Whitehead was remarkably prescient, as evidence has been
accumulating since the latter half of the twentieth century that
our Universe is 99.999% electric plasma. Gigantic plasma
currents and their magnetic elds are constantly engaged in
creating super-galaxy clusters, galaxies, and stars, in direct
contradiction to the conventional Big Bang theory based
solely on gravity and Einstein’s theory of general relativity. 2
I have taken Whitehead’s philosophy to heart. Not only is
nature an all-encompassing electromagnetic super-organism,
but the knower is also an electromagnetic organism maxi-
mally sensitive and responsive, fully engaged in mind and
body, intellect and feeling to other organisms, ultimately to
all nature.
the eLectrodynamic organism
attUned to the cosmos
There is substantial evidence that living things are funda-
mentally organized by electric elds and electromagnetic
activities. Whitehead’s concept of a “plan of the body”
that modies the motion of electrons within it anticipates
10 Life is Water Electric
Mae-Wan Ho
contents
Life, the Universe, and Everything ............................................................................................................................................. 93
The Electrodynamic OrganismAttuned to the Cosmos .............................................................................................................. 93
The Life-Field ............................................................................................................................................................................. 94
The L-Field is Stored Energy ...................................................................................................................................................... 95
Electrodynamic Activities and Pattern Formation ...................................................................................................................... 96
The Organism is One Uniaxial Liquid Crystal ........................................................................................................................... 98
Liquid Crystalline Water is Life .................................................................................................................................................. 99
Water is Weird and Wonderfully Fit for Life .............................................................................................................................. 99
Quantum Delocalization of Hydrogen Bond ............................................................................................................................ 100
Quantum coherent Water Makes Life on Earth ......................................................................................................................... 100
The Superconducting Electric Currents of Life ......................................................................................................................... 101
The Electromagnetic Language of Cells and Molecules .......................................................................................................... 102
To Conclude .............................................................................................................................................................................. 102
References ................................................................................................................................................................................. 103
K22937_C010.indd 938/13/2014 10:51:30 AM
94 Bioelectromagnetic and Subtle Energy Medicine
the discovery of physiologist Harold Saxton Burr at Yale
University, who began his work in the 1930s.
Burr’s book, The Blueprint for Immortality, 3 rst pub-
lished in 1972, offers a grand vision described on the book’s
backcover:
This is a breakthrough book—the rst comprehensive
account ever published of one of the most impor tant scientic
discoveries of this century. It reveals that all living things—
from men to mice, from trees to seeds—are moulded and
controlled by ‘electrodynamic elds’, which can be mea-
sured and mapped with standard modern voltmeters.
These ‘elds of life’, or L-elds, are the basic blueprints
of all life on this planet . Their discovery, therefore, is of
immense signicance to all of us.
To every man and woman in this troubled age it gives the
comforting certainty that life is no accident and that all of us
are integrated parts of the Universe, subjected to its laws and
sharing in its purpose and destiny ... the Universe has mean -
ing and so have we .
Since measurements of L-eld voltages can reveal physi-
cal and mental conditions, doctors will be able to use them to
diagnose illnesses before the usual symptoms develop and so
will have a better chance of successful treatment.
Burr and his many collaborators over a period of 40 years
documented L-elds in diverse organisms including eggs
and seeds; and dramatic changes in L-eld potentials closely
correlated with growth, development, mental states, and key
physiological events such as ovulation and cancer.
Burr attached electrodes to trees and simultaneously
recorded electric potential differences in the atmosphere and
in the earth continuously for 25 years. The records showed
that the air and earth potentials uctuated in phase with the
trees’ potentials. Statistical analysis revealed well-known
diurnal rhythms in all four records, as well as the lunar cycle
and the 11-year cycle of solar activity. These ndings leave
little doubt that trees in particular are sensitive to electric and
electromagnetic elds from earth and outer space, acting as
antennae to the universe. Trees connect us to the universe.
This may be why a walk in the woods or being near to woods
and forests is benecial to health. 4
Earth’s magnetic eld comes from the electric current gen -
erated in the conductive layer of molten iron in its outer core
moving across the sun’s magnetic eld, which in turn generates
a magnetic eld. Birds, bees, amphibians and other animals
are known to depend on earth’s magnetic eld for navigation.
There are reports that animals and humans in environments
shielded from earth’s magnetic eld aged faster, died more
readily, suffered stress and pains, and pathological changes in
the liver, kidneys, white blood cells, and urinary bladder. 5
Earth also has an electromagnetic spectrum or Schumann
resonance named after Winifred Otto Schumann (1888–
1974) who predicted them in 1952. Schumann resonances
are standing waves created in the space between the sur-
face of the earth and the conductive ionosphere, and natu-
rally excited by lightning discharges. Schumann resonances
range between 3 and 60 Hz, appearing as distinct peaks at
7.83, 14.3, 27.3, and 33.8Hz. These same frequencies are
prominent in human brain waves and strongly correlated
with different mental states. Evidence suggests that humans
and other organisms actually synchronize their biological
rhythms to the Schumann frequencies. 6,7
Earth’s electromagnetic activities are strongly affected
by those of the sun. The beautiful northern lights are gen-
erated during periods of intense solar activity, or magnetic
storms, when the solar wind carrying hot energetic plasmas
of ionized particles from the sun increases in density and
speed. The ionized particles are trapped by earth’s magnetic
eld and accelerated towards its magnetic poles. Collisions
between these ions and atmospheric atoms and molecules
(mainly oxygen and nitrogen) cause light to be emitted as the
excited atoms relax back to the ground state. Both higher and
lower than average levels of solar and geomagnetic activities
are associated with adverse health and psychological impacts
on humans worldwide, possibly due to the suppression of the
pineal gland secretion of melatonin as biological rhythms are
desynchronized. This is also partly why articial electro-
magnetic emissions from mobile phones, wireless, and high
tension power lines are having dire effects on humans and
wild life. 8–11
the Life-fieLd
Burr’s L-eld could be measured from the surface of the
body or the egg or seed, and detected away from the body
surface, as when measurements were done on salamanders
in water. This was sign of a true eld effect, as the eld was
not shorted out by water. When the salamander was rotated
under the electrodes positioned some millimeters away, it
acted like a dynamo as expected of a rotating electric eld,
giving a sine wave of rising and falling potentials.
L-elds of all organisms share some common features,
such as a positive potential at the anterior, versus a negative
potential at the posterior. However, the entire eld is made
up of subsidiary or local elds specic to the body plan (see
Figure10.1).
The L-elds are not static; Burr and his collaborators
found L-eldschanging slowly, increasingin strength during
development to a plateau in adulthood, and declining gradu-
ally as the organism ages.
The precise nature and origin of L-elds are not yet
known, and it would take rather more sophisticated equip-
ment to map them out properly. However, they are almost
certainly actively maintained by electric currents within the
body, forming closed circuits, rather than static DC elds.
These electric currents give rise to magnetic elds that can
be detected outside the human body including the brain, and
form the basis of magneto-encephalography (MEG), the
mapping of brain activity with very sensitive superconduct-
ing quantum interference devices (SQUID) magnetometers. 13
L-elds were conrmed by other laboratories working
independently of Burr, and later by orthopedic surgeon/
researcher Robert Otto Becker (1923–2008), who also doc-
umented DC potential changes during wound healing and
regeneration in animals and humans. Notably, he showed that
95 Life is Water Electric
potential changes from regenerating and nonregenerating
organisms differ markedly from each other (see Figure 10.2).
Becker’s ndings were described in numerous scientic
papers, and in one of the most gripping, moving accounts of
scientic discovery, The Body Electric, 12 published in 1985,
5 years after his research lab was shut down by scientists
and politicians in a bid to silence his warnings on the health
hazards of electromagnetic elds from overhead high tension
power lines and other electrical installations. (This debate has
continued to the present day over “nonthermal effects” includ -
ing brain cancer resulting from mobile phone use and other
electromagnetic smog in our environment; see Reference 14).
Becker knew that electromagnetic elds, when used accu -
rately with the correct polarity, at the right time and place, and
at the extremely weak levels characteristic of living organisms,
could indeed help to heal persistent wounds and fractures,
and even regenerate severed ngertips and nerves. However,
exposures to inappropriate electromagnetic elds were likely
to cause abnormal growth and cancer. Electromagnetic elds
are a powerful, double-edged weapon, and must be used with
utmost care and precision based on accurate knowledge from
painstaking research; only then could it help restore the lives
of people often reduced to utter despair.
Becker’s discoveries anticipated by decades the recent
ndings on the transformation of differentiated cells into
stem cells during healing and tissue regeneration, and
by manipulations of gene expression in the laboratory. 15
Research is now also focused on enhancing stem cell repair
in vivo without transplant by using drugs to encourage the
process. 16 There has been no investigation on the effect of
electric elds on the recruitment of stem cells thus far.
Today, it is possible to track electric potential changes
in cells and embryos, and it is widely acknowledged to
be involved in development, differentiation, regeneration,
and cancer. But they are interpreted solely, and mistak -
enly, in terms of membrane potential of cells 17with a major
emphasis on identifying downstream gene activities, while
important questions on the nature of the electrodynami -
cal life-eld and its relationship to health and disease are
largelyforgotten.
The most exciting serendipitous new discovery at Tufts
University is the “face” of the frog roughed out in potential
differences very early in development when the embryo is
still a shapeless ball of cells with very few anatomical fea-
tures. 18 A team led by Dany Adams used a combination of
voltage and pH sensitive dyes to follow the development of
Xenopus embryos under a microscope tted with a time-lapse
camera. It recorded “never-before-seen” dynamic patterns of
electrical potentials on the outermost cell layer. These are
clear signs of electrodynamic processes determining body
structures that appear much later on (more on this later).
the L-fieLd isstored energy
Burr’s insight was no less remarkable. 3He surmised that the
L-eld reects the energetic status of the organism; in partic -
ular, he assumed correctly that the energy ux of organisms
is associated with the chemical ux of metabolism, but the
L-eld represents energy stored inpotential differences across
the body. Variations in the L-eld, therefore, reect variations
in the ow of energy in the system. He wrote 3 (p.71):
If this assumption is true, it follows, then that by studying
potential differences during rest and during activity a record
+
+
figUre 10.1 L-elds of humans and salamanders, measured by
Robert O. Becker. (From Becker RO, Selden G. Electromagnetism
and the Foundation of Life . New York: Harper; 1985. With
+ 30
10
days
20
days
30
days
figUre 10.2 Electric potential changes at the cut end of the
stump after amputation in salamander (top), which regenerates
its amputated limb, and frog, which does not. (From Becker RO,
Selden G. Electromagnetism and the Foundation of Life. New
York: Harper; 1985. With permission.)
96 Bioelectromagnetic and Subtle Energy Medicine
could be made of a general level of immediately available
energy, as represented by algebraicly summated boundary
potentials.
In the face of the demand for activity this reservoir of
potential energy could be tapped. When the biological
system is at rest, the potentials could be recorded as DC
potentials, but when protoplasm is thrown into any kind of
activity, such as neural transmission, muscle contraction and
similar events, the rst sign of that activity would lie in the
sudden withdrawal from the reservoir of electrical energy; in
other words, a drop in potential difference. Then, mobiliza-
tion of chemical properties might be expected to re-establish
the original level of the potential difference.
The concept of storedenergy is the key to living organiza -
tion as emphasized in my book, The Rainbow and the Worm,
The Physics of Organisms. 19 Stored energy is coherent energy,
and the mobilization of coherent energy can be made with as
little dissipation as possible, giving rise in the ideal to the zero-
entropy quantum coherent organism (to be explained later).
As consistent with Burr’s observation, a drop in “mem-
brane potential”—depolarization precedes many important
cellular events including growth and regeneration. 17
eLectrodynamic activitiesand Pattern
formation
The L-eld is separate from, and independent of, the action
potentials of the brain or the electrical discharges from
the heart measured respectively in electroencephalograms
(EEGs) and electrocardiograms (ECGs). In fact, evidence
already available to Burr 3suggested that EEGs and ECGs
are controlled by variations in the L-eld, which would show
up as baseline potential changes under the action potentials
of the EEGs and ECGs, had they not been ltered away (!)
in most readings as noise or a nuisance rather than important
physiological and psychological information. For example,
Burr and colleagues discovered that high potential differ-
ences measured between the left and right index gures might
be predictive of mental instability.
Evidence that action potentials reect global eld poten-
tial changes also came from early embryonic development.
By far the most important unsolved problem in biology is
how a relatively featureless egg can transform into a shapely
highly differentiated organism in the process of development.
I was among a very small number of scientists who believe
electrodynamical processes are fundamentally involved in
pattern formation.
We carried out several series of experiments described in
a paper published more than 20 years ago, 20 which provided
evidence of highly coherent electrodynamic processes respon -
sible for generating body pattern during early development.
For our experiments, we collected synchronously develop-
ing batches of freshly laid fertilized eggs from Drosophila .
The rst series of experiments was carried out in the labora-
tory of electrophysiologist Charles Nicholson at New York
University Medical School, who patiently taught me how to
make microelectrodes to record the electrical activities from
individual developing embryos without damaging them. The
embryo, with its shell (chorion) removed, was attached by
hydrophobic interaction between the vitelline membrane and
the plastic surface of a petri dish. It was immersed in insect
Ringer to keep it from drying out. The electrode was carefully
inserted into the anterior or posterior polar pocket inside the
vitellline membrane without puncturing the embryo.
The results were amazing. A series of action potentials
from 1 to 30Hz appeared at least as early as 40min from
the start of development and persisted for hours thereafter
(see Figure 10.3). During most of the period in which pat-
tern determination takes place, there is little or no cellular
organization.
10 mV
1s
figUre 10.3 Action potentials at successive later time segments at nuclear migration stage (43–53 min from start of development). (From
Ho MW etal. J Sci Expl 1992;6:59–77.)
97 Life is Water Electric
The trace typically starts with clusters of 2, 3, or 4 volleys
of discharges (about 30Hz) each lasting 1 or 2 s, punctuated
by 2–3 s of relative quietude. The volleys increase in ampli-
tude and tend to coalesce into a continuous train. The peak
amplitudes are about 10–12mV. The highest frequency of
the spikes are about 30 Hz, but can be as low as 15 or 3 Hz.
Characteristically, the baseline potential shifts underneath
the spiking activities, often coinciding with the start and end
of the volleys, strongly suggesting that those shifts are global
in extent, and both initiate and end the volleys.
In the second set of experiments carried out in my own
laboratory, we exposed the synchronously developing batches
of fertilized eggs for 30min to weak static magnetic elds
(0.5–9mT) at different times during the rst 3h of devel-
opment when pattern determination is known to occur. This
resulted in high proportions of body pattern abnormalities
24 h later, when the rst instar larvae would have normally
hatched. The most frequent type of abnormalities is uniquely
associated with exposure to static magnetic elds, and con-
sists of variously twisted congurations of the segmental pat-
tern. As static magnetic elds were used, the effects must
have been due to moving electrical charges or more likely
global eld dynamics. As the energies in the weak magnetic
elds were many orders of magnitude below the thermal
threshold of random molecular motion, there could have been
no effect unless the electrodynamical processes were highly
coherent. 19–21
In the third series of experiments done in the laboratory of
Fritz Albert Popp, who taught me almost everything I know
about quantum physics, the ies were induced to lay eggs in a
quartz cuvette, then gently removed. The cuvette with freshly
laid eggs was placed in a light-tight chamber connected to
a sensitive photon counter, and the photons emitted were
recorded with or without a single ash of white light (l min,
4 W/m 2 ). Photon emission changed with developmental time,
which was not unexpected. Remarkably, when embryos less
than 40 min old were stimulated with light, an entirely new
phenomenon appeared that has never been observed before:
intense light ashes were re-emitted, thousands of times
stronger than the baseline. The ashes can be extremely brief
( < 1 s) or prolonged (minutes to hours), and can appear any time
from 1 to 20 min, and up to 8 h after light stimulation. 19,20The
results are reminiscent of super-radiance in quantum optics,
a collective resonant emission involving many, if not all indi -
viduals within the synchronously developing population.
These results together provide evidence of electrodynami-
cal activities accompanying pattern formation that are coher-
ent over the whole embryo and entire populations of embryos.
It would be great to look at these embryos again with voltage
sensitive dyes.
I was prompted to revisit these old forgotten ndings
on coming across a paper by Alexis Pietak from Kingston,
Ontario in Canada 22proposing a new mechanism for mor-
phogenesis: the formation of resonant electromagnetic modes
in a dielectric microwave resonator.
Resonant modes are standing wave patterns formed
when a wave is conned within a resonator and subjected
to reection from internal boundaries where incident
and reected waves combine. This is something like the
Schumann resonances generated in the cavity between the
earth’s surface and the ionosphere (see above), but on a much
smaller scale of 0.1–1mm, the dimensions of eggs and pri-
mordia. Consequently, the frequency of the electromagnetic
waves involved is much higher, in the microwave to sub-
millimeter range or GHz (10 9cycles per second). Using the
mathematical technique of nite element analysis Pietak pro-
duced resonant modes (in ellipses and a sphere) (Figure 10.4)
whose patterns resemble different kinds of leaves.
As Pietak noted, this type of mechanism is not restricted
to generating leaf patterns. The Drosophilaegg is a long
ellipse, and successive horizontal resonant modes are remi-
niscent of stages in the process of segment determination as
revealed by the famous gene transcript patterns, which are
most likely involved in downstream processes of pattern
formation.
Pietak emphasized that “the model rests on the validity of
biological coherence theories as described by Fröhlich. . .and/
or quantum eld theorists.” Herbert Fröhlich (1905–1991) 23
proposed that organisms are condensed matter systems, and
can be pumped by metabolic energy into states of coherent
excitations (resonant modes) in analogy with the solid-state
laser. Quantum eld theorists Emilio Del Giudice and col-
leagues propose that interaction between ambient electro-
magnetic elds and soft condensed matter such as liquid
water creates coherent domains oscillating in phase with the
electromagneticeld. 24 I have described the work of Fröhlich
in the Rainbow Worm 19and quantum eld electrodynamics
is treated in some detail in my new book 25 Living Rainbow
H 2O , both providing extensive evidence for the quantum
coherence of organisms.
Field theories of morphogenesis go back at least to the
1920s associated especially with Alexander Gur witsch (1874–
1954) in Russia and Paul Weiss (1898–1989) in Austria; but
they were rather vague [see the review in Order and Life 26
by Joseph Needham (1900–1995)]. A signicant advance
was made by John Totafurno and Lynn Trainor (1921–2008)
in a paper published in 1987 27using a vector-eld model to
predict bafing results of salamander limb regeneration. In
these experiments, a limb was amputated, and the regener-
ating cell mass was transplanted and/or rotated, leading to
abnormal limb regrowth that were determined by the way
the cell mass was transplanted. A vector-eld has both ori-
entation and continuity, and any disturbance to the eld lines
need to be smoothed out and reconnected, with the result that
extra limbs are generated in certain transplants.
I suggested that the morphogenetic eld could be
“written”—like memory—in liquid crystalline orientation
patterns, 19,28 which in turn determine gene transcription pat-
terns and growth, the latter reinforcing cellular memory, and
committing the cell to differentiation along a developmental
pathway.
Liquid crystals are well-known to respond to electric and
magnetic elds in generating patterns, as well as in chang -
ing their alignments. 28 Thus, resonant electromagnetic
98 Bioelectromagnetic and Subtle Energy Medicine
modes generated in the Drosophilaembryos could give
rise to segmental patterns in the liquid crystalline cortex
of the early embryos, which result in the well-known gene
transcription patterns that lead in turn to the differentiation
of the initially cryptic pattern. Static magnetic elds could
indeed have a dramatic effect on the liquid crystalline pat -
terning by resonant electromagnetic modes, and hence on
the body pattern.
Despite substantial evidence on the existence of L-elds,
and the fundamental importance of electrodynamic pro-
cesses in living organization and function, there is still little
clue as to how the L-eld is generated and where it resides. I
shall present evidence that liquid crystalline water in living
organisms is both the body electric and the L eld.
the organism is one UniaxiaL
LiqUid crystaL
The tantalizing evidence of a coherent electrodynamic eld
involved in pattern formation from our experiments 20 sug-
gested that we should be able to seesome sign of coherence,
specically, a birefringence indicative of ordered alignment
of liquid crystalline molecules in the early embryo.
Birefringence is an optical property of a crystal or liquid
crystal with atoms or molecules aligned by electric polar-
ity, so that plane-polarized white light (consisting of many
wavelengths vibrating in a single direction) is split into two
perpendicularly oriented rays, one travelling slower than
the other. When the two rays are recombined with a second
polarizer (the analyzer), the component wavelengths of light
interfere constructively or destructively. That is how the rain-
bow colors are generated. In order to amplify the birefrin-
gence, it is usual to add a full wave-plate—the wavelength
of green light—to the system, giving the characteristic pink
background (Figure 10.5).
I had been working with Drosophilafor over 15 years, yet
I was completely unprepared for what greeted me as I peered
down the polarizing microscope. A little larva was crawling
Series Mode 3M ode 4M ode 5M ode 6M ode 7
V-modes
SeriesMode 3M ode 4M ode 5M ode 6
V-modes
H-modes
N-modes
14.6 GHz21.1 GHz27.6 GHz34.1 GHz40.7 GHz 10.2 GHz14.5 GHz18.8 GHz23.1 GHz
16.8 GHz19.7 GHz22.7 GHz25.6 GHz28.6 GHz
H-modes
15.3 GHz18.3 GHz21.3 GHz24.2 GHz
22.7 GHz25.4 GHz28.4 GHz31.3 GHz34.2 GHz
N-modes
18.8 GHz21.6 GHz24.4 GHz27.3 GHz
Circle
5.1
14.5
15.6
17.3
17.8
18.1
8.0
10.6
11.4
13.2
figUre 10.4 (See also color plate section, page XX.) Resonant modes in elliptical and spherical resonators generated by nite ele-
ment analysis and the resonant frequencies in GHz; V, vertical, H, horizontal, N, nodal. (Rearranged from Pietak AM. J Phys Conf Ser
2011;329:012012.doi:10.1088/1742–6596/329/1/012012.)
Camera/
obser ver
Analyzer
Wa ve plate
Organism
Condenser
Polarizer
Light source
In te rf erence
Analyzer
F ast ray
Birefringent
cr ystal
P
olarizer
Light source
Slow ra y
figUre 10.5 Polarizing light microscope (left) and birefrin-
gence (right).
K22937_C010.indd 988/13/2014 10:51:36 AM
99 Life is Water Electric
out of its egg, carrying a rainbow inside. Even the fully devel-
oped larva was coherent, and coherent beyond our wildest
dreams. That is what the dancing rainbow inside its body was
telling us, only it took a while to gure that out. That sub-
lime vision was the immediate inspiration to writing. 19 The
Rainbow and the Worm, The Physics of Organisms .
Because the expert in charge of the polarizing microscope
was away, my colleague Michael Lawrence and I stumbled
upon a new setting that was especially good for viewing
biological liquid crystals. Instead of positioning the vibrat-
ing directions of the full wave plate at 45° to the polarizers,
we placed it at a small angle of 7.5° 29–31(Figure 10.6). The
brilliant rainbow colors tell us that all the liquid crystalline
molecules in the cells and tissues of the body are aligned,
and more importantly, moving coherently together. As
light vibrates much faster than the molecules can move, the
orderly alignment of the molecules remains apparent to the
light passing through. In fact, the most active parts are the
brightest, indicating that the molecular motions are the most
coherent.
Not only that, the entire organism is electrically polar-
ized from head to tail, behaving optically as a single uniaxial
crystal, like quartz. This is the life-eld unveiled. Only, it is
not just the macromolecules that are polarized; instead it is
the water making up 70%–90% by weight of cells and tis-
sues that is polarized together with all the macromolecules,
as our detailed analysis showed. 31,32In fact, it is the water that
makes all macromolecules liquid crystalline, because living
water, aligned along the abundant surfaces of membranes
and macromolecules is itself liquid crystalline. 19
LiqUid crystaLLine Water is Life
Liquid crystalline water softens the macromolecules, making
them exible and enabling them to act as quantum molecu -
lar machines that transfer and transform energy at close to
100% efciency. If organisms were working even with the
efciency of electronic machines say, our laptop computers,
already much enhanced (in both sensitivity and efciency)
over ordinary machines, such as the motor-car, the amount
of heat generated would burn them up before you could say
“Christopher Robin!” 33 The energy transactions in living
cells and tissues are much denser than those in a laptop (at
least a billion times as dense), therefore, organisms haveto
be a lot more efcient; in other words, they have to approach
the zero-entropy quantum coherent state. 19,34
The archetypal quantum molecular machine is the
enzyme. Enzymes speed up chemical reactions in organ-
isms by a factor of 10 10 –10 23. And they cannot do that without
water. Water giving exibility to proteins reduces the energy
barrier between reactants and products and increases the
probability of quantum tunneling by a transient compression
of the energy barrier.
The Rainbow Worm 19 presents empirical evidence and
theoretical arguments that the organism is quantum coher-
ent, and that liquid crystalline water plays the lead in creating
and maintaining the coherence of organisms.
However, the full extent to which life, and probably the
universe and everything depends on water is still unfolding.
Astronomers now think that water is the most abundant sub-
stance in the universe, and it may be present at the birth of
the universe. In July 2011, two groups of astronomers in the
United States discovered the largest, most distant reservoir
of water—equivalent to 140 trillion times the water in earth’s
oceans—surrounding a massive black hole in a quasar more
than 12 billion light-years away. 35The conventional (big bang
cosmology) view of quasars with hypothetical supermassive
black holes and their supposedly enormous distance from us
is seriously open to question, 2,36but the presence of water is
not in doubt. Could it be that the universe too, is powered by
water electricity, as organisms are powered by water electric-
ity? This makes Whitehead’s 1vision of the universe as an
organism all the more remarkable.
I wrote a sequel to Rainbow Wormdedicated to water in
living organisms in 25 Living Rainbow H 2 O , which synthe-
sizes recent ndings in the quantum physics and chemistry
of water that tell us why it is so t for life. Water is “the
means, medium and message of life, the beautiful rainbow
within that mirrors the one in the sky.” Already further new
evidence has turned up since the book was published, and I
shall bring the story up to date.
Water is Weird and
WonderfULLy fit for Life
The water molecule is a dipole with separated positive and
negative charges associated with the oxygen and the two
hydrogen atoms, respectively, therefore, it can engage in
dipole interactions with other molecules of water or other
dipoles (see Reference 25 and references therein). However,
it seems to prefer to hydrogen bond most of the time, where
the hydrogen atom of one molecule is shared between two
oxygen atoms in neighboring molecules. The preferred con-
guration is a tetrahedron in which a molecule accepts two
hydrogen atoms and donates two hydrogen atoms to neigh-
boring molecules. It is estimated that at ordinary tempera-
tures and pressures, over 90% of the water molecules are
hydrogen-bonded, although the hydrogen bonds icker on
and off randomly in a matter of pico (10 − 12 ) seconds.
Analyzer
Slow
ra y
ψ= 7.5° Slow
ra y
F ast ray
Polarizer P
olarizer
Analyzer
F ast ray
ψ= 45°
figUre 10.6 The new setting stumbled upon that is especially
good for biological liquid crystals.
K22937_C010.indd 998/13/2014 10:51:37 AM
100 Bioelectromagnetic and Subtle Energy Medicine
Water is notorious for a host of anomalous properties (see
Box 1), due to its propensity to form hydrogen-bonds; and the
same anomalies are widely regarded as precisely the quali-
ties that make water t and essential for life.
qUantUm deLocaLization
of hydrogen Bond
The key to water’s remarkable properties is the hydrogen-
bond interconnecting water molecules, which is usually
regarded as classical and electrostatic; but many observations
are inconsistent with that picture.
Nobel laureate chemist Linus Pauling (1901–1994) in 1935
was the rst to suggest that the hydrogen bond and covalent
bond in ice may switch places in view of residual entropy
(randomness) existing even at very low temperatures, 39 and
thus, the hydrogen bond must be at least partly covalent.
In 1999, researchers at Bell Labs New Jersey in the United
| https://www.researchgate.net/publication/279920534_Life_is_Water_Electric |
(PDF) A High-Level Comparison between the South African Protection of Personal Information Act and International Data Protection Laws
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A High-Level Comparison between the South African Protection of Personal Information Act and International Data Protection Laws
March 2017
Conference: The 12th International Conference on Cyber Warfare and Security (ICCWS)
At: Dayton, Ohio, USA
Volume: 12
Download full-text PDF
Abstract and Figures
Data protection and management of personal information has become an integral aspect for organisations and individuals in conducting business in the modern era. It has also become a major issue for legislators, regulators and consumers worldwide due to the widespread repercussions when personal information is negligently or maliciously used. Despite increased attention on personal information and the existence of data protection legislation internationally, data breaches remain a common occurrence. It has become crucial now, more than ever, for organisations to manage and safeguard personal information. As a nation, South Africa has addressed the need for increased protection - the Protection of Personal Information (PoPI) Act was signed into law in November 2013. This paper presents a comparison between the South African PoPI Act and other international data protection laws in order to highlight similarities and differences. These privacy legislations will be compared based on the principles set out by the PoPI Act. Other areas to be considered include data protection officers, enforcement, electronic marketing, online privacy and the year enacted. Data protection compliance is not straightforward and having the correct measurements and procedures in place is of utmost importance. These findings can be applied in future work to examine where South Africans can make use of already established international best practices to best enforce their privacy regulation.
National Comprehensive Data Protection/Privacy Laws and Bills 2016 (Banisar, 2016) …
Data Protection Laws in Africa (Fichet, 2015) …
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A High-L evel C omparis on bet ween the Sou th A frica n Pr otec tion of
Per sonal In fo rmati on Ac t and In tern ationa l Dat a Pr otect ion Law s
J. Botha 1, 2 , M.M. Grobler 1, 4 , J. Hahn 3 , M.M. E loff 2
1 Council for Scientific and Industrial Research (CSIR), Pretor ia, South Africa
2 Institute for Corporate Citizenship, University of South Africa (UNISA), Pretoria, South Africa
3 Boston University, Boston, United States of America
4 University of Johannesburg, Johannesburg, South Africa
1 [email protected]
1 [email protected]
3 [email protected]
2 [email protected]
Abstract: Data protection and management of personal information has become an integral aspect for
organisations and individuals in conducting business in the modern e ra. It has also become a major issue for
legislators, regulators an d consumers world wide due to the widespread repercus sions when personal
information is negligently or malicious ly used. Despite increased attention on personal information and the
existence of data protection legislation internationally, data breaches re main a common occurrence. It has
become crucial now, more th an ever, for organ isations to manage and safeguard personal information. As a
nation, South Africa ha s addressed the ne ed for increased p rotection - the Protection of Personal Information
(PoPI) Act was signed into law in November 201 3. This paper present s a comparison between the South
African PoPI Act and other international data protection laws in order to highlight similarities and differences.
These privacy legislations will be compared based on the principles set out by the PoPI Act. Other areas to b e
considered include data protection officers, enforcement, electronic marketing, online privacy and the year
enacted. Data protection compliance is not straight forward and h aving the correct measurements and
procedures in p lace is of utmost importance. These findin gs c an be applied in future work to examine where
South Africans can make use of already established internation al best practices to best enforce their privacy
regulation.
Keywords: Data Breach; Compliance; Personal Information; PII, PoPI Act; Privacy Laws
1. In troduction/Background
The risk of breaching data protection legislation an d regulation has grown significantly with th e increase of the
amounts of personal data b eing kept by various organi sations and individuals (The Privacy Advisor, 2008) .
Since it is a global right for individuals to have their personal information protected against any unlawful
collection, retention, dissemination and use, a significant number of data protection laws hav e b een enacted
intern ationally. Europe, for example, adopted the European Union’s (EU) Data Prote ction Directive (DPD)
already in 1995 (Birnhack, 2008). This Directive h as been revised in 2015 and u nified into a law known as th e
Ge neral Data Protection Regulation (GDPR). The United Kingdom (UK) adopted th e Data Protection Act (DPA)
in 1998 (U nited Kingdom Government Gazette, 1998) , together with the EU DPD and was implemente d in
2000. The United States does not have a specific data protection legislation, but has enacted a number of
privacy laws since 2001 (Information Shield, N.D.) .
In South Africa, the Protection of Personal Information (PoPI) Act has been signed on November 26 th 2013
(South African Government Gazette, 2013), although the full enforcement d ate of th e PoPI Act is still to be
determined by the country’s pr ivacy regulator. South Africa is in the process of complying with the Act, but is
facing implementation challen ges. The objecti ve of this paper is thus to perform a comparison between the
PoPI Act an d selected available international data protection laws i n order to assess th e PoPI Act’s
comparability with international laws. Although the positions and criticism raised against the PoPI Act are
controversial (Heyink, 2015; Luck, 2014), this comparative research study aims to show t hat the PoPI Act is not
a step back in terms of law evolution, but rather a step towards the worldwide t endency to modern personal
information protection. It is un deniable that regulating the digital world is difficult as it ev olves faster than
legislation can be passed, but it should b e noted that technology does not have to complicate regulation, it can
also be harnessed to assist regulators in their efforts.
2. Methodology
A brief overview is presented on intern ational data protection laws and the PoPI Act, based on a desktop
study. The principles of the PoPI Act are compared at a high level with African and non-African data protection
laws (see sections 4 and 5) . A basic literature review is co nducted to gain a better understanding in terms of
the PoPI Act and similar Acts globally . This will give a sense of the actions required for PoPI compliance . Data
has been collected using existing literature as well as govern mental and private industry reports.
3. An overview of International Data Protection Laws and the South African PoPI Act
Globally more than 100 countries, independent jurisdiction s and territori es have adopted comprehensive data
protection/privacy laws to pr otect personal data held by governments an d private companies (Banisar, 2016) .
Figure 1 pre sents a map indicating which jurisdictions have adopted laws and which are currently addressing
this need: countries highlighted in blue have ena cted comprehensive data protection laws, wh ereas countries
in red have a pending obligation to enact such a law. The countries highlighted in white either have no
initiatives to enact a specific singular data protection law or no information about such laws i s available online.
South Africa is the 15 th African country to implement a data p rotection law (Fichet, 2015). The PoPI Act will not
be compared to all the countries highlighted in Figure 1 , but only to a selected few countries, chosen primarily
for their territorial location, large economies and mature regu lations.
Figure 1: National Comprehensive Data Protection /Privacy Laws and Bills 2016 ( Banisar, 2016)
The PoPI Act presents a set of conditions and principles that prescribe the way in which personal information
may be processed (Michalsons, 2014). The Act was created based on the EU DPD (Birnhack, 2008;
DataGuidance, 2013) and the Organisation for Economic Co -operation and Developm ent (OECD) principles
(PLI, 2016). It was further in spired by models of data privacy from th e United States (US), Canada, Australia
and the UK (Kokutse, 2011). The intention was to have personal in formation privacy regulated in South Africa
in harmony with international laws in order to stimulate business and cross-border transfer (Pillay, 2016) .
According to the Norto n Cybercrime Report, South Afric a ranks third in the world for cybercrime victims
(Business Media Liv e, 2015). South Africa was only surpas sed by China and Russia (Lamprecht, 2013). The high
ranking in cybercrime clearly raises the need for enforcing data protection laws and raising compliance
awareness. Crime however is not the only reason companies should endeavour to comply with the PoPI Act.
When dealing with personal i dentifiable information (PII), the PoPI Act mandates significant changes in bo th
governmental departments and commercial organisations. Legislated penalti es for failing to comply with the
Act are significant and can even lead to incarceration for n egligent corporate officer s. Having this legislation in
place opens new implications for disclosing PII (Sou th African Government Gazette, 201 3). Organisations will
not be allowed to use, store or process PII without individuals’ consent and will face co nsequences for non -
compliance to this Act. Consequences include but may not b e limited to:
Damage to a company's reputation.
Losing customers.
Inability to attract new customers.
Pay-outs in damages as a result of civil class action.
Fines of up to R10 million.
Facing jail time of up to 10 years.
These consequences, as well as the organisations’ will to protect individuals’ sensitive information, enforce the
need for organ isations to conduct themselves in a responsible manner regard ing PII. It i s p redicted that PoPI
will become enforceable towards the end of 2017. Organi sations should therefore focus on cond ucting PoPI
audits and putting PoPI policies in place to p revent these consequences. It is be lieved that implementing the
PoPI Act would aid global competitiveness, cybercrime and th e right to privacy (Gunning, 2016).
Table 1 gives a short description of each of the eight princ iples that guide the PoPI Act. In addition to these
principles, there are other important definitions and structures set by the PoPI Act. For example, the Act
entitles an ind ependent Information Regulator to promote and monitor the compliance wi th the law. Similar
to the EU DPD, the PoPI Act also applies to a non-resident in the country as long as the automated or non-
automated processing is within the country’s bord ers (Svantesson, 2014).
Table 1: Principles of the PoPI Act
PoPI Principle
Description
Accountability
The responsible party must ensure that the principles are adhered to.
Processing
Limitation
There must be limits to the processing of information; processing must be lawful and not
excessive.
Purpose
Specification
Personal information must be collected for a specific, defined and lawful purpose that is related
to the responsible party’s activity; the subject should be aware of this purpose.
Further Processing
Limitation
Any further processing must be compatible with the purpose that the information was collected
for.
Information Quality
The responsible party must ensure that the personal information is complete, accurate and not
misleading; the information can be updated if necessary.
Openness
A notification must be given to the Information Protection Regulator before the information is
processed the subject must be notified that data is being collected about them.
Security Safeguards
The responsible party must ensure that the integrity of the collected personal information is
maintained.
Data Subject
Participation
The subject has the right to ask and be given the details of any information on him/her that the
responsible party might have, at no cost.
(South African Government Gazette, 2013)
Since the PoPI Act requires changes in the way organisations conduct themselves in terms of the use and
processing o f PII, a comparative study was conducted to determine how the PoPI Act compares with
international data protection laws. Table 2 compares the P oPI Act first to other African co untries, whilst T able
3 compares it to o ther well estab lished non- African countries. E ach country’s Act will first be compared to the
principles set out by the PoPI Act, before comparing it to the following criteria (sele cted based on a number of
online resources found comparing data protection laws):
Data Protection Officer (DPO) required;
Breach notification;
International data transfer permitted under certain condition s (country specific);
Electronic marketing prohibited;
Online privacy addressed;
Enacted date.
The next sections present a high-level comparison of selected data protection laws.
4. Comparison to African Countries
The prevalence of data protection laws in Africa is increasin g, probably as a result of many organisations in
Africa doing bu siness global ly. As a result of Africa’s fast mobile t echnolog y adoption and increase in
technological exposure and en gagement (ENECA, 2014), personal information is o ften transferred across the
borders of various African co untries and als o from African countries to other internat ional regions. As s uch,
organisations doing business across multiple regions should be familiar with privacy laws applicable in the
various African countries and whether they have adequate p rotection levels.
The laws in different countries vary and both criminal and civil sanctions may ap ply for violations. When doing
business with thes e countries on e must take into account the laws an d relevant territori es to consider its risks
and costs (Michalsons, 2015). Up to date, 16 African coun tries have adopted data protection legislation, five
have instantiated d ata protection bills and nine are rumoured to instantiate such a bill (Fichet, 2015). Sinc e
June 2014 when the African Union (AU) adopted a Convention on Cybersecurity and Personal Data Protection,
more African countries have made some p rogress in terms of data protection legislation (Ncube, 2016). As
with South Africa, in several African countries, the process has been initiated but not fully compl eted. The
remainder of this section will present some common elements foun d among those countries.
Table 2 presents a comparison o f the PoPI Act to data prot ection laws in Africa. The countries listed are African
countries that have a specific data protection law in place , refer to Figure 2. Some countries su ch as E gypt,
Nigeria and Zimbabwe, cater for privacy in other laws and do not have a specific data protection law in p lace
(Craig, Mcormack, Halpert, Lucente, & Cheuk, 2012) ; these countries will not be included in the comparison.
Figure 2. Data Protection Laws in Africa (Fichet, 2015)
4.1 PoPI Principles
The PoPI Act principles are in line with most of the African data protection laws, according to the result s in
Table 2. In most of the African countries, th e data protection laws are referred to as the Protection of Personal
Data (PPD) Act, or so me variation thereof. Angola refers to the Personal Data Law (PDL), whereas Ghana re fers
to the Data Protection Act (DPA). In Morocco, the law is called the Protection of In dividuals in Relation to the
Processing of Per sonal Data (PIRPPD). Not enou gh information cou ld be found on the Comorian data
protection law and will therefore not be in cluded in th e comparison . Based on the results of Table 2, all of the
laws ha ve proc essing l imitations, purpose specification and information quality in common. All of the laws
require organisations to retain the pers onal information for the time requir ed to achieve the purpose of the
processing. However, in most cases, the specific time periods are not defined in these la ws. In ad dition, South
Africa is the only country that states accountability a s one of the principles (Rich, 2014). A lthough other African
countries might not have accoun tability as a principle, the y might make provision for this in the context of the
legislation. In every jurisdiction, there are security obligation s that are enfor ced. There is al so some sort o f
notice requirements for organisations to disclose the kind of personal information that is being collected, why
it is collected, whether it is shared and for what time period . Moreover, organisations are required to prove
that the securing of data integrity is being respected (Rich, 2014) . All laws state that the data sub ject has rights
(access, rectification and opposition) and should be fully i nformed of the data proces sing related to him/her
(Fichet, 2015). These common elements enforce the applicability of data privacy regulation within the African
countries.
PoPI
2013
Angola
PDL
2004
Morocco
PIRP
PD
2009
Senegal
PPD
DPA
2003
Tunisia
DPA
2004
4.2 Breach Notification
South Africa is the second African country to adopt the breach notification requirement, after Ghana (Rich,
2014) . When it comes to notice obligation, all the laws in Africa are uniform in r equiring the organisation to
disclose the type of personal information being collected, the reason for that and with whom it is shar ed.
Consent is still not uniform thou gh. In Benin, only sensitive p ersonal information requires consent (Rich, 2014) ;
while the PoPI Act dictates c onsent for any personal data. None of the other African data protection laws
requires notification of breaches (Craig et al., 2012) .
4.3 DPO Required
In all legal systems, the challenge is to make a new law enforceable once it is promulgated. Having clear
governance steps and punishment mechan isms in place is the com mon approach to this challenge, altho ugh
the majority of African countries have not yet appointed a regulator. South Africa recently appointed a privacy
regulator in May 2016. In Madagascar, the role of a data privacy officer was incorporated in legislation and a
special commission is to be established as the independ ent regulator (Craig et al., 2012). In Ivory Coast, the
enforcement mission was given to an independent administrative body of telecom munications (Rich, 2014 ) .
Mauritius has one of the most active enforcement regi mes in terms of volume of imposed administrative fines
(Rich, 2014). No other African country has app ointed a privacy regulator (or no information is available online).
4.4 Cross-Border Data Transfer
The PoPI Act prohibits offshore transfers of p ersonal data, b ut provides a number of ex ceptions where the Act
includes rules and regulations for international data sharing (Kirby, Meiring, & Burger-Smidt, N.D.). All African
countries, with the exception of Ghana, impose restrictions on cross-border data transfer. In Angola , the
transfer of personal information to countries that do not ensure an adequ ate level of protection requires, as a
rule, the individual’s unambiguous, explicit and written consent, and prior authorisation from the DPA. In
(Rich, 2014) . In Cape V erde, Gabon, Madagascar and Mauritius, the individual’s consent overrules the lack of
adequate protection offered by th e receiving country. In contrast, the DPA in Seychelles has the whole power
to define if a transfer would violate the principles ( Rich, 2014).
4.5 Electronic Marketing
PoPI provides data subjects with certain rights with resp ect to unsolicited electronic communications and also
prohibits automated processing of personal information . Benin, Cape Verde and Morocco also pro vide rights
to electronic marketing whereas there is no provision for th is in the r emainder of the African countries (Craig
et al., 2012).
4.6 Online Privacy
In terms of online privacy, only Angola and Cap e Verde made certain provision (Ango la City Government, N.D.) .
It might be a concern that the PoPI Act does not contain any provision for online privacy (Craig et al., 201 2).
4.7 Enacted Year
With regards to maturity, the PoPI Act is r elatively new, enacted in 2013. Madaga scar’s PPD is the most rec ent,
enacted in 2015. Some Africa n countries have data protect ion laws in place for over ten y ears. Seychelles has
the oldest legislation, enacted already in 2003, b ut has not yet been in operation (Craig et al., 2012). Age,
however, does not necessarily equate to maturity or completeness.
As the digital economy grows in Africa, adequate regulation requirements are getting t ougher. Many African
countries have yet to incorp orate data protection legislation; those countr ies that have adopted data
protection laws ar e facing difficulties in terms of implementation. However, all 53 African states agreed on a
legal framework for regulating ICT activities such as electronic transactions, enhancing cyber security, control
cybercrime and protecting personal data. This is a major step forward for Africa in terms of data protection
(Fichet, 2015).
This section compares the PoPI Act to s elected non-African countries. The countries were s elected based on
their global influence and the maturity of their regimes. The purpose of comparing the PoPI Act to these
countries is to assist in the identification of growth opportunities in data protec tion for South Africa, in terms
of benchmarking against global influential countries.
The EU regulation has a great influence on data protection laws in Africa (Fichet, 2015). Since the EU DPD has
been revised and unified into the GDPR (only to be enforced in 2018 (Ashford, 2016)), both these laws are
included into the comparison in Table 3. The GDPR includes child privacy protections that are similar to the US
Children’s Online Pr ivacy Protection Act (COPPA). The UK data protection law, the DPA, are in line with the EU
DPD. The exception is the DPA’s stronger legal protection for more sensitive information, includ ing ethnic
background, political op inions, religious beliefs, health, sexual health an d criminal records (United Kingdom
Canada has two federal laws. The Privacy Act (PA) covers the personal information-handling practises of
federal government departments and agencies, whilst the Personal Information Prot ection and Electronic
Documents Act (PIPEDA) cat er for the private sector only (Privacy Commissioner of Canada, 2014). Data
protection in Australia is currently a mix of Federal an d State/Territory legislation (Craig et al., 2012) .
Australian States an d territories (ex cept for We stern Au stralia and South Australia) each have their own data
protection legislation applying to State Government agencies.
The US is the exception in th is regard as it does not have a specific data protection law in place. It has rou ghly
20 sector specific or medium specific national privacy or d ata security laws, and hundreds of state-specific
laws. California, for example, has more than 25 state privacy and data security laws (Craig et al., 2012). Due to
its global influence, the US will be added to the comparison d espite not having a specific data protection law.
Table 3 presents the high -level comparison between the PoPI Act and selected non-African countries. The
(Craig et al., 2012). The GDPR does make provision for online priva cy in a number of ways such a s the e-Pri vacy
Directive (Beaumont, 2016). In the US, online privacy is catered for in a number of laws as well as online
privacy for children with COPPA (Jay, 2015).
5.6 Enacted Year
The Australian PA 1988 was amended in 2012 and came in to f orce in 2014. The Canadian PA has evolved,
since the first instance in 1977, to include data privacy in 2000 and has also been amended in 2015. T he
PIPEDA received approval in April 2000 (Privacy Co mmissioner of Canada, 2014) . Base d on the countries in
Table 3, the GDPR is the youngest Act, adopted in 2016 and will supersede the EU DPD in 2018 ( Bird & Bird,
2016) . The UK DPA has been updated since 2000 and all changes will be in force from 20 October 2016 (United
Kingdom Government Gazette, 1998 ).
Based on the literature r eview, provisions are made for most or all of the criteria meas ured on in Table 3. Data
protection can no longer afford to be ignored as it is bec oming a major issue for legislators, regulator s and
consumers worldwide. Using this comparison as benchmark, South Africa can be regarded as on par with
international privacy laws.
6. Conclusion
The amounts of personal data stored by individuals and organisations have grown significantly. This can result
in potential high data breach risks and other unlaw ful activities. In an attempt to provide pro tection to citizens,
a significant number of data protection laws have b een enacted internationally. With these laws in place, i t can
be regarded as a right for individuals to have their personal information protected against unlawful collection,
retention, dissemination and use. The world’s privacy landscap e has evolved as a result.
The privacy landscape in Afric a has also evolv ed, with South Africa adop ting the PoPI Act in 2013. Based on the
comparisons presented in Table 2 and Table 3 , the PoPI Act’s principle s are on par with selected African and
non-African data protection laws. South Africa seems to be one of only fou r African countries that appointed a
privacy officer/regulator. In this regard, the PoPI Act is ahead of other African countries without a DPO.
Compared to other countries outside of Africa, though, appointin g a privacy officer/regulator is the norm. In
Africa, only three countries m andates data breach notification, including South Africa. Australia and the UK do
not cater for d ata breach notifications. Europe did not include this in the EU DPD bu t did make provision for
this in th e GDPR. Most countries agree that the cross -border transfer is prohibited if the destination country
has no adequate protection in place. This fact gives sustainab ility to the conclusion that having regulation in
place, as South Africa is aiming to do, facilitates internation al commerce. Rights against electronic marketing
are imple mented in th e PoPI Act and o nly three other African countries. Comparing this to the selected non -
African countries, only Australia an d the EU DPD does not make provision for electronic marketing. The GDPR
does cater for this. Online privacy is only included in the laws of Angola and Cape Verde in the African
countries. All the non-African countries considered, includ e online privacy legislation.
According to the comparisons don e in this paper, the PoPI Act compares relatively well with other countries
more mature in terms of data privacy l egislation. This compar ison is valuable in terms of reflecting a true need
of international work on future harmonisation of law s.
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... New threats to the integrity and confidentiality of personal information are introduced by the Internet of Things (IoT), cloud computing and Big Data, and data protection initiatives are required as a result
(Botha et al, 2017)
. Globally, over one hundred countries have implemented data protection laws. ...
... The General Data Protection Regulation (GDPR) is arguably considered the gold standard of privacy legislation. South Africa's PoPI Act has been formed based on GDPR principles, alongside models from the USA, Canada, Australia and the UK
(Botha et al, 2017)
. ...
... The legislation aims to protect Personal Information (PI), prevent theft, and uphold the fundamental human right to privacy (Nel, 2021). For the Act to effectively meet its aims, there are legal consequences for non-compliance, including civil class action, fines of up to R10 million and jail time of up to 10 years
(Botha et al., 2017)
. ...
Aligning South African Data and Cloud Policy with the PoPI Act
On 1 April 2021, the South African government released the Draft National Data and Cloud Policy for public comment. This policy aims to support the digital economy in South Africa by implementing initiatives to augment the development of digital infrastructure and skills, with a specific focus on cloud computing. The adoption of the policy would help position the country as a data-driven economy. However, the implementation of such a policy is predicated on the existence of supporting digital infrastructure and aligned inter-departmental goals. Currently, there are many technological and legal considerations that must be addressed in order for such a policy to be implemented successfully. One particularly important consideration is how this policy relates to South Africa’s Protection of Personal Information Act, which came into effect on 1 July 2021. The Act sets out legal imperatives for the collection, storage and use of personal information belonging to South African citizens. The aim of this paper is to analyze how the Draft National Data and Cloud Policy relates to the Protection of Personal Information Act in terms of what is proposed in the Policy and what is legislatively imperative in the Act. The overarching context for this evaluation is data governance in the cloud with an emphasis on the security of personal information. Macroeconomic threats and a shortage of critical ICT skills presupposes technical challenges for the implementation of a cloud service. Formal Concept Analysis is utilized to conceptualize and understand the relationships between the Draft National Data and Cloud Policy and the Protection of Personal Information Act. Classification, Confidentiality and Open Data are presented as technological challenges to cloud implementation. This paper aims to contribute towards an understanding of these challenges and how they are affected by South Africa’s legislation and policies. We therefore investigate how the Draft National Data and Cloud Policy is situated in the broader context of data protection in South Africa.
... It was during the post-1994 period that labour legislation such as the new Labour Relations Act (66 of 1995) (Nel et al., 2008), new Basic Conditions of Employment Act (75 of 1997) (Grogan, 2014b:5), new Skills Development Act (97 of 1998) (Venter & Levy, 2014) and, finally, an absolutely new legislation called the Employment Equity Act (55 of 1998) (EEA) (Grogan (2014b) were promulgated by the South African government. Another legislation of significance was promulgated in 2013 called the Protection of Personal Information Act 4 of 2013 (or the PoPI Act), which has a direct impact on the operation of small and medium businesses (Botha, Eloff & Swart, 2015) and government institutions in South Africa
(Botha et al., 2017;
Baloyi & Kotze, 2017a). ...
... The reason for this is that there are still questions as to how these enterprises will survive as their business mostly depends on direct marketing, which is based on personal data. This notion is supported by
Botha et al. (2017)
, who state that it is a fact that, in terms of the PoPI Act, organisations will no longer be allowed to collect, use, store or process personal information without the permission of the person concerned. ...
... It will be determined by mechanisms that are made available by the legislation to challenge any violation thereof and receive the expected recourse thereto. In response to the argument,
Botha et al. (2017)
reveal that those who fail to comply with the PoPI Act will not go unpunished as there are legislated penalties for failing to comply with the stipulations of the Act. These penalties are severe and may include incarceration. ...
Workplace Relationship in South African Organisations
... It is imperative that the confidentiality of all individuals participating in the educational process, including students, teachers, and anybody else, is always maintained. The General Data Protection Regulation (GDPR) in Europe and the Children's Online Privacy Protection Act (COPPA) in the United States both require organizations to protect the personal data of individuals
(Botha et al. 2017
, Berger 2022. These laws are similar in that they require organizations to do whatever they can to protect the personal data of individuals, including students. ...
Open AI in Education, the Responsible and Ethical Use of ChatGPT Towards Lifelong Learning
Significant changes have been brought about in society, the economy, and the environment as a result of the quick development of technology and the interconnection of the world. Artificial intelligence has advanced significantly in recent years, which has sparked the creation of groundbreaking technologies like Open AI's ChatGPT. Modern technology like the ChatGPT language model has the potential to revolutionize the educational landscape. This article's goals are to present a thorough analysis of the responsible and ethical usage of ChatGPT in education, as well as to encourage further study and debate on this important subject. The study found that the use of ChatGPT in education requires respect for privacy, fairness and non-discrimination, transparency in the use of ChatGPT, and a few other factors that were included in the paper. To sustain ethics and accountability in the global education sector, it is advised in this study that all these recommendations be carried out.
... On its part, the POPI Act presents some key differences from both the GDPR and the DPA. Despite contrasting views concerning the efficacy of the POPI Act, this law certainly represents a step forward in the protection of personal data within South Africa
(Botha et al. 2017)
. Differently from the DPA and GDPR, the POPI Act is state-centric more than subject-centric. ...
‘Data sovereignty’ or ‘Data colonialism’? Exploring the Chinese involvement in Africa’s ICTs: a document review on Kenya
Information and Communication Technologies (ICTs) have become a crucial sector of China–Africa relations. As scholars have noted, Africa’s 4th Industrial Revolution (4IR) risks transforming into a new ‘scramble’ with foreign actors harnessing Africa’s data. The present article explores this issue at a discursive level, i.e. delving into policies, bilateral agreements, and laws. The focus is specifically on Kenya in that it is one of the most developed ICT markets in Africa and it is here that the Chinese tech giant Huawei began its investments in 1998. Via a document review, the article provides a preliminary discursive assessment of the extent to which Kenyan actors are effectively (dis)empowered with regard to their own 4IR. The analysis shows that both pan-African and bilateral agreements remain at a high level of abstraction: while this is the typical Chinese way of framing discourses on technological innovation, it also leaves room for political manoeuvring and potential forms of data colonialism.
... Authors compared 32 African data privacy laws at a fine-grained level against 30 features of data privacy law such as data quality, access, and collection [40]. Further, researchers
[27]
highlighted the similarities and differences between the South African Protection of Personal Information Act (PoPI) and the international data protection laws. Similarly, in [33], the author discussed and analyzed Asian data privacy laws in-depth. ...
Creation and Analysis of an International Corpus of Privacy Laws
The landscape of privacy laws and regulations around the world is complex and ever-changing. National and super-national laws, agreements, decrees, and other government-issued rules form a patchwork that companies must follow to operate internationally. To examine the status and evolution of this patchwork, we introduce the Government Privacy Instructions Corpus, or GPI Corpus, of 1,043 privacy laws, regulations, and guidelines, covering 182 jurisdictions. This corpus enables a large-scale quantitative and qualitative examination of legal foci on privacy. We examine the temporal distribution of when GPIs were created and illustrate the dramatic increase in privacy legislation over the past 50 years, although a finer-grained examination reveals that the rate of increase varies depending on the personal data types that GPIs address. Our exploration also demonstrates that most privacy laws respectively address relatively few personal data types, showing that comprehensive privacy legislation remains rare. Additionally, topic modeling results show the prevalence of common themes in GPIs, such as finance, healthcare, and telecommunications. Finally, we release the corpus to the research community to promote further study.
Botha, Grobler, Hahn and Eloff (2017)
South Africa is in the process of complying with the Act, but is facing enforcement challenges. In order to fast track the enforcement PoPI Act the study recommends policy makers to carefully look at how other nations managed to enforce information privacy laws. ...
THE MODERATING EFFECT OF INFORMATION SECURITY ON THE ADOPTION OF MOBILE MARKETING TRANSACTIONS AMONG SOUTH AFRICAN TERTIARY STUDENTS
Despite the fast pace of development within the mobile commerce industry globally, marketers in developing countries are still lagging in understanding why and how consumers participate in mobile marketing transactions. The literature reporting on mobile marketing transactions’ adoption in a South African context remains largely inconsistent and fragmented as most previous studies are based on the experience of consumers in a non-South African (and non-developing country) context. Therefore, this study identifies a literature gap, in that there lacks a sufficient critical mass of studies into the moderating effect of information security on consumer adoption of mobile marketing transactions in South Africa particularly among the youth who have a strong affinity for constant mobile connectivity. Furthermore, confronted with rapid changes in emerging technology, previous models of technology adoption are slowly becoming outmoded. Consequently, this study considered testing a proposed model on the predictive power of marketing-related mobile activity to help improve understanding and prognosis of the adoption of mobile marketing transactions in South Africa. Specifically, in order to render these tests robust, perceived information security was applied as a moderator variable to increase the explanatory power of the model. The objectives set out for this research were measured utilising a single cross-sectional approach, guided by the positivist paradigm. In keeping with the dictates of ensuring the highest levels of reliability and validity, a measuring instrument developed from past studies was used. Using a self-administered questionnaire, data were collected from a sample of 810 students from selected South African universities. Descriptive and multivariate statistical tests including the moderated hierarchical regression analysis were used to analyse data. The implication of the study is that it provides both marketers and policymakers with a set of controllable variables that may be manipulated to promote the adoption of mobile marketing transactions.
... Another important component, which informs the way access control will operate, is South Africa's PoPI Act, which is similar to the European Union's General Data Protection Regulation (GDPR)
(Botha et al., 2017)
. The PoPI Act aims to protect personal information by specifying the conditions for the lawful processing of personal information (RSA Government Gazette, 2013). ...
A system architecture for ensuring interoperability in a South African national electronic health record system
Countries such as South Africa have attempted to leverage eHealth by digitising patients' medical records with the aim of improving the delivery of healthcare. This involves the use of an electronic health record (EHR) which is a longitudinal electronic record of a patient's information. The EHR includes all the patient's encounters that have been made with different health facilities. In the national context, the EHR is also known as a national EHR, which enables the sharing of patient information between points of care. However, a lack of interoperability exists between many South African health information systems making communication between these disparate systems impossible. As a result, the sharing of patient information is inhibited and the benefit of improving healthcare delivery cannot be realised. This paper proposes a system architecture for addressing interoperability challenges and indicates how interoperability can be ensured in a national EHR system. The proposed system architecture is differentiated from other national EHR system architectures found in the literature in order to emphasise its novelty. Secondary data obtained from a systematic literature review was analysed using content analysis, resulting in 9482 tags which informed the development of the proposed system architecture.
A Brief History of Privacy Discourse
Telecommunications in South Africa: Enforcement of Competition
The governance of data protection in South Africa
| https://www.researchgate.net/publication/311495321_A_High-Level_Comparison_between_the_South_African_Protection_of_Personal_Information_Act_and_International_Data_Protection_Laws |
Plane shot down over Syria puts Russia-Israel relations to the test - Al-Monitor: Independent, trusted coverage of the Middle East
A Russian plane downed by Syrian missiles responding to an Israeli strike has strained relations between Moscow and Tel Aviv and sent both sides into crisis-management mode.
Plane shot down over Syria puts Russia-Israel relations to the test
A Russian plane downed by Syrian missiles responding to an Israeli strike has strained relations between Moscow and Tel Aviv and sent both sides into crisis-management mode.
A Russian Il-20 aircraft takes off from the Rostov-on-Don military airport, Russia, March 6, 2014. - REUTERS/Sergey Pivovarov
MOSCOW — The downing of the Russian Il-20 transportation jet by Syrian air defense systems over what Moscow described as “Israeli provocation” is probably the single most important crisis Russia has experienced in Syria since the killing of dozens of its mercenaries in Deir ez-Zor at the hands of the US military in February. The downed plane carried 15 people and fell in Latakia province.
The first analogy that popped up immediately after the incident was Turkey's downing of a Russian jet in November, 2015. The similarity looked even more menacing just hours after Russia survived itsstress test with TurkeyoverIdlib.
Russian Defense Ministry was quick to announce that the plane disappeared from radar after “sudden” Israeli strikes on Syria and was eventually hit by Syrian S-200 anti-aircraft systems targeting Israeli jets. Israel was thus named responsible for the incident.
“The guilt for the downed plane lies fully with the Israeli party,” Russian Defense MinisterSergei Shoigutold his Israeli counterpart Avigdor Liberman in a phone conversation following the incident. Shoigu stressed that Moscow had repeatedly warned Israel against strikes on Syria via different channels.
“We consider these provocative actions by Israel to be hostile. The 15 Russian military service members died because of the irresponsible actions of the Israel military. It's absolutely contrary to spirit of Russian-Israeli partnership. We reserve theright to respondappropriately," the Russian Defense Ministry stated.
Russia’s initial complaint was two-fold: Israel violated the bilateral de-escalation agreement that helped prevent incidents in the past by warning Moscow of the attack on Idlib only a minute before first strikes were launched, leaving the Russians unable to withdraw the plane from a dangerous zone. The Israeli move was “unfriendly” as its jets used the Russian plane as cover from Syria’s air defense systems.
“As a result, the Il-20, which has an effective reflective surface an order of magnitude greater than that of the F-16 [which Israel used in the attacks] was hit by an S-200 missile,” commented the Defense Ministry's Igor Konashenkov.
One of Russia’s most authoritative military experts, Mikhail Khodarenok, argued that the French too bear a share of responsibility for the downed plane. HetoldRIA Novosti, “The French frigate 'Auvergne' contributed negatively to the situation in the skies over Syria by creating complications for Syrian combat units operating anti-aircraft systems. It was in the wrong place at the wrong time.”
Russian airspace control systems registeredmissile launches from a French frigatein the Mediterranean Sea on Sept. 17 around 8 p.m., prompting Moscow to initially blame Paris for the incident.
The immediate reaction by Russian decision-makers was mixed but strong. Senator Alexey Pushkov, who is on the US sanctions list and chairs the temporary Committee on Information Policies and Engagement at the Russian Council of the Federation, took a cautious stance, saying, “The degree of theintent by the Israeli partymust be precisely defined at this point and it will be done via closed channels.”
Backlash from his colleagues in the Senate and the Duma, however, varied from calls for “hard talk” with Israel over the incident to imposing sanctions and breaking diplomatic ties.
Military options presented to the Kremlin by policy-makers and experts in first few hours after the incident included deliveries of more advanced air defense systems to Syrians to guard from future Israeli attacks and “sealing off” the skies over Syria to any foreign power, including Israel, with Russia’s own S-400 missile system.
Few in either circle wondered about Syria's responsibility in the incident. What is under discussion is the Syrian army’s own ability to properly handle the advanced Russia-made anti-aircraft systems as well as whether they knew about the Russian plane before the Israeli attacks or saw it on their radar screens as they opened fire. If so, was there a decision to continue shooting the missiles, aware of potential risks for the Russian crew, or was it just a fatal mistake caused by an “indiscriminate missile launch” — the theory propagated by the Israeli military?
Russian PresidentVladimir Putincommented, “It’s a different situation,” when asked whether Russia will retaliate against Israel as it did against Turkey in 2015. “Back then, the Turkish jet deliberately targeted our aircraft. Here, rather, it appears to be a chain oftragic situational circumstancesbecause Israeli jets didn’t hit our [plane],” Putin explained at a press conference with Hungary’s President Viktor Orban.
Israeli Prime Minister Benjamin Netanyahu called Putin later that day to express condolences on the death of Russian servicemen and to promise a “thorough investigation” into the incident, the results of which will be brought to Moscow personally by the Israeli air force commander.
According to the Kremlin, Putin “reminded” Netanyahu that “such operations by the Israeli military are conducted in violation of Syrian sovereignty” and that in this particular case,Russian-Israeli agreementson the prevention of dangerous incidents were not observed.
“Mr. Putin called on the Israeli party to prevent such situations from happening in the future,” read the press release.
The Israeli forces went into crisis-management mode,communicating with Moscowabout the initial inquiry findings. While some commentators in Russia continue to insist that Israel “is playing a dangerous game,” the general backlash in Moscow and on social media gradually turned towardcriticism of the Russian governmentitself for its failure to prevent the killing of its servicemen. Putin was accused of growing “too cozy with Bibi,” which allegedly emboldened Israel, and blamed for Russia’s inability to act upon the Israeli strikes on Syria as they began. Military experts questioned the effectiveness of communication channels between both the Russian and Syrian militaries and between Russia and the Israelis.
The attack came at a bad time for the Russian president, whose ratings have been shaken by the unpopular pension reform. Pressure is on Putin to manage the crisis with Israel in a swift and convincing manner for his domestic constituency as more start questioning the meaning of the Russian presence in Syria — doubt that sprouts up every time Russia suffers human loses in the campaign.
The incident also came as a wake-up call for Moscow to rethink the security of its personnel that over the course of the Syrian campaign suffered loses from Turkish, American and now Syrian forces, not to mention terrorist and opposition militants. In a broader sense, the tragic incident exposed that no matter how effective the de-confliction channels that Moscow established with major stakeholders operating in Syria, they cannot perfectly prevent potential collisions when there are far too many military actors operating in a relatively small terrain and air space.
“We should have seen it coming,” a Russian diplomat speaking not for attribution told Al-Monitor, adding, “When you have that many forces that close to one another the risk of an accidental mistake is high. You think the war is coming to its end but parties are acting in an even more uncompromised way and we, sadly, may end up seeing more of such incidents.”
| https://www.al-monitor.com/originals/2018/09/russia-israel-syria-downed-plane.html |
Zip code 02382 Massachusetts Education data and school information 02333 and 02351
Zip code 02382 Massachusetts Education data with local analysis and research 02333 and 02351
ZIP code 02382 Education Attainment Charts
This section of charts contains education data for ZIP code 02382 Massachusetts based mainly on the latest year 2022 Census data using the American Community Survey but also the survey from Common Core Data available for Public Elementary through Secondary Schools. In
Figure 1
, the percent of all people aged 25 years or older, who have either graduated from high school or completed the Graduate Equivalency Degree (GED) or some equivalent certification/credential.
02382
depicts it has a High School Grad or higher of 95% which is the second most percent high school graduates or better of all the zip codes in the greater ZIP code 02382 region. The zip code with the highest percent high school graduates or better in the area is
02333
which shows a high school graduates of 96% ( about the same size).
In
Figure 2
, the percentage of people aged 25 years or older who have graduated from college/university with at least a bachelor's degree is provided. Note that the bachelor's degree is also called a four-year degree because it normally takes four years of full-time study to finish the course curriculum required to obtain the degree. This chart portrays the proportion of the population in this region who are college graduates with at least a bachelor degree or higher. In many ways, this analysis alongside the prior chart are very quick measures of the level of education in any particular area. ZIP code 02382 shows it has a Bachelors Degree or higher of 27% which is the second smallest when ranked by percent with a bachelors degree or higher of all the other zip codes in the greater region. The zip code with the highest percent with a bachelors degree or higher in the area is
02351
which indicates a percent with a bachelors degree of 41% (55.4% larger).
Figure 4
shows the percentage of people 25 years of age or older who either have no schooling at all or dropped out of school before being able to complete high school. Additionally, these are people who also do not have a Graduate Equivalency Degree (GED) or some other high school level type credential/student achievement. This analysis, along with the last two charts, provides another high level review and comparative data on the ZIP code 02382 Massachusetts educational level.
02382
shows it has a School Dropout Rate of 5% which is the second smallest as measured by percent who dropped out of school of all the other zip codes in the local area. The zip code with the highest percent who dropped out of school in the area is
02302
which depicts a percent who dropped out of school of 16% (approximately 3.4 times bigger).
Figure 5
provides a more detailed look at the educational attainment for ZIP code 02382 Massachusetts. This chart provides the proportion of people aged 25 years of age or older and what was their level of educational attainment. The chart provides 5 broad categories including: No Education/No School, Some High School, High School or equivalent, Some college or Associates Degree, and Bachelors Degree or higher. ZIP code 02382 has the percentage of percent of people with no schooling in the mid range of other zip codes in the area at 4% of the total. Second, it has the largest proportion of percent of people with high school degree, ged, or equivalent at 35% of the total and is ranked #1.
The next chart shows a break down of people who have received a bachelor's degree or higher advanced degree generally in a campus learning environment. In particular,
Figure 6
, provides the proportional breakdown of all the people who have received a postsecondary education along with what the level of advanced degree that was obtained. Note that these categories do not include any type professional development type activities such as those related to maintaining professional credentials in workshop lessons. Note Professional Degree includes medical, dental, lawyers, etc. ZIP code 02382 has the percentage of percent of people with an associate degree the second smallest in terms of percent of people with an associate degree of all the other zip codes in the local area at 45% of the total. Second, it has the smallest proportion of percent of people with a masters degree at 2% of the total.
The chart in
Figure 7
shows the broad area of academic concentration or the discipline for people who have received a bachelors degree. This high level classification is essentially the field of study for which a degree was obtained. ZIP code 02382 has the percentage of percent of people with a degree in a science or engineering related the second smallest in order of percent of people with a science or engineering degree of all the other zip codes in the local area at 23.7% of the total. Second, it has the smallest proportion of percent of people with an arts, humanities, or other degree at 14.1% of the total. Third, it has the largest proportion of percent of people with a business degree at 17.5% of the total and is ranked #1.
The next chart (
Figure 8
) provides a more detailed deep dive on the category of major degree obtained for people aged 25 years or older who earned a bachelor's degree or higher. Specifically, this frequency distribution details out what the major field of study was the degree obtained. ZIP code 02382 has the smallest proportion of percent of people with a degree in science and engineering related fields at 14.1% of the total. Second, it has the largest proportion of percent of people with a degree in business at 17.5% of the total and is ranked #1.
Figure 9
provides comparative data between the places in the greater ZIP code 02382 Massachusetts region for broad educational attainment. This analysis uses provides five broad education attainment categories including: No Education/No School, Some High School, High School or equivalent, Some college or Associates Degree, and Bachelors Degree or higher. ZIP code 02382 has the largest proportion of percent of people with high school (or ged) at 35.5% of the total and is ranked #1.
A more detailed frequency distribution of educational attainment is provided in
Figure 10
. In particular this illustration breaks out the highest levels of university educational opportunities beyond the four year college degree. Included in the breakout are the relative proportion of masters degrees, PhD/Doctorate/Doctorial holders, and professional degrees such as medicine, dentistry, lawyers, etc. ZIP code 02382 has the percentage of percent of people with no schooling in the middle range of other zip codes in the surrounding region at 4.3% of the total. Second, it has the largest proportion of percent of people with some college but not a graduate at 13.5% of the total and is ranked #1. The next exhibit (
Figure 11
) provides detailed cross tabulation analysis that provides education success data broken out or cross tabulated by age group. Please note that the columns add to 100% and you must use the pagination buttons at the bottom of the table to see all the rows.
Figure 12
is a cross tabulation analysis that shows large educational success categories and is broken out or cross tabulated by racial group. Please note that the columns add to 100% and you must use the pagination buttons at the bottom of the table to see all the rows.The final cross tabulation analysis is provided in
Figure 13
and shows education success broken out by gender. Please note that the columns add to 100% and you must use the pagination buttons at the bottom of the table to see all the rows.
ZIP code 02382 School Enrollment Charts
The next section of chart resources look at school enrollment by a variety of educational institutions and are categorized into a number of other groupings.
Figure 14
provides the overall school enrollment by broad range of school age/level groupings. ZIP code 02382 has the largest proportion of percent of children in grades 5 to 8 at 30.9% of the total and is ranked #1.
Figure 15
provides a simple high level comparison of the proportion of students that are enrolled in public schools versus students enrolled in private schools in the ZIP code 02382 Massachusetts region. ZIP code 02382 depicts percent enrolled in public schools substantially bigger as the percent enrolled in private schools.
The next comparison provided in
Figure 16
shows the proportion of students enrolled in private schools versus students enrolled public schools for students enrolled in Kindergarten through 8th grade (grade 8) or (K through 8). ZIP code 02382 indicates percent of children enrolled in public k-8 grades very much bigger as the percent of children enrolled in private k-8 grades.
Figure 17
provides a comparative analysis all students enrolled in a public high school versus those students who are enrolled in private high school schools. ZIP code 02382 shows percent enrolled in a public high school very much bigger as the percent enrolled in a private high school.
The next chart (
Figure 18
) provides a similar analysis to the last chart but provides the data for public post secondary education versus private higher education colleges. ZIP code 02382 depicts percent enrolled in a public college 13.8% larger as the percent enrolled in a private college.
Figure 19
shows another view of students enrolled in public or private schools-postsecondary schools or colleges/universities. This analysis shows the proportion for all graduate and professional schools (such as law or medical school) and whether those students are enrolled in private or public institutions. ZIP code 02382 depicts percent enrolled in a public gradudate or professional school approximately three-fourths the size as the percent enrolled in a private gradudate or professional school.
The next chart in this series of resources shown in
Figure 20
looks at the total number of students enrolled in any educational institution for each place in the greater ZIP code 02382 region. (Total enrollment in this case includes all students from preschool all the way through students enrolled in graduate school.) ZIP code 02382 depicts it has a Total Enrolled of 3,953 which is the second most total enrolled of all the zip codes in the greater ZIP code 02382 region. The zip code with the highest total population enrolled in school in the area is
02302
which shows a total population enrolled in school of 9,337 (approximately 2.4 times bigger). Comparing total population enrolled in school to the
United States
average of 81,076,829, ZIP code 02382 is only about 0.0% the size. Also, benchmarked against the state of
Massachusetts
, total population enrolled in school of 1,720,058, ZIP code 02382 is only about 0.2% the size.
The final chart in this series is
Figure 22
and provides analysis data for the school year shown. The chart shows the proportion of kids/children that are enrolled in a pre-school public district versus those kids/children who are enrolled in a private pre-school oriented tuition institution (private salary/superintendent/etc.) ZIP code 02382 Massachusetts has the percentage of public preschool enrollment the second smallest when ranked by percent enrolled in public preschool of all the other zip codes in the metro area at 28% of the total.
ZIP code 02382 Area Schools Charts
Figure 23
lists all the schools in the area along with the school district, county location and other program information/credential such as if they are a public charter school or private charter school or magnet school. Some of the Area Schools are: Louise A Conley, Whitman Middle, John H Duval, Whitman Hanson Regional, and Center Elementary School. The next illustration in
Figure 24
shows the total child school enrollment for all grades (through 12th grade) at the school shown using NCES data (Common Core of Data, Public Elementary-Secondary School Universe Survey.) Looking at Enrollment for Area Schools we find that Whitman Hanson Regional ranks the largest with a value of 1,192 enrolled students. The next largest values are for: Mary E. Baker School (755), Beaver Brook Elementary School (685), John H Duval (626), and Downey (582). The difference between the highest value (Whitman Hanson Regional) and the next highest (Mary E. Baker School) is that the enrolled students is about 57.9% larger.
Figure 25
show the ratio of the number of students to the number of teachers in the classroom. A good student to teacher ratio should be low because it indicates that there are less students for any one teacher to educate in a class and generally a better learning environment, better success and optimal teaching excellence. Teachers includes all educational staff such as special education teachers and any other educator. Note that distance learning (online learning/remote learning) is not included in these values. Looking at Student to Teacher Ratio for Area Schools we find that East Middle School ranks the largest with a value of 10.1 student to teacher ratio. The next largest values are for: Ashfield Middle School (12.3), Abington High (12.8), R Stewart Esten (13.9), and Downey (15.0). The difference between the lowest value (East Middle School) and the next lowest (Ashfield Middle School) is that the student to teacher ratio is 22.0% larger.
The next chart,
Figure 26
, shows the racial mix of students at each location in this district of the state of Massachusetts department of education.
Zip code 02382, Massachusetts Education Data
Demographics
Housing
Figure 1: 02382, MA At least High School Education Figure 2: 02382, MA Bachelors Degree or Better Education 0% 50% 100% 02302 United States Massachusetts Boston-Worcester- Providence 02343 02341 02370 02351 02382 02333 Place High School Grad or higher 02302 84% United States 89% Massachusetts 91% Boston-Worcester-Providence 91% 02343 93% 02341 94% 02370 94% 02351 95% 02382 95% 02333 96% Providence 0% 50% 100% 02302 02382 02343 02333 02370 United States 02341 02351 Boston-Worcester- Providence Massachusetts Place Bachelors Degree or higher 02302 18% 02382 27% 02343 30% 02333 30% 02370 32% United States 34% 02341 35% 02351 41% Boston-Worcester-Providence 44% Massachusetts 45% Providence
Figure 3: Advertisement Figure 4: 02382, MA School Dropout Rate 0% 10% 20% 02333 02382 02351 02370 02341 02343 Boston-Worcester- Providence Massachusetts United States 02302 Place School Dropout Rate 02333 4% 02382 5% 02351 5% 02370 6% 02341 6% 02343 7% Boston-Worcester-Providence 9% Massachusetts 9% United States 11% 02302 17% Providence
Figure 5: 02382, MA Education Attainment Breakdown Figure 6: Higher Education Attainment (100%=All People with Bachelor or better) Some college or Associates Degree High School or GED Bachelors Degree or higher Less than High School No schooling 35.5% 26.6% 33.1% Place 02382 Some college or Associates Degree 0.355 High School or GED 0.331 Bachelors Degree or higher 0.266 Less than High School 0.043 No schooling 0.005 No schooling Bachelors degree % Associate degree % Masters degree % Professional school degree % Doctorate degree % 44.9% 18.6% 33.7% Place 02382 Bachelors degree % 0.449 Associate degree % 0.337 Masters degree % 0.186 Professional school degree % 0.018 Doctorate degree % 0.009 Doctorate degree
Figure 7: 02382, MA Bachelors Degrees Field of Study Science & Engineering Science and Engineeri… Arts, Humanities, Other Business Education 02382 02333 02351 02302 02370 02341 02343 United States Massachusetts Boston-Worcester-Provi… 0% 50% 100% Place Science & Engineering Science and Engineering Related Arts, Humanities, Other Business Education 02382 34.8% 9.9% 23.7% 14.1% 17.5% 02333 29% 13.2% 28.4% 18.7% 10.7% 02351 30.4% 9.3% 33.9% 17.3% 9.1% 02302 35.2% 7.4% 27.8% 19.6% 10.1% 02370 29.4% 5.9% 31.7% 23.2% 9.8% 02341 36.3% 9.4% 21.8% 18.4% 14.1% 02343 41.4% 12.3% 27.3% 15% 4.1% United States 35.8% 9.7% 23.7% 19.6% 11.2% Massachusetts 41.2% 8.5% 25.1% 16.9% 8.3% Boston-Worcester-Providence 40.6% 8.6% 24.6% 17.6% 8.5% Science and Engineerin…
Figure 8: 02382, MA Bachelors Degree Obtained Computers, Mathemat… Biological, Agricultura… Physical and Related S… Psychology Social Sciences Engineering Multidisciplinary Studies Science and Engineering Related Business Education Literature and Languages Liberal Arts and History 1/2 02382 0% 5% 10% 15% 20% Place Computers, Mathematics and Statistics Biological, Agricultural, and Environmental Sciences Physical and Related Sciences Psychology Social Sciences Engineering Multidisciplinary Studies Science and Engineering Related Business Education Literature and Languages Liberal Arts and History Visual and Performing Arts Communications Other 02382 4.2% 4.1% 2.6% 7.7% 8.8% 7.4% 0% 9.9% 14.1% 17.5% 3.7% 6.2% 2.9% 3.7% 7.3% 0/0
Figure 9: 02382, MA Education Attainment by Level Comparison (Age 25+) No schooling Less than High School High School or GED Some college or Associates Degree Bachelors Degree or higher 02382 02333 02351 02302 02370 02341 02343 United States Massachusetts Boston-Worcester-Provi… 0% 50% 100% Place No schooling Less than High School High School or GED Some college or Associates Degree Bachelors Degree or higher 02382 0.5% 4.3% 33.1% 35.5% 26.6% 02333 0.9% 3.3% 31.6% 33.8% 30.4% 02351 0.9% 4.1% 28.7% 25.1% 41.3% 02302 3.5% 12.9% 36.8% 29.2% 17.5% 02370 1.8% 3.8% 31.8% 31.1% 31.5% 02341 0.9% 5% 32.6% 26.4% 35.1% 02343 0.7% 6.2% 29.1% 33.7% 30.3% United States 1.6% 9.5% 26.5% 28.7% 33.7% Massachusetts 1.6% 7.2% 23.2% 22.8% 45.2% Boston-Worcester-Providence 1.5% 7.1% 23.9% 23.6% 43.9% Bachelors Degree or higher
Figure 10: 02382, MA Education Attainment Detailed Comparison (Age 25+) No schooling Less than High School High School or GED Some college Not Graduate Associate degree Bachelors degree Masters degree Professional school degree Doctorate degree 02382 0% 20% 40% Place No schooling Less than High School High School or GED Some college Not Graduate Associate degree Bachelors degree Masters degree Professional school degree Doctorate degree 02382 0.5% 4.3% 33.1% 22% 13.5% 18% 7.4% 0.7% 0.4% Doctorate degree
Figure 11: 02382, MA Detailed Education Attainment Breakout by Age Group (Age 18+) Education 18 to 24 years 25 to 34 years 35 to 44 years 45 to 64 years 65 years and over 9th to 12th grade, no diploma 13% 3% 2% 4% 5.4% Associates degree 10% 13% 12% 15% 12.1% Bachelors degree 11% 25% 30% 13% 8.6% Graduate or professional degree 6% 11% 13% 6% 7.4% 1 2
Figure 12: 02382, MA Detailed Education Attainment Breakout by Race (Age 25+) Education White Black American Indian Asian Native Hawaiian Hispanic Bachelors degree or higher 26% 51% 31% 38% 0% 13.0% High school graduate or GED 34% 22% 0% 20% 0% 15.2% Less than high school diploma 4% 5% 0% 13% 0% 27.8% Some college or associates degree 36% 22% 69% 28% 0% 43.9%
Figure 13: 02382, MA Detailed Male and Female breakdown of Educational Attainment Education Total Male Female Associates Degree 14% 13% 14.1% Bachelors Degree 18% 14% 21.3% Doctorate degree 0% 1% 0.1% High school/GED 33% 39% 27.6% Less than High School 4% 3% 5.1% Masters degree 7% 5% 9.7% No schooling completed 1% 1% 0.5% Professional school degree 1% 0% 1.1% Some college-No Degree 22% 24% 20.4% Total 100% 48% 51.8%
Figure 14: 02382, MA School Enrollment by Aggregate Categories Kindergarten Grade 1 to 4 Grade 5 to 8 Grade 9 to 12 College, undergraduate Graduate or prof school 02382 02333 02351 02302 02370 02341 02343 United States Massachusetts Boston-Worcester-Provi… 0% 50% 100% Place Kindergarten Grade 1 to 4 Grade 5 to 8 Grade 9 to 12 College, undergraduate Graduate or prof school 02382 5.1% 21.4% 21.1% 30.9% 17.4% 4.1% 02333 5.5% 22.9% 23.5% 23.6% 16.8% 7.6% 02351 5.1% 21.3% 28% 22.7% 17% 5.9% 02302 5.2% 19.6% 24.9% 24.7% 19.4% 6.3% 02370 8.4% 21.3% 26.3% 20.8% 18.5% 4.6% 02341 3.3% 31.5% 17.3% 19.3% 25% 3.6% 02343 1.8% 13.6% 24.9% 26.3% 28% 5.3% United States 5.3% 21.1% 22.3% 22.6% 23% 5.8% Massachusetts 4.7% 18.2% 19.8% 21.4% 26.9% 9% Boston-Worcester-Providence 4.7% 18.6% 20.2% 21.6% 26.3% 8.6% Graduate or prof school
Figure 15: 02382, MA Overall Public vs. Private School Enrollment Figure 16: 02382, MA Public vs. Private K-8 School Enrollment Public Sc… Private S… 0% 50% 100% 02382 02333 02351 02302 02370 02341 02343 United States Massachusetts Boston-Worcester- Providence Place Public School Enrollment Private School Enrollment 02382 86% 14% 02333 87% 13% 02351 75% 25% 02302 83% 17% 02370 80% 20% 02341 77% 23% 02343 73% 27% United States 83% 17% Massachusetts 73% 28% Boston-Worcester-Providence 73% 27% Private Sc… Public K-… Private K… 0% 50% 100% 02382 02333 02351 02302 02370 02341 02343 United States Massachusetts Boston-Worcester- Providence Place Public K-8 Enrollment Private K-8 Enrollment 02382 97% 3% 02333 98% 2% 02351 86% 14% 02302 90% 10% 02370 94% 6% 02341 84% 16% 02343 91% 9% United States 88% 12% Massachusetts 91% 9% Boston-Worcester-Providence 90% 10% Private K-…
Figure 17: 02382, MA Public vs. Private High School Enrollment Figure 18: 02382, MA Public vs. Private College Enrollment Public Hi… Private… 0% 50% 100% 02382 02333 02351 02302 02370 02341 02343 United States Massachusetts Boston-Worcester- Providence Place Public High School Enrollment Private High School Enrollment 02382 94% 6% 02333 91% 9% 02351 89% 11% 02302 90% 10% 02370 84% 16% 02341 90% 10% 02343 80% 20% United States 89% 11% Massachusetts 88% 12% Boston-Worcester-Providence 88% 13% Private H… Public C… Private C… 0% 50% 100% 02382 02333 02351 02302 02370 02341 02343 United States Massachusetts Boston-Worcester- Providence Place Public College Enrollment Private College Enrollment 02382 53% 47% 02333 81% 19% 02351 44% 56% 02302 76% 24% 02370 53% 47% 02341 60% 40% 02343 59% 41% United States 78% 22% Massachusetts 50% 50% Boston-Worcester-Providence 51% 49% Private Co…
Figure 19: 02382, MA Public vs. Private Graduate or Professional School Enrollment Figure 20: 02382, MA Total Enrolled in Schools Public Gr… Private… 0% 50% 100% 02382 02333 02351 02302 02370 02341 02343 United States Massachusetts Boston-Worcester- Providence Place Public Gradudate or Pro school enrollment Private Gradudate or Pro school enrollment 02382 41% 59% 02333 18% 83% 02351 52% 48% 02302 39% 61% 02370 32% 68% 02341 100% 0% 02343 63% 37% United States 60% 40% Massachusetts 32% 68% Boston-Worcester-Providence 33% 68% Private G… 0 5,000 10,000 02341 02343 02333 02351 02370 02382 02302 Place Total Enrolled 02341 2,379 02343 2,506 02333 3,523 02351 3,760 02370 3,863 02382 3,953 02302 9,337 ...
Figure 21: Advertisement Figure 22: 02382, MA Public vs. Private Preschool Public pr… Private p… 0% 50% 100% 02382 02333 02351 02302 02370 02341 02343 United States Massachusetts Boston-Worcester- Providence Place Public preschool enrollment Private preschool enrollment 02382 72% 28% 02333 76% 25% 02351 50% 50% 02302 63% 37% 02370 62% 38% 02341 46% 54% 02343 23% 77% United States 59% 41% Massachusetts 50% 50% Boston-Worcester-Providence 49% 51% Private pr…
Figure 24: 02382, MA School Enrollment (2013) Enrollment Center Elementary School R Stewart Esten Jefferson Elementary School Frolio Middle School East Middle School Hanson Middle School Ashfield Middle School Abington High Louise A Conley Whitman Middle Downey John H Duval Beaver Brook Elementary School Mary E. Baker School Whitman Hanson Regional 0 1000 2000 School Name Enrollment Center Elementary School 190 R Stewart Esten 301 Jefferson Elementary School 309 Frolio Middle School 344 East Middle School 426 Hanson Middle School 473 Ashfield Middle School 478 Abington High 502 Louise A Conley 564 Whitman Middle 572 Downey 582 John H Duval 626 Beaver Brook Elementary School 685 Mary E. Baker School 755 Whitman Hanson Regional 1,192 Enrollment
Figure 25: Student to Teacher Ratios (2013) - Low Scores Are Better Student to Teacher Ratio East Middle School Ashfield Middle School Abington High R Stewart Esten Downey Frolio Middle School Jefferson Elementary School Whitman Middle Hanson Middle School Mary E. Baker School Beaver Brook Elementary School Louise A Conley Whitman Hanson Regional John H Duval Center Elementary School 0 20 40 School Name Student to Teacher Ratio East Middle School 10.1 Ashfield Middle School 12.3 Abington High 12.8 R Stewart Esten 13.9 Downey 15 Frolio Middle School 15.3 Jefferson Elementary School 16 Whitman Middle 16.2 Hanson Middle School 16.3 Mary E. Baker School 18 Beaver Brook Elementary School 18.8 Louise A Conley 19.1 Whitman Hanson Regional 19.4 John H Duval 20.4 Center Elementary School 21 Student to Teacher Ratio
Figure 26: 02382, MA School Racial Mix (2013) White Black Hispanic Asian Pacific Islander American Indian Two or More Races East Middle School Downey Mary E. Baker School Ashfield Middle School R Stewart Esten Jefferson Elementary School Louise A Conley John H Duval Abington High Whitman Hanson Regional Center Elementary School Frolio Middle School Whitman Middle Hanson Middle School Beaver Brook Elementary School 0% 50% 100% School Name White Black Hispanic Asian Pacific Islander American Indian Two or More Races East Middle School 16.7% 66.7% 12.4% 0.5% 0.2% 0.2% 3.3% Downey 26.6% 46.9% 17.7% 1.5% 0.9% 0.2% 6.2% Mary E. Baker School 33.1% 45.7% 12.6% 2.1% 0.1% 0.4% 6% Ashfield Middle School 43.1% 42.3% 8.8% 2.1% 0.2% 1.3% 2.3% R Stewart Esten 77.1% 9.3% 8.6% 1.3% 0% 0% 3.7% Jefferson Elementary School 78.6% 4.9% 9.7% 0.3% 0% 0% 6.5% Louise A Conley 89.9% 2% 3.5% 1.1% 0.2% 0.5% 2.8% John H Duval 90.9% 2.1% 3.8% 0.6% 0.6% 0.3% 1.6% Abington High 91.6% 2.6% 3.4% 1.4% 0% 0.2% 0.8% Whitman Hanson Regional 91.8% 2.8% 2.3% 0.4% 0.2% 0.3% 2.3% Center Elementary School 92.1% 1.1% 1.6% 3.7% 0% 1.6% 0% Frolio Middle School 92.7% 1.5% 5.8% 0% 0% 0% 0% Whitman Middle 93.4% 2.3% 2.4% 0.3% 0% 0.2% 1.4% Hanson Middle School 94.9% 1.1% 0.6% 0.6% 0% 0.4% 2.3% Beaver Brook Elementary School 95% 1.5% 1.6% 1.8% 0% 0.1% 0% Two or More Races
Cities marked with an asterisk ("*") should resemble a city or town but do not have their own government (i.e. Mayor, City Council, etc.) These places should be recognizable by the local community but their boundaries have no legal status. Technically these include both Census Designated Places (CDP) and Census County Divisions (CCD) which are defined by the Census Bureau along with local authorities. (For more information, see: Census Designated Place or "CDP") and Census County Division "CCD".) For comparison purposes, the US national average and the state average value are provided. Additionally, the "Combined Statistical Area" or CSA is shown that is closest to the city, county, or zip code shown. A CSA is a large grouping of adjacent metropolitan areas that identified by the Census Bureau based on social and economic ties. (See: Combined Statistical Area ) Data sources - Mouse over icon in upper right corner of each chart for information.
| https://www.towncharts.com/Massachusetts/Education/02382-Zipcode-MA-Education-data.html |
Long-time behavior of a nonlocal Cahn-Hilliard equation with reaction
2018, Volume 38 , Issue 8 : 3765-3788. Doi: 10.3934/dcds.2018163
Long-time behavior of a nonlocal Cahn-Hilliard equation with reaction
Annalisa Iuorio 1 , , and
Stefano Melchionna 2 ,
1.
2.
Faculty of Mathematics, University of Vienna, Oskar-Morgenstern-Platz 1, 1090, Vienna, Austria
* Corresponding author: Annalisa Iuorio
* Corresponding author: Annalisa Iuorio
Received: June 30, 2017
Revised: December 31, 2017
Published: May 2018
The authors would like to acknowledge the Austrian Science Fund (FWF) for financial support (AI through project W1245, SM through project P27052-N25)
Abstract
Abstract
In this paper we study the long-time behavior of a nonlocal Cahn-Hilliard system with singular potential, degenerate mobility, and a reaction term. In particular, we prove the existence of a global attractor with finite fractal dimension, the existence of an exponential attractor, and convergence to equilibria for two physically relevant classes of reaction terms.
Keywords:
Nonlocal Cahn-Hilliard equation ,
reaction term ,
global attractor ,
exponential attractor ,
convergence to equilibria .
Mathematics Subject Classification: Primary: 37L30; Secondary: 45K05.
Citation:
Full Text(HTML)
Figure 1.Illustration of r κfor a reaction term gsatisfying (A1), (A2).
References
References
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| https://www.aimsciences.org/article/doi/10.3934/dcds.2018163?viewType=html |
dbm_clearerr(3p) - Linux manual page
dbm_clearerr(3p) — Linux manual page
DBM_CLEARERR(3P) POSIX Programmer's Manual DBM_CLEARERR(3P)
PROLOG top
This manual page is part of the POSIX Programmer's Manual. The
Linux implementation of this interface may differ (consult the
corresponding Linux manual page for details of Linux behavior),
or the interface may not be implemented on Linux.
NAME top
dbm_clearerr, dbm_close, dbm_delete, dbm_error, dbm_fetch,
dbm_firstkey, dbm_nextkey, dbm_open, dbm_store — database
functions
SYNOPSIS top
#include <ndbm.h>
int dbm_clearerr(DBM *
db
);
void dbm_close(DBM *
db
);
int dbm_delete(DBM *
db
, datum
key
);
int dbm_error(DBM *
db
);
datum dbm_fetch(DBM *
db
, datum
key
);
datum dbm_firstkey(DBM *
db
);
datum dbm_nextkey(DBM *
db
);
DBM *dbm_open(const char *
file
, int
open_flags
, mode_t
file_mode
);
int dbm_store(DBM *
db
, datum
key
, datum
content
, int
store_mode
);
DESCRIPTION top
These functions create, access, and modify a database.
A
datum
consists of at least two members,
dptr
and
dsize
. The
dptr
member points to an object that is
dsize
bytes in length.
Arbitrary binary data, as well as character strings, may be
stored in the object pointed to by
dptr
.
A database shall be stored in one or two files. When one file is
used, the name of the database file shall be formed by appending
the suffix
.db
to the
file
argument given to
dbm_open
(). When
two files are used, the names of the database files shall be
formed by appending the suffixes
.dir
and
.pag
respectively to
the
file
argument.
The
dbm_open
() function shall open a database. The
file
argument
to the function is the pathname of the database. The
open_flags
argument has the same meaning as the
flags
argument of
open
()
except that a database opened for write-only access opens the
files for read and write access and the behavior of the O_APPEND
flag is unspecified. The
file_mode
argument has the same meaning
as the third argument of
open
().
The
dbm_open
() function need not accept pathnames longer than
{PATH_MAX}-4 bytes (including the terminating null), or pathnames
with a last component longer than {NAME_MAX}-4 bytes (excluding
the terminating null).
The
dbm_close
() function shall close a database. The application
shall ensure that argument
db
is a pointer to a
dbm
structure
that has been returned from a call to
dbm_open
().
These database functions shall support an internal block size
large enough to support key/content pairs of at least 1023 bytes.
The
dbm_fetch
() function shall read a record from a database. The
argument
db
is a pointer to a database structure that has been
returned from a call to
dbm_open
(). The argument
key
is a
datum
that has been initialized by the application to the value of the
key that matches the key of the record the program is fetching.
The
dbm_store
() function shall write a record to a database. The
argument
db
is a pointer to a database structure that has been
returned from a call to
dbm_open
(). The argument
key
is a
datum
that has been initialized by the application to the value of the
key that identifies (for subsequent reading, writing, or
deleting) the record the application is writing. The argument
content
is a
datum
that has been initialized by the application
to the value of the record the program is writing. The argument
store_mode
controls whether
dbm_store
() replaces any pre-existing
record that has the same key that is specified by the
key
argument. The application shall set
store_mode
to either
DBM_INSERT or DBM_REPLACE. If the database contains a record that
matches the
key
argument and
store_mode
is DBM_REPLACE, the
existing record shall be replaced with the new record. If the
database contains a record that matches the
key
argument and
store_mode
is DBM_INSERT, the existing record shall be left
unchanged and the new record ignored. If the database does not
contain a record that matches the
key
argument and
store_mode
is
either DBM_INSERT or DBM_REPLACE, the new record shall be
inserted in the database.
If the sum of a key/content pair exceeds the internal block size,
the result is unspecified. Moreover, the application shall ensure
that all key/content pairs that hash together fit on a single
block. The
dbm_store
() function shall return an error in the
event that a disk block fills with inseparable data.
The
dbm_delete
() function shall delete a record and its key from
the database. The argument
db
is a pointer to a database
structure that has been returned from a call to
dbm_open
(). The
argument
key
is a
datum
that has been initialized by the
application to the value of the key that identifies the record
the program is deleting.
The
dbm_firstkey
() function shall return the first key in the
database. The argument
db
is a pointer to a database structure
that has been returned from a call to
dbm_open
().
The
dbm_nextkey
() function shall return the next key in the
database. The argument
db
is a pointer to a database structure
that has been returned from a call to
dbm_open
(). The
application shall ensure that the
dbm_firstkey
() function is
called before calling
dbm_nextkey
(). Subsequent calls to
dbm_nextkey
() return the next key until all of the keys in the
database have been returned.
The
dbm_error
() function shall return the error condition of the
database. The argument
db
is a pointer to a database structure
that has been returned from a call to
dbm_open
().
The
dbm_clearerr
() function shall clear the error condition of
the database. The argument
db
is a pointer to a database
structure that has been returned from a call to
dbm_open
().
The
dptr
pointers returned by these functions may point into
static storage that may be changed by subsequent calls.
These functions need not be thread-safe.
RETURN VALUE top
The
dbm_store
() and
dbm_delete
() functions shall return 0 when
they succeed and a negative value when they fail.
The
dbm_store
() function shall return 1 if it is called with a
flags
value of DBM_INSERT and the function finds an existing
record with the same key.
The
dbm_error
() function shall return 0 if the error condition is
not set and return a non-zero value if the error condition is
set.
The return value of
dbm_clearerr
() is unspecified.
The
dbm_firstkey
() and
dbm_nextkey
() functions shall return a key
datum
. When the end of the database is reached, the
dptr
member
of the key is a null pointer. If an error is detected, the
dptr
member of the key shall be a null pointer and the error condition
of the database shall be set.
The
dbm_fetch
() function shall return a content
datum
. If no
record in the database matches the key or if an error condition
has been detected in the database, the
dptr
member of the content
shall be a null pointer.
The
dbm_open
() function shall return a pointer to a database
structure. If an error is detected during the operation,
dbm_open
() shall return a (
DBM *
)0.
ERRORS top
No errors are defined. The following sections are informative.
EXAMPLES top
None.
APPLICATION USAGE top
The following code can be used to traverse the database:
for(key = dbm_firstkey(db); key.dptr != NULL; key = dbm_nextkey(db))
The
dbm_
* functions provided in this library should not be
confused in any way with those of a general-purpose database
management system. These functions do not provide for multiple
search keys per entry, they do not protect against multi-user
access (in other words they do not lock records or files), and
they do not provide the many other useful database functions that
are found in more robust database management systems. Creating
and updating databases by use of these functions is relatively
slow because of data copies that occur upon hash collisions.
These functions are useful for applications requiring fast lookup
of relatively static information that is to be indexed by a
single key.
Note that a strictly conforming application is extremely limited
by these functions: since there is no way to determine that the
keys in use do not all hash to the same value (although that
would be rare), a strictly conforming application cannot be
guaranteed that it can store more than one block's worth of data
in the database. As long as a key collision does not occur,
additional data may be stored, but because there is no way to
determine whether an error is due to a key collision or some
other error condition (
dbm_error
() being effectively a Boolean),
once an error is detected, the application is effectively limited
to guessing what the error might be if it wishes to continue
using these functions.
The
dbm_delete
() function need not physically reclaim file space,
although it does make it available for reuse by the database.
After calling
dbm_store
() or
dbm_delete
() during a pass through
the keys by
dbm_firstkey
() and
dbm_nextkey
(), the application
should reset the database by calling
dbm_firstkey
() before again
calling
dbm_nextkey
(). The contents of these files are
unspecified and may not be portable.
Applications should take care that database pathname arguments
specified to
dbm_open
() are not prefixes of unrelated files. This
might be done, for example, by placing databases in a separate
directory.
Since some implementations use three characters for a suffix and
others use four characters for a suffix, applications should
ensure that the maximum portable pathname length passed to
dbm_open
() is no greater than {PATH_MAX}-4 bytes, with the last
component of the pathname no greater than {NAME_MAX}-4 bytes.
RATIONALE top
Previously the standard required the database to be stored in two
files, one file being a directory containing a bitmap of keys and
having
.dir
as its suffix. The second file containing all data
and having
.pag
as its suffix. This has been changed not to
specify the use of the files and to allow newer implementations
of the Berkeley DB interface using a single file that have
evolved while remaining compatible with the application
programming interface. The standard developers considered
removing the specific suffixes altogether but decided to retain
them so as not to pollute the application file name space more
than necessary and to allow for portable backups of the database.
FUTURE DIRECTIONS top
None.
SEE ALSO top
| https://www.man7.org/linux/man-pages/man3/dbm_store.3p.html |
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| https://ir-library.ku.ac.ke/handle/123456789/2372;jsessionid=80A704DEA9E7E7915CF580033684262E |
Network Working Group M. Baugher
Request for Comments: 4046 Cisco
Category: Informational R. Canetti
IBM
L. Dondeti
Qualcomm
F. Lindholm
Ericsson
April 2005
Multicast Security (MSEC) Group Key Management Architecture
Status of This Memo
This memo provides information for the Internet community. It does
not specify an Internet standard of any kind. Distribution of this
memo is unlimited.
Copyright Notice
Copyright (C) The Internet Society (2005).
Abstract
This document defines the common architecture for Multicast Security
(MSEC) key management protocols to support a variety of application,
transport, and network layer security protocols. It also defines the
group security association (GSA), and describes the key management
protocols that help establish a GSA. The framework and guidelines
described in this document permit a modular and flexible design of
group key management protocols for a variety of different settings
that are specialized to applications needs. MSEC key management
protocols may be used to facilitate secure one-to-many, many-to-many,
or one-to-one communication.
Table of Contents
1
. Introduction: Purpose of this Document ..........................
2
2
. Requirements of a Group Key Management Protocol .................
4
3
. Overall Design of Group Key Management Architecture .............
6
3.1
. Overview ...................................................
6
3.2
. Detailed Description of the GKM Architecture ...............
8
3.3
. Properties of the Design ..................................
11
3.4
. Group Key Management Block Diagram ........................
11
4
. Registration Protocol ..........................................
13
4.1
. Registration Protocol via Piggybacking or Protocol Reuse ..13
4.2
. Properties of Alternative Registration Exchange Types .....
14
Baugher, et al. Informational [Page 1]
RFC 4046 MSEC Group Key Management Architecture April 2005
4.3. Infrastructure for Alternative Registration
Exchange Types ............................................15
4.4. De-registration Exchange ..................................16
5. Rekey Protocol .................................................16
5.1. Goals of the Rekey Protocol ...............................17
5.2. Rekey Message Transport and Protection ....................17
5.3. Reliable Transport of Rekey Messages ......................18
5.4. State-of-the-art on Reliable Multicast Infrastructure .....20
5.5. Implosion .................................................21
5.6. Incorporating Group Key Management Algorithms .............22
5.7. Stateless, Stateful, and Self-healing Rekeying
Algorithms ................................................22
5.8. Interoperability of a GKMA ................................23
6. Group Security Association .....................................24
6.1. Group Policy ..............................................24
6.2. Contents of the Rekey SA ..................................25
6.2.1. Rekey SA Policy ....................................26
6.2.2. Group Identity .....................................27
6.2.3. KEKs ...............................................27
6.2.4. Authentication Key .................................27
6.2.5. Replay Protection ..................................27
6.2.6. Security Parameter Index (SPI) .....................27
6.3. Contents of the Data SA ...................................27
6.3.1. Group Identity .....................................28
6.3.2. Source Identity ....................................28
6.3.3. Traffic Protection Keys ............................28
6.3.4. Data Authentication Keys ...........................28
6.3.5. Sequence Numbers ...................................28
6.3.6. Security Parameter Index (SPI) .....................28
6.3.7. Data SA Policy .....................................28
7. Scalability Considerations .....................................29
8. Security Considerations ........................................31
9. Acknowledgments ................................................32
10. Informative References ........................................33
1. Introduction: Purpose of this Document
This document defines a common architecture for Multicast Security
(MSEC) key management protocols to support a variety of application-,
transport-, and network-layer security protocols. It also defines
the group security association (GSA) and describes the key management
protocols that help establish a GSA. The framework and guidelines
described in this document permit a modular and flexible design of
group key management protocols for a variety of different settings
that are specialized to applications needs. MSEC key management
protocols may be used to facilitate secure one-to-many, many-to-many,
or one-to-one communication.
Baugher, et al. Informational [Page 2]
RFC 4046 MSEC Group Key Management Architecture April 2005
Group and multicast applications in IP networks have diverse security
requirements [TAXONOMY]. Their key management requirements, briefly
reviewed in Section 2.0, include support for internetwork-,
transport- and application-layer security protocols. Some
applications achieve simpler operation by running key management
messaging over a pre-established secure channel (e.g., TLS or IPsec).
Other security protocols benefit from a key management protocol that
can run over an already-deployed session initiation or management
protocol (e.g., SIP or RTSP). Finally, some benefit from a
lightweight key management protocol that requires few round trips.
For all these reasons, application-, transport-, and IP-layer data
security protocols (e.g., SRTP [RFC3711] and IPsec [RFC2401]) benefit
from different group key management systems. This document defines a
common architecture and design for all group key management (GKM)
protocols.
This common architecture for group key management is called the MSEC
group key management architecture. It is based on the group control
or key server model developed in GKMP [RFC2094] and assumed by group
key management algorithms such as LKH [RFC2627], OFT [OFT], and MARKS
[MARKS]. There are other approaches that are not considered in this
architecture, such as the highly distributed Cliques group key
management protocol [CLIQUES] or broadcast key management schemes
[FN93,Wool]. MSEC key management may in fact be complementary to
other group key management designs, but the integration of MSEC group
key management with Cliques, broadcast key management, or other group
key systems is not considered in this document.
Key management protocols are difficult to design and validate. The
common architecture described in this document eases this burden by
defining common abstractions and an overall design that can be
specialized for different uses.
This document builds on and extends the Group Key Management Building
Block document of the IRTF SMuG research group [GKMBB] and is part of
the MSEC document roadmap. The MSEC architecture [MSEC-Arch] defines
a complete multicast or group security architecture, of which key
management is a component.
The rest of this document is organized as follows. Section 2
discusses the security, performance and architectural requirements
for a group key management protocol. Section 3 presents the overall
architectural design principles. Section 4 describes the
registration protocol in detail, and Section 5 does the same for
rekey protocol. Section 6 considers the interface to the Group
Security Association (GSA). Section 7 reviews the scalability issues
for group key management protocols and Section 8 discusses security
considerations.
Baugher, et al. Informational [Page 3]
RFC 4046 MSEC Group Key Management Architecture April 2005
2. Requirements of a Group Key Management Protocol
A group key management (GKM) protocol supports protected
communication between members of a secure group. A secure group is a
collection of principals, called members, who may be senders,
receivers, or both receivers and senders to other members of the
group. Group membership may vary over time. A group key management
protocol helps to ensure that only members of a secure group can gain
access to group data (by gaining access to group keys) and can
authenticate group data. The goal of a group key management protocol
is to provide legitimate group members with the up-to-date
cryptographic state they need for secrecy and authentication.
Multicast applications, such as video broadcast and multicast file
transfer, typically have the following key management requirements
(see also [TAXONOMY]). Note that the list is neither applicable to
all applications nor exhaustive.
1. Group members receive security associations that include
encryption keys, authentication/integrity keys, cryptographic
policy that describes the keys, and attributes such as an index
for referencing the security association (SA) or particular
objects contained in the SA.
2. In addition to the policy associated with group keys, the group
owner or the Group Controller and Key Server (GCKS) may define and
enforce group membership, key management, data security, and other
policies that may or may not be communicated to the entire
membership.
3. Keys will have a pre-determined lifetime and may be periodically
refreshed.
4. Key material should be delivered securely to members of the group
so that they are secret, integrity-protected and verifiably
obtained from an authorized source.
5. The key management protocol should be secure against replay
attacks and Denial of Service(DoS) attacks (see the Security
Considerations section of this memo).
6. The protocol should facilitate addition and removal of group
members. Members who are added may optionally be denied access to
the key material used before they joined the group, and removed
members should lose access to the key material following their
departure.
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RFC 4046 MSEC Group Key Management Architecture April 2005
7. The protocol should support a scalable group rekey operation
without unicast exchanges between members and a Group Controller
and Key Server (GCKS), to avoid overwhelming a GCKS managing a
large group.
8. The protocol should be compatible with the infrastructure and
performance needs of the data security application, such as the
IPsec security protocols AH and ESP, and/or application layer
security protocols such as SRTP [RFC3711].
9. The key management protocol should offer a framework for replacing
or renewing transforms, authorization infrastructure, and
authentication systems.
10. The key management protocol should be secure against collusion
among excluded members and non-members. Specifically, collusion
must not result in attackers gaining any additional group secrets
than each of them individually are privy to. In other words,
combining the knowledge of the colluding entities must not result
in revealing additional group secrets.
11. The key management protocol should provide a mechanism to
securely recover from a compromise of some or all of the key
material.
12. The key management protocol may need to address real-world
deployment issues such as NAT-traversal and interfacing with
legacy authentication mechanisms.
In contrast to typical unicast key and SA negotiation protocols such
as TLS and IKE, multicast group key management protocols provide SA
and key download capability. This feature may be useful for point-
to-point as well as multicast communication, so that a group key
management protocol may be useful for unicast applications. Group
key management protocols may be used for protecting multicast or
unicast communications between members of a secure group. Secure
sub-group communication is also plausible using the group SA.
There are other requirements for small group operation with many all
members as potential senders. In this case, the group setup time may
need to be optimized to support a small, highly interactive group
environment [RFC2627].
The current key management architecture covers secure communication
in large single-sender groups, such as source-specific multicast
groups. Scalable operation to a range of group sizes is also a
desirable feature, and a better group key management protocol will
support large, single-sender groups as well as groups that have many
Baugher, et al. Informational [Page 5]
RFC 4046 MSEC Group Key Management Architecture April 2005
senders. It may be that no single key management protocol can
satisfy the scalability requirements of all group-security
applications.
It is useful to emphasize two non-requirements: technical protection
measures (TPM) [TPM] and broadcast key management. TPM are used for
such things as copy protection by preventing the device user from
getting easy access to the group keys. There is no reason why a
group key management protocol cannot be used in an environment where
the keys are kept in a tamper-resistant store, using various types of
hardware or software to implement TPM. For simplicity, however, the
MSEC key management architecture described in this document does not
consider design for technical protection.
The second non-requirement is broadcast key management when there is
no back channel [FN93,JKKV94] or for a non-networked device such as a
digital videodisc player. We assume IP network operation with two-
way communication, however asymmetric, and authenticated key-exchange
procedures that can be used for member registration. Broadcast
applications may use a one-way Internet group key management protocol
message and a one-way rekey message, as described below.
3. Overall Design of Group Key Management Architecture
The overall group key management architecture is based upon a group
controller model [RFC2093,RFC2094,RFC2627,OFT,GSAKMP,RFC3547] with a
single group owner as the root-of-trust. The group owner designates
a group controller for member registration and GSA rekeying.
3.1. Overview
The main goal of a group key management protocol is to securely
provide group members with an up-to-date security association (SA),
which contains the needed information for securing group
communication (i.e., the group data). We call this SA the Data SA.
In order to obtain this goal, the group key management architecture
defines the following protocols.
(1) Registration Protocol
This is a unicast protocol between the Group Controller and Key
Server (GCKS) and a joining group member. In this protocol, the
GCKS and joining member mutually authenticate each other. If the
authentication succeeds and the GCKS finds that the joining member
is authorized, then the GCKS supplies the joining member with the
following information:
Baugher, et al. Informational [Page 6]
RFC 4046 MSEC Group Key Management Architecture April 2005
(a) Sufficient information to initialize the Data SA within the
joining member. This information is given only if the group
security policy calls for initializing the Data SA at
registration, instead of, or in addition to, as part of the
rekey protocol.
(b) Sufficient information to initialize a Rekey SA within the
joining member (see more details about this SA below). This
information is given if the group security policy calls for a
rekey protocol.
The registration protocol must ensure that the transfer of
information from GCKS to member is done in an authenticated and
confidential manner over a security association. We call this SA
the Registration SA. A complementary de-registration protocol
serves to explicitly remove Registration SA state. Members may
choose to delete Registration SA state.
(2) Rekey Protocol
A GCKS may periodically update or change the Data SA, by sending
rekey information to the group members. Rekey messages may result
from group membership changes, from changes in group security
policy, from the creation of new traffic-protection keys (TPKs,
see next section) for the particular group, or from key
expiration. Rekey messages are protected by the Rekey SA, which
is initialized in the registration protocol. They contain
information for updating the Rekey SA and/or the Data SA and can
be sent via multicast to group members or via unicast from the
GCKS to a particular group member.
Note that there are other means for managing (e.g., expiring or
refreshing) the Data SA without interaction between the GCKS and
the members. For example in MARKS [MARKS], the GCKS pre-
determines TPKs for different periods in the lifetime of the
secure group and distributes keys to members based on their
membership periods. Alternative schemes such as the GCKS
disbanding the secure group and starting a new group with a new
Data SA are also possible, although this is typically limited to
small groups.
Rekey messages are authenticated using one of the two following
options:
(1) Using source authentication [TAXONOMY], that is, enabling each
group member to verify that a rekey message originates with
the GCKS and none other.
Baugher, et al. Informational [Page 7]
RFC 4046 MSEC Group Key Management Architecture April 2005
(2) Using only group-based authentication with a symmetric key.
Members can only be assured that the rekey messages originated
within the group. Therefore, this is applicable only when all
members of the group are trusted not to impersonate the GCKS.
Group authentication for rekey messages is typically used when
public-key cryptography is not suitable for the particular
group.
The rekey protocol ensures that all members receive the rekey
information in a timely manner. In addition, the rekey protocol
specifies mechanisms for the parties to contact the GCKS and re-
synch if their keys expired and an updated key has not been
received. The rekey protocol for large-scale groups offers
mechanisms to avoid implosion problems and to ensure reliability
in its delivery of keying material.
Although the Rekey SA is established by the registration protocol,
it is updated using a rekey protocol. When a member leaves the
group, it destroys its local copy of the GSA. Using a de-
registration message may be an efficient way for a member to
inform the GCKS that it has destroyed, or is about to destroy, the
SAs. Such a message may prompt the GCKS to cryptographically
remove the member from the group (i.e., to prevent the member from
having access to future group communication). In large-scale
multicast applications, however, de-registration can potentially
cause implosion at the GCKS.
3.2. Detailed Description of the GKM Architecture
Figure 1 depicts the overall design of a GKM protocol. Each group
member, sender or receiver, uses the registration protocol to get
authorized and authenticated access to a particular Group, its
policies, and its keys. The two types of group keys are the key
encryption keys (KEKs) and the traffic encryption keys (TEKs). For
group authentication of rekey messages or data, key integrity or
traffic integrity keys may be used, as well. We use the term
protection keys to refer to both integrity and encryption keys. For
example, the term traffic protection key (TPK) is used to denote the
combination of a TEK and a traffic integrity key, or the key material
used to generate them.
The KEK may be a single key that protects the rekey message,
typically containing a new Rekey SA (containing a KEK) and/or Data SA
(containing a TPK/TEK). A Rekey SA may also contain a vector of keys
that are part of a group key membership algorithm
[RFC2627,OFT,TAXONOMY,SD1,SD2]. The data security protocol uses TPKs
to protect streams, files, or other data sent and received by
Baugher, et al. Informational [Page 8]
RFC 4046 MSEC Group Key Management Architecture April 2005
the data security protocol. Thus the registration protocol and/or
the rekey protocol establish the KEK(s) and/or the TPKs.
+------------------------------------------------------------------+
| +-----------------+ +-----------------+ |
| | POLICY | | AUTHORIZATION | |
| | INFRASTRUCTURE | | INFRASTRUCTURE | |
| +-----------------+ +-----------------+ |
| ^ ^ |
| | | |
| v v |
| +--------------------------------------------------------------+ |
| | | |
| | +--------------------+ | |
| | +------>| GCKS |<------+ | |
| | | +--------------------+ | | |
| | REGISTRATION or | REGISTRATION or | |
| | DE-REGISTRATION | DE-REGISTRATION | |
| | PROTOCOL | PROTOCOL | |
| | | | | | |
| | v REKEY v | |
| | +-----------------+ PROTOCOL +-----------------+ | |
| | | | (OPTIONAL) | | | |
| | | SENDER(S) |<-------+-------->| RECEIVER(S) | | |
| | | | | | | |
| | +-----------------+ +-----------------+ | |
| | | ^ | |
| | v | | |
| | +-------DATA SECURITY PROTOCOL-------+ | |
| | | |
| +--------------------------------------------------------------+ |
| |
+------------------------------------------------------------------+
Figure 1: Group Security Association Model
There are a few distinct outcomes to a successful registration
Protocol exchange.
o If the GCKS uses rekey messages, then the admitted member
receives the Rekey SA. The Rekey SA contains the group's rekey
policy (note that not all of the policy need to be revealed to
members), and at least a group KEK. In addition, the GCKS
sends a group key integrity key for integrity protection of
rekey messages. If a group key management algorithm is used
for efficient rekeying, the GCKS also sends one or more KEKs as
specified by the key distribution policy of the group key
management algorithm.
Baugher, et al. Informational [Page 9]
RFC 4046 MSEC Group Key Management Architecture April 2005
o If rekey messages are not used for the Group, then the admitted
member receives TPKs (as part of the Data Security SAs) that
are passed to the member's Data Security Protocol (as IKE does
for IPsec).
o The GCKS may pass one or more TPKs to the member even if rekey
messages are used, for efficiency reasons and according to
group policy.
The GCKS creates the KEK and TPKs and downloads them to each member,
as the KEK and TPKs are common to the entire group. The GCKS is a
separate logical entity that performs member authentication and
authorization according to the group policy that is set by the group
owner. The GCKS may present a credential signed by the group owner
to the group member, so that member can check the GCKS's
authorization. The GCKS, which may be co-located with a member or be
physically separate, runs the rekey protocol to push rekey messages
containing refreshed KEKs, new TPKs, and/or refreshed TPKs to
members. Note that some group key management algorithms refresh any
of the KEKs (potentially), whereas others only refresh the group KEK.
Alternatively, the sender may forward rekey messages on behalf of the
GCKS when it uses a credential mechanism that supports delegation.
Thus, it is possible for the sender, or other members, to source
keying material (TPKs encrypted in the Group KEK) as it sources
multicast or unicast data. As mentioned above, the rekey message can
be sent using unicast or multicast delivery. Upon receipt of a TPK
(as part of a Data SA) via a rekey message or a registration protocol
exchange, the member's group key management functional block will
provide the new or updated security association (SA) to the data
security protocol. This protects the data sent from sender to
receiver.
The Data SA protects the data sent on the arc labeled DATA SECURITY
PROTOCOL shown in Figure 1. A second SA, the Rekey SA, is optionally
established by the key management protocol for rekey messages as
shown in Figure 1 by the arc labeled REKEY PROTOCOL. The rekey
message is optional because all keys, KEKs and TPKs, can be delivered
by the registration protocol exchanges shown in Figure 1, and those
keys may not need to be updated. The registration protocol is
protected by a third, unicast, SA between the GCKS and each member.
This is called the Registration SA. There may be no need for the
Registration SA to remain in place after the completion of the
registration protocol exchanges. The de-registration protocol may be
used when explicit teardown of the SA is desirable (such as when a
phone call or conference terminates). The three SAs compose the GSA.
The only optional SA is the Rekey SA.
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Figure 1 shows two blocks that are external to the group key
management protocol: The policy and authorization infrastructures
are discussed in Section 6.1. The Multicast Security Architecture
document further clarifies the SAs and their use as part of the
complete architecture of a multicast security solution [MSEC-Arch].
3.3. Properties of the Design
The design of Section 3.2 achieves scalable operation by (1) allowing
the de-coupling of authenticated key exchange in a registration
protocol from a rekey protocol, (2) allowing the rekey protocol to
use unicast push or multicast distribution of group and data keys as
an option, (3) allowing all keys to be obtained by the unicast
registration protocol, and (4) delegating the functionality of the
GCKS among multiple entities, i.e., to permit distributed operation
of the GCKS.
High-capacity operation is obtained by (1) amortizing
computationally-expensive asymmetric cryptography over multiple data
keys used by data security protocols, (2) supporting multicast
distribution of symmetric group and data keys, and (3) supporting key
revocation algorithms such as LKH [RFC2627,OFT,SD1,SD2] that allow
members to be added or removed at logarithmic rather than linear
space/time complexity. The registration protocol may use asymmetric
cryptography to authenticate joining members and optionally establish
the group KEK. Asymmetric cryptography such as Diffie-Hellman key
agreement and/or digital signatures are amortized over the life of
the group KEK. A Data SA can be established without the use of
asymmetric cryptography; the TPKs are simply encrypted in the
symmetric KEK and sent unicast or multicast in the rekey protocol.
The design of the registration and rekey protocols is flexible. The
registration protocol establishes a Rekey SA or one or more Data SAs
or both types of SAs. At least one of the SAs is present (otherwise,
there is no purpose to the Registration SA). The Rekey SA may update
the Rekey SA, or establish or update one or more Data SAs.
Individual protocols or configurations may use this flexibility to
obtain efficient operation.
3.4. Group Key Management Block Diagram
In the block diagram of Figure 2, group key management protocols run
between a GCKS and member principal to establish a Group Security
Association (GSA). The GSA consists of a Data SA, an optional Rekey
SA, and a Registration SA. The GCKS may use a delegated principal,
such as the sender, which has a delegation credential signed by the
GCKS. The Member of Figure 2 may be a sender or receiver of
multicast or unicast data. There are two functional blocks in Figure
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2 labeled GKM, and there are two arcs between them depicting the
group key-management registration (reg) and rekey (rek) protocols.
The message exchanges are in the GSA establishment protocols, which
are the registration protocol and the rekey protocol described above.
Figure 2 shows that a complete group-key management functional
specification includes much more than the message exchange. Some of
these functional blocks and the arcs between them are peculiar to an
operating system (OS) or vendor product, such as vendor
specifications for products that support updates to the IPsec
Security Association Database (SAD) and Security Policy Database
(SPD) [RFC2367]. Various vendors also define the functions and
interface of credential stores, CRED in Figure 2.
+----------------------------------------------------------+
| |
| +-------------+ +------------+ |
| | CONTROL | | CONTROL | |
| +------^------+ +------|-----+ +--------+ |
| | | +-----| CRED | |
| | | | +--------+ |
| +----v----+ +----v--v-+ +--------+ |
| | <-----Reg-----> |<->| SAD | |
| | GKM -----Rek-----> GKM | +--------+ |
| | | | | +--------+ |
| | ------+ | |<->| SPD | |
| +---------+ | +-^-------+ +--------+ |
| +--------+ | | | | |
| | CRED |----->+ | | +-------------------+ |
| +--------+ | | +--------------------+ | |
| +--------+ | +-V-------+ +--------+ | | |
| | SAD <----->+ | |<->| SAD <-+ | |
| +--------+ | |SECURITY | +--------+ | |
| +--------+ | |PROTOCOL | +--------+ | |
| | SPD <----->+ | |<->| SPD <----+ |
| +--------+ +---------+ +--------+ |
| |
| (A) GCKS (B) MEMBER |
+----------------------------------------------------------+
Figure 2: Group Key Management Block in a Host
The CONTROL function directs the GCKS to establish a group, admit a
member, or remove a member, or it directs a member to join or leave a
group. CONTROL includes authorization that is subject to group
policy [GSPT] but its implementation is specific to the GCKS. For
large scale multicast sessions, CONTROL could perform session
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announcement functions to inform a potential group member that it may
join a group or receive group data (e.g., a stream of file transfer
protected by a data security protocol). Announcements notify group
members to establish multicast SAs in advance of secure multicast
data transmission. Session Description Protocol (SDP) is one form
that the announcements might take [RFC2327]. The announcement
function may be implemented in a session directory tool, an
electronic program guide (EPG), or by other means. The Data Security
or the announcement function directs group key management using an
application programming interface (API), which is peculiar to the
host OS in its specifics. A generic API for group key management is
for further study, but this function is necessary to allow Group
(KEK) and Data (TPKs) key establishment to be scalable to the
particular application. A GCKS application program will use the API
to initiate the procedures for establishing SAs on behalf of a
Security Protocol in which members join secure groups and receive
keys for streams, files, or other data.
The goal of the exchanges is to establish a GSA through updates to
the SAD of a key management implementation and particular Security
Protocol. The Data Security Protocol ("SECURITY PROTOCOL") of Figure
2 may span internetwork and application layers or operate at the
internetwork layer, such as AH and ESP.
4. Registration Protocol
The design of the registration protocol is flexible and can support
different application scenarios. The chosen registration protocol
solution reflects the specific requirements of specific scenarios.
In principle, it is possible to base a registration protocol on any
secure-channel protocol, such as IPsec and TLS, which is the case in
tunneled GSAKMP [tGSAKMP]. GDOI [RFC3547] reuses IKE Phase 1 as the
secure channel to download Rekey and/or Data SAs. Other protocols,
such as MIKEY and GSAKMP, use authenticated Diffie-Hellman exchanges
similar to IKE Phase 1, but they are specifically tailored for key
download to achieve efficient operation. We discuss the design of a
registration protocol in detail in the rest of this section.
4.1. Registration Protocol via Piggybacking or Protocol Reuse
Some registration protocols need to tunnel through a data-signaling
protocol to take advantage of already existing security
functionality, and/or to optimize the total session setup time. For
example, a telephone call has strict bounds for delay in setup time.
It is not feasible to run security exchanges in parallel with call
setup, since the latter often resolves the address. Call setup must
complete before the caller knows the callee's address. In this case,
it may be advantageous to tunnel the key exchange procedures inside
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call establishment [H.235,MIKEY], so that both can complete (or fail,
see below) at the same time.
The registration protocol has different requirements depending on the
particular integration/tunneling approach. These requirements are
not necessarily security requirements, but will have an impact on the
chosen security solution. For example, the security association will
certainly fail if the call setup fails in the case of IP telephony.
Conversely, the registration protocol imposes requirements on the
protocol that tunnels it. In the case of IP telephony, the call
setup usually will fail when the security association is not
successfully established. In the case of video-on-demand, protocols
such as RTSP that convey key management data will fail when a needed
security association cannot be established.
Both GDOI and MIKEY use this approach, but in different ways. MIKEY
can be tunneled in SIP and RTSP. It takes advantage of the session
information contained in these protocols and the possibility to
optimize the setup time for the registration procedure. SIP requires
that a tunneled protocol must use at most one roundtrip (i.e., two
messages). This is also a desirable requirement from RTSP.
The GDOI approach takes advantage of the already defined ISAKMP phase
1 exchange [RFC2409], and extends the phase 2 exchange for the
registration. The advantage here is the reuse of a successfully
deployed protocol and the code base, where the defined phase 2
exchange is protected by the SA created by phase 1. GDOI also
inherits other functionality of the ISAKMP, and thus it is readily
suitable for running IPsec protocols over IP multicast services.
4.2. Properties of Alternative Registration Exchange Types
The required design properties of a registration protocol have
different trade-offs. A protocol that provides perfect forward
secrecy and identity protection trades performance or efficiency for
better security, while a protocol that completes in one or two
messages may trade security functionality (e.g., identity protection)
for efficiency.
Replay protection generally uses either a timestamp or a sequence
number. The first requires synchronized clocks, while the latter
requires retention of state. In a timestamp-based protocol, a replay
cache is needed to store the authenticated messages (or the hashes of
the messages) received within the allowable clock skew. The size of
the replay cache depends on the number of authenticated messages
received during the allowable clock skew. During a DoS attack, the
replay cache might become overloaded. One solution is to over-
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provision the replay cache, but this may lead to a large replay
cache. Another solution is to let the allowable clock skew be
changed dynamically during runtime. During a suspected DoS attack,
the allowable clock skew is decreased so that the replay cache
becomes manageable.
A challenge-response mechanism (using Nonces) obviates the need for
synchronized clocks for replay protection when the exchange uses
three or more messages [MVV].
Additional security functions become possible as the number of
allowable messages in the registration protocol increase. ISAKMP
offers identity protection, for example, as part of a six-message
exchange. With additional security features, however, comes added
complexity: Identity protection, for example, not only requires
additional messages, but may result in DoS vulnerabilities since
authentication is performed in a late stage of the exchange after
resources already have been devoted.
In all cases, there are tradeoffs with the number of message
exchanged, the desired security services, and the amount of
infrastructure that is needed to support the group key management
service. Whereas protocols that use two or even one-message setup
have low latency and computation requirements, they may require more
infrastructure such as secure time or offer less security such as the
absence of identity protection. What tradeoffs are acceptable and
what are not is very much dictated by the application and application
environment.
4.3. Infrastructure for Alternative Registration Exchange Types
The registration protocol may need external infrastructures to handle
authentication and authorization, replay protection, protocol-run
integrity, and possibly other security services such as secure
synchronized clocks. For example, authentication and authorization
may need a PKI deployment (with either authorization-based
certificates or a separate management) or may be handled using AAA
infrastructure. Replay protection using timestamps requires an
external infrastructure or protocol for clock synchronization.
However, external infrastructures may not always be needed; for
example pre-shared keys are used for authentication and
authorization. This may be the case if the subscription base is
relatively small. In a conversational multimedia scenario (e.g., a
VoIP call between two or more people), it may be the end user who
handles the authorization by manually accepting/rejecting the
incoming calls. In that case, infrastructure support may not be
required.
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4.4. De-registration Exchange
The session-establishment protocol (e.g., SIP, RTSP) that conveys a
registration exchange often has a session-disestablishment protocol
such as RTSP TEARDOWN [RFC2326] or SIP BYE [RFC3261]. The session-
disestablishment exchange between endpoints offers an opportunity to
signal the end of the GSA state at the endpoints. This exchange need
only be a unidirectional notification by one side that the GSA is to
be destroyed. For authentication of this notification, we may use a
proof-of-possession of the group key(s) by one side to the other.
Some applications benefit from acknowledgement in a mutual, two-
message exchange signaling disestablishment of the GSA concomitant
with disestablishment of the session, e.g., RTSP or SIP session. In
this case, a two-way proof-of-possession might serve for mutual
acknowledgement of the GSA disestablishment.
5. Rekey Protocol
The group rekey protocol is for transport of keys and SAs between a
GCKS and the members of a secure communications group. The GCKS
sends rekey messages to update a Rekey SA, or initialize/update a
Data SA or both. Rekey messages are protected by a Rekey SA. The
GCKS may update the Rekey SA when group membership changes or when
KEKs or TPKs expire. Recall that KEKs correspond to a Rekey SA and
TPKs correspond to a Data SA.
The following are some desirable properties of the rekey protocol.
o The rekey protocol ensures that all members receive the rekey
information in a timely manner.
o The rekey protocol specifies mechanisms allowing the parties to
contact the GCKS and re-sync when their keys expire and no
updates have been received.
o The rekey protocol avoids implosion problems and ensures
reliability in delivering Rekey information.
We further note that the rekey protocol is primarily responsible for
scalability of the group key management architecture. Hence, it is
imperative that we provide the above listed properties in a scalable
manner. Note that solutions exist in the literature (both IETF
standards and research articles) for parts of the problem. For
instance, the rekey protocol may use a scalable group key management
algorithm (GKMA) to reduce the number of keys sent in a rekey
message. Examples of a GKMA include LKH, OFT, Subset difference
based schemes etc.
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5.1. Goals of the Rekey Protocol
The goals of the rekey protocol are:
o to synchronize a GSA,
o to provide privacy and (symmetric or asymmetric)
authentication, replay protection and DoS protection,
o efficient rekeying after changes in group membership or when
keys (KEKs) expire,
o reliable delivery of rekey messages,
o member recovery from an out-of-sync GSA,
o high throughput and low latency, and
o support IP Multicast or multi-unicast.
We identify several major issues in the design of a rekey protocol:
1. rekey message format,
2. reliable transport of rekey messages,
3. implosion,
4. recovery from out-of-sync GSA,
5. incorporating GKMAs in rekey messages, and
6. interoperability of GKMAs.
Note that interoperation of rekey protocol implementations is
insufficient for a GCKS to successfully rekey a group. The GKMA must
also interoperate, i.e., standard versions of the group key
management algorithms such as LKH, OFT, or Subset Difference must be
used.
The rest of this section discusses these topics in detail.
5.2. Rekey Message Transport and Protection
Rekey messages contain Rekey and/or Data SAs along with KEKs and
TPKs. These messages need to be confidential, authenticated, and
protected against replay and DoS attacks. They are sent via
multicast or multi-unicast from the GCKS to the members.
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Rekey messages are encrypted with the Group KEK for confidentiality.
When used in conjunction with a GKMA, portions of the rekey message
are first encrypted with the appropriate KEKs as specified by the
GKMA. The GCKS authenticates rekey messages using either a MAC,
computed using the group Authentication key, or a digital signature.
In both cases, a sequence number is included in computation of the
MAC or the signature to protect against replay attacks.
When group authentication is provided with a symmetric key, rekey
messages are vulnerable to attacks by other members of the group.
Rekey messages are digitally signed when group members do not trust
each other. When asymmetric authentication is used, members
receiving rekey messages are vulnerable to DoS attacks. An external
adversary may send a bogus rekey message, which a member cannot
identify until after it performs an expensive digital signature
operation. To protect against such an attack, a MAC may be sent as
part of the rekey message. Members verify the signature only upon
successful verification of the MAC.
Rekey messages contain group key updates corresponding to a single
[RFC2627,OFT] or multiple membership changes [SD1,SD2,BatchRekey] and
may contain group key initialization messages [OFT].
5.3. Reliable Transport of Rekey Messages
The GCKS must ensure that all members have the current Data Security
and Rekey SAs. Otherwise, authorized members may be inadvertently
excluded from receiving group communications. Thus, the GCKS needs
to use a rekey algorithm that is inherently reliable or employ a
reliable transport mechanism to send rekey messages.
There are two dimensions to the problem. Messages that update group
keys may be lost in transit or may be missed by a host when it is
offline. LKH and OFT group key management algorithms rely on past
history of updates being received by the host. If the host goes
offline, it will need to resynchronize its group-key state when it
comes online; this may require a unicast exchange with the GCKS. The
Subset Difference algorithm, however, conveys all the necessary state
in its rekey messages and does not need members to be always online
or keeping state. The Subset Difference algorithm does not require a
back channel and can operate on a broadcast network. If a rekey
message is lost in transmission, the Subset Difference algorithm
cannot decrypt messages encrypted with the TPK sent via the lost
rekey message. There are self-healing GKMAs proposed in the
literature that allow a member to recover lost rekey messages, as
long as rekey messages before and after the lost rekey message are
received.
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Rekey messages are typically short (for single membership change as
well as for small groups), which makes it easy to design a reliable
delivery protocol. On the other hand, the security requirements may
add an additional dimension to address. There are some special cases
in which membership changes are processed as a batch, reducing the
frequency of rekey messages but increasing their size. Furthermore,
among all the KEKs sent in a rekey message, as many as half the
members need only a single KEK. We may take advantage of these
properties in designing a rekey message(s) and a protocol for their
reliable delivery.
Three categories of solutions have been proposed:
1. Repeatedly transmit the rekey message. In many cases rekey
messages translate to only one or two IP packets.
2. Use an existing reliable multicast protocol/infrastructure.
3. Use FEC for encoding rekey packets (with NACKs as feedback)
[BatchRekey].
Note that for small messages, category 3 is essentially the same as
category 1.
The group member might be out of synchrony with the GCKS if it
receives a rekey message having a sequence number that is more than
one greater than the last sequence number processed. This is one
means by which the GCKS member detects that it has missed a rekey
message. Alternatively, the data-security application, upon
detecting that it is using an out-of-date key, may notify the group
key management module. The action taken by the GCKS member is a
matter of group policy. The GCKS member should log the condition and
may contact the GCKS to rerun the re-registration protocol to obtain
a fresh group key. The group policy needs to take into account
boundary conditions, such as reordered rekey messages when rekeying
is so frequent that two messages might get reordered in an IP
network. The group key policy also needs to take into account the
potential for denial of service attacks where an attacker delays or
deletes a rekey message in order to force a subnetwork or subset of
the members to simultaneously contact the GCKS.
If a group member becomes out-of-synch with the GSA then it should
re-register with the GCKS. However, in many cases there are other,
simpler methods for re-synching with the group:
o The member can open a simple unprotected connection (e.g., TCP)
with the GCKS and obtain the current (or several recent) rekey
messages. Note that there is no need for authentication or
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encryption here, since the rekey message is already signed and
is multicast in the clear. One may think that this opens the
GCKS to DoS attacks by many bogus such requests. This,
however, does not seem to worsen the situation; in fact,
bombarding the GCKS with bogus resynch requests would be much
more problematic.
o The GCKS can post the rekey messages on some public site (e.g.,
a web site) and the out-of-synch member can obtain the rekey
messages from that site.
The GCKS may always provide all three ways of resynching (i.e., re-
registration, simple TCP, and public posting). This way, the member
may choose how to resynch; it also avoids adding yet another field to
the policy token [GSPT]. Alternatively, a policy token may contain a
field specifying one or more methods supported for resynchronization
of a GSA.
5.4. State-of-the-art on Reliable Multicast Infrastructure
The rekey message may be sent using reliable multicast. There are
several types of reliable multicast protocols with different
properties. However, there are no standards track reliable multicast
protocols published at this time, although IETF consensus has been
reached on two protocols that are intended to go into the standards
track [NORM,RFC3450]. Thus, this document does not recommend a
particular reliable multicast protocol or set of protocols for the
purpose of reliable group rekeying. The suitability of NAK-based,
ACK-based or other reliable multicast methods is determined by the
application needs and operational environment. In the future, group
key management protocols may choose to use particular standards-based
approaches that meet the needs of the particular application. A
secure announcement facility may be needed to signal the use of a
reliable multicast protocol, which could be specified as part of
group policy. The reliable multicast announcement and policy
specification, however, can only follow the establishment of reliable
multicast standards and are not considered further in this document.
Today, the several MSEC group key management protocols support
sequencing of the rekey messages through a sequence number, which is
authenticated along with the rekey message. A sender of rekey
messages may re-transmit multiple copies of the message provided that
they have the same sequence number. Thus, re-sending the message is
a rudimentary means of overcoming loss along the network path. A
member who receives the rekey message will check the sequence number
to detect duplicate and missing rekey messages. The member receiver
will discard duplicate messages that it receives. Large rekey
messages, such as those that contain LKH or OFT tree structures,
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might benefit from transport-layer FEC in the future, when
standards-based methods become available. It is unlikely that
forward error correction (FEC) methods will benefit short rekey
messages that fit within a single message. In this case, FEC
degenerates to simple retransmission of the message.
5.5. Implosion
Implosion may occur due to one of two reasons. First, recall that
one of the goals of the rekey protocol is to synchronize a GSA. When
a rekey or Data SA expires, members may contact the GCKS for an
update. If all, or even many, members contact the GCKS at about the
same time, the GCKS might not be able to handle all those messages.
We refer to this as an out-of-sync implosion.
The second case is in the reliable delivery of rekey messages.
Reliable multicast protocols use feedback (NACK or ACK) to determine
which packets must be retransmitted. Packet losses may result in
many members sending NACKs to the GCKS. We refer to this as feedback
implosion.
The implosion problem has been studied extensively in the context of
reliable multicasting. The proposed feedback suppression and
aggregation solutions might be useful in the GKM context as well.
Members may wait a random time before sending an out-of-sync or
feedback message. Meanwhile, members might receive the necessary key
updates and therefore not send a feedback message. An alternative
solution is to have the members contact one of several registration
servers when they are out-of-sync. This requires GSA synchronization
between the multiple registration servers.
Feedback aggregation and local recovery employed by some reliable
multicast protocols are not easily adaptable to transport of rekey
messages. Aggregation raises authentication issues. Local recovery
is more complex because members need to establish SAs with the local
repair server. Any member of the group or a subordinate GCKS may
serve as a repair server, which can be responsible for resending
rekey messages.
Members may use the group SA, more specifically the Rekey SA, to
authenticate requests sent to the repair server. However, replay
protection requires maintaining state at members as well as repair
servers. Authentication of repair requests is meant to protect
against DoS attacks. Note also that an out-of-sync member may use an
expired Rekey SA to authenticate repair requests, which requires
repair servers to accept messages protected by old SAs.
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Alternatively, a simple mechanism may be employed to achieve local
repair efficiently. Each member receives a set of local repair
server addresses as part of group operation policy information. When
a member does not receive a rekey message, it can send a "Retransmit
replay message(s) with sequence number n and higher" message to one
of the local repair servers. The repair server can either ignore the
request if it is busy or retransmit the requested rekey messages as
received from the GCKS. The repair server, which is also another
member may choose to serve only m requests in a given time period
(i.e., rate limits responses) or per a given rekey message. Rate
limiting the requests and responses protects the repair servers as
well as other members of the group from DoS attacks.
5.6. Incorporating Group Key Management Algorithms
Group key management algorithms make rekeying scalable. Large group
rekeying without employing GKMAs is prohibitively expensive.
Following are some considerations in selecting a GKMA:
o Protection against collusion.
Members (or non-members) should not be able to collaborate to
deduce keys for which they are not privileged (following the
GKMA key distribution rules).
o Forward access control
The GKMA should ensure that departing members cannot get access
to future group data.
o Backward access control
The GKMA should ensure that joining members cannot decrypt past
data.
5.7. Stateless, Stateful, and Self-healing Rekeying Algorithms
We classify group key management algorithms into three categories:
stateful, stateless, and self-healing.
Stateful algorithms [RFC2627,OFT] use KEKs from past rekeying
instances to encrypt (protect) KEKs corresponding to the current and
future rekeying instances. The main disadvantage in these schemes is
that if a member were offline or otherwise failed to receive KEKs
from a past rekeying instance, it may no longer be able to
synchronize its GSA even though it can receive KEKs from all future
rekeying instances. The only solution is to contact the GCKS
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explicitly for resynchronization. Note that the KEKs for the first
rekeying instance are protected by the Registration SA. Recall that
communication in that phase is one to one, and therefore it is easy
to ensure reliable delivery.
Stateless GKMAs [SD1,SD2] encrypt rekey messages with KEKs sent
during the registration protocol. Since rekey messages are
independent of any past rekey messages (i.e., that are not protected
by KEKs therein), a member may go offline but continue to decipher
future communications. However, stateless GKMAs offer no mechanisms
to recover past rekeying messages. Stateless rekeying may be
relatively inefficient, particularly for immediate (not batch)
rekeying in highly dynamic groups.
In self-healing schemes [Self-Healing], a member can reconstruct a
lost rekey message as long as it receives some past and some future
rekey messages.
5.8. Interoperability of a GKMA
Most GKMA specifications do not specify packet formats, although many
group key management algorithms need format specification for
interoperability. There are several alternative ways to manage key
trees and to number nodes within key trees. The following
information is needed during initialization of a Rekey SA or included
with each GKMA packet.
o GKMA name (e.g., LKH, OFT, Subset Difference)
o GKMA version number (implementation specific). Version may
imply several things such as the degree of a key tree,
proprietary enhancements, and qualify another field such as a
key ID.
o Number of keys or largest ID
o Version-specific data
o Per-key information:
- key ID,
- key lifetime (creation/expiration data) ,
- encrypted key, and
- encryption key's ID (optional).
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Key IDs may change in some implementations in which case one needs to
send:
o List of <old id, new id> pairs.
6. Group Security Association
The GKM architecture defines the interfaces between the registration,
rekey, and data security protocols in terms of the Security
Associations (SAs) of those protocols. By isolating these protocols
behind a uniform interface, the architecture allows implementations
to use protocols best suited to their needs. For example, a rekey
protocol for a small group could use multiple unicast transmissions
with symmetric authentication, while a rekey protocol for a large
group could use IP Multicast with packet-level Forward Error
Correction and source authentication.
The group key management architecture provides an interface between
the security protocols and the group SA (GSA). The GSA consists of
three SAs: Registration SA, Rekey SA, and Data SA. The Rekey SA is
optional. There are two cases in defining the relationships between
the three SAs. In both cases, the Registration SA protects the
registration protocol.
Case 1: Group key management is done WITHOUT using a Rekey SA. The
registration protocol initializes and updates one or more Data SAs
(having TPKs to protect files or streams). Each Data SA
corresponds to a single group, which may have more than one Data
SA.
Case 2: Group key management is done WITH a Rekey SA to protect the
rekey protocol. The registration protocol initializes the one or
more Rekey SAs as well as zero or more Data SAs, upon successful
completion. When a Data SA is not initialized in the registration
protocol, initialization is done in the rekey protocol. The rekey
protocol updates Rekey SA(s) AND establishes Data SA(s).
6.1. Group Policy
Group policy is described in detail in the Group Security Policy
Token document [GSPT]. Group policy can be distributed through group
announcements, key management protocols, and other out-of-band means
(e.g., via a web page). The group key management protocol carries
cryptographic policies of the SAs and the keys it establishes, as
well as additional policies for the secure operation of the group.
Baugher, et al. Informational [Page 24]
RFC 4046 MSEC Group Key Management Architecture April 2005
The acceptable cryptographic policies for the registration protocol,
which may run over TLS [TLS], IPsec, or IKE, are not conveyed in the
group key management protocol since they precede any of the key
management exchanges. Thus, a security policy repository having some
access protocol may need to be queried prior to establishing the
key-management session, to determine the initial cryptographic
policies for that establishment. This document assumes the existence
of such a repository and protocol for GCKS and member policy queries.
Thus group security policy will be represented in a policy repository
and accessible using a policy protocol. Policy distribution may be a
push or a pull operation.
The group key management architecture assumes that the following
group policy information may be externally managed, e.g., by the
content owner, group conference administrator or group owner:
o the identity of the Group owner, the authentication method, and
the delegation method for identifying a GCKS for the group;
o the group GCKS, authentication method, and delegation method
for any subordinate GCKSs for the group;
o the group membership rules or list and authentication method.
There are two additional policy-related requirements external to
group key management.
o There is an authentication and authorization infrastructure
such as X.509 [RFC3280], SPKI [RFC2693], or a pre-shared key
scheme, in accordance with the group policy for a particular
group.
o There is an announcement mechanism for secure groups and
events, which operates according to group policy for a
particular group.
Group policy determines how the registration and rekey protocols
initialize or update Rekey and Data SAs. The following sections
describe potential information sent by the GCKS for the Rekey and
Data SAs. A member needs the information specified in the next
sections to establish Rekey and Data SAs.
6.2. Contents of the Rekey SA
The Rekey SA protects the rekey protocol. It contains cryptographic
policy, Group Identity, and Security Parameter Index (SPI) [RFC2401]
to uniquely identify an SA, replay protection information, and key
protection keys.
Baugher, et al. Informational [Page 25]
RFC 4046 MSEC Group Key Management Architecture April 2005
6.2.1. Rekey SA Policy
o GROUP KEY MANAGEMENT ALGORITHM
This represents the group key revocation algorithm that
enforces forward and backward access control. Examples of key
revocation algorithms include LKH, LKH+, OFT, OFC, and Subset
Difference [RFC2627,OFT,TAXONOMY,SD1,SD2]. If the key
revocation algorithm is NULL, the Rekey SA contains only one
KEK, which serves as the group KEK. The rekey messages
initialize or update Data SAs as usual. However, the Rekey SA
itself can be updated (the group KEK can be rekeyed) when
members join or the KEK is about to expire. Leave rekeying is
done by re-initializing the Rekey SA through the rekey
protocol.
o KEK ENCRYPTION ALGORITHM
This specifies a standard encryption algorithm such as 3DES or
AES, and also the KEK KEY LENGTH.
o AUTHENTICATION ALGORITHM
This algorithm uses digital signatures for GCKS authentication
(since all shared secrets are known to some or all members of
the group), or some symmetric secret in computing MACs for
group authentication. Symmetric authentication provides weaker
authentication in that any group member can impersonate a
particular source. The AUTHENTICATION KEY LENGTH is also to be
specified.
o CONTROL GROUP ADDRESS
This address is used for multicast transmission of rekey
messages. This information is sent over the control channel
such as in an ANNOUNCEMENT protocol or call setup message. The
degree to which the control group address is protected is a
matter of group policy.
o REKEY SERVER ADDRESS
This address allows the registration server to be a different
entity from the server used for rekeying, such as for future
invocations of the registration and rekey protocols. If the
registration server and the rekey server are two different
entities, the registration server sends the rekey server's
address as part of the Rekey SA.
Baugher, et al. Informational [Page 26]
RFC 4046 MSEC Group Key Management Architecture April 2005
6.2.2. Group Identity
The group identity accompanies the SA (payload) information as an
identifier if the specific group key management protocol allows
multiple groups to be initialized in a single invocation of the
registration protocol, or multiple groups to be updated in a single
rekey message. It is often simpler to restrict each registration
invocation to a single group, but such a restriction is unnecessary.
It is always necessary to identify the group when establishing a
Rekey SA, either implicitly through an SPI or explicitly as an SA
parameter.
6.2.3. KEKs
Corresponding to the key management algorithm, the Rekey SA contains
one or more KEKs. The GCKS holds the key encrypting keys of the
group, while the members receive keys following the specification of
the key management algorithm. When there are multiple KEKs for a
group (as in an LKH tree), each KEK needs to be associated with a Key
ID, which is used to identify the key needed to decrypt it. Each KEK
has a LIFETIME associated with it, after which the KEK expires.
6.2.4. Authentication Key
The GCKS provides a symmetric or public key for authentication of its
rekey messages. Symmetric key authentication is appropriate only
when all group members can be trusted not to impersonate the GCKS.
The architecture does not rule out methods for deriving symmetric
authentication keys at the member [RFC2409] rather than pushing them
from the GCKS.
6.2.5. Replay Protection
Rekey messages need to be protected from replay/reflection attacks.
Sequence numbers are used for this purpose, and the Rekey SA (or
protocol) contains this information.
6.2.6. Security Parameter Index (SPI)
The tuple <Group identity, SPI> uniquely identifies a Rekey SA. The
SPI changes each time the KEKs change.
6.3. Contents of the Data SA
The GCKS specifies the data security protocol used for secure
transmission of data from sender(s) to receiving members. Examples
of data security protocols include IPsec ESP [RFC2401] and SRTP
[RFC3711]. While the contents of each of these protocols are out of
Baugher, et al. Informational [Page 27]
RFC 4046 MSEC Group Key Management Architecture April 2005
the scope of this document, we list the information sent by the
registration protocol (or the rekey protocol) to initialize or update
the Data SA.
6.3.1. Group Identity
The Group identity accompanies SA information when Data SAs are
initialized or rekeyed for multiple groups in a single invocation of
the registration protocol or in a single Rekey message.
6.3.2. Source Identity
The SA includes source identity information when the group owner
chooses to reveal source identity to authorized members only. A
public channel such as the announcement protocol is only appropriate
when there is no need to protect source or group identities.
6.3.3. Traffic Protection Keys
Regardless of the data security protocol used, the GCKS supplies the
TPKs, or information to derive TPKs for traffic protection.
6.3.4. Data Authentication Keys
Depending on the data authentication method used by the data security
protocol, group key management may pass one or more keys, functions
(e.g., TESLA [TESLA-INFO,TESLA-SPEC]), or other parameters used for
authenticating streams or files.
6.3.5. Sequence Numbers
The GCKS passes sequence numbers when needed by the data security
protocol, for SA synchronization and replay protection.
6.3.6. Security Parameter Index (SPI)
The GCKS may provide an identifier as part of the Data SA contents
for data security protocols that use an SPI or similar mechanism to
identify an SA or keys within an SA.
6.3.7. Data SA policy
The Data SA parameters are specific to the data security protocol but
generally include encryption algorithm and parameters, the source
authentication algorithm and parameters, the group authentication
algorithm and parameters, and/or replay protection information.
Baugher, et al. Informational [Page 28]
RFC 4046 MSEC Group Key Management Architecture April 2005
7. Scalability Considerations
The area of group communications is quite diverse. In
teleconferencing, a multipoint control unit (MCU) may be used to
aggregate a number of teleconferencing members into a single session;
MCUs may be hierarchically organized as well. A loosely coupled
teleconferencing session [RFC3550] has no central controller but is
fully distributed and end-to-end. Teleconferencing sessions tend to
have at most dozens of participants. However, video broadcast that
uses multicast communications and media-on-demand that uses unicast
are large-scale groups numbering hundreds to millions of
participants.
As described in the Requirements section, Section 2, the group key
management architecture supports multicast applications with a single
sender. The architecture described in this paper supports large-
scale operation through the following features.
1. There is no need for a unicast exchange to provide data keys to a
security protocol for members who have previously registered in
the particular group; data keys can be pushed in the rekey
protocol.
2. The registration and rekey protocols are separable to allow
flexibility in how members receive group secrets. A group may use
a smart-card based system in place of the registration protocol,
for example, to allow the rekey protocol to be used with no back
channel for broadcast applications such as television conditional
access systems.
3. The registration and rekey protocols support new keys, algorithms,
authentication mechanisms and authorization infrastructures in the
architecture. When the authorization infrastructure supports
delegation, as in X.509 and SPKI, the GCKS function can be
distributed as shown in Figure 3 below.
The first feature in the list allows fast keying of data security
protocols when the member already belongs to the group. While this
is realistic for subscriber groups and customers of service providers
who offer content events, it may be too restrictive for applications
that allow member enrollment at the time of the event. The MSEC
group key management architecture suggests hierarchically organized
key distribution to handle potential mass simultaneous registration
requests. The Figure 3 configuration may be needed when conventional
clustering and load balancing solutions of a central GCKS site cannot
meet customer requirements. Unlike conventional caching and content
Baugher, et al. Informational [Page 29]
RFC 4046 MSEC Group Key Management Architecture April 2005
distribution networks, however, the configuration shown in Figure 3
has additional security ramifications for physical security of a
GCKS.
+----------------------------------------+
| +-------+ |
| | GCKS | |
| +-------+ |
| | ^ |
| | | |
| | +---------------+ |
| | ^ ^ |
| | | ... | |
| | +--------+ +--------+ |
| | | MEMBER | | MEMBER | |
| | +--------+ +--------+ |
| v |
| +-------------+ |
| | | |
| v ... v |
| +-------+ +-------+ |
| | GCKS | | GCKS | |
| +-------+ +-------+ |
| | ^ |
| | | |
| | +---------------+ |
| | ^ ^ |
| | | ... | |
| | +--------+ +--------+ |
| | | MEMBER | | MEMBER | |
| | +--------+ +--------+ |
| v |
| ... |
+----------------------------------------+
Figure 3: Hierarchically Organized Key Distribution
More analysis and work is needed on the protocol instantiations of
the group key management architecture, to determine how effectively
and securely the architecture can support large-scale multicast
applications. In addition to being as secure as pairwise key
management against man-in-the-middle, replay, and reflection attacks,
group key management protocols have additional security needs.
Unlike pairwise key management, group key management needs to be
secure against attacks by group members who attempt to impersonate a
GCKS or disrupt the operation of a GCKS, as well as by non-members.
Baugher, et al. Informational [Page 30]
RFC 4046 MSEC Group Key Management Architecture April 2005
Thus, secure groups need to converge to a common group key when
members are attacking the group, joining and leaving the group, or
being evicted from the group. Group key management protocols also
need to be robust when DoS attacks or network partition leads to
large numbers of synchronized requests. An instantiation of group
key management, therefore, needs to consider how GCKS operation might
be distributed across multiple GCKSs designated by the group owner to
serve keys on behalf of a designated GCKS. GSAKMP [GSAKMP] protocol
uses the policy token and allows designating some of the members as
subordinate GCKSs to address this scalability issue.
8. Security Considerations
This memo describes MSEC key management architecture. This
architecture will be instantiated in one or more group key management
protocols, which must be protected against man-in-the-middle,
connection hijacking, replay, or reflection of past messages, and
denial of service attacks.
Authenticated key exchange [STS,SKEME,RFC2408,RFC2412,RFC2409]
techniques limit the effects of man-in-the-middle and connection
hijacking attacks. Sequence numbers and low-computation message
authentication techniques can be effective against replay and
reflection attacks. Cookies [RFC2522], when properly implemented,
provide an efficient means to reduce the effects of denial of service
attacks.
This memo does not address attacks against key management or security
protocol implementations such as so-called type attacks that aim to
disrupt an implementation by such means as buffer overflow. The
focus of this memo is on securing the protocol, not on implementing
the protocol.
While classical techniques of authenticated key exchange can be
applied to group key management, new problems arise with the sharing
of secrets among a group of members: group secrets may be disclosed
by a member of the group, and group senders may be impersonated by
other members of the group. Key management messages from the GCKS
should not be authenticated using shared symmetric secrets unless all
members of the group can be trusted not to impersonate the GCKS or
each other. Similarly, members who disclose group secrets undermine
the security of the entire group. Group owners and GCKS
administrators must be aware of these inherent limitations of group
key management.
Another limitation of group key management is policy complexity.
While peer-to-peer security policy is an intersection of the policy
of the individual peers, a group owner sets group security policy
Baugher, et al. Informational [Page 31]
RFC 4046 MSEC Group Key Management Architecture April 2005
externally in secure groups. This document assumes there is no
negotiation of cryptographic or other security parameters in group
key management. Group security policy, therefore, poses new risks to
members who send and receive data from secure groups. Security
administrators, GCKS operators, and users need to determine minimal
acceptable levels of security (e.g., authentication and admission
policy of the group, key lengths, cryptographic algorithms and
protocols used) when joining secure groups.
Given the limitations and risks of group security, the security of
the group key management registration protocol should be as good as
the base protocols on which it is developed, such as IKE, IPsec, TLS,
or SSL. The particular instantiations of this group key management
architecture must ensure that the high standards for authenticated
key exchange are preserved in their protocol specifications, which
will be Internet standards-track documents that are subject to
review, analysis, and testing.
The second protocol, the group key management rekey protocol, is new
and has unknown risks. The source-authentication risks described
above are obviated by the use of public-key cryptography. The use of
multicast delivery may raise additional security issues such as
reliability, implosion, and denial-of-service attacks based upon the
use of multicast. The rekey protocol specification needs to offer
secure solutions to these problems. Each instantiation of the rekey
protocol, such as the GSAKMP Rekey or the GDOI Groupkey-push
operations, need to validate the security of their rekey
specifications.
Novelty and complexity are the biggest risks to group key management
protocols. Much more analysis and experience are needed to ensure
that the architecture described in this document can provide a well-
articulated standard for security and risks of group key management.
9. Acknowledgments
The GKM Building Block [GKMBB] I-D by SMuG was a precursor to this
document; thanks to Thomas Hardjono and Hugh Harney for their
efforts. During the course of preparing this document, Andrea
Colegrove, Brian Weis, George Gross, and several others in the MSEC
WG and GSEC and SMuG research groups provided valuable comments that
helped improve this document. The authors appreciate their
contributions to this document.
Baugher, et al. Informational [Page 32]
RFC 4046 MSEC Group Key Management Architecture April 2005
10. Informative References
[BatchRekey] Yang, Y. R., et al., "Reliable Group Rekeying: Design
and Performance Analysis", Proc. ACM SIGCOMM, San
Diego, CA, August 2001.
[CLIQUES] Steiner, M., Tsudik, G., and M. Waidner, "CLIQUES: A
New Approach to Group Key Agreement", IEEE ICDCS 97,
May 1997
[FN93] Fiat, A. and M. Naor, "Broadcast Encryption, Advances
in Cryptology", CRYPTO 93 Proceedings, Lecture Notes
in Computer Science, Vol. 773, pp. 480-491, 1994.
[GKMBB] Harney, H., M. Baugher, and T. Hardjono, "GKM
Building Block: Group Security Association (GSA)
Definition," Work in Progress, September 2000.
[GSAKMP] Harney, H., Colegrove, A., Harder, E., Meth, U., and
R. Fleischer, "Group Secure Association Key
Management Protocol", Work in Progress, February
2003.
[GSPT] Hardjono, T., Harney, H., McDaniel, P., Colegrove,
A., and P. Dinsmore, "The MSEC Group Security Policy
Token", Work in Progress, August 2003.
[H.235] International Telecommunications Union, "Security and
Encryption for H-Series (H.323 and other H.245-based)
Multimedia Terminals", ITU-T Recommendation H.235
Version 3, Work in progress, 2001.
[JKKV94] Just, M., Kranakis, E., Krizanc, D., and P. van
Oorschot, "On Key Distribution via True
Broadcasting", Proc. 2nd ACM Conference on Computer
and Communications Security, pp. 81-88, November
1994.
[MARKS] Briscoe, B., "MARKS: Zero Side Effect Multicast Key
Management Using Arbitrarily Revealed Key Sequences",
Proc. First International Workshop on Networked
Group Communication (NGC), Pisa, Italy, November
1999.
[MIKEY] Arkko, J., Carrara, E., Lindholm, F., Naslund, M.,
and K. Norrman, "MIKEY: Multimedia Internet KEYing",
RFC 3830, August 2004.
Baugher, et al. Informational [Page 33]
RFC 4046 MSEC Group Key Management Architecture April 2005
[MSEC-Arch] Hardjono, T. and B. Weis, "The Multicast Group
Security Architecture", RFC 3740, March 2004.
[MVV] Menzes, A.J., van Oorschot, P.C., and S.A. Vanstone,
"Handbook of Applied Cryptography", CRC Press, 1996.
[NORM] Adamon, B., Bormann, C., Handley, M., and J. Macker,
"Negative-acknowledgment (NACK)-Oriented Reliable
Multicast (NORM) Protocol", RFC 3940, November 2004.
[OFT] Balenson, D., McGrew, P.C., and A. Sherman, "Key
Management for Large Dynamic Groups: One-Way Function
Trees and Amortized Initialization", IRTF Work in
Progress, August 2000.
[RFC2093] Harney, H. and C. Muckenhirn, "Group Key Management
Protocol (GKMP) Specification", RFC 2093, July 1997.
[RFC2094] Harney, H., and C. Muckenhirn, "Group Key Management
Protocol (GKMP) Architecture" RFC 2094, July 1997.
[RFC2326] Schulzrinne, H., Rao, A., and R. Lanphier, "Real Time
Streaming Protocol (RTSP)", RFC 2326, April 1998.
[RFC2327] Handley, M. and V. Jacobson, "SDP: Session
Description Protocol", RFC 2327, April 1998.
[RFC2367] McDonald, D., Metz, C., and B. Phan, "PF_KEY Key
Management API, Version 2", RFC 2367, July 1998.
[RFC2401] Kent, S. and R. Atkinson, "Security Architecture for
the Internet Protocol", RFC 2401, November 1998.
[RFC2408] Maughan, D., Schertler, M., Schneider, M., and J.
Turner, "Internet Security Association and Key
Management Protocol (ISAKMP)", RFC 2408, November
1998.
[RFC2409] Harkins, D. and D. Carrel, "The Internet Key Exchange
(IKE)", RFC 2409, November 1998.
[RFC2412] Orman, H., "The OAKLEY Key Determination Protocol",
RFC 2412, November 1998.
[RFC2522] Karn, P. and W. Simpson, "Photuris: Session-Key
Management Protocol", RFC 2522, March 1999.
Baugher, et al. Informational [Page 34]
RFC 4046 MSEC Group Key Management Architecture April 2005
[RFC2693] Ellison, C., Frantz, B., Lampson, B., Rivest, R.,
Thomas, B., and T. Ylonen, "SPKI Certificate Theory",
RFC 2693, September 1999.
[RFC3261] Rosenberg, J., Schulzrinne, H., Camarillo, G.,
Johnston, A., Peterson, J., Sparks, R., Handley, M.,
and E. Schooler, "SIP: Session Initiation Protocol",
RFC 3261, June 2002.
[RFC3280] Housley, R., Polk, W., Ford, W., and D. Solo,
"Internet X.509 Public Key Infrastructure Certificate
and Certificate Revocation List (CRL) Profile", RFC
3280, April 2002.
[RFC2627] Wallner, D., Harder, E., and R. Agee, "Key Management
for Multicast: Issues and Architectures", RFC 2627,
June 1999.
[RFC3450] Luby, M., Gemmell, J., Vicisano, L., Rizzo, L., and
J. Crowcroft, "Asynchronous Layered Coding (ALC)
Protocol Instantiation", RFC 3450, December 2002.
[RFC3547] Baugher, M., Weis, B., Hardjono, T., and H. Harney,
"The Group Domain of Interpretation", RFC 3547, July
2003.
[RFC3550] Schulzrinne, H., Casner, S., Frederick, R., and V.
Jacobson, "RTP: A Transport Protocol for Real-Time
Applications", STD 64, RFC 3550, July 2003.
[RFC3711] Baugher, M., McGrew, D., Naslund, M., Carrara, E.,
and K. Norrman, "The Secure Real-time Transport
Protocol (SRTP)", RFC 3711, March 2004.
[SD1] Naor, D., Naor, M., and J. Lotspiech, "Revocation and
Tracing Schemes for Stateless Receiver", Advances in
Cryptology - CRYPTO, Santa Barbara, CA: Springer-
Verlag Inc., LNCS 2139, August 2001.
[SD2] Naor, M. and B. Pinkas, "Efficient Trace and Revoke
Schemes", Proceedings of Financial Cryptography 2000,
Anguilla, British West Indies, February 2000.
[Self-Healing] Staddon, J., et. al., "Self-healing Key Distribution
with Revocation", Proc. 2002 IEEE Symposium on
Security and Privacy, Oakland, CA, May 2002.
Baugher, et al. Informational [Page 35]
RFC 4046 MSEC Group Key Management Architecture April 2005
[SKEME] H. Krawczyk, "SKEME: A Versatile Secure Key Exchange
Mechanism for Internet", ISOC Secure Networks and
Distributed Systems Symposium, San Diego, 1996.
[STS] Diffie, P. van Oorschot, M., and J. Wiener,
"Authentication and Authenticated Key Exchanges",
Designs, Codes and Cryptography, 2, 107-125 (1992),
Kluwer Academic Publishers.
[TAXONOMY] Canetti, R., et. al., "Multicast Security: A Taxonomy
and some Efficient Constructions", IEEE INFOCOM,
1999.
[TESLA-INFO] Perrig, A., Canetti, R., Song, D., Tygar, D., and B.
Briscoe, "TESLA: Multicast Source Authentication
Transform Introduction", Work in Progress, December
2004.
[TESLA-SPEC] Perrig, A., R. Canetti, and Whillock, "TESLA:
Multicast Source Authentication Transform
Specification", Work in Progress, April 2002.
[tGSAKMP] Harney, H., et. al., "Tunneled Group Secure
Association Key Management Protocol", Work in
Progress, May 2003.
[TLS] Dierks, T. and C. Allen, "The TLS Protocol Version
1.0," RFC 2246, January 1999.
[TPM] Marks, D. and B. Turnbull, "Technical protection
measures: The Intersection of Technology, Law, and
Commercial Licenses", Workshop on Implementation
Issues of the WIPO Copyright Treaty (WCT) and the
WIPO Performances and Phonograms Treaty (WPPT), World
Intellectual Property Organization, Geneva, December
6 and 7, 1999.
[Wool] Wool, A., "Key Management for Encrypted broadcast",
5th ACM Conference on Computer and Communications
Security, San Francisco, CA, Nov. 1998.
Baugher, et al. Informational [Page 36]
RFC 4046 MSEC Group Key Management Architecture April 2005
Authors' Addresses
Mark Baugher
Cisco Systems
5510 SW Orchid St.
Portland, OR 97219, USA
Phone: +1 408-853-4418
EMail: [email protected]
Ran Canetti
IBM Research
30 Saw Mill River Road
Hawthorne, NY 10532, USA
Phone: +1 914-784-7076
EMail: [email protected]
Lakshminath R. Dondeti
Qualcomm
5775 Morehouse Drive
San Diego, CA 92121
Phone: +1 858 845 1267
EMail: [email protected]
Fredrik Lindholm
Ericsson Research
SE-16480 Stockholm, Sweden
Phone: +46 8 58531705
EMail: [email protected]
Baugher, et al. Informational [Page 37]
| https://www.potaroo.net/ietf/rfc/rfc4046.html |
Cancers | Free Full-Text | Small Extracellular Vesicles and Metastasis—Blame the Messenger
Cancer is a complex disease, driven by genetic defects and environmental cues. Systemic dissemination of cancer cells by metastasis is generally associated with poor prognosis and is responsible for more than 90% of cancer deaths. Metastasis is thought to follow a sequence of events, starting with loss of epithelial features, detachment of tumor cells, basement membrane breakdown, migration, intravasation and survival in the circulation. At suitable distant niches, tumor cells reattach, extravasate and establish themselves by proliferating and attracting vascularization to fuel metastatic growth. These processes are facilitated by extensive cross-communication of tumor cells with cells in the primary tumor microenvironment (TME) as well as at distant pre-metastatic niches. A vital part of this communication network are small extracellular vesicles (sEVs, exosomes) with a size of 30–150 nm. Tumor-derived sEVs educate recipient cells with bioactive cargos, such as proteins, and in particular, major nucleic acid classes, to drive tumor growth, cell motility, angiogenesis, immune evasion and formation of pre-metastatic niches. Circulating sEVs are also utilized as biomarker platforms for diagnosis and prognosis. This review discusses how tumor cells facilitate progression through the metastatic cascade by employing sEV-based communication and evaluates their role as biomarkers and vehicles for drug delivery.
Small Extracellular Vesicles and Metastasis—Blame the Messenger
by Tanja Seibold , Mareike Waldenmaier , Thomas Seufferlein † and Tim Eiseler *,†
Cancers 2021 , 13 (17), 4380; https://doi.org/10.3390/cancers13174380
Received: 30 July 2021 / Revised: 23 August 2021 / Accepted: 26 August 2021 / Published: 30 August 2021
Abstract
:
Simple Summary
Abstract
Keywords:
cancer
metastasis
small extracellular vesicles (sEVs)
exosomes
immune evasion
organotropism
pre-metastatic niche
1. Tumor Metastasis and Nucleic Acid Cargo in Small Extracellular Vesicles
2. sEVs and Their Highly Abundant Exosome-sEV Sub-Population
sEVs are lipid bilayer-engulfed extracellular vesicles with a diameter of 30–150 nm [ 19 ]. Based on their size, sEVs are made up mainly by exosomes, but also a sub-population of microvesicles, such as arrestin domain-containing protein 1 (ARRDC1)-mediated microvesicles (ARMMs), with a diameter that reaches below 100 nm, was described [ 20 ]. Due to the high abundance of exosomes in the sEV group, this review is mainly focused on the role of exosomes in cancer progression and metastasis. For the sake of an easy communication with the reader, we have however attributed biological effects and in vivo functions to the broader specification “sEVs”, which is often used instead of the term “exosomes” in the literature [ 21 ]. The exosome-sEV population is formed as intraluminal vesicles (ILVs) in endosomal-derived multivesicular bodies (MVBs) and released at the plasma membrane. sEVs are present in various body fluids, such as blood, saliva or urine [ 22 ]. Omics characterization identified various sEV cargo subtypes, including proteins, lipids and nucleic acids [ 8 , 16 , 17 , 18 , 23 ]. Due to the endosomal origin of respective sEVs, cargo proteins implicated in biogenesis of ILVs, such as tetraspanins (CD9, CD63, CD81, CD82, CD53 and CD37), ALG-2 interacting protein X (ALIX) or the tumor susceptibility gene 101 protein (TSG101), are utilized as markers, e.g., tetraspanins are enriched around 100-fold in sEVs when compared to their parental cells [ 8 , 23 ]. It has to be noted that not all of these proteins are exclusively found in sEVs, and some markers can be detected in microvesicles as well [ 24 ]. Moreover, not all tetraspanins are always expressed in a specific cancer cell line. Therefore, the Kalluri group recently performed broad-spectrum mass spectrometry of sEVs across different cancer lines and reported that synthenin-1 was the ideal global marker for sEVs released from cancer cells [ 25 ]. sEVs are also enriched in annexins, small Rab-GTPases and lipid-raft-associated factors (e.g., flotillin), as well as major histocompatibility complex class I and II receptors (MHC I and MHC II), heat shock proteins (e.g., Hsp70 and Hsp90), cytoskeleton components (myosin, actin and tubulin), cell membrane receptors, such as integrins, and epidermal growth factor receptor (EGFR), but also cytokines or cytosolic components (e.g., signaling proteins, metabolic enzymes) [ 26 , 27 ]. In addition, sEVs were shown to have a conserved lipid composition that is required for sEV biogenesis, morphology and homeostasis upon uptake. They are enriched in cholesterol, sphingomyelin, glycosphingolipids, phosphatidylserine and ceramide [ 28 , 29 ]. sEVs also contain a large number of nucleic acid classes: mRNAs, miRNAs, long-non-coding RNAs (lncRNAs), circular RNAs (circRNAs), ribosomal RNAs (rRNAs), transfer RNAs (tRNAs) and other RNA subclasses, but DNA was also described [ 9 , 26 , 27 ]. Thus, sEVs are generated by almost every cell type using multiple biogenesis pathways under physiological and pathophysiological conditions, which vitally determines their respective cargo profiles [ 30 , 31 ].
2.1. sEV Biogenesis and Cargo Loading
Biogenesis of exosome-sEVs starts at the endosomal compartment by maturing early endosomes into late endosomes or MVBs, where membranes invaginate to generate ILVs [ 8 , 32 ]. Subsequently, MVBs can either fuse with lysosomes and degrade their content, or are transported along microtubules to the cell periphery, where they fuse with the plasma membrane to release ILVs as sEVs [ 33 ]. The biogenesis of ILVs can be facilitated by two major pathways: (1) The endosomal sorting complex required for transport (ESCRT) mediates ILV formation by the ESCRT machinery, which is assembled into four larger complexes, ESCRT-0, -I, -II and -III, and aided by the associated proteins AAA-ATPase VPS4, VTA1 and ALIX [ 34 ] ( Figure 1 ). To facilitate packaging by the ESCRT complex, cargo proteins need to display post-translational modifications, such as ubiquitination [ 35 ]. The ESCRT-0 complex then binds these tagged cargos, segregates the cargo proteins into microdomains and coordinates the additional interaction of ESCRT-1 with these cargos [ 36 , 37 ]. ESCRT-1 in turn recruits ESCRT-2 to facilitate ILV formation and loading of cytosolic proteins or RNAs into ILVs. Subsequently, ESCRT-2 recruits ESCRT-3 to the newly formed vesicles to promote scission of the cargo-laden ILVs together with VPS4, while ubiquitin and ESCRT subunits are released in the cytosol for recycling [ 36 , 37 , 38 ].
(2) Additional studies have suggested that MVB biogenesis can also work without the ESCRT complex. It was reported that ILVs formed in MVBs even when vital ESCRT subunits were silenced, indicating ESCRT-independent biogenesis [ 39 ]. These mechanisms are dependent on tetraspanins and lipids, such as ceramide that is generated by neutral sphingomyelinase 2 (nSMase2). Thus, an inhibitor of nSMase, GW4869, was able to effectively reduce sEV-release in several studies [ 32 , 40 , 41 , 42 ]. Mechanistically, lipid-mediated ILV biogenesis is facilitated by spontaneous budding of limited membranes due to incorporation of ceramide, lysophospho- or glycosphingo-lipids. Interestingly, enzymatic conversion of ceramide to sphingosine and sphingosin1-phosphate (S1P), and thus activation of sphingosine1-phosphate receptors on limiting membranes, was also implicated in the sorting of tetraspanins into ILVs [ 43 ]. Tetraspanins are major sEV membrane markers, characterized by four transmembrane domains. At the plasma membrane, they are sequestered in tetraspanin-enriched microdomains (TEMs) and interact with a wide variety of associated factors, that can be recycled together with their tetraspanin binding partners into MVBs and eventually ILVs [ 44 ] (see Figure 1 ).
RNA is also loaded in ILVs by a lipid-mediated mechanism. To this end, specific RNA sequences increase the affinity for lipid structures, such as lipid rafts, hydrophobic lipids or sphingosine [ 45 ]. In addition, a number of RNA-binding proteins were reported to load mRNAs or miRNAs into sEVs [ 46 ]. Concerning miRNAs, Teng et al. demonstrated removal of the tumor-suppressor miR-193 from cells during colon cancer progression by packaging in sEVs, utilizing the miRNA-binding protein, major vault protein (MVP) [ 47 ]. Thus, sEVs are used by cancer cells in order to rebalance their content of tumor-suppressive and oncogenic miRNA populations [ 47 ].
Upon completion of ILV biogenesis, MVBs are transported along microtubules to the plasma membrane, where ILVs are released [ 48 , 49 ]. Here, several factors are involved on the way, which include small Rab family GTPases as molecular switches, microtubules and their associated regulatory proteins, molecular motors that transport the MVBs and soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) that mediate final membrane fusion. In particular, the Rab-GTPases are vital regulators of vesicular trafficking and ILV budding or release, e.g., Rab27a/b or Rab11 regulate different aspects of ESCRT-dependent or independent sEV-release [ 9 , 50 , 51 ] ( Figure 1 ). The efficient fusion and sEV-release at the plasma membrane also requires the presence of branched actin filaments. Branched actin is either stabilized or debranched by the actin-regulatory proteins Cortactin and Coronin-1, respectively [ 52 ]. Cortactin also facilitates Arp2/3-complex-dependent synergistic nucleation of branched actin filaments together with nucleation-promoting factors [ 53 ]. Our group has recently shown that Cortactin together with WAVE2 is required for sEV-release from pancreatic ductal adenocarcinoma (PDAC) cells. In this study, we have also described Protein Kinase D1 (PRKD1) as a vital inhibitory upstream regulator, that phosphorylates Cortactin at S298 [ 54 , 55 ]. When phosphorylation of this site was abrogated, Cortactin induced synergistic nucleation of branched filaments required for sEV-release, thus drastically increasing the respective sEV-secretion [ 54 ]. Interestingly, PRKD1 expression is reduced in a majority of PDACs and other invasive cancer cells [ 54 , 56 ]. In summary, sEV biogenesis can occur in an ESCRT-dependent and independent manner in a highly regulated process that involves the coordinated action of multiple cellular compartments as well as tight spatio-temporal control.
2.2. sEV-Uptake in Recipient Cells
Once released into the extracellular milieu or the circulation, sEVs can interact with recipient cells by different mechanisms. They can either bind to membrane receptors and activate specific signaling pathways, or cargo is transferred upon uptake into the respective cells. Mechanisms for uptake and delivery of active biomolecules include direct membrane fusion, clathrin- or lipid raft (Caveolae/caveolin-1)-mediated endocytosis, macro-pinocytosis and phagocytosis [ 57 ] (see Figure 1 ). In addition, molecular and cellular stress conditions were shown to modify sEV-release and -uptake rates, as well as their respective cargo composition [ 9 ].
2.3. Modifiers of sEV-Release in Tumor Cells
Tumor cells are associated with strongly increased sEV-release [ 58 , 59 , 60 , 61 ], which further display a significantly altered cargo profile to act as signaling hubs for intercellular communication during tumor metastasis. Thus, quantitative and qualitative changes in sEV populations were identified in the blood circulation of cancer patients, corroborating a function of sEVs as diagnostic and prognostic markers [ 62 , 63 , 64 , 65 ]. The molecular mechanisms involved in sEV trafficking and release are complex and not fully understood. However, it has become evident that cellular and molecular stresses, such as environmental cues and oncogenic transformation, have a crucial role in triggering sEV secretion [ 66 , 67 ]. One hallmark of the TME is low pH, which was shown to be a key factor for sEV-release, but also sEV-uptake in recipient cells [ 66 ]. Similar observations were made for hypoxic conditions, where the low oxygen concentrations not only quantitatively alter sEV-release, but also facilitate qualitative changes in the sEV cargo content to promote vascularization and cell proliferation [ 67 ]. Since ESCRT-dependent and independent pathways are major regulators of sEV biogenesis, interference with the respective pathways was able to potently modulate secretion [ 68 , 69 , 70 , 71 ]. A recent study has demonstrated that oncogenes found in many cancer entities, such as MYC, aurora kinase B (AURKB) and HRAS, trigger hyperactivation of ESCRT and ceramide pathways, as well as the inhibition of lysosome genes causing abundant sEV secretion. Again, the oncogenes mediated a shift in cargo composition, in particular for proteins and miRNA, thus promoting a pro-tumorigenic phenotype [ 71 ]. In another setting, oncogenic HRAS induced considerable release of sEVs from epithelial cell lines, which were shown to contain the whole cancer cell genome, including the mutant HRAS oncogene [ 72 , 73 ]. Moreover, several lines of evidence suggest that the KRAS oncogene was able to enhance sEV-release and modulate their functional cargo compared to wild-type KRAS. Mutated, oncogenic KRAS-sEVs were characterized by tumor-promoting proteins, including mutant KRAS, and an altered miRNA content, enabling oncogenic transfer and metabolic reprograming in recipient cells [ 74 , 75 , 76 ]. Different mechanisms are thought to be involved in RAS-dependent regulation of sEV-release, e.g., the activation of syndecan-1, as well as the RHO pathway, which have both functions in sEV biogenesis [ 77 , 78 , 79 ]. In addition, the Wnt protein WNT5A, an oncogene correlating with metastasis and poor prognosis, was able to trigger Ca2+-dependent release of sEVs with pro-angiogenic and immunosuppressive features [ 80 ]. There are opposing observations and hypotheses regarding the miRNA content of oncogene-induced sEVs. Several studies report the release of pro-tumor miRNAs through sEVs by cancer cells to reprogram recipient malignant and non-malignant cells, enabling cancer progression [ 81 ]. On the other hand, oncogene-induced sEVs were found to be enriched in miRNAs with tumor-suppressor functions, supporting the hypotheses that tumor cells eliminate undesirable cellular miRNAs as cargo in these sEVs [ 71 , 75 ].
Since nucleic acids and in particular miRNAs have vital functions during tumor progression and metastasis, we were prompted to focus this review on delineating the contribution of sEV-based nucleic acid transfer during progression through the metastatic cascade.
3. Role of sEVs in Local Stroma Invasion
82
83
84
3.1. Epithelial-to-Mesenchymal Transition (EMT)
During EMT, cells lose epithelial traits and transform into a motile, mesenchymal state. EMT can be observed during embryonic development and wound-healing processes, where the loss of adhesion properties, polarity and basement anchoring are important physiological events. However, when cancer cells activate the EMT program, they gain stemness and migratory abilities, which contribute to invasiveness and ultimately metastasis [ 85 ]. On a molecular level, EMT includes loss of epithelial markers, such as E-cadherin, and upregulation of mesenchymal proteins, e.g., vimentin, fibronectin, N-cadherin, as well as the change to a fibroblast-like cell [ 3 ]. The downregulation of E-cadherin and upregulation of mesenchymal markers during EMT is orchestrated by zinc-finger transcription factors, such as SNAIL, SLUG, TWIST and ZEB-1/2, downstream of growth factor signaling induced by hepatocyte growth factor (HGF), epidermal growth factor (EGF) and transforming growth factor beta (TGFβ), or Wnt/β-catenin pathways [ 84 , 86 , 87 , 88 ]. However, the transcriptional deregulation and induction of EMT is also prominently facilitated by uptake of sEVs, which modulate signaling of the respective pathways, e.g., upon transfer of mir-301a in sEVs, targeting p63 and thus release/activation of ZEB1/2 [ 89 ]. EMT is also promoted by the transfer of constitutively active β-catenin or Wnt ligands (Wnt1 and Wnt3a), as well as sEV-resident miRNAs mir-92a [ 90 ], miR-191 [ 14 ] and miR-1260b [ 91 ], implicated in modulating Wnt/β-catenin signaling. However, loss of epithelial characteristics and detachment from the ECM also pose a risk for cancer cells by triggering anoikis, a form of programmed cell death to prevent metastasis. Thus, cancer cells need to acquire anoikis resistance, which can occur via several mechanisms, such as the transfer of sEVs containing miRNA-210 and miR-222-3p, as shown for non-small-cell lung cancer (NSCLC) and gastric cancer cells (GC) [ 92 , 93 ].
3.2. ECM Degradation
The invasion of cancer cells is further supported by the degradation of the BM and other ECM structures in the tissue. Key players in ECM remodeling are matrix metalloproteinases (MMPs), whose activity is controlled by transcriptional and post-translational regulation. Cancer cells have acquired different mechanisms to deactivate this tight control of MMPs and render them highly active. Enhanced function of several MMPs was shown to regulate ECM stiffness via integrins and contributed to invasive phenotypes of cancer cells [ 94 ]. Moreover, MMP expression was shown to release growth factors, such as TGFβ, from the TME by influencing their bioavailability or functionality, thus enabling cell proliferation [ 95 , 96 ]. Interestingly, a study by Yokoi and colleagues in 2017 established that sEVs may play a crucial role in fostering MMP activity. Here, no MMP protein was found in sEVs, as shown in various studies [ 97 , 98 , 99 ], but the selective packaging of MMP1 mRNA into sEVs derived from ovarian cancer (OC) cells was found. These sEVs then triggered destruction of the peritoneal mesothelium and BM in vitro and in vivo, ultimately promoting metastatic behavior [ 100 ]. Several studies have found miR-21 to be overexpressed in different cancer types and demonstrated its transfer via sEVs to recipient cells [ 101 , 102 , 103 ]. miR-21 positively correlated with the expression of ECM mediators MMP-2, MMP-9 and MMP-11, due to the potent inhibition of phosphatase and tensin homolog (PTEN) and inhibitor of metalloproteinases 3 (TIMP-3) [ 102 , 104 ]. Similar effects have been established for miR-181b during carcinogenesis in hepatocellular carcinomas (HCC) and esophageal cancer (ESCC) [ 105 , 106 ].
4. sEV-Based Communication in the Tumor Microenvironment (TME)
Once cancer cells have breached the BM, they invade the stroma, where they are exposed to stromal cells. These non-malignant cells comprise fibroblasts, myofibroblasts, vascular and lymphatic endothelial cells, adipocytes and infiltrating immune cells [ 107 ]. The immediate ECM and cellular components of the stroma make up the TME. The classical theory suggests that upon cancer initiation, adjacent non-transformed stromal cells are recruited and reprogrammed, which is accompanied by extensive intercellular communication via cytokines, chemokines and vesicles to generate a dedicated favorable TME [ 108 ]. Chronic inflammation and wound-healing processes in an aberrant microenvironment also promote tumorigenesis [ 109 , 110 , 111 ]. Research in recent years has reinforced the crucial role of crosstalk between cancer cells and cellular components of their TME to create a supportive environment, thus enhancing the aggressive and invasive behaviors of tumors. Reprogrammed stroma cells enable the supply with essential nutrients in order to meet the high demand of proliferating tumor cells, but also to remodel the ECM and escape immune surveillance [ 107 ]. This communication is largely dependent on soluble factors and the transfer of sEVs. Tumor-sEVs or sEV-based crosstalk have been described for many cell types in the TME, such as cancer-associated fibroblasts (CAFs), which facilitate cancer progression either in an autocrine or paracrine fashion, e.g., by inducing EMT or stemness [ 112 ]. Infiltrating innate and adaptive immune cells, such as tumor-associated macrophages or T regulatory cells (T reg ), also generate an immunosuppressive TME [ 113 ]. Moreover, tumor angiogenesis is induced by tumor-derived-sEVs [ 114 , 115 ]. Once sEVs have entered the circulation, they were recently also described to foster metastasis in distant organs by establishing favorable PMNs [ 5 , 54 , 116 ].
4.1. sEV-Based Crosstalk with Cancer-Associated Fibroblasts (CAFs)
CAFs are the most common constituent of the TME. Their crosstalk with tumor cells and the extended tumor stroma influences invasion, metastasis as well as therapeutic responses. When normal fibroblasts (NFs) are converted into CAFs, they acquire the expression of specific protein markers, including fibroblast activation protein (FAP), alpha-smooth muscle actin (α-SMA) and fibronectin. Activated CAFs in turn secrete growth factors, e.g., vascular endothelial growth factor (VEGF), TGFβ, cytokines (IL6, IL10, IL1β), collagen and ECM-modifying enzymes, but also sEVs. These secreted mediators then act on tumor cells in a paracrine manner to alter the ECM and further facilitate tumor invasion across tissues [ 117 ]. sEVs have shown the ability to act on the TME and convert NFs into CAFs. A mechanism involved in cellular differentiation of fibroblasts to CAFs by sEVs is activation of the TGF-β/Smad pathway. This is either accomplished by direct transfer of growth factors on sEVs or by transcriptional reprogramming induced by the introduction of ncRNAs. In prostate cancer (PC) cells, the direct delivery of TGFβ to fibroblasts by sEVs initiated a phenotype resembling stromal cells from cancerous prostate tissue and the elimination of sEVs in vivo abolished CAF formation [ 6 ]. Similar observations were made for breast cancer (BC) [ 118 ], OC [ 119 ] and GC [ 120 ]. Additional examples for a role of sEVs in CAF conversion include melanosomes, sEVs derived from melanocytes, containing mir-211, which targets the tumor suppressor insulin-like growth factor 2 receptor in normal fibroblasts, resulting in the activation of mitogen-activated protein kinase (MAPK), thus enabling CAF reprogramming [ 12 ]. MiR-9 is upregulated in several BC cell lines and can be transferred via sEVs to recipient breast fibroblasts, thereby inducing CAF-like properties [ 121 ], whereas in PDAC, miR-155 was shown to activate NFs [ 122 ]. Once CAFs are transformed and activated in the TME, they also secrete a plethora of functional non-tumor sEVs with altered ncRNA composition and the ability to promote cancer progression as well as metastasis ( Table 1 ). For example, sEVs released from CAFs were shown to regulate BC cell migration and invasion by transfer of mir-181d-5p, targeting CDC2 and HOXA5 to enhance proliferation, EMT and aggressiveness [ 123 ]. In addition to CAFs, the TME is also characterized by the infiltration of immunosuppressive cells, which help the tumors to avoid immune surveillance.
4.2. sEVs in Immune Suppression
Tumor-derived sEVs are targeted towards different innate and adaptive immune cells in the TME or at metastatic sites to facilitate immune evasion. Usually, antitumor immunity is triggered by the release of tumor-associated antigens (TAAs) and the subsequent activation of innate and adaptive effector cells, e.g., natural killer cells (NKs) and CD8+ T effector cells. In particular, the activation of CD8+ T effector or CD4+ T helper cells was shown to be suppressed by tumor-derived sEVs, e.g., upon targeting antigen-presenting dendritic cells (DC), thus impairing lymphocyte activation and survival [ 162 ].
In immunologically cold tumors, such as PDAC, the TME is also spiked with a large number of immunosuppressive regulatory T-cells (T regs ), M2-polarized tumor-associated macrophages (TAMs) and immature myeloid-derived suppressor cells (iMDSCs), which inhibit functional CD8+ T-cell responses and impede proper antigen presentation by DCs or anti-tumor responses by M1-polarized macrophages [ 163 ].
Besides, sEVs secreted by tumor cells often reflect the parental protein composition, and thus were shown to present TAAs on MHC class I and II receptors. These sEV-based TAAs are able to stimulate NK- and T-cell-dependent cytotoxicity, but were further shown to decoy anti-TAA-antibodies and thus prevent complement-mediated cytotoxicity, impairing functional anti-tumor B-cell responses [ 164 ].
To escape immune surveillance, tumors have acquired diverse mechanisms that target the innate and adaptive immune defense by sEVs. The respective concepts, targeted cells and the role of nucleic acids are summarized in the following section. A more extensive overview is available in Table 1 .
4.2.1. Innate Antitumor Defense—Natural Killer Cells (NKs)
NKs mediate the innate defense against tumors or infected cells [ 165 ]. The antitumor cytotoxicity of NKs can be blocked by inhibiting the activating NK cell surface receptor NK group 2-member D (NKG2D). To this end, membrane-bound ligands MICA, MICB and ULBP against NKG2D are transferred by sEVs, thus alleviating NK-mediated cytotoxic responses [ 166 , 167 ]. Hypoxic tumor MVs, comprising of tumor sEVs and microvesicles (MVs), also impaired NK cell cytotoxicity against different tumor cells in vitro and in vivo. This was mediated by EV-resident TGF-β1, decreasing the expression of NKG2D, while miR-23a synergistically targeted CD107a expression in NK cells. Another mechanism to impair NK cell function is the sEV-mediated transfer of the circular RNA:ubiquitin-like PHD and ring finger domain 1 (circUHRF1), which was associated with the suppression of miR-449c-5p and enhanced expression of TIM-3. Interestingly, in HCC patients, increased levels of plasma-circUHRF1 were also correlated with resistance to anti-PD-1 therapy [ 131 ]. The cytotoxicity of NK cells was further inhibited by tumor sEVs from different cancer cell lines [ 133 ] by suppressing the secretion of granzyme-B via miR-378a-3p.
4.2.2. M2-Polarized Macrophages
In addition to NKs, tumor sEVs facilitate the transformation (polarization) of TAMs into immunosuppressive M2 subtypes, e.g., sEVs derived from hypoxic PDAC cells convert macrophages to the M2 phenotype in a HIF1a- or HIF2a-dependent manner. miR-301a-3p is highly expressed in the respective cells as well as sEVs under hypoxic conditions. Upon uptake by macrophages, M2-polarization is induced via the activation of PTEN/PI3Kγ signaling. The respective macrophages in turn also promote tumor-invasive behavior. The circulating exosomal miR-301a-3p levels were thus positively associated with depth of invasion, lymph node metastasis, late TNM stage and poor prognosis in patients [ 132 ].
4.2.3. Adaptive Antitumor Immunity—Targeting Antigen-Presenting Dendritic Cells (DCs) and Anti-Tumor T-Cells
effector
helper
regs
136
168
134
regs
reg
135
Additionally, the different T-cell populations are impacted by various sEVs-dependent mechanisms. This includes induction of apoptosis, as well as inhibition of CD8+/CD4+ T-cell activation, expansion and conversion towards immunosuppressive T reg phenotypes [ 169 ]. Apoptosis in CD8+ T-cells is mediated by different proteins and nucleic acid cargos, e.g., the interaction between Fas ligand (FasL) on sEVs and Fas receptors (CD95) on the respective T-cell clones, resulting in caspase activation [ 170 ]. The presence of FasL on sEVs was reported for different cancer entities, such as melanoma [ 171 ], PC [ 172 ] as well as head and neck cancer [ 173 ]. In melanoma, tumor sEVs also induce the mitochondrial apoptotic pathway in CD4+ T-cells, and this is mediated by transfer of miRNA cargos miR-690, miR-677 as well as miR-29b [ 130 ]. Another mechanism of immune evasion involves binding of programmed death-ligand 1 (PD-L1) expressed on tumor cells and other cells in the TME to its receptor programmed cell death protein 1 (PD-1) on activated T-cells, thus triggering T-cell exhaustion by suppressing activation and expansion [ 174 , 175 ]. Interestingly, tumor-derived sEVs were also described to transfer PD-L1 to other cell populations in the TME, thereby amplifying immunosuppression. Metastatic melanomas release PD-L1-positive sEVs, which enable tumor growth due to the suppression of CD8+ T-cell cytotoxicity. The level of PD-L1 in circulating sEVs could even be utilized for the stratification of early-stage responders and non-responders after anti-PD-1 therapy [ 176 ]. Release of PD-L1-positive sEVs has been observed for BC [ 177 ], NSCLC [ 178 ], glioblastoma (GBM) [ 179 ], GC [ 180 ] as well as other cancer entities. In cervical cancer (CeC), increased PD-L1 levels can also be traced back to the upregulation of miR-18a, which targets PTEN and SOX6 [ 137 ], whereas in HCC, miR-23a-3p induced elevated PD-L1 levels in macrophages [ 138 ]. For both miR-18a and miR-23a-3p, transfer by tumor sEVs has been reported [ 139 , 181 ]. sEVs-based signaling further interfered with T-cell polarization and cytokine release. Here, sEV-resident miRNAs, hsa-miR-24-3p, hsa-miR-891a, hsa-miR-106a-5p, hsa-miR-20a-5p and hsa-miR-1908, are upregulated in the serum of patients with nasopharyngeal carcinomas. The respective sEVs impeded T-cell proliferation and Th1/Th17 differentiation in vitro, accompanied by decreased levels of IFNγ, IL-2 and IL-17, while on the other hand, immunosuppressive T regs were promoted. This was facilitated by altered mitogen-activated protein kinase (MAPK) and STAT signaling [ 129 ].
4.2.4. Myeloid-Derived Suppressor Cells (MDSCs)
MDSCs are immature myeloid cells with immunosuppressive features that are present in the TME of many tumors. MDSCs decrease the cytotoxicity of effector immune cells and increase T reg cell responses, thus contributing to cancer progression. In several cancer subtypes, circulating MDSC levels were shown to correlate with the clinical stage and therapeutic response in patients [ 182 ].
A study by Guo and colleagues established a role for glioma cell-derived sEVs in potentiating the activation of MDSCs, targeting RAR-related orphan receptor alpha (RORα) and PTEN with miR-10a and miR-21. These findings were further corroborated by inoculation experiments in mice, where glioma cells with miR-10a or miR-21 knockout generated a lower number of MDSCs than normal glioma cells [ 140 ]. In PDAC, loss of the tumor suppressor SMAD4 was associated with poor prognosis as well as production of sEVs containing miR-1260a and miR-494-3p. The respective sEVs were reported to reprogram granulocytic and monocytic g/mMDSCs to bolster proliferation and glycolysis, thus facilitating the establishment of an immunosuppressive TME [ 183 ].
In summary, tumor sEVs and nucleic acid cargos have vital functions in evading immunosurveillance by the innate and adaptive immune system, fostering tumor growth and progression towards metastasis.
4.3. sEVs in Angiogenesis
As tumors grow and disseminate, they are critically dependent on access to blood vessels. Angiogenesis is a multi-step process initiated during carcinogenesis to form new blood vessels from pre-existing ones. Angiogenesis facilitates the adequate supply of oxygen and nutrients, as well as the removal of waste products from cancer cells, and is therefore essential for tumor proliferation and metastasis [ 184 ]. Hypoxic and acidic conditions, encountered in the TME of most tumors, promote new vascularization due to the release of pro-angiogenic factors, such as VEGF [ 185 ]. Tumor-derived sEVs are further implicated in pro-angiogenetic signaling, e.g., sEVs from GBM stem-like cells were shown to transport VEGF-A to brain endothelial cells in order to activate the VEGF pathway, initiating blood vessel growth and enhanced vascular permeability [ 114 ]. The presence of VEGF has also been reported in melanoma-derived sEVs, thus enhancing the angiogenic capacity of respective tumors [ 80 ]. Besides VEGF, tumor-derived sEVs transfer many more proteins, e.g., MMPs [ 186 ], involved in blood vessels’ formation. Moreover, several miRNAs present in tumor-derived sEVs were found to prominently facilitate angiogenesis in endothelial cells ( Table 1 ). miR-17-5p is loaded in sEVs of nasopharyngeal carcinoma cells suppressing the transmembrane protein BMP and activin membrane-bound inhibitor (BAMBI). As a consequence, expression of AKT/VEGF-A and thus angiogenetic activity of HUVEC cells was increased. A positive correlation between miR-17-5p in the serum of nasopharyngeal carcinoma patients and tumor angiogenic activity further demonstrated the importance of this miRNA in vivo [ 115 ]. In GC, sEV-resident miR-155 was show to target Forkhead box O3 (FOXO3a) as well as c-MYB, thus enhancing the expression of VEGF in vascular cells to induce angiogenesis and tumor growth [ 150 ]. In PDAC, mir-27a in sEVs induced vascularization through inhibition of BTG anti-proliferation factor 2 (BTG2) [ 13 ]. Interestingly, sEVs secreted under hypoxic conditions showed the greatest potential to promote blood vessel formation, when compared to normoxic sEVs due to their enrichment of pro-angiogenic miRNAs, such as miR-135b, miR-210, miR-21 and miR-23a [ 151 , 152 , 153 , 187 ]. In addition to miRNAs, other ncRNAs are also packed in sEVs to foster tumor angiogenesis. In OC, high expression of the lncRNA MALAT1 (metastasis-associated lung adenocarcinoma transcript-1) was correlated with angiogenesis and metastasis, and MALAT1 was found in sEVs, which induce pro-angiogenic gene expression upon uptake in HUVEC cells [ 154 ].
Additionally, lymphatic vessels play crucial roles in tissue homeostasis, fluid balance, immune function as well as transport of metabolic molecules, and are therefore important for tumor proliferation [ 188 ]. Furthermore, they lack the presence of a complete BM and are more permeable to tumor cells, thus fostering metastasis [ 189 ]. Tumor cells have been shown to secrete growth factors such as VEGF-C or FGF to induce the formation of new lymphatic vessels (lymph-angiogenesis), correlating with lymph node as well as distant metastasis [ 190 , 191 , 192 ]. Besides, tumor-derived ncRNAs were shown to influence lymphatic vessel growth. miR-221-3p packaged into sEVs of CeC was identified to promote expansion of lymphatic vessels by targeting vasohibin-1 (VASH-1), a negative regulator of lymph-angiogenesis [ 156 ]. Additionally, the lncRNA lymph node metastasis-associated transcript 2 (LNMAT2) in sEVs secreted from bladder cancer was reported to facilitate lymph-angiogenesis via VEGF-C-independent mechanisms [ 157 ].
5. Intravasation of Tumor Cells and Survival in the Circulation
One of the most crucial steps enabling metastasis is the intravasation of tumor cells into the blood circulation. Neo-angiogenesis and lymph-angiogenesis induced by tumors, as well as tumor-derived sEVs, favor this process, since the newly developed vasculature is more prone to leakiness [ 193 ]. Thus, a weak interaction between endothelial cells facilitates transmigration of cancer cells through the endothelial monolayer into the circulation. Additionally, intravasation is promoted by TGFβ, enhancing penetration of tumor cells through microvessel walls [ 194 ], as well as TAMs, which foster paracrine interactions with tumor cells and an altered microvessel density [ 195 ]. Moreover, sEV-derived miRNAs, which disrupt endothelial stability, promote the process of tumor cell intravasation ( Table 1 ). For example, miR-939 transferred by BC-sEVs targeted vascular endothelial (VE) cadherin, the main constituent of adherens junctions, causing enhanced leakiness of blood vessels, whereas miR-105 downregulated the tight junction protein ZO-1 [ 147 , 148 ]. Upon their successful intravasation, cancer cells can disseminate widely in the blood stream as circulating tumor cells (CTCs) and travel to distant sites, where they seed metastatic lesions. However, CTCs must survive in the circulation, and this is challenged by a variety of stress conditions, such as risk of anoikis in the absence of anchorage, shear forces and immunologic surveillance [ 196 ]. CTCs can be detected as single cells or dense clusters from 2 up to >100 cells with strong cell–cell junctions [ 107 ]. The aggregation of CTCs is of advantage, since clustered cells are protected from shear stress and anoikis. Thus, the presence of CTC clusters is associated with a poor prognosis and an earlier onset of metastasis [ 197 , 198 , 199 ]. CTC clusters directly derive from the primary tumor or develop via intravascular aggregation of single CTCs [ 200 , 201 ]. In HCC, tumor-derived sEVs were shown to transfer SMAD Family Member 3 (SMAD3) protein and mRNA to detached HCC cells and promote their homotypic adhesion [ 202 ]. Furthermore, sEVs have the ability to indirectly facilitate CTC clustering via the regulation of adhesion proteins, as well as the conversion of fibroblasts into CAFs, which also play a major role in cluster formation [ 203 , 204 , 205 , 206 ]. Furthermore, CTCs directly interact with blood platelets, which then accompany cancer cells and protect them from recognition and lysis by NKs [ 207 , 208 ]. The importance of platelets was further corroborated, since their depletion inhibited the formation of metastasis in mice [ 209 ]. This phenomenon can also lead to an imbalance in the normal blood clotting, which is often observed in cancer patients with a poor prognosis [ 210 , 211 , 212 ]. Thrombotic events and the activation of platelets in cancer patients are strongly correlated with the overexpression of tissue factor (TF), which can be transferred to endothelial cells via tumor-derived sEVs. The ECs are then reprogrammed into a procoagulant phenotype and generate high levels of thrombin, one of the most important activators of platelets [ 213 ]. In turn, platelets secrete sEVs with pro-metastatic cargoes, such as TGFβ, integrins, P-selectin and glycoprotein IIb–IIIa, that reprogram endothelial cells, leukocytes and tumor cells [ 214 , 215 , 216 ]. Moreover, the aggregation of platelets and inhibition of coagulation inhibitors are triggered by the formation of neutrophil extracellular traps (NETs), that can also be induced by tumor-derived sEVs [ 217 ].
At the moment, the influence of sEV-derived miRNAs during the clustering of CTCs as well as the activation of platelets and NETs is unclear, and further research is needed to unravel potential mechanisms. However, several miRNAs contained in sEVs play a crucial role in protecting CTCs in the blood stream from being recognized by the immune surveillance due to suppression of immune cells or recruitment of T regs , which is reviewed as part of Section 4.2 .
6. Extravasation from the Circulation
Extravasation occurs when CTCs transmigrate through the endothelial wall in order to enter the parenchyma of distant tissues. This process is dependent on enhanced vascular permeability and the disruption of cell–cell junctions, which normally maintain a physical barrier for fluid proteins and cells. Several secreted factors from cancer cells are involved in the disruption of endothelia barriers, e.g., TGFβ, angiopoetin-like 4 (ANGPTL4), VEGF, MMPs and ADAM12 [ 218 , 219 , 220 ]. Additionally, the association of platelet-cancer cell hybrids to the vessel wall is a step in the extravasation of CTCs, and this is guided by interactions of platelet selectins with ECs [ 221 ]. As described for intravasation, several miRNAs in sEVs support transendothelial migration by weakening endothelial cell–cell junctions, thus enabling vascular permeability ( Table 1 ). However, the question arises if extravasation occurs just randomly or if CTCs are specifically directed towards distinct organs niches, facilitating organotropic metastasis.
7. sEV-Mediated Organotropism and Formation of Pre-Metastatic Niches
The concept of organotropism describes the homing of circulating tumor cells to specific organs as a consequence of complex tumor–stroma interactions. Although organotropic metastasis was first hypothesized 1889 by Stephen Paget, the exact underlying mechanism is not yet fully unraveled. Recent studies have indicated that sEVs may play a crucial role in organotropism. sEVs prepare PMNs by recruiting bone marrow-derived cells (BMDCs), endothelial progenitor cells and mesenchymal cells, but also induce the upregulation of proinflammatory molecules and facilitate vascular leakiness to create a suitable niche environment [ 222 , 223 ]. These alterations in distant organs are already observed before the arrival of cancer cells. Interestingly, various studies indicate that sEVs from different types of tumors preferably migrate to distinct organs, e.g., melanoma sEVs to sentinel lymph nodes, BC-sEVs to the lung and PDAC-sEVs to the liver [ 224 , 225 , 226 ]. Thus, the question arises of how sEVs are directed to specific sites to enable organotropic metastasis. In 2015, Hoshino et al. established that the expression of integrin patterns in sEVs and their interaction with ECM molecules, such as laminin and fibronectin, is crucially important for governing the formation of organ-specific PMNs. Integrins α6β4 and α6β1 were shown to promote lung tropism, and their uptake by lung fibroblasts triggered expression of the pro-inflammatory S100A proteins, heat shock proteins (HSPs), laminin and fibronectin, as well as annexin A6 and CD44 [ 5 , 227 , 228 , 229 ]. sEVs positive for integrins avß5 and macrophage migration-inhibitory factor (MIF) favor liver organotropism, a common site for metastasis associated with a poor prognosis in many types of cancer [ 226 ]. These sEVs bind to the fibronectin-enriched ECM in the liver and educate liver-resident macrophages (Kupffer cells) to increase the expression of TGFβ. High TGFβ levels in turn activate the secretion of fibronectin and pro-inflammatory mediators from hepatic stellate cells, thus preparing the PMN for the tumors [ 5 , 226 ].
Our group has recently observed that in PDAC, PRKD1 expression is downregulated compared to non-tumor tissue. Impaired PRKD1 expression was associated with increased sEVs secretion from different PDAC cell lines as well as altered expression and loading of sEVs with integrin α6β4. The respective sEVs also displayed low levels of integrin β5, impairing the formation of functional αvβ5 dimers, due to transcriptional downregulation of integrin β5 expression upon PRKD1 loss. In line with the model of Hoshino et al., injection of PRKD1 KO -sEVs from Panc-1 cells in subcutaneously xenografted mice promoted lung metastasis, and this was corroborated in an autochthonous Prkd1 KO KC mouse model, were predominant lung and no macroscopic liver metastasis was detected [ 54 ].
Interestingly, another mechanism for sEV-mediated liver metastasis was recently established by Zhang et al. Here, the transfer of EGFR by GC-sEVs into the liver facilitated HGF activation via miR-26a/b suppression. HGF was shown to bind c-MET on cancer cells and thus rendered the liver a preferable metastatic site for multiple tumors [ 230 ].
The establishment of bone metastasis can be observed for many solid tumors and often occurs in advanced disease stages. In bone metastasis, the homeostatic balance between bone-producing osteoblasts and bone-resorbing osteoclasts is disrupted and metastatic lesions are either osteolytic or osteoblastic. There are various studies assigning a crucial role for sEVs in inducing said imbalance, e.g., via transfer of amphiregulin, causing osteoclastogenesis through upregulation of receptor-activator of NF-κB ligand (RANKL), a mechanism that is observed in NSCLC [ 231 ].
Although most studies have defined a crucial role for integrins and other protein cargos in the establishment of organ-specific PMNs, a few miRNAs are also known to contribute to organotropic metastasis. One important mediator is miR-141-3p, and its presence in sEVs was associated with metastatic PC, promoting osteoblast activity and bone metastasis [ 15 ]. Similarly, miR-940 from PC and BC cells was reported to facilitate osteoblastic lesions by targeting Rho-GTPase-activating protein 1 (ARHGAP1) and family with sequence-similarity 134, member A (FAM134A) [ 158 ]. In the PMN, sEV-derived miRNAs further reprogram non-tumor stromal cells, promoting a pro-tumor environment. Thus, alterations in glucose metabolism are frequently observed in the PMN in order to fuel nutrient demand of incoming cancer cells. Here, miR-122 from BC-sEVs was described to target and downregulate pyruvate kinase, in order to impair glucose uptake in lung- and brain-resident cell populations to supply cancer cells with the remaining glucose [ 116 ]. Similar to the primary tumor site, the sEV-induced conversion of fibroblasts into CAFs is also observed in the PMN. Relevant nucleic acid targets are listed in Table 1 . One specifically important cargo for the lung PMN is miR-1247-3p, that is secreted in sEVs from highly metastatic HCC and induces the activation of NF due to the upregulation of NFκB signaling, enabling the release of pro-inflammatory cytokines to further niche formation [ 159 ].
In summary, PMN formation has emerged as a vital step during metastasis and is crucially determined by tumor-derived sEVs. Although most of the important sEV cargos involved in the regulation of niche establishment are proteins, some miRNAs have been described to facilitate or aid niche formation, and thus more research is needed to unlock the full potential of nucleic acids in the regulation of organotropic metastasis.
8. sEVs as Biomarker Platforms and Therapeutic Vehicles
Since sEVs are representative for their cells of origin and are released in large quantities by cancer cells in the bloodstream [ 22 , 64 ], they are ideal biomarker platforms for liquid biopsy to facilitate early detection and prognosis [ 62 , 63 ]. Different sEV cargo classes can be utilized as promising prognostic and diagnostic biomarkers upon liquid biopsy, e.g., proteins, lipids and nucleic acids are intensively investigated. For example, glypican-1 was identified as a promising diagnostic protein biomarker for PDAC [ 232 ], but the ratio of lipids in plasma or serum sEVs was also used for cancer diagnosis and prognosis (reviewed in [ 233 ]). To this end, specific ratios of lysophosphatidylcholine (LPC), phosphatidylcholine (PC) and phosphatidylethanolamine (PE) in sEVs were associated with the tumor stage of PDAC, and PE was even linked to overall patient survival [ 234 ]. However, this review mainly focuses on the role of nucleic acids, and in particular ncRNAs in sEVs, as markers for diagnosis and prognosis in different cancer entities. A major obstacle for the use of sEVs as reliable biomarkers in the clinical routine is reproducibility and specificity due to different isolation and detection methods. sEV isolation for biomarker studies so far is not standardized, and each method, such as ultracentrifugation, sucrose gradients, size exclusion chromatography, affinity-based purification, isolation by asymmetric flow field–flow fractionation or microfluidic devices, has its own advantages and downsides [ 235 , 236 , 237 ]. This has become evident in the most studied sEV marker for PDAC diagnosis, glypican-1. Glypican-1 was discovered by Melo et al. in animal and human cell lines and was described to demonstrate a sensitivity/specificity of 100%, upon detection by transmission electron microscopy on sEVs. Detection of glypican-1-positive sEVs by ELISA reduced the sensitivity and specificity to 82.14% and 75%, respectively [ 232 ]. A validation study with alternative sEV-purification techniques after sampling sEVs from peripheral or portal vein blood has reported a drastically reduced sensitivity of 64%, whereas the specificity was still at 90%. Nevertheless, this was more sensitive than fine-needle biopsy and the currently used clinical tumor marker CA19-9 [ 238 ]. However, another attempt as part of a study using ELISAs to detect sEVs identified no significant difference in glypican-1 for PDAC patients with respect to benign pancreatic conditions. Thus, further validation and standardization of sEV-purification as well as detection methods is vitally required to allow for routine clinical use of sEVs as diagnostic and prognostic biomarkers [ 239 ]. However, sEV-based analysis of biomarkers also has advantages. The nanovesicles protect proteins from proteolytic cleavage and prevent degradation of enclosed nucleic acids [ 30 ]. This is why a large number of miRNAs, but also other ncRNAs, in sEVs have been characterized as biomarkers for prognosis and treatment response during tumor progression and metastasis (see Table 2 ), e.g., mir-21 in sEVs has been associated with lymph node metastasis in PDAC [ 240 ], bone metastasis in BC [ 241 ], tumor spinal/ventricle metastasis in glioma [ 242 ], lymph node metastasis in laryngeal squamous cell carcinoma (LSCC) [ 243 ], metastasis in general in ESCC [ 243 ], as well as in multi-miR panels with peritoneal metastasis of GC [ 244 ], and metastasis in PC [ 245 ] or CRC [ 246 ]. In addition to RNA, sEV-DNA was also described as a biomarker for the detection of cancer-specific mutations, since sEV-DNA fragments were shown to stochastically represent the entire genome of cancer cells, including mitochondrial DNA [ 247 , 248 ]. Several studies indicated that PDAC-sEVs could be used to probe the mutational landscape of tumors, e.g., for KRAS or TP53 [ 17 , 18 , 249 ], and an increased mutational allelic frequency in the pool of sEV-DNAs was even correlated with poor prognosis and survival [ 18 , 249 ]. Moreover, to further increase specificity and sensitivity during EV analysis of biomarkers, a strategy for the tumor-specific enrichment of sEVs has been developed [ 250 ] for PDAC. Here, a panel of six surface markers on sEVs has been identified to immuno-purify PDAC-specific sEVs after liquid biopsy, thus enabling a more sensitive detection of mutated KRAS alleles [ 251 ]. Similar strategies may be applied to enrich sEVs from other cancer entities and different prognostic cargos. As shown in Table 2 , nucleic acids, and in particular ncRNAs, in sEVs have a great potential to act as biomarkers for tumor metastatic behavior.
In addition to a role as biomarkers, sEVs have been proposed as therapeutic vehicles, but practical applications are still in their early development phase. sEVs have been explored as novel drug delivery agents due to their inherent non-toxic, biodegradable properties and their ability to cross endogenous barriers, such as the blood–brain barrier [ 252 ]. This was demonstrated using engineered sEVs loaded with siRNAs, which targeted the central nervous system (CNS) by expressing Lamp2-RVG on their surface to specifically knockdown genes in the CNS after systemic administration [ 253 ]. Another promising study by Kamerkar et al. in 2017 modified sEVs from fibroblast-like mesenchymal cells with siRNAs or shRNAs against mutated and wild-type KRAS G12D (iExosomes), and the treatment of mice with PDAC tumors in a Kras G12D background demonstrated a significant reduction in tumor size, compared to the control. Interestingly, tumors treated with iExosomes also showed superior size reduction with respect to liposomes loaded with the same cargo [ 254 ]. A corresponding clinical study is currently on the way as part of a Phase I trial in PDAC patients with a KRAS G12D mutation (NCT03608631). Cancer progression and metastasis in different cancer entities is often associated with downregulation of tumor-suppressor miRNAs. The re-introduction of such miRNAs as EV-based therapies may thus reduce tumor proliferation and invasion. For efficient treatment, the mode of delivery is also a crucial factor, e.g., intra-tumoral injection of miR-335-containing EVs caused cancer inhibition in hepatocellular carcinoma xenograft models [ 255 ]. EVs for therapeutic approaches can be obtained from different sources, such as fibroblasts [ 256 ], stromal cells [ 257 ], red blood cells [ 258 ] and umbilical cord stem cells [ 259 ], which are subsequently loaded with therapeutic miRNA. NK cell-derived sEVs with miR-186 were used to impair immune escape of neuroblastoma [ 260 ], whereas red blood cell-sEVs loaded with miR-125b were shown to inhibit cell proliferation of leukemia and BC in xenografted mice [ 258 ]. As discussed earlier, concepts for targeted drug-delivery using engineered sEVs are still in development. It will be necessary to further optimize sEVs to exploit natural tropisms for specific organs and cell populations, or modify sEVs with artificial targeting constructs to increase specificity and uptake in recipient cells. In addition, strategies for loading of sEVs with cargos, e.g., specific siRNAs by electroporation [ 261 ], have to be adapted and optimized to increase efficacy for future clinical applications.
9. Conclusions and Perspectives
Here, we have discussed the role of sEVs and the important major cargo class, nucleic acids, in the progression of tumors through different aspects of the metastatic cascade ( Figure 2 , Table 1 ), as well as their role as biomarker platforms and vehicles for treatment ( Table 2 ). Tumors release large quantities of sEVs with an altered cargo profile, and this is directed by genetic alteration as well as environmental cues, such as low pH or hypoxia ( Section 1 and Section 2 ). Oncogenes, e.g., mutated KRAS, not only trigger activation of ESCRT and ceramide synthesis pathways to drive enhanced sEV-release from tumor cells, but also change the sEV miRNA content, enabling oncogenic transfer and metabolic reprograming ( Section 2.3 ). Thus, it would be interesting to systematically assess how cancer-relevant genes and mutations affect sEV secretion as well as alterations of cargo content. Nucleic acids, in particular ncRNA cargo, such as miRNAs are vital cargos for the education of recipient cells during metastasis ( Table 1 ). Extensive research in the last years has indicated that tumor sEVs and sEV-based crosstalk with other cell populations in the TME influence local invasion of tumor cells by facilitating EMT, ECM remodeling, stroma reprogramming, immune evasion and angiogenesis ( Section 3 and Section 4 ). In addition, sEVs have been implicated in the establishment of distant organ-specific PMNs with a pro-inflammatory microenvironment ( Section 7 , Figure 2 , Table 1 ). The intercellular communication network enabled by sEVs, as well as their systemic distribution, are vital factors in determining whether tumor cells successfully metastasize. It has to be noted, however, that the same sEV-cargos, in particular miRNAs, may have different functions dependent on the investigated cancer entities, e.g., miR-21 drives various routes of metastasis, when compared to BC, PDAC or glioma [ 240 , 241 , 242 ]. Nevertheless, ample evidence has indicated that circulating sEVs can be employed as effective biomarker platforms for diagnosis or prognosis ( Section 8 , Table 2 ). sEVs are released in all body fluids and are thought to generally reflect the state of their parental cells [ 22 ]. Multiple liquid biopsy studies have indicated that sEVs, and in particular miRNAs, can be used as biomarkers for various cancer subtypes, disease progression, metastasis as well as treatment response ( Section 8 , Table 2 ). Moreover sEV-DNA fragments, which statistically cover the entire genome and mutational landscape, were used to assess mutated genes in tumors as prognostic markers ( Section 8 ). sEVs are ideal vehicles in this context, since they protect nucleic acid cargos from degradation. However, there are also caveats, which have so far prevented the broad adoption of sEV profiling in the clinical routine. Different isolation techniques and detection methods have yielded drastically different results, and thus rigorous standardization will be required to promote clinical sEV analysis ( Section 8 ). Another issue might be the heterogeneity of sEVs in liquid biopsy samples, which are not only derived from tumor cells but many other cell types [ 251 ]. Thus, to increase specificity and sensitivity, first, steps towards immuno-enrichment of tumor-specific sEVs have been conducted by identifying and utilizing a panel of surface markers to enrich PDAC-derived sEVs [ 251 ]. Interestingly, sEVs can also be engineered as vehicles for delivery of therapeutic agents, such as siRNAs and miRNAs to target cancer cells in order to downregulate oncogenes or tumor-promoting factors. For example, transfer of miR-122 was shown to induce chemosensitivity in HCC [ 280 ], whereas sEVs loaded with siRNAs against mutated KRAS G12D impaired PDAC tumor growth in mice [ 254 ]. The latter study has even resulted in a first phase I clinical trial [ 254 ]. However, research on therapeutic sEVs is only at the beginning. Once established and transferred into the clinic, these approaches have immense potential and will open up new avenues to promising treatment options, as shown for sEVs loaded with drugs, such as paclitaxel or doxorubicin [ 281 , 282 , 283 ]. A major necessity for the design of new sEV-based therapeutic options is improved understanding of molecular mechanisms for sEV-mediated tumorigenesis and metastasis. Additionally, technical issues need to be optimized, such as modification of sEV with cell-specific targeting constructs [ 284 , 285 ], or how natural tropisms of different sEV populations may be exploited to further target and improve uptake in tumor cells [ 15 , 286 , 287 ]. Nevertheless, sEV research over the last years has greatly contributed to a better understanding of the complex mechanisms that drive tumor progression and metastatic dissemination, and these studies will hopefully help to translate sEV-based applications into clinical use.
Author Contributions
Conceptualization, T.S. (Thomas Seufferlein) and T.E.; collection and review of the literature, T.S. (Tanja Seibold), M.W. and T.E.; writing, T.S. (Tanja Seibold) and T.E.; review and editing, T.S. (Tanja Seibold), T.S. (Thomas Seufferlein) and T.E. All authors have read and agreed to the published version of the manuscript.
Funding
This study was supported by DFG-GRK-2254 (HEIST project No. 288342734) to T.S. (Thomas Seufferlein) and T.E., as well as DFG project No. 380319649 (EI792/7-1 and BL-1186/5-1) to T.E.
Conflicts of Interest
The authors declare no conflict of interest.
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Figure 1. Mechanisms of sEV biogenesis and uptake.
Figure 1. Mechanisms of sEV biogenesis and uptake.
Figure 2. Functions of sEVs and ncRNA cargos in the metastatic cascade.
Figure 2. Functions of sEVs and ncRNA cargos in the metastatic cascade.
Table 1. Origin and biological effects of sEV-derived ncRNA.
Table 1. Origin and biological effects of sEV-derived ncRNA.
Step Molecule Cell of Origin Effect Ref. EMT miR-301a GBM, PC Activation of Wnt/β-catenin signaling, suppression of TCEAL7, p63 and E-cadherin [ 89 , 124 ] miR-92a NSCLC Activation of PTEN/PI3K/AKT [ 90 ] miR-191 Melanoma Activation of MAPK signaling [ 14 ] miR-1260b LC Activation of Wnt/β-catenin signaling via inhibition of sFRP1 and Smad4 [ 91 ] miR-181d-5p CAFs in BC Suppression of CDC2 and HOXA5 miR-23a NSCLC Induction of TGFβ signaling and inhibition of E-cadherin [ 125 ] miR-21 miR-143 miR-378e CAFs in BC Upregulation of NANOG, SOX2, SNAIL and ZEB [ 126 ] miR-499a-5p LC Activation of mTOR signaling [ 127 ] miR-19b-3p CCRCC Downregulation of PTEN [ 127 ] miR-382-5p CAFs in OSCC Upregulation of ß-catenin and N-cadherin [ 128 ] ECM degradation miR-21 CRC, EC MMP activation via inhibition of PDCD4 and TIMP-3 [ 101 , 102 , 104 ] miR-181b HCC, ESCC MMP activation via inhibition of TIMP-3 [ 105 , 106 ] MMP1 mRNA OC Enhanced MMP1 expression in recipient cells [ 100 ] miR-382-5p CAFs in OSCC Upregulation of MMP-9 and MMP-3 [ 128 ] Anoikis resistance miR-210 CRC [ 92 ] miR-222-3p NSCLC Inhibition of SOCS3 [ 93 ] Stroma miR-9 BC CAF formation [ 121 ] miR-211 Melanoma CAF formation via MAPK activation [ 12 ] miR-155 PDAC CAF formation via downregulation of TP53INP1 [ 122 ] Immune modulation miR-24-3p, miR-891a, miR-106a-5p, miR-20a-5p, miR-1908 NPC T-cell exhaustion via downregulation of the MARK1 signaling pathway [ 129 ] miR-690, miR-677, miR-29b Melanoma CD4+ T-cell apoptosis, increase of caspase-3, caspase-7 and caspase-9, downregulation of BCL-2 [ 130 ] circUHRF1 HCC NK dysfunction via inhibition of IFN-γ and TNF-α secretion [ 131 ] miR-301a-3p PDAC M2 macrophage polarization via activation of PTEN/PI3Kγ signaling [ 132 ] miR-378a-3p Various cell lines Decreased NK cytotoxicity via inhibition of granzyme B [ 133 ] miR-212-3p PDAC DC dysfunction via PFXAP inhibition and compromised MHCII expression [ 134 ] miR-150-5p, miR-142-3p T regs DC exhaustion [ 135 ] miR-203 PDAC DC dysfunction via TLR4 inhibition [ 136 ] miR-18a CeC T-cell exhaustion, suppression of PTEN, WNK2 and SOX6, and enhanced PD-L1 levels [ 137 ] miR-23a HCC T-cell exhaustion, suppression of PTEN and enhanced PD-L1 levels [ 138 , 139 ] miR-10a, miR-21 Glioma MDSC expansion by targeting RAR and PTEN [ 140 ] miR-1246 Mutant p53 cancer cell lines M2 macrophage polarization via targeting TERF2IP [ 141 , 142 ] Let7 Hypoxic tumor cells M2 polarization and metabolic reprogramming in macrophages via suppression of AKT-mTOR signaling [ 143 ] miR-29a-3p and miR-21-5p TAMs in OC Suppression of STAT3 in CD4 T-cells and corresponding T reg induction [ 144 ] miR-125b-5p Melanoma M2 macrophage polarization via downregulation of LIPA [ 145 ] miR-27a-3p BC PD-L1-mediated immune evasion via targeting MAGI2/PTEN/PI3K signaling [ 146 ] Intra- vasation miR-939 BC Downregulation of VE-Cadherin in ECs [ 147 ] miR-105 BC Downregulation of ZO-1 in ECs [ 148 ] miR-181c BC Destruction of blood–brain barrier and promotion of brain metastasis via downregulation of PDPK1 [ 149 ] Angio- genesis miR-17-5p NPC Promoting angiogenic activity in ECs via AKT/VEGF-A expression [ 115 ] Mir-155 GC Suppression of FOXO3a and c-MYC to enhance the expression of VEGF in ECs [ 150 ] miR-27a PDAC Proliferation of ECs via inhibition of BTG2 [ 13 ] miR-135b, miR-210, miR-21, miR-23a Hypoxic tumor cells Induction of blood vessel formation [ 151 , 152 , 153 ] MALAT1 OC Pro-angiogenic gene expression in HUVECs [ 154 ] miR-205 OC Promotes angiogenesis in ECs via PTEN-AKT signaling [ 127 ] lncRNA-Ccat2 Glioma Proliferation of ECs via upregulation of VEGF-A and TGFβ. Inhibition of apoptosis by targeting Bax and caspase-3 [ 155 ] lncRNA-Pouf3 Glioma Pro-angiogenic gene expression in ECs [ 155 ] Lymphangiogenesis miR-221-3p CeC Expansion of lymphatic vessels via downregulation of VASH [ 156 ] LNMAT2 Bladder cancer Growth of lymphatic vessels via upregulation of PROX1 [ 157 ] Organo- tropism miR-141-3p PC Bone metastasis via increased osteoblast activity [ 15 ] miR-940 PC, BC Bone metastasis via increased osteoblast activity [ 158 ] PMN miR-122 BC Suppression of glycolytic enzymes in non-tumor cells [ 116 ] miR-1247-3p HCC CAF formation [ 159 ] miR-451 CAFs in ESCC Pro-tumor PMN formation [ 160 ] miR-25-3p CRC Enhanced vascular permeability and angiogenesis in PMN via targeting KLF2 and KLF4 [ 161 ]
Abbreviations: BC: breast cancer; CCRCC: clear cell renal cell carcinoma; CeC: cervical cancer; CRC: colorectal cancer; ESCC: esophageal squamous cell carcinoma; GBM: glioblastoma; GC: gastric cancer; HCC: hepatocellular carcinoma; LC: lung cancer; NPC: nasopharyngeal carcinoma; NSCLC: non-small-cell lung cancer; OC: ovarian cancer; OSCC: oral squamous cell carcinoma; PC: prostate cancer; PDAC: pancreatic ductal adenocarcinoma; TAM: tumor-associated macrophage; CAF: cancer-associated fibroblast; PMN: pre-metastatic niche.
Table 2. sEV-ncRNA cargo used as diagnostic and prognostic biomarkers in cancer.
Table 2. sEV-ncRNA cargo used as diagnostic and prognostic biomarkers in cancer.
Cancer sEV Cargo Source Diagnostic/Prognostic Value Reference CRC miR-92a-3p Serum Liver and lung metastasis [ 262 ] miR-193a Plasma Liver metastasis [ 47 ] miR-25-3p Serum Metastasis (Liver and lung metastasis in mice; involved PMN formation) [ 161 ] miR-141-3p miR-375 Plasma Liver metastasis [ 263 ] miR-21-5p Plasma Liver metastasis [ 264 ] lncRNA CRNDE-h Serum Regional lymph node and distant metastasis [ 265 ] miR-19b, miR-21, miR-222, miR-92a Serum Metastasis [ 246 ] Low miR-548c-5p Serum Liver metastasis [ 266 ] PC miR-141 miR-375 Serum Metastasis [ 267 , 268 ] Low miR-636 High miR-21 High miR-16 High miR-142-3p High miR-451 Urine Metastasis [ 245 ] miR-1246 Serum Metastasis [ 269 ] GC miR-21 miR-1225-5p PLF Peritoneal metastasis [ 270 ] miR-21-5p miR-92a-3p miR-223-3p miR-342-3p PLF Peritoneal metastasis [ 244 ] miR-423-5p Serum Lymph node metastasis [ 271 ] miR-10b-5p Plasma Lymph node metastasis [ 272 ] miR-101-3p Plasma Ovarian metastasis [ 272 ] miR-143-5p Plasma Liver metastasis [ 272 ] OC miR-200b miR-200c Serum Lymph node metastasis [ 273 ] ESCC miR-21 Serum Metastasis [ 274 ] HCC miR-665 Serum Metastasis [ 275 ] miR-1247-3p Serum Lung metastasis [ 159 ] LSCC miR-21 Serum Lymph node metastasis [ 243 ] Glioma miR-21 CSF Tumor spinal/ventricle metastasis [ 242 ] BC miR-105 serum Distant metastasis [ 148 ] miR-21 Serum Bone metastasis [ 241 ] NSCLC circSATB2 Serum Lymphatic metastasis [ 276 ] PDAC miR-17-5p Serum Metastasis [ 277 ] Circ-IARS Plasma Tumor-node metastasis and liver metastasis [ 278 ] miR-21 Plasma Lymph node metastasis [ 240 ] Melanoma miR-17 miR-19a miR-21 miR-126 miR-149 Plasma Metastasis [ 279 ]
Abbreviations: BC: breast cancer; CRC: colorectal cancer; ESCC: esophageal squamous cell carcinoma; GC: gastric cancer; HCC: hepatocellular carcinoma; LSCC: Laryngeal squamous cell carcinoma; NSCLC: non-small cell lung cancer; OC: ovarian cancer; PC: prostate cancer; PDAC: pancreatic ductal adenocarcinoma; CSF: cerebrospinal fluid; PLF: peritoneal lavage fluid.
MDPI and ACS Style
Seibold, T.; Waldenmaier, M.; Seufferlein, T.; Eiseler, T. Small Extracellular Vesicles and Metastasis—Blame the Messenger. Cancers 2021, 13, 4380.
https://doi.org/10.3390/cancers13174380
AMA Style
Seibold T, Waldenmaier M, Seufferlein T, Eiseler T. Small Extracellular Vesicles and Metastasis—Blame the Messenger. Cancers. 2021; 13(17):4380.
https://doi.org/10.3390/cancers13174380
Chicago/Turabian Style
Seibold, Tanja, Mareike Waldenmaier, Thomas Seufferlein, and Tim Eiseler. 2021. "Small Extracellular Vesicles and Metastasis—Blame the Messenger" Cancers13, no. 17: 4380.
https://doi.org/10.3390/cancers13174380
Seibold T, Waldenmaier M, Seufferlein T, Eiseler T. Small Extracellular Vesicles and Metastasis—Blame the Messenger. Cancers. 2021; 13(17):4380.
https://doi.org/10.3390/cancers13174380
Chicago/Turabian Style
Seibold, Tanja, Mareike Waldenmaier, Thomas Seufferlein, and Tim Eiseler. 2021. "Small Extracellular Vesicles and Metastasis—Blame the Messenger" Cancers13, no. 17: 4380.
https://doi.org/10.3390/cancers13174380
| https://www.mdpi.com/2072-6694/13/17/4380#B27-cancers-13-04380 |
Social Security and Other Legislation Amendment (Income Support Bonus) Act 2013
C2013A00005
- C2013A00005
In force - Latest Version
Act No. 5 of 2013 as made An Act to amend the law relating to social security, farm household support and taxation, and for related purposes Administered by: Social Services Originating Bill: Social Security and Other Legislation Amendment (Income Support Bonus) Bill 2012
Registered 07 Mar 2013 Date of Assent 05 Mar 2013
Details
C2013A00005
Table of contents.
Text
1 Short title
2 Commencement
3 Schedule(s)
Schedule 1—Amendments
Part 1—Main amendments
Social Security Act 1991 Social Security (Administration) Act 1999
Part 2—Consequential amendments
Farm Household Support Act 1992 Income Tax Assessment Act 1997 Social Security Act 1991 Social Security (Administration) Act 1999
TOC
Social Security and Other Legislation Amendment (Income Support Bonus) Act 2013
No. 5, 2013
An Act to amend the law relating to social security, farm household support and taxation, and for related purposes
Contents
1............ Short title............................................................................................. 2
2............ Commencement................................................................................... 2
3............ Schedule(s)......................................................................................... 2
Schedule 1—Amendments 3
Part 1—Main amendments 3
Social Security Act 1991 3
Social Security (Administration) Act 1999 6
Part 2—Consequential amendments 8
Farm Household Support Act 1992 8
Income Tax Assessment Act 1997 8
Social Security Act 1991 10
Social Security (Administration) Act 1999 10
Social Security and Other Legislation Amendment (Income Support Bonus) Act 2013
No. 5, 2013
An Act to amend the law relating to social security, farm household support and taxation, and for related purposes
[ Assented to 5 March 2013 ]
The Parliament of Australia enacts:
1Short title
This Act may be cited as the Social Security and Other Legislation Amendment (Income Support Bonus) Act 2013.
2Commencement
This Act commences on the day this Act receives the Royal Assent.
3Schedule(s)
Each Act that is specified in a Schedule to this Act is amended or repealed as set out in the applicable items in the Schedule concerned, and any other item in a Schedule to this Act has effect according to its terms.
Schedule 1 — Amendments
Part 1 — Main amendments
Social Security Act 1991
1 Subsection 23(1)
Insert:
income support bonusmeans income support bonus under section 919.
2 Subsection 23(1)
Insert:
income support bonus test dayhas the meaning given by section 919.
3 After paragraph 23(4AA)(ab)
Insert:
(ac) paragraph 919(1)(a);
4 After Part 2.18A
Insert:
Part 2.18B— Income support bonus
919Qualification for an income support bonus
Qualification—social security payments
(1) A person is qualified for an income support bonus on an income support bonustest day if:
(a) the person is receiving one of the following payments in respect of that day:
(i) newstart allowance;
(ii) youth allowance;
(iii) parenting payment;
(iv) sickness allowance;
(v) austudy payment;
(vi) special benefit; and
(b) if the person is receiving parenting payment, austudy payment or special benefit in respect of that day—the person is under pension age on that day.
Note: For pension agesee section 23.
Qualification—ABSTUDY payment and farm payments
(2) A person is qualified for an income support bonus on an income support bonustest day if:
(a) one of the following payments is payable to the person in respect of a period that includes that day:
(i) a payment under the ABSTUDY Scheme that includes an amount identified as living allowance;
(ii) exceptional circumstances relief payment under the Farm Household Support Act 1992;
(iii) transitional farm family payment under the program administered by the Commonwealth known as the Transitional Farm Family Payment program; and
(b) if a payment under the ABSTUDY Scheme that includes an amount identified as living allowance is payable to the person in respect of a period that includes that day—the person is under pension age on that day.
Note: For pension agesee section 23.
One income support bonus only in respect of an income support bonus test day
(3) A person cannot receive more than one income support bonus under this section in respect of an income support bonustest day, regardless of how many times the person qualifies under this section on that day.
Definition
(4) In this Act:
income support bonus test daymeans:
(a) 20 March 2013; and
(b) 20 September 2013; and
(c) each later 20 March; and
(d) each later 20 September.
920Amount of income support bonus
The amount of a person’s income support bonus under section 919 is the amount, specified in column 2 of an item in the following table, that corresponds to the person’s family situation, specified in column 1 of that item, on the income support bonus test day:
Amount of income support bonus Item Column 1 Person’s family situation Column 2 Amount1Not a member of a couple$1052Member of a couple, not covered by item 3, 4 or 5$87.503Member of illness separated couple$1054Member of respite care couple$1055Partnered (partner in gaol)$105
Note 1: For member of a couple, illness separated couple, respite care coupleand partnered (partner in gaol)see section 4.
Note 2: The amounts specified are indexed twice a year in line with CPI increases (see sections 1190 to 1194).
921Non‑receipt of social security payment
(1) This section applies for the purposes of a provision of this or another Act if:
(a) the provision provides a benefit (whether the benefit is a pension, benefit, payment, supplement or any other sort of benefit) if a person meets specified criteria; and
(b) one of the specified criteria is that the person is receiving a social security payment, or is a recipient of a social security payment.
(2) For the purposes of the provision, a person is not taken to be receiving a social security payment, or to be a recipient of a social security payment, merely because the person receives an income support bonus.
5 Section 1190 (at the end of the table)
Add:
Income support bonus71.income support bonusincome support bonussection 920—table—items 1, 2, 3, 4 and 5
6 Subsection 1191(1) (at the end of the table)
Add:
Income support bonus43.income support bonus(a) 20 March(b) 20 September(a) December(b) Junehighest June or December quarter before reference quarter (but not earlier than December quarter 2012)$0.10
7 At the end of section 1192
Add:
(10) The first indexation of amounts under item 43 of the CPI Indexation Table in subsection 1191(1) is to take place on 20 September 2013.
Social Security (Administration) Act 1999
8 After section 12K
Insert:
12LIncome support bonus
A claim is not required for an income support bonus.
9 Subsection 47(1) (at the end of the definition of lump sum benefit)
Add:
; or (m) income support bonus.
10 After section 47DAA
Insert:
47DABPayment of income support bonus
If a person is qualified for an income support bonus on an income support bonus test day, the Secretary must pay the bonus to the person in a single lump sum:
(a) on the day that the Secretary considers to be the earliest day on which it is reasonably practicable for the bonus to be paid; and
(b) in such manner as the Secretary considers appropriate.
Part 2 — Consequential amendments
Farm Household Support Act 1992
11 After subsection 24A(8)
Insert:
Income support bonus disregarded
(8A) To avoid doubt, in calculating a rate referred to in subsection (1), any income support bonus under the Social Security Act 1991is to be disregarded.
12 After subsection 24AA(10)
Insert:
Income support bonus disregarded
(10A) To avoid doubt, in calculating a rate referred to in subsection (1), any income support bonus under the Social Security Act 1991is to be disregarded.
13 At the end of section 24B
Add:
(6) To avoid doubt, in calculating a rate referred to in this section, any income support bonus under the Social Security Act 1991is to be disregarded.
Income Tax Assessment Act 1997
14 Section 11‑15 (table item headed “social security or like payments”)
After:
Household Stimulus Package Act (No. 2) 2009 , payments under the scheme determined under Schedule 4 to the..............................................................52‑165
insert:
income support bonus under the Social Security Act 1991 ....................................................................................52‑10 income support bonus under the scheme prepared under Part VII of the Veterans’ Entitlements Act 1986 ....................................................................................52‑65 income support bonus under the scheme determined under section 258 of the Military Rehabilitation and Compensation Act 2004 .........................................52‑114
15 At the end of subsection 52‑10(1) (before the note)
Add:
; or (zc) income support bonus under the Social Security Act 1991.
16 Before subsection 52‑10(2)
Insert:
(1M) Income support bonus under the Social Security Act 1991is exempt from income tax.
17 After paragraph 52‑65(1)(b)
Insert:
(c) payments of income support bonus under the scheme prepared under Part VII (about educating veterans’ children) of the Veterans’ Entitlements Act 1986; or
18 Before subsection 52‑65(2)
Insert:
(1K) Payments of income support bonus under the scheme prepared under Part VII (about educating veterans’ children) of the Veterans’ Entitlements Act 1986are exempt from income tax.
19 Section 52‑75 (after table item 5C)
Insert:
5DIncome support bonus under Veterans’ Children Education SchemePart VIINot applicable
20 Section 52‑114 (before table item 17)
Insert:
16AIncome support bonus under the education scheme for certain eligible young persons (section 258)ExemptNot applicable
Social Security Act 1991
21 Paragraph 1231(1AA)(b)
Omit “or farmers hardship bonus”, substitute “, farmers hardship bonus or income support bonus”.
Social Security (Administration) Act 1999
22 Section 123TC (after paragraph (e) of the definition of category I welfare payment)
Insert:
(f) income support bonus; or
23 Section 123TC (after paragraph (a) of the definition of category Q welfare payment)
Insert:
(aa) income support bonus; or
[ Minister’s second reading speech made in—
House of Representatives on 29 November 2012
Senate on 25 February 2013]
(222/12)
| https://www.legislation.gov.au/Details/C2013A00005 |
Fast highly efficient and robust one-step M-estimators of scale based on Qn | Request PDF
Request PDF | Fast highly efficient and robust one-step M-estimators of scale based on Qn | A parametric family of M-estimators of scale based on the Rousseeuw-Croux Qn-estimator is proposed; estimator’s bias and efficiency are studied. A... | Find, read and cite all the research you need on ResearchGate
Fast highly efficient and robust one-step M-estimators of scale based on Qn
DOI: 10.1016/j.csda.2014.04.013
Abstract
A parametric family of M-estimators of scale based on the Rousseeuw-Croux Qn-estimator is proposed; estimator’s bias and efficiency are studied. A low-complexity one-step M-estimator is obtained allowing a considerably faster computation with greater than 80% efficiency and the highest possible 50% breakdown point. Analytical and Monte Carlo modeling results confirm the effectiveness of the proposed approach.
... The proof of the theorem is given in Ref.
[9]
. It is based on integrating the estimator of the MQ n -estimate under consideration. ...
... The asymptotic efficiency of such MQ n -estimates with estimators of the form (7) is 81%. This is only 1% less than the asymptotic efficiency of Q n -estimates on the Gaussian distribution, with a significant gain in computational speed
[9]
. ...
... The proof of the theorem is also given in Ref.
[9]
. ...
High-efficiency and robust M -estimates of the scale parameter on the Q -estimate basis
Article
Full-text available
Sep 2017
Pavel O. Smirnov
Ivan S. Shirokov
Georgy Shevlyakov
The commonly employed highly efficient and robust Q-estimate of the scale parameter proposed by Rousseeuw and Croux (1993) has been approximated using computationally fast Huber M-estimates. The suggested M-estimates were shown to be robust and highly efficient for an arbitary underlying data distribution due to correctly choosing the approximation parameters. The following indicators of the efficiency and robustness of M-estimates of scale were computed: their asymptotic variances, influence functions and breakdown points. Special attention was given to the particular cases of the Gaussian and Cauchy distributions. It is noteworthy that for the Cauchy distribution, the suggested robust estimate of scale coincides with the maximal likelihood estimate. Finally, the computation time of these highly efficient and robust estimates of scale is 3-4 times less than for the corresponding Q-estimates.
... In
[SS14]
, a parametric family of M-estimators of scale based on the Q n estimator is presented, which allows obtaining even higher statistical efficiency. ...
Finite-sample Rousseeuw-Croux scale estimators
Preprint
Full-text available
Sep 2022
Andrey Akinshin
The Rousseeuw-Croux $S_n$, $Q_n$ scale estimators and the median absolute deviation $\operatorname{MAD}_n$ can be used as consistent estimators for the standard deviation under normality. All of them are highly robust: the breakdown point of all three estimators is $50\%$. However, $S_n$ and $Q_n$ are much more efficient than\ $\operatorname{MAD}_n$: their asymptotic Gaussian efficiency values are $58\%$ and $82\%$ respectively compared to $37\%$ for\ $\operatorname{MAD}_n$. Although these values look impressive, they are only asymptotic values. The actual Gaussian efficiency of $S_n$ and $Q_n$ for small sample sizes is noticeable lower than in the asymptotic case. The original work by Rousseeuw and Croux (1993) provides only rough approximations of the finite-sample bias-correction factors for $S_n$, $Q_n$ and brief notes on their finite-sample efficiency values. In this paper, we perform extensive Monte-Carlo simulations in order to obtain refined values of the finite-sample properties of the Rousseeuw-Croux scale estimators. We present accurate values of the bias-correction factors and Gaussian efficiency for small samples ($n \leq 100$) and prediction equations for samples of larger sizes.
... Still, it is worth examining whether the correlations identified in the previous analysis might be primarily driven by a small population of individuals who exhibit very low rates of forgetting. To this end, we re-assessed all of the previous analysis using a robust correlation method developed by
Smirnov and Shevlyakov (2014)
, which greatly reduces the effect of outliers in the data (Shevlyakov & Smirnov, 2011) and is implemented in the package "robcor" for the R statistical language. In general, the robust correlation method reduced the absolute value of most (but not all) correlation coefficients. ...
Reflections of idiographic long-term memory characteristics in resting-state neuroimaging data
Article
Mar 2021
COGNITION
Peiyun Zhou
Florian Sense
Hedderik van Rijn
Andrea Stocco
Translational applications of cognitive science depend on having predictive models at the individual, or idio-graphic, level. However, idiographic model parameters, such as working memory capacity, often need to be estimated from specific tasks, making them dependent on task-specific assumptions. Here, we explore the possibility that idiographic parameters reflect an individual's biology and can be identified from task-free neuro-imaging measures. To test this hypothesis, we correlated a reliable behavioral trait, the individual rate of forgetting in long-term memory, with a readily available task-free neuroimaging measure, the resting-state EEG spectrum. Using an established, adaptive fact-learning procedure, the rate of forgetting for verbal and visual materials was measured in a sample of 50 undergraduates from whom we also collected eyes-closed resting-state EEG data. Statistical analyses revealed that the individual rates of forgetting were significantly correlated across verbal and visual materials. Importantly, both rates correlated with resting-state power levels in the low (13-15 Hz) and upper (15-17 Hz) portion of the beta frequency bands. These correlations were particularly strong for visuospatial materials, were distributed over multiple fronto-parietal locations, and remained significant even after a correction for multiple comparisons (False Discovery Rate) and after robust correlation methods were applied. These results suggest that computational models could be individually tailored for prediction using idiographic parameter values derived from inexpensive, task-free imaging recordings.
... The F estimator can be obtained through faster computation with more than 80% efficiency and with 50% breakdown point. The efficiency of F estimator is confirmed through simulations (
Smirnov and Shevlyakov, 2014
). ...
The EWMA control chart based on robust scale estimators
Article
Dec 2016
Nadia Saeed
Shahid Kamal
The exponentially weighted moving average (EWMA) chart is very popular in statistical process control for detecting the small shifts in process mean and variance. This chart performs well under the assumption of normality but when data violate the assumption of normality, the robust approaches are needed. We have developed the EWMA charts under different robust scale estimators available in literature and also compared the performance of these charts by calculating expected out-of-control points and expected widths under non-symmetric distributions (i.e. gamma and exponential). The simulation studies are being carried out for the purpose and results showed that amongst six robust estimators, the chart based on estimator Qn relatively performed well for non-normal processes in terms of its shorter expected width and more number of expected out-of-control points which shows its sensitivity to detect the out of control signal.
Robust Point M-Scale Estimators for Monitoring the Mean of EWMA Control Chart under the Normal Process
Article
Nov 2022
Ala'a Mahmoud Falih Bataineh
Nadia Saeed
Alaa Fakri Sulaiman Obeidat
Moustafa Omar Ahmed Abu-Shawiesh
The Exponentially Weighted Moving Average (EWMA) control chart is well known in statistical process control (SPC) for identifying small shifts in process parameters. In general, the EWMA control chart is focused on data set estimates of the process characteristics under study. In this research, for observing the process mean, we modify the control limits of the EWMA control chart by using robust point M-scale estimators under the normal process. We compare five robust point M-scale estimators proposed in SPC literature, namely Sn, Qn, MAD, Tauτ^ and FQn. The traditional control limits are evaluated and distinctions are also made based on true process control limits. The control charts performances under study are estimated via a Monte-Carlo simulation analysis by calculating the interval widths (IWs) and optimal out-of-control average run length (ARL1). From the simulation studies results, it is seen that although all proposed and traditional control limits are closely approximating the true limits of the process but the proposed control limits based on robust FQn, Tauτ^ and MAD estimators are comparatively more stringent for detecting the small shifts in process mean. Moreover the results demonstrates that at optimal size of interval L, the control charts based on MAD, Tauτ^ as well as FQn estimators demonstrate higher sensitivity in comparison to the traditional control chart based on sample standard deviation (S) and proposed control charts based on QnandSn estimators in terms of having smaller ARL1 values. The OC curves of ARL1 indicate similar findings. For the purposes of illustration, a real-life data set is analyzed that also confirms our conclusions from the simulation analysis to a certain degree.
Robust interval forecasting algorithm based on a probabilistic cluster model
Article
Apr 2018
Yury Krakovsky
Aleksandr Luzgin
For substantiation of managerial decisions the forecasting results of dynamic indicators are used. Therefore, forecasting accuracy of these indicators must be acceptable. Consequently, forecasting algorithms are constantly improved to get the acceptable accuracy. This paper considers a variant of the method of forecasting binary outcomes. This method allows prediction of whether or not a future value of the indicator exceeds a predetermined value. This method ‘interval forecasting’ was named. In this paper a robust interval forecasting algorithm based on a probabilistic cluster model is proposed. The algorithm’s accuracy was compared with an algorithm based on logistic regression. The indicators with different statistical properties were chosen. The obtained results have shown the accuracy of both the algorithms is approximately similar in most cases. However, the cases when the algorithm based on logistic regression demonstrated unacceptable accuracy, unlike the presented algorithm have been identified. Thus, this new algorithm is more accurate.
Applications to Time Series Analysis: Robust Spectrum Estimation
Chapter
Sep 2016
Georgy Shevlyakov
Hannu Oja
Conventional methods of power spectrum estimation are very sensitive to the presence of outliers in the data; thus generally the issues of robustness are of vital importance within this area of statistics of random processes. This chapter considers various robust versions of the conventional methods of power spectra estimation. It is found that the best robust estimates of power spectrum are based on robust highly efficient estimates of autocovariances. Several open problems for future research are formulated. The chapter proposes a contamination model dubbed as a disorder contamination describing the violations of the thin structure of a random process, when an autoregressive (AR)-process is shortly changed for another and then it returns to the previous state. The chapter applies the robust analogs of the discrete Fourier transform (DFT) as well as the highly robust and efficient estimates of scale and correlation to the classical nonparametric estimation of power spectrum.
View
Robust Estimation of Scale
Chapter
Sep 2016
Georgy Shevlyakov
Hannu Oja
This chapter presents the problem of robust estimation of scale is treated as the problem subordinate to robust estimation of correlation, as measures of correlation are defined via the measures of scale. Special attention is paid to the former robust Huber minimax variance and bias estimates of scale under e-contaminated normal distributions as well as to the proposed Rousseeuw and Croux highly robust and efficient estimates of scale with their fast low-complexity modifications, for they are applied to the problems of robust estimation of the correlation coefficient. The chapter gives the Huber minimax variance solution under e-contaminated normal distributions, as this solution is for constructing the minimax variance estimate of the correlation coefficient, and discusses the parametric family of M-estimates of scale based on the Rousseeuw-Croux Qn-estimate, and provides their estimate bias and effciency. It maintains a comparative performance study of several estimates of scale under the standard Gaussian, contaminated Gaussian, and Cauchy underlying distributions.
Robust Estimation of Correlation Coefficients
Chapter
Sep 2016
Georgy Shevlyakov
Hannu Oja
This chapter examines several groups of robust estimates of the correlation coefficient under contaminated bivariate normal, independent component bivariate, and heavy-tailed Cauchy bivariate distributions with the use of influence function techniques in asymptotics and by the Monte Carlo method on finite samples. As a result of the comparative study of various robust estimates, the chapter exposes the best in each group and showed that some of them possess optimal robustness properties. In particular, the asymptotically minimax variance and bias robust estimate of the correlation coefficient is given by the MAD correlation coefficient, a correlation analog of the sample median, and median absolute deviation estimates of location and scale.The chapter shows that the robust estimates of the correlation coefficient based on highly efficient robust estimates of scale outperform many of their competitors. The generalization of those results for the case of robust estimation of correlation matrices of independent component multivariate distributions is an open problem.
Robust Scale Estimation Based on the Improved Median Absolute Deviations
Article
Jan 2015
苹莉 杨
本文基于Smirnor-Shevlyakov在2014年针对位置参数已知为0的稳健尺度估计(即改进的中位数绝对偏差FQn)，提出了位置参数未知时的稳健尺度估计(称之为广义中位数绝对偏差GMAD)。数据分析表明：FQn在位置参数未知时不稳健，但GMAD估计在位置参数为0以及未知时均稳健。 Robust scale estimation with unknown location parameters which is called general median absolute deviations (GMAD) was proposed based on a robust scale estimation with location parameters of 0 (improved median absolute deviations FQn) given by Smirnor-Shevlyakov in 2014. The data analysis showed that FQn loses robustness when location parameters are unknown, but GMAD is robust when location parameters are zero or unknown.
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Robust Estimation of the Correlation Coefficient: An Attempt of Survey
Article
Full-text available
Jan 2011
Georgy Shevlyakov
Pavel O. Smirnov
Various groups of robust estimators of the correlation coefficient are introduced. The performance of most prospective estimators is examined at contaminated normal distributions both on small and large samples, and the best of the proposed robust estimators are revealed.
On approximation of the Qn-estimate of scale by fast M-estimates
Conference Paper
Full-text available
Jun 2010
Pavel O. Smirnov
Georgy Shevlyakov
Robust versions of the Tukey boxplot with their application to detection of outliers
Conference Paper
Full-text available
Oct 2013
Acoust Speech Signal Process
Georgy Shevlyakov
Kliton Andrea
Choudur Lakshminarayan
Natalia Vassilieva
The need for fast on-line algorithms to analyze high data-rate measurements is a vital element in production settings. Given the ever-increasing number of data sources coupled with increasing complexity of applications, and workload patterns, anomaly detection methods should be light-weight and must operate in real-time. In many modern applications, data arrive in a streaming fashion. Therefore, the underlying assumption of classical methods that the data is a sample from a stable distribution is not valid, and Gaussian and non-parametric based methods such as the control chart and boxplot are inadequate. Streaming data is an ever-changing superposition of distributions. Detection of such changes in real-time is one of the fundamental challenges. We propose low-complexity robust modifications to the conventional Tukey boxplot based on fast highly efficient robust estimates of scale. Results using synthetic as well as real-world data show that our methods outperform the Tukey boxplot and methods based on Gaussian limits.
Some remarks on robust estimation of power spectra
Conference Paper
Full-text available
Sep 2013
Georgy Shevlyakov
Nikolay Lyubomishchenko
Pavel O. Smirnov
Various robust modifications of the classical methods of power spectra esti-
mation, both nonparametric and parametric, are considered. Their performance
evaluation is studied in autoregressive models with contamination. It is found
out that prospective robust estimates of power spectra are based on robust highly
efficient estimates of autocovariances and on robust filtering algorithms. Several
open problems for future research are formulated.
Time-Efficient Algorithms for Two Highly Robust Estimators of Scale
Article
Full-text available
Jan 1992
Christophe Croux
Peter Rousseeuw
In this paper we present deterministic algorithms of time O(n log n) and space O(n) for two robust scale estimators with maximal breakdown point. The actual source codes are included, and execution times are compared.
| https://www.researchgate.net/publication/262057690_Fast_highly_efficient_and_robust_one-step_M-estimators_of_scale_based_on_Qn |
Question about those back saving hook on the faucet water changers | Water Change Forum
Okay... so here is my question. I have been eyeing those water changers that are out there. My local store has one by Aqueon. It has a 50' hose a vacuum...
Question about those back saving hook on the faucet water changers
Okay... so here is my question. I have been eyeing those water changers that are out there. My local store has one by Aqueon. It has a 50' hose a vacuum attatchment and connection that you hook to your faucet. So far so good. I can see how easy it would be to fill the line with water to get the siphon started and empty the desired level from my tank...
But... When it comes to adding water back to my tank. I can see how to get the temp where I want it. But I don't have a way to remove the
Chlorine
and Chloramine from the water
before
it gets to my tank. The only thing I can think of is to dose the tank with
Prime
before adding the water and carefully monitor the temp as I add the water to make sure the temp does not change.
What do the rest of you do?
Exactly that. I found however, that a water changer is pretty hard to use if you're going at it solo...or you need to be a really quick runner from tank to faucet With 2 people they work great...well for filling...still having problems getting it to siphon.
Thank you. I thought that might be the answer, but I have never added water to my tank that I did not treat in a bucket first. It seemed like a scary thought. I will keep researching.
I bought the aqueon and it sucks, then I got the Python its amazing. I highly recommend the python you will love it.
Exactly that. I found however, that a water changer is pretty hard to use if you're going at it solo...or you need to be a really quick runner from tank to faucet With 2 people they work great...well for filling...still having problems getting it to siphon.
I can't tell you how many times I have splashed water all over my bathroom because I didn't move fast enough from my tank to the sink. LOL!
Edit- but I still love my python....sure beats lugging buckets.
I've not used a Python yet, although I did research it somewhat. I found the reviews to be amazing, and the only negative I've read about it thus far is not making sure beforehand that the attachment will actually fit on your faucet. (Some people who were renting found they needed a completely different faucet.)
That's a good question though, and one Id not thought of... getting the dechlorinator into the water.
Okay... so here is my question. I have been eyeing those water changers that are out there. My local store has one by Aqueon. It has a 50' hose a vacuum attatchment and connection that you hook to your faucet. So far so good. I can see how easy it would be to fill the line with water to get the siphon started and empty the desired level from my tank...
But... When it comes to adding water back to my tank. I can see how to get the temp where I want it. But I don't have a way to remove the Chlorine and Chloramine from the water
before
it gets to my tank. The only thing I can think of is to dose the tank with Prime before adding the water and carefully monitor the temp as I add the water to make sure the temp does not change.
What do the rest of you do?
If your local water utility is still using chlorine you can just agitate it to off gas the chlorine with all but the most sensitive fish.
With Chloramine you will want to add the water conditioner for the amount of tap water you are going to be adding to the tank directly to the tank as you are filling it. Not that big of a deal.
for these
automatic water changers
you can cut the hose near the "tank end" and add a shutoff valve. Ta Da no more spills, no more running to shut off the water.
I PRIME (for chlorine and chloramine) for the entire volume of my tank (75G) after removing 50%, and before adding any new water. You can safely overdose with PRIME up to 5x the dosage. I find that this also helps my fish adjust to the change in water conditions.
I've found that they're great for water changes on large tanks; adding and removing 37 gallons of water by hand sucks the big one. However, I've found that the suction created isn't really enough for a good substrate vac, so I use it only for water changes, and use my battery-powered gravel-vac for my substrate cleaning. It gives me something to do while I hang out watching the water level go down. Also; more trouble than it's worth on a small tank (<20G).
PS. remove your bathroom rug before using it. Trust me. Even when you have a second person, sometimes bad things happen. Like 37 gallons of water on your bathroom floor.
Thanks for all the info. After getting help here and watching the tutorial videos from both Aqueon and Python... I think I will purchase the Python in the near future. I need to do a little more investigation into the faucet types I have to see what will work. I know that the ones I have upstairs don't accept these types of units because we used to have a waterbed and they use the same type of connection. Luckily all the tanks are downstairs. We were looking lastnight at the kitchen faucet, it has one of those sprayer faucets... you know the kind that is a faucet and sprayer in one. It still has an aerator that can be removed so may be doable. It is also the closest sink to all my tanks... hahaha... I now have two more in the works, hence the questions about water changers.
Mine doesn't have enough suction to be used as a travel vac, so I use a gravel vac into a bucket and put the water changer into the bucket until I am done gravel vacing. Then I just put it into the tank to drain/refill the rest
I tried one. Didn't work out for me. I now use a simple hose from my Laundry faucet. Y valve splitter with individual shut-offs on hot and cold faucet. Hook Washing machine to one side of each splitter, the other side of each goes to a short Y hose connector (to get both hot and cold mixed into one hose. Attached to this is a 50 foot hose with another shut-off at the working end. I think all together I spent about $25 and it is permanently attached to the faucet and MUCH more secure than the Aqueon system. Not a single leak when using this hose. Since the Aqueon system was very bad at siphoning, I just use an ordinary gravel vac and siphon into 5 gal buckets. Dumping these was never a problem, but refilling the aquarium is MUCH easier now.
I bought just the piece that attaches to the faucet. Then I bought one of those flexible hoses like they advertise on TV. I got a 50' hose in Walmart for $20. I do a full tank dose of Prime before I start filling and go from there. The hose has an on off switch on it so you can stop the water flow at either end and don't have to run back and forth. And the nice part is that it shrinks back up real small when the water is drained out of it so it is easy to store.
The aqueon water changer has a on/off valve at both ends. The problem is that the pressure causes the hose to burst off of one end and spray water everywhere. Hence the running lol
This is the I was talking about, it's not a siphon or a water changer of any kind; no buckets necessary, and I can use it while I'm doing my water change. It's easy to clean, works great, and worth every last penny.
| https://www.fishlore.com/aquariumfishforum/threads/question-about-those-back-saving-hook-on-the-faucet-water-changers.144342/ |
(PDF) Decreased Antibiotic Consumption Coincided with Reduction in Bacteremia Caused by Bacterial Species with Respiratory Transmission Potential during the COVID-19 Pandemic
PDF | Nonpharmaceutical interventions implemented during the COVID-19 pandemic (2020–2021) have provided a unique opportunity to understand their impact... | Find, read and cite all the research you need on ResearchGate
(PDF) Decreased Antibiotic Consumption Coincided with Reduction in Bacteremia Caused by Bacterial Species with Respiratory Transmission Potential during the COVID-19 Pandemic
Article PDF Available
Decreased Antibiotic Consumption Coincided with Reduction in Bacteremia Caused by Bacterial Species with Respiratory Transmission Potential during the COVID-19 Pandemic
May 2022 Antibiotics 11(6):746
DOI: 10.3390/antibiotics11060746
License CC BY 4.0
Authors:
Vincent Chi-Chung Cheng
Vincent Chi-Chung Cheng
This person is not on ResearchGate, or hasn't claimed this research yet.
Shuk-Ching Wong
Shuk-Ching Wong
This person is not on ResearchGate, or hasn't claimed this research yet.
Simon Yung Chun So
Queen Mary Hospital
Jonathan HK Chen
The University of Hong Kong
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Citations (10)
References (68)
Figures (8)
Abstract and Figures
Nonpharmaceutical interventions implemented during the COVID-19 pandemic (2020–2021) have provided a unique opportunity to understand their impact on the wholesale supply of antibiotics and incidences of infections represented by bacteremia due to common bacterial species in Hong Kong. The wholesale antibiotic supply data (surrogate indicator of antibiotic consumption) and notifications of scarlet fever, chickenpox, and tuberculosis collected by the Centre for Health Protection, and the data of blood cultures of patients admitted to public hospitals in Hong Kong collected by the Hospital Authority for the last 10 years, were tabulated and analyzed. A reduction in the wholesale supply of antibiotics was observed. This decrease coincided with a significant reduction in the incidence of community-onset bacteremia due to Streptococcus pyogenes, Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis, which are encapsulated bacteria with respiratory transmission potential. This reduction was sustained during two pandemic years (period 2: 2020–2021), compared with eight pre-pandemic years (period 1: 2012–2019). Although the mean number of patient admissions per year (1,704,079 vs. 1,702,484, p = 0.985) and blood culture requests per 1000 patient admissions (149.0 vs. 158.3, p = 0.132) were not significantly different between periods 1 and 2, a significant reduction in community-onset bacteremia due to encapsulated bacteria was observed in terms of the mean number of episodes per year (257 vs. 58, p < 0.001), episodes per 100,000 admissions (15.1 vs. 3.4, p < 0.001), and per 10,000 blood culture requests (10.1 vs. 2.1, p < 0.001), out of 17,037,598 episodes of patient admissions with 2,570,164 blood culture requests. Consistent with the findings of bacteremia, a reduction in case notification of scarlet fever and airborne infections, including tuberculosis and chickenpox, was also observed; however, there was no reduction in the incidence of hospital-onset bacteremia due to Staphylococcus aureus or Escherichia coli. Sustained implementation of non-pharmaceutical interventions against respiratory microbes may reduce the overall consumption of antibiotics, which may have a consequential impact on antimicrobial resistance. Rebound of conventional respiratory microbial infections is likely with the relaxation of these interventions.
Epidemic curve of laboratory-confirmed COVID-19 cases in Hong Kong (from 2020 to 2021). Antibiotics 2022, 11, x FOR PEER REVIEW 6 of 17
…
Supply of antibiotics as a marker of antimicrobial consumption in community and healthcare settings in Hong Kong (from 2014 to 2021).
…
Number of patient admission and blood culture requests in public hospitals in Hong Kong before and during COVID-19.
…
Community-onset bacteremia due to selected pathogens before and during COVID-19 in Hong Kong. Note: the selected microorganisms included pathogens with potential respiratory transmission (Streptococcus pyogenes, Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis), and pathogens commonly identified in the blood culture including methicillin-sensitive Staphylococcus aureus (MSSA), methicillin-resistant S. aureus (MRSA), and Escherichia coli, were used as controls. Statistical analysis is shown in Table 1.
…
+3
Community-onset bacteremia due to pathogens with respiratory transmission potential before and during COVID-19 in Hong Kong. Note: the pathogens with.
…
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Citation: Cheng, V .C.-C.; Wong, S.-C.;
So,
S.Y
.-C.;
Chen,
J.H.-K.;
Chau,
P
.-H.;
Au,
A.K.-W.;
Chiu,
K.H.-Y
.;
Li,
X.;
Ip,
P
.;
Chuang,
V
.W.-M.;
et
al.
Decreased
Antibiotic
Consumption
Coincided
with
Reduction
in
Bacteremia
Caused
by
Bacterial
Species
with
Respiratory
Transmission
Potential
during
the
COVID-19
Pandemic. Antibiotics
2022 , 11 , 746. https://doi.org/
10.3390/antibiotics11060746
Academic
Editor:
Marcello
Covino
Received:
4
May
2022
Accepted:
27
May
2022
Published:
31
May
2022
Publisher’s
Note: MDPI stays neutral
with
regard
to
jurisdictional
claims
in
published
maps
and
institutional
affil-
iations.
Copyright: © 2022 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
(https://
creativecommons.org/licenses/by/
4.0/).
antibiotics
Article
Decreased
Antibiotic
Consumption
Coincided
with
Reduction
in
Bacteremia
Caused
by
Bacterial
Species
with
Respiratory
T
ransmission
Potential
during
the
COVID-19
Pandemic
Vincent
Chi-Chung
Cheng 1,2 ,†
,
Shuk-Ching
Wong 1, †
,
Simon
Yung-Chun
So 2
,
Jonathan
Hon-Kwan
Chen 2
,
Pui-Hing
Chau 3 , Albert Ka-Wing Au 4 , Kelvin Hei-Y eung Chiu 2 , Xin Li 5 , Patrick Ip 6,7 ,
Vivien
W
ai-Man
Chuang 8
,
David
Christopher
Lung 9 , 10
,
Cindy
Wing-Sze
T
se 11
,
Rodney
Allan
Lee 12
,
Kitty
Sau-Chun
Fung 13
,
Wing-Kin
T
o 14
,
Raymond
Wai-Man
Lai 8,15
,
T
ak-Lun
Que 16
,
Janice
Yee-Chi
Lo 4
and
Kwok-Yung
Y
uen 5 ,
*
1 Infection Control T eam, Queen Mary Hospital, Hong Kong West Cluster , Hong Kong, China;
[email protected]
(V
.C.-C.C.);
[email protected]
(S.-C.W
.)
2 Department of Microbiology , Queen Mary Hospital, Hong Kong, China; [email protected] (S.Y .-C.S.);
[email protected]
(J.H.-K.C.);
[email protected]
(K.H.-Y
.C.)
3 School of Nursing, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China;
[email protected]
4 Centre for Health Protection, Department of Health, Hong Kong, China; [email protected] .hk (A.K.-W .A.);
[email protected]
.hk
(J.Y
.-C.L.)
5 Department of Microbiology , Li Ka Shing Faculty of Medicine, The University of Hong Kong,
Hong
Kong,
China;
[email protected]
6 Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine,
The
University
of
Hong
Kong,
Hong
Kong,
China;
[email protected]
7
Department
of
Paediatrics
and
Adolescent
Medicine,
The
Hong
Kong
Children’s
Hospital,
Hong
Kong,
China
8 Quality & Safety Division, Hospital Authority , Hong Kong, China; [email protected] (V .W .-M.C.);
[email protected]
(R.W
.-M.L.)
9 Department of Pathology , Queen Elizabeth Hospital, Hong Kong, China; [email protected]
10 Department of Pathology , The Hong Kong Children’s Hospital, Hong Kong, China
11 Department of Pathology , Kwong Wah Hospital, Hong Kong, China; [email protected] g.hk
12 Department of Pathology , Pamela Youde Nethersole Eastern Hospital, Hong Kong, China; [email protected] g.hk
13 Department of Pathology , United Christian Hospital, Hong Kong, China; [email protected]
14 Department of Pathology , Princess Margaret Hospital, Hong Kong, China; [email protected]
15 Department of Pathology , Prince of Wales Hospital, Hong Kong, China
16 Department of Pathology , Tuen Mun Hospital, Hong Kong, China; [email protected] g.hk
* Correspondence: [email protected]
†
These
authors
contributed
equally
to
this
work.
Abstract:
Nonpha
rmaceut
ical
int
erventi
ons
imple
mented
d
uring
the
C
OVID-19
p
andemic
(2020–
2021)
have
provided
a
unique
opportunity
to
understand
their
impact
on
the
wholesale
supply
of
antibiotics
and
incidences
of
infections
represented
by
bacteremia
due
to
common
bacterial
species
in
Hong
Kong.
The
wholesale
antibiotic
supply
data
(surrogate
indicator
of
antibiotic
consumption)
and
notifications
of
scarlet
fever,
chickenpox,
and
tuber
culosis
collected
by
the
Centre
for
Health
Protec-
tion,
and
the
data
of
blood
cultures
of
patients
admitted
to
public
hospitals
in
Hong
Kong
collected
by
the
Hospital
Authority
for
the
last
10
years,
were
tabulated
and
analyzed.
A
reduction
in
the
wholesale
supply
of
antibiotics
was
observed.
This
decrease
coincided
with
a
significant
reduction
in
the
incidence
of
community-onset
bacteremia
due
to Streptococcus pyogenes , Streptococcus pneumoniae
,
Haemophilus
influenzae , and
Neisseria
meningitidis , which are encapsulated bacteria with respira-
tory
transmission
potential.
This
reduction
was
sustained
during
two
pandemic
years
(period
2:
2020–2021),
compared
with
eight
pre-pandemic
years
(period
1:
2012–2019).
Although
the
mean
number
of
patient
admissions
per
year
(1,704,079
vs.
1,702,484, p
=
0.985)
and
blood
culture
requests
per
1000
patient
admissions
(149.0
vs.
158.3, p
=
0.132)
were
not
significantly
dif
ferent
between
periods
1
and
2,
a
significant
reduction
in
community-onset
bacteremia
due
to
encapsulated
bacteria
was
observed
in
terms
of
the
mean
number
of
episodes
per
year
(257
vs.
58, p
<
0.001),
episodes
per
100,000
admissions
(15.1
vs.
3.4, p
<
0.001),
and
per
10,000
blood
culture
requests
(10.1
vs.
2.1,
Antibiotics 2022 , 11 , 746. https://doi.org/10.3390/antibiotics11060746 https://www.mdpi.com/journal/antibiotics | https://www.researchgate.net/publication/360986190_Decreased_Antibiotic_Consumption_Coincided_with_Reduction_in_Bacteremia_Caused_by_Bacterial_Species_with_Respiratory_Transmission_Potential_during_the_COVID-19_Pandemic |
A cyclopolymerizable, doubly Irgacure 2959 functionalized quaternary ammonium salt photoinitiator and its water soluble copolymer with diallyldimethylammonium chloride | Request PDF
Request PDF | A cyclopolymerizable, doubly Irgacure 2959 functionalized quaternary ammonium salt photoinitiator and its water soluble copolymer with diallyldimethylammonium chloride | A new cyclopolymerizable, doubly 2-hydroxy-4’-(2-hydroxyethoxy)-2-methylpropiophenone (Irgacure 2959 or I2959) functionalized allyl-acrylate... | Find, read and cite all the research you need on ResearchGate
A cyclopolymerizable, doubly Irgacure 2959 functionalized quaternary ammonium salt photoinitiator and its water soluble copolymer with diallyldimethylammonium chloride
DOI: 10.1039/D2PY01449A
Abstract
A new cyclopolymerizable, doubly 2-hydroxy-4’-(2-hydroxyethoxy)-2-methylpropiophenone (Irgacure 2959 or I2959) functionalized allyl-acrylate quaternary ammonium salt (2xI2959-QS) and its copolymer with diallyldimethylammonium chloride (DADMAC) are synthesized. The water soluble polymer, p-DADMAC-co-2xI2959-QS, with...
Volumetric additive manufacturing with light is an advanced technology in diverse conventional fields. However, with the raising awareness of environmental concerns and the growing interest in biomedical applications, the safety and water solubility of the existing photoinitiators are challenged. Herein, we developed a photoinitiating system based on a blue food colorant, i.e., indigo carmine. The indigo carmine-based photoinitiating system induced a rapid photochemical reaction and photobleaching under blue and green LEDs in the alkaline medium. The unprecedented photoinitiation ability of the indigo carmine-based photoinitiating system in terms of rate of photopolymerization and the final monomer conversion was achieved under the irradiation of low-intensity light sources. Subsequently, a sophisticated 3D printing in high fidelity was carried out and a 2D seashell was designed and printed with the function of 2D-3D reversible switching. These findings demonstrated that the indigo carmine-based photoinitiating system could resolve the safety and water solubility challenges and be involved in the 3D printing of biomedical materials.
Miglė Lebedevaitė
Wiktoria Tomal
Jieping Wang
Marica Markovic
Robert Liska
The monoacylphosphineoxide (MAPO) salts Na-TPO and Li-TPO and the bisacylphosphineoxide (BAPO) salts BAPO-ONa and BAPO-OLi define an important and in the latter case a new class of water-soluble photoinitiators (PIs) for radical polymerization. These compounds showed excellent water-solubility of at least 29 g/L for Na-TPO and up to 60 g/L for BAPO-ONa in deionized water, thus exceeding the solubility of the state of the art PI for water-based systems Irgacure 2959 (I2959) 6- to 12-fold. However, biocompatibility, storage stability, and reactivity were equally important to replace the state of the art compounds. Concerning these properties, the MAPO and BAPO salts were at least in the same range (biocompatibility, stability) or showed even better results (reactivity) and had the additional advantage of visible light initiation. Na-TPO and Li-TPO achieved double bond conversions of an aqueous solution of N-acryloylmorpholine over 97% with broad band irradiation (320–500 nm), Li-TPO showed additionally very good biocompatibility (LC50 = 3.1 mmol/L) and BAPO-OLi showed highest reactivity with visible light irradiation. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015
Structure Design of Naphthalimide Derivatives: Toward Versatile Photoinitiators for Near-UV/Visible LEDs, 3D Printing, and Water-Soluble Photoinitiating Systems
Apr 2015
Jing Zhang
Frédéric Dumur
Pu Xiao
Jacques Lalevée
Seven naphthalimide derivatives (NDP1-NDP7) with different substituents have been designed as versatile photoinitiators (PIs), and some of them when combined with an iodonium salt (and optionally N-vinylcarbazole) or an amine (and optionally chlorotriazine) are expected to exhibit an enhanced efficiency to initiate the cationic polymerization of epoxides and the free radical polymerization of acrylates under different irradiation sources (i.e., the LED at 385, 395, 405, 455, or 470 nm or the polychromatic visible light from the halogen lamp). Remarkably, some studied naphthalimide derivative based photoinitiating systems (PIS) are even more efficient than the commercial type I photoinitiator bisacylphosphine oxide and the well-known camphorquinone-based systems for cationic or radical photopolymerization. A good efficiency upon a LED projector at 405 nm used in 3D printers is also found: a 3D object can be easily created through an additive process where the final object is constructed by coating down successive layers of material. As another example of their broad potential, a NDP compound enveloped in a cyclodextrin (CD) cavity, leads to a NDP-CD complex which appears as a very efficient water-soluble photoinitiator when combined with methyldiethanol amine to form a hydrogel. The high interest of the present photoinitiator (NDP2) is its very high reactivity, allowing synthesis in water upon LED irradiation as a green way for polymer synthesis.The structure/reactivity/efficiency relationships as well as the photochemical mechanisms associated with the generation of the active species (radicals or cations) are studied by different techniques including steady state photolysis, fluorescence, cyclic voltammetry, laser flash photolysis, and electron spin resonance spin-trapping methods.
Cyclopolymerization
Oct 2000
J POLYM SCI POL CHEM
George B. Butler
The background and summary of the events that led to the discovery and confirmation of an unusual and unexpected mode of polymerization of certain vinyl monomers is presented. Originally, the process was described as an alternating intra-intermolecular chain propagation mechanism. For convenience and because cyclic structures are introduced into the polymer chain, the term cyclopolymerization has been adopted. Early attempts to determine the relationship of cyclopolymerization to stereochemical control and to ladder polymer formation are reviewed. Also, it is pointed out that within 10 years of the introduction of the cyclopolymerization concept, worldwide commercialization of certain cyclopolymers and cyclocopolymers had begun. The extent of the research activity in this area of chemistry and its relationship to commercialization are emphasized. Two areas of research activity that are featured are chirality induction into well-known polymers and synthesis of conjugated polymers via cyclopolymerization. Both areas are discussed, and suitable examples are included. © 2000 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 38: 3451–3461, 2000
View
Initiating gradient photopolymerization and migration of a novel polymerizable polysiloxane α-hydroxy alkylphenones photoinitiator
POLYMER
Fang Sun
Yanxia Li
Nan Zhang
Jun Nie
This paper reported a photocleavage type polymerizable organosilicon macromolecular photoinitiator (HHMP-Si-CC), which was synthesized based on traditional photoinitiator 2-hydroxy-1-[4-(2-hydroxyethoxy) phenyl]-2-methyl propan-l-one (HHMP) and amino polysiloxane. HHMP-Si-CC cannot only spontaneously form a concentration gradient in the photopolymerization system, initiate gradient photopolymerization and effectively mitigate inhibition of oxygen, but also overcome the migration of photolysis fragments of the photoinitiator from UV-curable material. Its structure was confirmed by proton nuclear magnetic resonance (H-1 NMR), C-13 NMR, Si-29 NMR and Fourier transform infrared spectroscopy (FTIR) and gel permeation chromatography (GPC). The kinetics of photopolymerization of HHMP-Si-CC was studied by real-time infrared spectroscopy (RTIR). Moreover, it was proved by X-ray photoelectron spectroscopy (XPS) and UV absorption that HHMP-Si-CC had relatively good self-floating ability. The polymer initiated by HHMP-Si-CC presented a gradient change in the degree of polymerization, molecular weight, thermostability and glass transition temperature (Tg). The surface morphology of poly(triethylene glycol diacrylate) (PTPGDA) initiated by HHMP-Si-CC was studied by scanning electron microscopy (SEM). More importantly, the migration of photolysis fragments of the HHMP-Si-CC from UV-curable materials was also investigated by high performance liquid chromatography (HPLC). The results showed that the migration more was effectively mitigated by introducing polymerizable groups into the HHMP-Si-CC. HHMP-Si-CC should have potential applications for preparing more environmentally friendly gradient materials.
Synthesis and Cyclopolymerization of Novel Allyl-Acrylate Quaternary Ammonium Salts
J POLYM SCI POL CHEM
Duygu Avcı
Lon J Mathias
Novel allyl-acrylate quaternary ammonium salts were synthesized using two different methods. In the first (method 1), N,N-dimethyl-N-2-(ethoxycarbonyl)allyl allylammonium bromide and N,N-dimethyl-N-2-(tert-butoxycarbonyl)allyl allylammonium bromide were formed by reacting tertiary amines with allyl bromide. The second (method 2) involved reacting N,N-dialkyl-N-allylamine with either ethyl α-chloromethyl acrylate (ECMA) or tert-butyl α-bromomethyl acrylate (TBBMA). The monomers obtained with the method 2 were N,N-diethyl-N-2-(ethoxycarbonyl)allyl allylammonium chloride, N,N-diethyl-N-2-(tert-butoxycarbonyl)allyl allylammonium bromide, and N,N-piperidyl-N-2-(ethoxycarbonyl)allyl allylammonium chloride. Higher purity monomers were obtained with the method 2. Solution polymerizations with 2,2′-azobis(2-amidinopropane) dihydrochloride (V-50) in water at 60–70°C gave soluble cyclopolymers which showed polyelectrolyte behavior in pure water. Intrinsic viscosities measured in 0.09M NaCl ranged from 0.45 to 2.45 dL/g. 1H- and 13C-NMR spectra indicated high cyclization efficiencies. The ester groups of the tert-butyl polymer were hydrolyzed completely in acid to give a polymer with zwitterionic character. © 1999 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 37: 901–907, 1999
Photoinitiators with Functional Groups. Part IV. Water-Soluble Photoinitiators Containing Quaternary Ammonium Groups
Article
Simone Knaus
H. F. Gruber
The syntheses and properties of a series of new water-soluble hydroxyalkylphenone-based photoinitiators (PIs) for UV curing of water-borne systems is described. By reaction of tosyl- (2), chloro- (3), and dimethylamino- (4) derivatives of the commercially available PI 2-hydroxy-1-[4-(2-hydroxy-ethoxy)phenyl]-2-methylpropan-1-one (1, Darocur 2959) with tertiary amines and halogenides, respectively, PIs containing quaternary ammonium groups exhibiting high water solubility were obtained. Preliminary photocalorimetric tests of the activity demonstrated excellent efficiencies for the PIs in a commercial water-based acrylate formulation, exceeding the photoactivity of the reference PI (1) substantially.
Cyclopolymerization of ether dimers of α-(hydroxymethyl)acrylic acid and its alkyl esters: substituent effect on cyclization efficiency and microstructures
POLYMER
Takashi Tsuda
Lon J Mathias
Free-radical cyclopolymerization of six ether dimers of α-(hydroxymethyl)acrylic acid and its alkyl esters was kinetically investigated to evaluate the factors that control the cyclopolymerizability. A strong effect of ester substituent on cyclopolymerizability was observed and cyclization efficiency at 80°C increased in the following order: methyl, ethyl, isobornyl, t-butyl and adamantyl esters. That is, cyclization efficiency is found to be affected by the number of carbons linked to the central ester carbon (which defines the ‘effective’ bulkiness) rather than by the ‘apparent’ bulkiness, which encompasses the total mass or size of the whole substituent. Kinetic considerations of the temperature dependence of cyclization efficiency indicated that a strong contribution of the steric factor for bulky substituents (which inhibits intermolecular monomer addition) resulted in high cyclization efficiency despite a disadvantage in activation energy for cyclization. A linear relationship between the difference of activation energies (Ec − Ei) and the logarithm of the ratio of collision frequency factors () observed for various esters led to recognition of an iso-efficiency point at which all esters show the same cyclization efficiency ( at −45°C). This phenomenon is caused by the fact that both parameters change in proportion to the bulkiness of the ester substituent. The ether dimer of α-(hydroxymethyl)acrylic acid showed unexpectedly high cyclization efficiency (intermediate between secondary and tertiary esters) despite having the lowest substituent bulkiness. The kinetic parameters obtained showed some deviation from the linearity observed for the ester derivatives. The large obtained was attributed to the capability of hydrogen-bond formation between acid groups, which causes a favourable conformation for cyclization. Microstructures of the cyclopolymers were investigated by observation of carbonyl carbon peaks in the 13C nuclear magnetic resonance spectra. The peaks observed were assigned to four microstructures based on the combination of trans/cis configuration of the tetrahydropyran ring and racemic/meso configuration between the rings. Both the trans and racemic ratios increased with the bulkiness of the ester substituent. The values of Ecis − Etrans and for the t-butyl ester cyclopolymer indicated that trans formation is slightly favourable in both activation energy and steric factor, a result similar to that reported for the racemic/meso ratio in radical polymerization of some alkyl methacrylates. On the other hand, racemic formation between rings was suggested to be sterically unfavourable by the . The glass transition temperatures for the cyclopolymers were found to be much higher than for the corresponding acrylates or methacrylates, and the thermal stabilities of some of the derivatives, especially the adamantyl compound, were also high.
Thermal degradation behavior of radiation synthesized polydiallyldimethylammonium chloride
Jun 2007
EUR POLYM J
Sanju Francis
Lalit Varshney
Sunil Sabharwal
Thermogravimetric analysis (TGA) and differential scanning calorimetric (DSC) studies were carried out on gamma radiation synthesized polydiallyldimethylammonium chloride (PDADMAC). The polymer was found to undergo thermal degradation in two stages. The first stage showed a weight loss of 33% and the second stage showed a weight loss of 67%. The DSC thermogram shows two endothermic peaks corresponding to the two stages in the TG thermogram and the experimental enthalpy change associated with the first and second stages were 650Jg−1 and 129.5Jg−1, respectively. The nth-order kinetic parameters (order of the reaction, activation energy and the pre-exponential factor) were determined from a single dynamic DSC or thermogravimetric (TG) thermogram by the method of least square. Theoretical TG/differential thermogravimetric (DTG) and DSC thermograms derived from the calculated kinetic parameters were in good agreement with the experimental ones at the heating rate employed. However, the kinetic parameters determined using TG and DSC were different. This leads to the conclusion that the degradation mechanism could be complicated and may consists of a number of parallel or consecutive reactions. The glass transition temperature (Tg) of the polymer was found to be around 150°C depending on the test method employed.
Photoinitiators with functional groups. III. Water-soluble photoinitiators containing carbohydrate residues
Apr 1995
J POLYM SCI POL CHEM
Simone Knaus
H. F. Gruber
A series of new water-soluble photoinitiators (PIs) for UV curing of water-borne systems was synthesized by covalent bonding of carbohydrate residues such as D-glucose, sucrose, maltose, 1-amino-D-sorbitol and D-gluconicacid-δ-lactone to the commercially available PI 2-hydroxy-1-[4-(2-hydroxy-ethoxy)phenyl]-2-methylpropan-1-one (Darocur 2959) (1). In addition, new functional derivatives of 1 containing tosyl- or chloride residues as well as primary or secondary amino groups were prepared. Preliminary photocalorimetric tests of the activity demonstrated excellent efficiencies of the PIs in a commercial water-based acrylate formulation exceeding the photoactivity of the reference PI (1) substantially. © 1995 John Wiley & Sons, Inc.
Cyclocopolymerization of allyl-acrylate quaternary ammonium salts with diallyldimethylammonium chloride
Mar 2001
J POLYM SCI POL CHEM
Duygu Avcı
Katina Lemopulo
Lon J Mathias
A series of copolymers of N,N-dialkyl-N-2-(methoxycarbonyl)allyl allyl ammonium chloride, N,N-dialkyl-N-2-(ethoxycarbonyl)allyl allyl ammonium chloride, and N,N-dialkyl-N-2-(t-butoxycarbonyl)allyl allyl ammonium bromide with diallyldimethylammonium chloride (DADMAC) were prepared in water at 60 °C with 2,2′-azo-bis(2-amidinopropane)dihydrochloride. A strong effect of ester substituents on cyclopolymerization was observed. The methyl and ethyl ester monomers showed high cyclization efficiencies during homopolymerizations and copolymerizations. Unexpectedly, the t-butyl ester derivatives showed high crosslinking tendencies. Water-soluble copolymers were obtained only with a decrease in the molar fraction of t-butyl ester monomer below 30%. Relative reactivities of the allyl-acrylate monomers in photopolymerizations were compared with the relative reactivity of DADMAC. Allyl-acrylate monomers were much more reactive than DADMAC; the photopolymerization rate decreased in the following order: N,N-morpholine-N-2-(t-butoxycarbonyl)allyl allyl ammonium bromide > N,N-piperidyl-N-2-(t-butoxycarbonyl)allyl allyl ammonium bromide > N,N-dibutyl-N-2-(ethoxycarbonyl)allyl allyl ammonium chloride > N,N-piperidyl-N-2-(ethoxycarbonyl)allyl allyl ammonium chloride ∼ N,N-morpholine-N-2-(ethoxycarbonyl)allyl allyl ammonium chloride ∼ N,N-piperidyl-N-2-(methoxycarbonyl)allyl allyl ammonium chloride > N-methyl-N-butyl-N-2-(ethoxycarbonyl)allyl allyl ammonium chloride. Intrinsic viscosities of the polymers measured in 0.09 M NaCl ranged from 1.06 to 3.20 dL/g. The highest viscosities were obtained for copolymers of the t-butyl ester monomers with piperidine and morpholine substituents. The copolymer of the t-butyl ester with piperidine substituent and DADMAC was hydrolyzed in acid to give a polymer with zwitterionic character. © 2001 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 39: 640–649, 2001
Photoinitiated Polymerization: Advances, Challenges, and Opportunities
Article
| https://www.researchgate.net/publication/368488229_A_cyclopolymerizable_doubly_Irgacure_2959_functionalized_quaternary_ammonium_salt_photoinitiator_and_its_water_soluble_copolymer_with_diallyldimethylammonium_chloride |
Whistleblower cites Twitter's security concerns before US Senate
Peiter 'Mudge' Zatko accused the social media giant of violating the terms of a federal settlement by falsely claiming to protect the security and privacy of its users.
Whistleblower cites Twitter's security concerns before US Senate
Peiter 'Mudge' Zatko accused the social media giant of violating the terms of a federal settlement by falsely claiming to protect the security and privacy of its users.
Twitter whistleblower Peiter Zatko testifies to a Senate Judiciary hearing examining data security at risk, Tuesday, September 13, 2022, in Washington. JACQUELYN MARTIN / AP
The former security chief at Twitter told Congress that the social media platform is plagued by weak cyber defenses that make it vulnerable to exploitation by "teenagers, thieves and spies" and put the privacy of its users at risk. Peiter "Mudge" Zatko, a respected cybersecurity expert, appeared before the Senate Judiciary Committee to lay out his allegations on Tuesday, September 13.
"I am here today because Twitter leadership is misleading the public, lawmakers, regulators and even its own board of directors," Mr. Zatko said as he began his sworn testimony.
Among his most serious accusations is that Twitter violated the terms of a 2011 FTC settlement by falsely claiming that it had put stronger measures in place to protect the security and privacy of its users.
"They don’t know what data they have, where it lives and where it came from and so, unsurprisingly, they can’t protect it," Mr. Zatko said. "It doesn’t matter who has keys if there are no locks." Mr. Zatko said "Twitter leadership ignored its engineers," in part because "their executive incentives led them to prioritize profit over security."
His message echoed one brought to Congress against another social media giant last year, but unlike that Facebook whistleblower, Frances Haugen, Mr. Zatko hasn't brought troves of internal documents to back up his claims.
Slow tackling of privacy violations
Senator Dick Durbin, an Illinois Democrat who heads the Judiciary Committee, said Mr. Zatko has detailed flaws "that may pose a direct threat to Twitter’s hundreds of millions of users as well as to American democracy." "Twitter is an immensely powerful platform and can’t afford gaping vulnerabilities," he said.
Unknown to Twitter users, there’s far more personal information disclosed than they – or sometimes even Twitter itself – realize, Mr. Zatko testified. He said "basic systemic failures" that were brought forward by company engineers were not addressed. The FTC has been "a little over its head", and far behind European counterparts, in policing the sort of privacy violations that have occurred at Twitter, Mr. Zatko said.
Mr. Zatko's claims could also affect Tesla billionaire Elon Musk's attempt to back out of his 44-billion-dollar deal to acquire the social platform. Mr. Musk claims that Twitter has long underreported spam bots on its platform and cites that as a reason to nix the deal he struck in April.
Many of Mr. Zatko’s claims are uncorroborated and appear to have little documentary support. Twitter has called Mr. Zatko’s description of events "a false narrative ... riddled with inconsistencies and inaccuracies" and lacking important context.
Among the assertions from Mr. Zatko that drew attention from lawmakers on Tuesday was that Twitter knowingly allowed the government of India to place its agents on the company payroll, where they had access to highly sensitive data on users. Twitter’s lack of ability to log how employees accessed user accounts made it hard for the company to detect when employees were abusing their access, Mr. Zatko said.
Mr. Zatko also accused the company of deception in its handling of automated "spam bots," or fake accounts. That allegation is at the core of billionaire tycoon Elon Musk’s attempt to back out of his $44 billion deal to buy Twitter.
Mr. Musk and Twitter are locked in a bitter legal battle, with Twitter having sued Mr. Musk to force him to complete the deal. The Delaware judge overseeing the case ruled last week that Musk can include new evidence related to Mr. Zatko's allegations in the high-stakes trial, which is set to start October 17.
Twitter CEO refuses to testify
Senator Charles Grassley, the committee's ranking Republican, said Tuesday that Twitter CEO Parag Agrawal declined to testify at the hearing, citing the ongoing legal proceedings with Mr. Musk. But the hearing is "more important than Twitter’s civil litigation in Delaware," Mr. Grassley said. Twitter declined to comment on Mr. Grassley's remarks.
In his complaint, Mr. Zatko accused Mr. Agrawal as well as other senior executives and board members of numerous violations, including making "false and misleading statements to users and the FTC about the Twitter platform’s security, privacy and integrity."
Mr. Zatko, 51, first gained prominence in the 1990s as a pioneer in the ethical hacking movement and later worked in senior positions at an elite Defense Department research unit and at Google. He joined Twitter in late 2020 at the urging of then-CEO Jack Dorsey.
| https://www.lemonde.fr/en/pixels/article/2022/09/13/whistleblower-cites-twitter-s-security-concerns-before-us-senate_5996830_13.html |
Ramdulal Dey: The Millionaire Bengal Merchant, 1752-1825 – PURONOKOLKATA
রামদুলাল দে, ১৭৫২-১৮২৫ Backdrop Ramdulal Dey, the millionaire Bengal merchant of late 18th and early 19th centuries, was the foremost name in the chronicle of Indo-American maritime trade. Trading in Calcutta was one of the very important mercantile experiences of America during her early phase of modern globalization. They reached Calcutta in 1775, on…
Ramdulal Dey: The Millionaire Bengal Merchant, 1752-1825
Frans Balthazar Solvyns captured this American East Indiaman at anchor in Calcutta harbour in 1794. His painting offers a tantalizing glimpse of America’s forgotten India trade in its prime. Courtesy: Peabody Essex Museum.
রামদুলাল দে, ১৭৫২-১৮২৫
Backdrop
Ramdulal Dey, the millionaire Bengal merchant of late 18th and early 19th centuries, was the foremost name in the chronicle of Indo-American maritime trade. Trading in Calcutta was one of the very important mercantile experiences of America during her early phase of modern globalization. They reached Calcutta in 1775, on the ship Hydra, jointly owned by the Americans and the English. It was a critical time for the newly independent Americans. Being cut off from the West Indies and deprived of their traditional market, they were on the look for a new opportunity for trading. In the context of Napoleonic wars, the opportunity came their way to replace Europe’s East India trade. The wars kept all British ships busy in territorial defense. The European colonial powers were in constant conflict around Indian and Atlantic oceans. America, being a neutral nation, held a strategic position to exploit seaborne trading across troubled seas.American’s trade with British India began to grow extensively from 1790. In an average America sent 30 to 50 ships annually to Calcutta only. As it was estimated in 1806, within some years America had imported goods from Calcutta worth of at least three millions of dollars. ‘Calcutta was the most active Indian port for their commerce. Americans in India never established a commercial house as they did in China. Nor did they use the European agency houses. Instead they made use of the services of the banians, or the Indian brokers. With East India Company background, the banians at Calcutta were already reputed professionals. A small number of banians took advantages of the situation and became specialists in the American trade. Ramdulal Dey, Asutosh Dey and Promathanath Dey, Rajindra Datta, Kalidas Datta, Rajkrishna and Radhakrishana Mitra, Ramchandra Banarjee, Kalisankar and Durgaprasad Ghose were some of the early banians who carried on big business in Calcutta with the Americans. Among them Ramdulal Dey was the first and most famous banian connected with the American trade.
Early Life
Ramdulal Dey was also known as ‘Ramdulal Sarkar’, ‘ Sarkar’ being a honorific title used in his family. Ramdulal also wore a compound surname ‘ DeSarkar’ combining his hereditary title and the surname, comparable with the DeSarkars– common in some parts of eastern India. In intimate circles Ramdulal was better known by his sobriquet ‘Dulal’, ‘Doolal’ or ‘Dolloll’. In later years when he married his grandson off to a girl of higher caste, Ramdulal changed his family surname ‘Dey’ or its variant ‘De” into Brahmin sounding honorific ‘Deb’. (See Huttum /Kaliprasanna Singha)
Ramdulal De
Ramdulal Dey, alias Dulal Sarkar was the eldest son of Balaram Sarkar, a poor villager of Rekjani, a hamlet near Dumdum. His only occupation was to impart Bengali writing skill to the children of the peasants backed by his rudimentary knowledge of Bengali and the gifted skill in calligraphic art he had. During the Mahratta invasion of 1751-52, Balaram with his expectant wife fled from his ancestral home for good. On their way, Ramdulal was born and began his journey of life with empty hands. Balaram, before he died, could give him nothing, not even rudiments of his own vernacular to his child. Ramdulal had already lost his mother. It was his maternal grandfather, Ramsundar Biswas who took the orphan boy to Calcutta where he lived ‘upon the fruits of beggary’, and his wife used to husk rice for the market until she could secure a stable job of a cook in the house of a wealthy merchant at Hatkhola. She brought in her grandson, Dulal, to stay with her. The master of the house, Madanmohan Dutta, Dewan of Export Warehouses, ‘the rival in wealth of Rajah Navokrishna’, did not mind adding Ramdulal to the long list of his dependents. Here Ramdulal managed to receive his first lessons from the pundit engaged for the sons of his master. He had only to buy erasable palm leaves for mastering alphabets, and plantain leaves for copying texts. His will and energy made him soon an excellent penman and a fast accountant. He also picked up by then some broken English.Madanmohan must have found in Ramdulal his qualities before offering him the job of Bill Sarkaron a salary of Rs 5/- a month. ‘Even out from this contemptible amount he contrived by rigid parsimony to save as much as a hundred rupees’, which he invested in a timber depot at Bagbazarwith the purpose of helping his grandpa. Being much impressed with these admirable traits in the character of his young protégé, Madanmohan promoted Ramdulal to Ship Sarkaron pay of 10 rupees a month, ‘with lots of buxies, alternated of course by blows from ship captains, mates and crew.’ In all weathers, he was to go out into the mouth of the river at Diamond Harbour to superintendent the loading and unloading and discharge of cargo. After Khejuri Diamond Harbourwas the place of anchorage for foreign vessels. In one of his trips he chanced to see a foundering vessel with full cargo close to the mouth of the Hooghly. Out of habit Ramdulal assess the nature of the wreck, cost of recovery and its worth.After a short while, Ramdulal was sent to attend an auction at Tulloh and Companyfor certain items to buy. Sadly, all those items were sold out before Ramdulal stepped in. Right that moment, the auctioneer was lustily crying up a wreck – an item out of their next lot. The wreck was no other than the one Ramdulal had recently witnessed. He was tempted to bid with his master’s money. His bid, perhaps the only bid, was accepted. Ramdulal bought the wreck paying fourteen thousand rupees out of his master’s money. Before he left the place, an English gentleman rushed to him insisting on reselling the ship to him. After a long-drawn haggling the Englishman stumped out handsomely and got the sale transferred in his favour.
Diamond Harbour Cargo Ships Courtesy: Alamy
Back to his master, Ramdulal narrated the whole sequence before he humbly handed over to him the entire resale amount of nearly a lakh of rupees. His master, one of the progenitors of the Nimtala Duttas, had a princely soul. He blessed the boy – so unlike the world, so Roman in his honesty, and said, “Ramdoolal, the money is yours … you sowed the seed and you shall reap the harvest.” It was a treasure to a sarkarof 10 rupees a month. The windfall gift made up the working capital for his business venture that made him exceedingly rich and one of the richest in Calcutta during the lifetime of Madan Dutta. Ramdulal, however, never missed the occasion of receiving from his master his ten-rupee stipend and his blessings on pay days.
Banian of American Merchants
Launching of Merchant Ship at Old Fort ghat Calcutta. c.1798. Artist Francis Balthazar. Courtesy: PEM
In no time Ramdulal made a fortune by careful investment and good luck. During growth of consignment trade and agency houses, he was attached to Fairly Fergusson & Company as their banianagent. At the same time he worked independently for other traders, equipped with his outstanding negotiation skills, market intelligence, and his all-round support service, including, establishing local market connections, organizing dadnymerchants, market promotion, and financial assistance as well. He was on great demand. His cooperation was also sought by all British agency houses. Ramdulal partnered with the American traders rather than the European companies or English private merchants. Apart maritime trade, Ramdulal had active interest in stocks and shares, and real estates. The genius of Ramdulal, according to his biographer, could transform dross into gold. However, he owed his earthly prosperity mostly to the American merchants whom he served as their local agent, and also invested his own capital with them. American merchants used his credit in their coasting trade in the Bay of Bengal region and shared profit with Ramdulal.
From 1790 American trade with British India grew fast. Mostly the merchant houses of Boston, Salem, Beverly, Philadelphia, Providence, Marblehead, Yankee and New York sent their ships regularly to buy Bengal goods. Every house had its own baniansstationed in Calcutta.
Scene along the Salem waterfront c.1770-80 Courtesy: PEM
Annually 30 to 50 ships sailed to Calcutta, carrying cargo of dollars, iron, lead, brandy, Madeira and other wines, fish, spermaceticandles, mackerel, beef, beer, ice, variety of Europeans articles, tar, large and small spars. On their return the ships took varied types of Bengal goods, including tea, sugar, indigo, linseed, saltpeter, gunny bags, and most importantly, textiles. Many advertisements included lists of Indian textiles, such as bafta, gurrah, mamoody, and bandannaas well as names of the towns, like Alliabad, Dacca, Gaurypore, etc. where the cloths were made. ‘Every housewife in Salem knew the difference between gurrahsand mamoodies’. Of all the textiles exported to America, white cotton goods were by far the most common, although printed and dyed cottons, silk goods, especially handkerchiefs, mixed silk, cotton goods, and woollen shawls were also important. [See Bean] As recorded, the total American trade for the ten-year period beginning from 1795/6 exceeded by about one-fourth that carried on under the flags of all overseas partners including European nations. [See: Islam, ‘Yankee Maritime’]
The Americans carried on the bulk of their trade through the Indian brokers. It was not simply because of economic reasons they did it, but for the strategic advantage of having the highly competent and experienced Calcutta baniansby their side.
Calcutta Banians (clay models) Courtesy: Peabody Museum
The early Americans had treated the Indians with informality, humour and respect. Ramdulal Dey was the most prominent among them, and became a household name among the contemporary American business houses. He exhibited the greatest activity and fascination in alluring the trade of the America to the horbours of Bengal. The bulk of American business passed through Ramdulal’s hands. He came to be quoted as an authority in American commercial circles. So great was the confidence which his constituents in the new hemisphere reposed on his ability and his integrity, that for the first time in the history of Indian commerce, the merchants of America dispensed with European Agents in Bengal altogether. [See: Grish]
The extent of Ramdual Dey’s American connection may be guessed from the array of merchants of whom he was the sole agent in Bengal. The list found from the books of the period immediately following his death.
BOSTONG.R. Minot, G. Warren, J.Young, J.S. Amory, T. Wigglesworth, J.I. Coleridge,H. Irving, J.J. Bowditch, B.Rich and Son, E. Rhodes, F.W. Everitt, W. Godard,Mackie and coleridge, H.Lee, O. Godwin, Theuring and Perkins.NEW YORKMessrs. Lennox & sons, G.S. Higginson, Messrs. C & D. Skinner, Messrs.Singleton & Mezick, S. Austin Junior, W.C. Appleton, E.B. Crocker, E.Davies, J.J. Dixwell, W.A. Brown, A. Baker junior, G. Brown. T.C. Bacon, M.Curtis, Baring Brothers
PHILADELPHIAMessrs. Grant & Stone.
SALEMPickering Dodge, W. London
NEWBERRYThe Hon’ble E.S. Rant, J.H. Telcombe.
MARVELHEAD.J. Hooper
One of the American merchants fondly dedicated a vessel to ‘ Ram Dolloll’ and named after him. The vessel sailed carrying Ramdulal’s consignment to Calcutta thrice during his lifetime. Among the ships he owned, Kamala, and Vimalawere named after his two daughters, and the ship ‘ David Clerk’ was named after one his American business partners and a personal friend.
Salem Harbor. Originally served as a sign over the door of the first East India Marine Hall. Oil. 1803. Courtesy: PEM
American trade brought about ‘a new dimension to the cultural and commercial milieu of the city’. The American way of conducting the business helped in fostering some sort of cultural intercourse between Bengal and America. The Peabody Museum, Salem and the Essex institute in Massachusetts still hold nine portraits of baniansin their collections are the potent survivors of such relationships. The portraits were commissioned by the baniansfor presentation to the Americans and business associates. The practice of commissioning and exchanging portraits is a tantalizing indication of cordial relationships as between equals. ‘In 1801 twenty-two American merchants in gratitude presented a life-sized oil on canvas, the first portrait of George Washington by William Winstanley . . . to their banianRamdoolal Dey under whose guidance they had all prospered in the Bengal trade.’ [See: Bean]
Rags to Riches
The illustrious shipping magnet may serve as a striking example of ‘vertical mobility’ from poverty to wealth. Like two contemporaries, Akrur Dutta, and Krishnakanta Nandy (1720-95), Ramdulal rose to eminence from humble and obscure origins. Ramdulal Dey, the millionaire of the early 19th century, left estates worth of Rs 33,01,424 of which the Calcutta and suburban properties accounted for Rs 6,17,750, yielding an annual rent of Rs 25,314 (1825-26). By contrast the rural properties, all close to Calcutta, were worth only Rs 58,5000. He also left behind sundry promissory notes of the Hon’ble Company, shares in various insurance companies, sundry bonds mainly from Europeans, sundry bills including China supercargoes bill, notes from Rustomji Turner & Company, Davidson & Company, Palmer & Company, etc; ship David Clerk, shares in Sauger Island Society; and balances due from different companies. When one of the two sons of Ramdulal Dey died in 1854 his estates in Calcutta were worth Rs Rs 3,62,862 and the value of his zamindariproperties was more than Rs 2,00,000. The proportion of zamindariproperties to urban real estate demonstrated a substantial increase in one generation.
Ramdulal had a noble heart and a humanitarian mindset. His charity was proverbial. He liberally donated for the cause of education and social welfare unquestioningly. He was a benefactor to the greatest educational institution of early colonial Calcutta, the Hindu College. Ramdulal was ready to extend help to suffering humanity anywhere; He had sent donations to the flood and famine victims in Bakhargunge, Madras, and as far as in Ireland. Ramdulal established ‘ Atithisala’ an asylum for the destitute in Belgachia. At Beneras, he erected 13 Shiva temples. For sanctification of the temples alone Ramdulal spent around Rs 2,22,000. Besides, public charity, Ramdulal in private helped the poor and needy in many ways. He kept aside Rs 70 a day for the relief of distressed persons. He employed three physicians for visiting the poor patients to administer medicines and provide medical comforts at his expense.
End of Journey
Ramdulal was a pious man. In spite of being fabulously wealthy he lived a simple life. The only regret he had, that his ambition for ‘ Gostopati’ or the community leader of the Kayastha samajremained unfulfilled. Ramdulal and his adversary, Raja Nabakrishna, were engaged in constant wrangling, backed up by their respective bands of supporters, বাবুর দল ( Babur Dawl) and রাজার দল ( Rajaar Dawl), where bards, jesters, and common citizens took part. The power struggle between the leaders also encouraged local talents to compose street music, street plays, cartoons etc. contributing to urban folk art and literature of lasting entertainment value and historical significance.Ramdulal breathed his last on April 1, 1825. His two sons, Asutosh, and Pramathanath, famously known as ‘ Chhatu Babu‘, and ‘ Latu Babu‘, respectively, performed the ‘ Sradh’ ceremony of their father with unprecedented grandeur spending nearly five lakhs of Rupees. Asutosh alias Chhatu Babu, himself a musician, was one of the leading connoisseurs and patrons of classical music. His nach gharwas famed for the performance of the celebrated musicians and dancers of the country. The family maintains the cultural tradition till now. Because of their social graces, Asutosh and Pramathanath, noted for their largesse, were called as the ‘ Babus of Bengal’. The epithet highlights their refined taste, affluence and extravagance. The two brothers kept up the social and cultural status to a large extent, but not the level of prosperity Ramdulal had passed on to them. The vast wealth of Ramdulal Dey was rapidly dwindled down due to many a reason. With the failure of Union Bank in 1848, the condition of Banians declined in all respect, and Deys were no exception. Their unfortunate commercial speculations and land investments were among the other reasons, besides the extravagance of his successors who frenziedly pursued their fads and hobbies as well as their noble craze for the performing arts. The house of Ramdulal Dey and his sons, delinked with its eventful past, remains a glorious centre of patronage of classical music and stage art in Bengal.
SELECT REFERENCE LIST Bean, Susan S,’Calcutta Banians for the American Trade: Portraits of Early Nineteenth-Century Bengali Merchants in the Collections of the Peabody Museum, Salem and Essex Institute’, Bombay 1990. – ‘The American Market for Indian Textiles, 1785-1820: In the Twilight of Traditional Cloth Manufacture’, Peabody Museum of Salem, 1990. Chakrabarti,Ranjan, ‘The Brown ships in the Indian Ocean: The American Merchants and the Bengali Banians 1790-1880’, in Business history of India, Kalpaz, Delhi, 2006. Chakrabarti, Shubhra, ‘Collaboration and Resistance: Bengal Merchants and the English East India Company, 1757-1833,’ Studies in History, 1994, vol. 10, No. 1. Chaudhuri,Sushil, ‘European Companies and Pre-modern South Asian Commercial System- A study of Bengal in the Eighteenth Century’, Calcutta Historical Journal, XI: 1-2 (1986-87). Ghose, Benoy, ‘Some Old Family Founders in 18th Century Calcutta’, Bengal Past and Present, Vol. 79, No. 147, 1960 +Ghosh, Grish. C., Ramdulal Dey: The Bengali Millionaire, Calcutta, 1868. Islam, Sirajul, ‘Americans in Calcutta Bazaars in the Early Nineteenth Century: Images and Interpretations’, Journal of the Asiatic Society of Bangladesh, Golden Jubilee Volume (1956-2005), 2005. *Rahman, Murshida Bintey, Banians in the Bengal economy, 18th and 18th century. Dacca University. 2013 Roy, Tirthankar. What is modern and Indian about the business history [ Book review] LSEPS, 2015 Verny, Michael A, ‘An Eye for Prices, an Eye for Souls: Americans in the Indian Subcontinent, 1784-1838.’ Journal of the Early Republic 33: 3 (2013) * Used extensively in this write up. + Courtesy : Dr Alok Ray for providing access and help
| https://puronokolkata.com/2016/09/07/ramdulal-dey-the-millionaire-bengal-merchant-1752-1825/?like_comment=9420&_wpnonce=d7e9afae15 |
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User Manual for 2measure models including: 230009 Digital Terrarium Thermometer And Hygrometer, 230009, Digital Terrarium Thermometer And Hygrometer, Terrarium Thermometer And Hygrometer, Thermometer And Hygrometer
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INSTRUKCJA OBSLUGI ELEKTRONICZNY TERMOMETR I HIGROMETR DO TERRARIUM
USER MANUAL ELECTRONIC THERMOMETER AND HYGROMETER FOR TERRARIUMS
BEDIENUNGSANLEITUNG DIGITALES INNEN- / AUßENTHERMOMETER FÜR TERRARIUM
NOTICE D'UTILISATION THERMOMETRE ELECTRONIQUE ET HYGROMETRE POUR TERRARIUMS
NAUDOJIMO INSTRUKCIJA ELEKTRONINIS TERARIUMO TERMOMETRAS IR DRGMMATIS
LIETOSANAS PAMCBA ELEKTRONISKAIS TERMOMETRS TERRIJAM
KASUTUSJUHEND ELEKTROONILINE TERMOMEETER JA HÜGROMEETER TERRAARIUMI JAOKS
NÁVOD K OBSLUZE ELEKTRONICKÝ TEPLOMR A VLHKOMR DO TERRARIA
INSTRUCIUNI DE UTILIZARE TERMOMETRU ELECTRONIC I HIGROMETRU DE TERARIU
NÁVOD NA POUZITIE DIGITÁLNY TEPLOMER A VLHKOMER DO TERRARIA
INSTRUKTIONSMANUAL DIGITAL TERMOMETER OCH HYGROMETER FÖR TERRARIUM
*zdjcie pogldowe / pictorial photo
No 230009
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INSTRUKCJA OBSLUGI ELEKTRONICZNY TERMOMETR I HIGROMETR DO TERRARIUM
Ta instrukcja jest czci produktu i powinna by przechowywana w sposób umoliwiajcy zapoznanie si z jej treci w przyszloci. Zawiera istotne informacje o ustawieniach i pracy urzdzenia.
Pomiar temperatury wewntrz pomieszcze (32 F - 122 F/0 C - 50 C) Pomiar wilgotnoci wewntrz pomieszcze (20% - 99%) Ergonomiczna przyssawka zaokienna ulatwiajca przymocowanie sondy Zasilanie bateri DC 3V typ AG10 lub LR1130 Bateria zalczona w zestawie Dokladno ±1 C i ±5% Przycisk C/F sluy do zmiany jednostki wywietlanej temperatury Przycisk MIN/MAX sluy do wywietlenia minimalnej i maksymalnej zanotowanej temperatury Przycisk reset sluy do wyczyszczenia wszystkich dotychczas zanotowanych parametrów
Uwaga!
Kade gospodarstwo jest uytkownikiem sprztu elektrycznego i elektronicznego, a co za tym idzie potencjalnym wytwórc niebezpiecznego dla ludzi i rodowiska odpadu, z tytulu obecnoci w sprzcie niebezpiecznych substancji, mieszanin oraz czci skladowych. Z drugiej strony zuyty sprzt to cenny material, z którego moemy odzyska surowce takie jak mied, cyna, szklo, elazo i inne.
Symbol przekrelonego kosza na mieci umieszczany na sprzcie, opakowaniu lub dokumentach do niego dolczonych oznacza, e produktu nie wolno wyrzuca lcznie z innymi odpadami. Oznakowanie oznacza jednoczenie, e sprzt zostal wprowadzony do obrotu po dniu 13 sierpnia 2005 r. Obowizkiem uytkownika jest przekazanie zuytego sprztu do wyznaczonego punktu zbiórki w celu wlaciwego jego przetworzenia. Informacje o dostpnym systemie zbierania zuytego sprztu elektrycznego mona znale w punkcie informacyjnym sklepu oraz w urzdzie miasta/gminy. Odpowiednie postpowanie ze zuytym sprztem zapobiega negatywnym konsekwencjom dla rodowiska naturalnego i ludzkiego zdrowia!
USER MANUAL ELECTRONIC THERMOMETER AND HYGROMETER FOR TERRARIUMS
This instruction constitutes a part of the product and should be stored in a manner allowing to read its contents in the future. It contains significant information on the setting and operation of the device.
Indoor temperature measurement (32 F to 122 F/0 C to 50 C) Indoor humidity (20% to 99 %) Ergonomic window suction cup for attaching the probe easily Power source: DC 3V battery type AG10 or LR1130 Battery included in the kit Accuracy ± 1 C C/F button for changing the displayed temperature unit MIN/MAX mutton for displaying the minimum and maximum recorded temperatures Reset button for clearing all previously recorded parameters
Caution!
Every household uses electrical and electronic appliances, and thus is a potential source of waste, hazardous to humans and the environment, due to the presence of hazardous substances, mixtures, and components in the equipment. On the other hand, discarded equipment is a valuable resource from which raw materials like copper, tin, glass, iron, and others can be recovered.
The symbol of the crossed out wheelie bin placed on the equipment, packaging, or documentation attached to it, means that the product must not be disposed of together with other waste. The labelling simultaneously means that the equipment was introduced to the market after the date of August 13th, 2005. It is the responsibility of the user to transfer the used equipment to a designated collection point for proper recycling. Information on the available collection system for electrical equipment can be found in the shop's information and at the municipal office. Proper handling of discarded equipment prevents negative consequences for the environment and human health!
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BEDIENUNGSANLEITUNG DIGITALES INNEN- / AUSSENTHERMOMETER FÜR TERRARIUM
Diese Bedienungsanleitung ist Bestandteil des Produkts und soll so aufbewahrt werden, dass man den Inhalt auch in Zukunft lesen kann. Sie enthält wichtige Informationen über die Einstellungen und den Betrieb des Gerätes. Temperaturmessung in Innenräumen (32 F - 122 F/0 C - 50 C) Temperaturmessung in Außenräumen (20% - 99%) Ergonomischer Saugnapf für den Fensteraußenrahmen, der die Befestigung der Sonde erleichtert. Versorgung mittels einer DC 3V-Batterie Typ AG10 oder LR1130 Batterie im Set enthalten Genauigkeit ±1 C und ±5% Die Taste C/F dient zum Wechsel der angezeigten Temperatureinheit Die Taste MIN/MAX dient zur Anzeige der minimalen und maximalen verzeichneten Temperatur Die Taste Reset dient zum Löschen aller bisher verzeichneten Parameter.
ACHTUNG!
Jedes Haushalt ist Benutzer der elektrischen und elektronischen Geräte, und was danach folgt der potenzielle Erzeuger der gefährlichen für die Menschen und die Umwelt Abfälle, aus dem Titel des Anwesenheit in den Geräten der gefährlichen Substanzen, Mischungen und Bestandteile. Von der zweiten Seite ist das verbrauchte Gerät das wertvolle Material, aus dem wir solche Rohstoffe wie Kupfer, Zinn, Glas, Eisen und andere Rohstoffe gewinnen können.
Dieses Symbol, das auf dem Gerät, Verpackung oder den beigefügten Unterlagen untergebracht wird, bedeutet, dass das gekaufte Produkt nicht zusammen mit den gewöhnlichen Abfällen aus dem Haushalt beseitigt sein soll. Die Kennzeichnung bedeutet gleichzeitig, dass das Gerät zum Umsatz nach dem 13. August 2005 eingeführt worden ist. Die Pflicht des Benutzers ist, es in die entsprechende Stelle abgeben, die sich mit der Sammlung und Recycling der elektrischen und elektronischen Geräten beschäftigt. Informationen über das zugängliche System der Sammlung der verbrauchten elektrischen Geräte kann man im Informationspunkt des Geschäfts und im Amt der Stadt/der Gemeinde finden. Die Beseitigung der Geräte auf die richtige Weise und ihr Recycling helfen gegenüber den potentiell negativen Folgen für die Umwelt und menschliche Gesundheit.
NOTICE D'UTILISATION THERMOMETRE ELECTRONIQUE ET HYGROMETRE POUR TERRARIUMS
Cette notice fait partie du produit et doit être conservée de manière à vous permettre de lire son contenu ultérieurement. Elle contient des informations importantes sur les paramètres et le fonctionnement de l'appareil.
Mesure de la température intérieure (32 F - 122 F/0 C - 50 C) Mesure de l'humidité intérieure (20% - 99%) Ventouse ergonomique pour une fixation facile de la sonde Alimentation avec pile DC 3V - type AG10 ou LR1130 Pile fournie Précision ±1 C et ±5%. La touche C/F permet de changer l'unité de la température affichée. La touche MIN/MAX permet d'afficher la température minimale et maximale enregistrée. La touche de réinitialisation permet d'effacer tous les paramètres précédemment enregistrés.
Attention!
Chaque ménage utilise des appareils électriques et électroniques et constitue donc une source potentielle de déchets dangereux pour les humains et l'environnement, en raison de la présence de substances dangereuses, de mélanges et de composants dans l'équipement. D'autre part, l'équipement mis au rebut est une ressource précieuse à partir de laquelle des matières premières comme le cuivre, l'étain, le verre, le fer et d'autres peuvent être récupérées.
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Le symbole de la poubelle barrée sur l'équipement, l'emballage ou la documentation qui y est attachée signifie que le produit ne doit pas être jeté avec les autres déchets. L'étiquetage signifie simultanément que l'équipement a été mis sur le marché après la date du 13 août 2005. Il est la responsabilité de l'utilisateur de transférer l'équipement utilisé à un point de collecte désigné pour un recyclage approprié. Des informations sur le système de collecte disponible pour les équipements électriques peuvent être trouvées dans les informations du magasin et au bureau municipal.
NAUDOJIMO INSTRUKCIJA ELEKTRONINIS TERARIUMO TERMOMETRAS IR DRGMMATIS
Si instrukcija yra gaminio sudedamoji dalis ir ji turi bti saugoma taip, kad bt visada prieinama ir bt galima susipazinti su jos turiniu. Joje pateikiama svarbi informacija apie renginio parametrus ir jo veikimo princip.
Matuoja patalp vidaus temperatr (32 F 122 F / 0 C 50 C) Matuoja patalp vidaus drgn (20 % 99 %) Ergonomiskas siurbtukas, kad bt lengviau zond pritvirtinti uz lango Maitinamas tipo DC 3 V AG10 arba LR1130 baterija Baterija pridedama Tikslumas ±1 C ir ±5 % Mygtukas C/F rodomos temperatros vienetams keisti Mygtukas MIN/MAX uzfiksuotai zemiausiai ir auksciausiai temperatrai rodyti Mygtukas ,,reset" visiems uzfiksuotiems parametrams istrinti
Atsargiai!
Kiekvienas nam kis naudoja elektros ir elektroninius prietaisus, ir tai yra potencialus eikvojimo saltinis, pavojingas zmonms ir aplinkai dl pavojing medziag, misini ir rangos sudedamj dali. Kita vertus, rangoje yra vertingi istekliai, is kurio galima gauti zaliavas, tokias kaip varis, alavas, stiklas, gelezis ir kt.
Simbolis, kuriame pavaizduotas uzbraukta siuksliadz reiskia, kad produktas negali bti salinamas kartu su kitomis buitinmis atliekomis. Etiket reiskia, kad ranga buvo pateikta rink po 2005 m. rugpjcio 13 d. Naudotojo atsakomyb yra perduoti panaudot rang nurodyt surinkimo punkt tinkamam perdirbimui. Informacija apie galim elektros rangos surinkimo sistem pateikiama parduotuvs informacijoje ir savivaldybs biure. Tinkamai ismesta ranga pasalina neigiamas pasekmes aplinkai ir zmoni sveikatai!
LIETOSANAS PAMCBA ELEKTRONISKAIS TERMOMETRS TERRIJAM
S rokasgrmata ir produkta sastvdaa, un t juzglab t, lai ar vlk vartu to izlast. Taj ir svarga informcija par ierces iestatjumiem un darbbu.
Temperatras mrsana iekstelps (32 F - 122 F/0 C - 50 C) Mitruma mrsana iekstelps (20% - 99%) Ergonomisks loga piesceknis rai zondes stiprinsanai Barosana no baterijas DC 3 AG10 tipa vai LR1130 Baterija ietilpst komplekt Precizitte ±1 C i ±5% Poga C/F tiek lietota temperatras mrvienbas atainojuma mainsanai Poga MIN/MAX tiek lietota minimls un maksimls fiksts temperatras atainosanai Poga reset tiek lietota visu ieprieks fiksto parametru dzsanai
Uzmanbu! Ikviena mjsaimniecba izmanto elektrisks un elektronisks ierces un tdjdi ir potencils atkritumu avots, kas ir bstams cilvkiem un videi bstamu vielu, maisjumu un sastvdau kltbtnes d iekrt. No otras puses, nolietots iekrtas ir vrtgs resurss, no kura var atgt izejvielas, piemram, varu, alvu, stiklu, dzelzi un citus. Prsvtrots atkrituma konteinera simbols, kas novietots uz iekrtm, iepakojumiem vai dokumentcijas, nozm, ka
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produktu nedrkst izncint kop ar citiem atkritumiem. Vienlaikus marjums nozm, ka iekrta tika ieviesta tirg pc 2005. gada 13. augusta. Lietotja pienkums ir nodot lietoto aprkojumu noteiktajam savksanas punktam pareizai otrreizjai prstrdei. Informcija par pieejamo elektroiekrtu savksanas sistmu atrodama veikala informcij un pasvaldbas biroj. Nolietots iekrtas piencga apstrde novrs negatvas sekas videi un cilvku veselbai!
KASUTUSJUHEND ELEKTROONILINE TERMOMEETER JA HÜGROMEETER TERRAARIUMI JAOKS
Käesolev juhend on toote osaks. Hoidke see alles, et saaksite selle sisuga ka tulevikus tutvuda. Kasutusjuhend sisaldab teavet seadme seadistamise ja töötamise kohta.
Temperatuuri mõõtmine siseruumis (32 F - 122 F/0 C - 50 C) Niiskusesisalduse mõõtmine siseruumis (20% - 99%) Ergonoomiline iminapp sondi mugavaks kinnitamiseks klaasi külge Patareitoide DC 3 tüüp AG10 või LR1130 Patarei kuulub komplekti Täpsus ±1 C i ±5% Nuppu C/F kasutatakse kuvatava temperatuuri mõõtühiku muutmiseks Nuppu MIN/MAX kasutatakse minimaalse ja maksimaalse fikseeritud temperatuuri kuvamiseks Nuppu reset kasutatakse kõigi eelnevalt fikseeritud parameetrite nullimiseks
Hoiatus!
Iga majapidamine kasutab elektrilisi ja elektroonilisi masinaid ja seega on potentsiaalne inimestele ja keskkonnale kahjulike jäätmete allikas, seda tänu ohtlike ainete, segude ja komponentide olemasolule seademetes. Teisalt on kasutusest kõrvaldatud seadmed väärtuslik allikas, millest võib taaskasutada toormaterjale nagu vask, tina, klaas, raud ja muu.
Läbikriipsutatud jäätmekonteineri sümbol, kui see on märgitud seadmele, pakendile, sellega kaasas olevale dokumentatsioonile, tähendab, et toodet ei tohi jäätmetega koos ära visata. Samal ajal tähendab märgistus ka seda, et seade toodi turule peale 2005. aasta 13. augustit. Kasutaja vastutab seadme transportimise eest kindlaksmääratud kogumispunkti, kus see õigesti ümber töödeldakse. Elektriseadmete kogumissüsteemi kohta võib infot leida poe info hulgast ja omavalitsusest. Kasutusest kõrvaldatud seadmete korrektne käitlemine hoiab ära negatiivsed tagajärjed keskkonnale ja inimeste tervisele!
NÁVOD K OBSLUZE ELEKTRONICKÝ TEPLOMR A VLHKOMR DO TERÁRIA
Tato pírucka je soucástí výrobku a mla by být ulozena zpsobem, který vám umozní pecíst si její obsah v budoucnu. Obsahuje dlezité informace o nastavení a provozu zaízení.
Mení teploty v místnostech (32 F - 122 F/0 C - 50 C) Mení vlhkosti v místnostech (20% - 99%) Ergonomická okenní písavka usnadující upevnní cidla Napájení baterií DC 3V typ AG10 nebo LR1130 Baterie je soucástí sady Pesnost ±1 C i ±5% Tlacítko C/F slouzí ke zmn jednotky zobrazované teploty Tlacítko MIN/MAX slouzí k zobrazení minimální a maximální zaznamenané teploty Tlacítko reset slouzí k vymazání vsech parametr, které byly dosud zaznamenány
Pozor!
Elektrická a elektronická zaízení pouzívaná v domácnostech po jejich doslouzení pedstavují nebezpecný odpad, protoze obsahují nkteré nebezpecné látky, smsi anebo soucásti. Na druhé stran takový odpad slouzí jako zdroj druhotných surovin, ze kterého získává nap. m, cín, sklo, zelezo a dalsí suroviny.
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Symbol peskrtnuté popelnice umístný na zaízení, obalu nebo v návodu znamená, ze tento výrobek poté, co doslouzí, nesmí být vyhozen do bzného odpadu. Toto oznacení zárove znamená, ze takové zaízení bylo uvedeno na trh po 13. srpnu 2005. Uzivatel odpovídá za pedání tohoto zaízení na urcené sbrné místo pro recyklaci. Informace o sbrném systému elektrických zaízení lze zjistit v obchod nebo na obecním úad. Správné tídní odpad chrání zivotní prostedí a lidské zdraví ped negativními dopady!
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(32 F - 122 F/0 C - 50 C) (20% - 99%) DC 3 AG10 LR1130 ±1 C i ±5% C/F MIN/MAX
reset
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INSTRUCIUNI DE UTILIZARE TERMOMETRU ELECTRONIC I HIGROMETRU DE TERARIU
Aceast instruciune este parte component a produsului i trebuie pstrat într-un mod care v permite s citii coninutul acesteia în viitor. Conine informaii importante despre setrile i funcionarea dispozitivului.
Msurarea temperaturii în interiorul încperilor (32 F - 122 F/0 C - 50 C) Msurarea umiditii în interiorul încperilor (20% - 99%) Ventuz ergonomic pentru geam pentru fixarea uoar a sondei Alimentare cu baterie DC 3V tip AG10 sau LR1130 Baterie inclus în set. Precizie ±1 C i ±5% Butonul C/F servete pentru schimbarea unitii de afiare a temperaturii Butonul MIN/MAX servete pentru afiarea temperaturii minime i maxime înregistrate Butonul reset servete pentru tergerea tuturor parametrilor înregistrai pân în prezent
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Atenie!
Fiecare gospodrie utilizeaz aparate electrice i electronice i, prin urmare, reprezint o surs potenial de deeuri, periculoas pentru oameni i mediu, datorit prezenei substanelor, amestecurilor i componentelor periculoase în echipament. Pe de alt parte, echipamentul aruncat este o resurs valoroas din care pot fi recuperate materii prime cum ar fi cuprul, staniul, sticla, fierul i altele.
Simbolul coului de gunoi barat plasat pe echipament, ambalaj sau documentaia ataat acestuia înseamn c produsul nu trebuie aruncat împreun cu alte deeuri. Etichetarea înseamn totdat c echipamentul a fost introdus pe pia dup data de 13 august 2005. Este responsabilitatea utilizatorului s transfere echipamentul uzat într-un punct de colectare desemnat pentru o reciclare adecvat. Informaiile privind sistemul de colectare disponibil pentru echipamentele electrice pot fi gsite la biroul de informaii al magazinului i la biroul municipal. Manipularea corespunztoare a echipamentului aruncat împiedic consecinele negative asupra mediului i sntii umane!
NÁVOD NA POUZITIE DIGITÁLNY TEPLOMER A VLHKOMER DO TERÁRIA
Tento návod na obsluhu tvorí neoddelitenú súcas výrobku, preto by sa mal uchováva tak, aby bol dostupný na pouzitie v budúcnosti. Obsahuje dôlezité údaje o nastaveniach a práci zariadenia.
Meranie teploty v interiéroch (32 F - 122 F/0 C - 50 C) Meranie vlhkosti v interiéroch (20% - 99%) Ergonomická prisavka na sklo pre jednoduché pripevnenie sondy Batéria DC 3V typ AG10 alebo LR1130 Batéria je súcasou dodávky Presnos ±1 C a ±5% Tlacidlo C/F sa pouzíva na zmenu zobrazovanej jednotky teploty Tlacidlo MIN/MAX sa pouzíva na zobrazenie minimálnej a maximálnej zistenej teploty Tlacidlo reset sa pouzíva na vynulovanie vsetkých zistených velicín
Výstraha!
Kazdá domácnos pouzíva elektrické a elektronické zariadenia a je preto potenciálnym zdrojom odpadu, ktorý je nebezpecný pre udí a zivotné prostredie kvôli prítomnosti nebezpecných látok, zmesí a komponentov v danom zariadení. Na druhej strane vyradené zariadenia sú cenným zdrojom, z ktorého mozno získa suroviny ako me, cín, sklo, zelezo a iné.
Symbol preciarknutého kosa, umiestnený na zariadení, obale alebo dokumentácii, ktorá je k nemu pripojená, znamená, ze výrobok sa nesmie likvidova spolu s iným odpadom. Toto oznacenie súcasne znamená, ze zariadenie bolo uvedené na trh po dátume 13. augusta 2005. Je povinnosou pouzívatea likvidova pouzité zariadenie na urcenom zbernom mieste pre správnu recykláciu. Informácie o dostupnom zbernom bode pre elektrické zariadenia vám môzu poskytnú v predajni a na obecnom úrade. Správne zaobchádzanie s vyradeným zariadením zabrauje negatívnym následkom pre zivotné prostredie a udské zdravie!
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(32 F - 122 F/0 C - 50 C) (20% - 99%) 3 AG10 LR1130 ± 1 ° C ± 5% C/F
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MIN/MAX
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INSTRUKTIONSMANUAL DIGITAL TERMOMETER OCH HYGROMETER FÖR TERRARIUM
Den här handboken är en del av produkten och bör sparas för framtida användning. Den innehåller viktig information om inställningar och användning av enheten.
Mätning av inomhustemperatur (32 F - 122 F/0 C - 50 C) Mätning av luftfuktighet inomhus (20 % - 99 %) Ergonomisk rund sugkopp för enkel fastsättning av sonden Strömförsörjning via DC 3V-batteri - typ AG10 eller LR1130. Batteri ingår Noggrannhet ±1 C och ±5 %. C/F-knappen används för att ändra den visade temperaturenheten. MIN/MAX-knappen används för att visa den lägsta och högsta registrerade temperaturen. Återställningsknappen används för att rensa alla tidigare registrerade parametrar.
Uppmärksamhet! Alla hushåll använder elektrisk och elektronisk utrustning och kan därför potentiellt generera avfall som är farligt för människor och miljö på grund av förekomsten av farliga ämnen, blandningar och komponenter i utrustningen. Å andra sidan är avfallsmaskiner ett värdefullt material från vilket vi kan återvinna råvaror som koppar, tenn, glas, järn och andra.
Symbolen med en överkryssad soptunna på utrustningen, förpackningen eller medföljande dokument innebär att produkten inte får kastas tillsammans med annat avfall. Märkningen visar också att utrustningen har släppts ut på marknaden efter den 13 augusti 2005. Det är användarens ansvar att lämna in begagnad utrustning till en utsedd insamlingsplats för korrekt behandling. Information om det tillgängliga insamlingssystemet för begagnad elutrustning finns i butikens informationsdisk och på kommunens kontor. Korrekt hantering av begagnad utrustning förebygger negativa konsekvenser för miljön och människors hälsa!
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WARUNKI GWARANCJI
1. Niniejsza gwarancja jest udzielana przez firm BROWIN Spólka z ograniczon odpowiedzialnoci Sp. k. z siedzib przy ul. Pryncypalnej 129/141; 93-373 Lód, nazywan w dalszej czci gwarancji Gwarantem.
2. Niniejsza gwarancja dotyczy wylcznie sprztu uywanego na terytorium Polski. 3. Okres gwarancji na produkt wynosi 12 miesicy od daty zakupu sprztu. 4. W przypadku wad uniemoliwiajcych korzystanie ze sprztu, okres gwarancji ulega przedlueniu o czas od dnia
zgloszenia wady do dnia wykonania naprawy. 5. Gwarancja uprawnia do bezplatnych napraw nabytego sprztu, polegajcych na usuniciu wad fizycznych, które ujawnily
si w okresie gwarancyjnym, z zastrzeeniem punktu 11. 6. Zgloszenie wady sprztu powinno zawiera:
dowód zakupu towaru; nazw i model towaru wraz ze zdjciami uzasadniajcymi reklamacj. 7. Reklamujcy powinien spakowa produkt, odpowiednio zabezpieczajc go przed uszkodzeniem w czasie transportu. 8. Gwarant w terminie 14 dni od daty zgloszenia wady ustosunkuje si do zgloszonej reklamacji. Jeeli do dokonania naprawy wystpi konieczno sprowadzenia czci zamiennych z zagranicy, termin naprawy moe ulec przedlueniu do czasu sprowadzenia niezbdnej elementów, lecz maksymalnie do 30 dni roboczych od daty otrzymania towaru do naprawy. 9. Gwarancja obejmuje wszelkie wady materialowe i produkcyjne ujawnione w czasie normalnej eksploatacji zgodnie z przeznaczeniem sprztu i zaleceniami podanymi na opakowaniu lub w instrukcji uytkowania. Warunkiem udzielenia gwarancji jest uytkowanie sprztu zgodnie z instrukcj. 10. Zakres czynnoci naprawy gwarancyjnej nie obejmuje czyszczenia, konserwacji, przegldu technicznego, wydania ekspertyzy technicznej. 11. Gwarancja nie obejmuje: uszkodze mechanicznych, chemicznych, termicznych i korozji; uszkodze spowodowanych dzialaniem czynników zewntrznych, niezalenych od producenta, a w szczególnoci
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Biomolecules | Free Full-Text | Glycation Interferes with the Activity of the Bi-Functional UDP-N-Acetylglucosamine 2-Epimerase/N-Acetyl-mannosamine Kinase (GNE)
Mutations in the gene coding for the bi-functional UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE), the key enzyme of the sialic acid biosynthesis, are responsible for autosomal-recessive GNE myopathy (GNEM). GNEM is an adult-onset disease with a yet unknown exact pathophysiology. Since the protein appears to work adequately for a certain period of time even though the mutation is already present, other effects appear to influence the onset and progression of the disease. In this study, we want to investigate whether the late onset of GNEM is based on an age-related effect, e.g., the accumulation of post-translational modifications (PTMs). Furthermore, we also want to investigate what effect on the enzyme activity such an accumulation would have. We will particularly focus on glycation, which is a PTM through non-enzymatic reactions between the carbonyl groups (e.g., of methylglyoxal (MGO) or glyoxal (GO)) with amino groups of proteins or other biomolecules. It is already known that the levels of both MGO and GO increase with age. For our investigations, we express each domain of the GNE separately, treat them with one of the glycation agents, and determine their activity. We demonstrate that the enzymatic activity of the N-acetylmannosamine kinase (GNE-kinase domain) decreases dramatically after glycation with MGO or GO& mdash;with a remaining activity of 13% & plusmn; 5% (5 mM MGO) and 22% & plusmn; 4% (5 mM GO). Whereas the activity of the UDP-N-acetylglucosamine 2-epimerase (GNE-epimerase domain) is only slightly reduced after glycation& mdash;with a remaining activity of 60% & plusmn; 8% (5 mM MGO) and 63% & plusmn; 5% (5 mM GO).
Glycation Interferes with the Activity of the Bi-Functional UDP- N -Acetylglucosamine 2-Epimerase/ N -Acetyl-mannosamine Kinase (GNE)
Kaya Bork 1 ,
Rüdiger Horstkorte 1 and
Astrid Gesper 1,*
1
Institute for Physiological Chemistry, Medical Faculty, Martin-Luther-University Halle-Wittenberg, 06114 Halle, Germany
2
Leibniz-Forschungsinstitut für Molekulare Pharmakologie im Forschungsverbund Berlin e.V. (FMP), Campus Berlin-Buch, Robert-Roessle-Str. 10, 13125 Berlin, Germany
3
Institut für Chemie, Humboldt Universität zu Berlin, Brook-Taylor-Str. 2, 12489 Berlin, Germany
*
Author to whom correspondence should be addressed.
Biomolecules 2023 , 13 (3), 422; https://doi.org/10.3390/biom13030422
Received: 23 December 2022 / Revised: 17 February 2023 / Accepted: 20 February 2023 / Published: 23 February 2023
(This article belongs to the Special Issue Glycoconjugates in Health, Disease, and Therapy—An Update )
Abstract
:
Mutations in the gene coding for the bi-functional UDP-
N
-acetylglucosamine 2-epimerase/
N
-acetylmannosamine kinase (GNE), the key enzyme of the sialic acid biosynthesis, are responsible for autosomal-recessive GNE myopathy (GNEM). GNEM is an adult-onset disease with a yet unknown exact pathophysiology. Since the protein appears to work adequately for a certain period of time even though the mutation is already present, other effects appear to influence the onset and progression of the disease. In this study, we want to investigate whether the late onset of GNEM is based on an age-related effect, e.g., the accumulation of post-translational modifications (PTMs). Furthermore, we also want to investigate what effect on the enzyme activity such an accumulation would have. We will particularly focus on glycation, which is a PTM through non-enzymatic reactions between the carbonyl groups (e.g., of methylglyoxal (MGO) or glyoxal (GO)) with amino groups of proteins or other biomolecules. It is already known that the levels of both MGO and GO increase with age. For our investigations, we express each domain of the GNE separately, treat them with one of the glycation agents, and determine their activity. We demonstrate that the enzymatic activity of the
N
-acetylmannosamine kinase (GNE-kinase domain) decreases dramatically after glycation with MGO or GO—with a remaining activity of 13% ± 5% (5 mM MGO) and 22% ± 4% (5 mM GO). Whereas the activity of the UDP-
N
-acetylglucosamine 2-epimerase (GNE-epimerase domain) is only slightly reduced after glycation—with a remaining activity of 60% ± 8% (5 mM MGO) and 63% ± 5% (5 mM GO).
Keywords:
GNE-myopathy
;
glycation
;
methylglyoxal
;
sialylation
;
post-translational modification
;
adult-onset disease
1. Introduction
GNE myopathy (GNEM; OMIM 605820) is an autosomal-recessive disease, caused by mutations in the gene encoding the bi-functional UDP- N -acetylglucosamine 2-epimerase/ N -acetylmannosamine kinase (GNE), which is the key enzyme of the sialic acid biosynthesis [ 1 , 2 ]. Sialic acids have a plethora of functions; they are important for cellular and molecular recognition [ 3 ], they play a role in cell adhesion [ 4 , 5 ] and migration [ 4 , 6 ], and they can be involved in the transport of charged molecules [ 3 ]. Until now, more than 200 mutations have been known which lead to GNEM [ 7 , 8 ]. Beside them are certain so-called founder mutations, e.g., M743T (Note: In the original paper the mutation was named M712T [ 9 ]. Nevertheless, a change in the nomenclature of GNE-variants led to a rename into M743T [ 10 ].), which is a founder mutation in the Middle Eastern population [ 9 ], or V603L, which is a founder mutation in Japanese individuals [ 11 , 12 ].
Another genetically related disease that is also based on mutations in GNE is sialuria (OMIM 269921) [ 13 , 14 , 15 ]. GNEM is associated with hyposialylation [ 16 , 17 , 18 ]—but it should be noted here, however, that the connection between (hypo)sialylation and GNEM has not yet been finally clarified [ 19 , 20 ].
The GNE gene consists of 14 exons, exon A1 and exons 1 to 13 [ 21 ]. So far, nine different mRNA splice variants are known, leading to the six already found GNE isoforms 1-6 (two transcripts, NM_001190388.2 and NM_001374798.1, are leading to isoform 3 [ 22 ]), and the two predicted isoforms X1 and X2 [ 23 , 24 ]. Furthermore, GNE and its different isoforms are unevenly expressed in different tissues, with high RNA expression in the liver and low RNA expression in skeletal muscle [ 23 , 25 , 26 , 27 ].
The two domains of the GNE—the epimerase (E.C. 5.1.3.14; [ 28 , 29 , 30 ]) and the kinase (E.C. 2.7.1.60; [ 31 , 32 , 33 ])—are linked and act as a bi-functional enzyme [ 34 , 35 ]. Nevertheless, they also show activities, albeit lower than the wild-type enzyme, when considered individually [ 36 ]. One benefit of a bi-functional enzyme with two domains at once is the possibility for substrate channeling, as for example is already known for the formiminotransferase cyclodeaminase (FTCD) [ 37 ] or the dihydrofolate reductase-thymidylate synthase [ 38 ]. Overall, there are different ways of transferring the substrate between the two active centers of an enzyme, e.g., through a kind of tunnel in the enzyme [ 39 ] or via its surface [ 38 ]. Although it has not yet been shown for GNE, which is particularly the case since no 3D structure is available for the entire enzyme, substrate channeling could also be a possibility for substrate handover here.
The epimerase domain catalyzes the formation of N -acetylmannosamine (ManNAc) from uridine diphosphate N -acetylglucosamine (UDP-GlcNAc) with a simultaneous cleavage of UDP [ 29 , 30 ] ( Figure 1 ). The so-formed ManNAc is then phosphorylated by the kinase domain whereby ATP is converted to ADP at the same time [ 32 ]. Accordingly, the newly formed substance is called ManNAc-6-phosphate. Alternatively, this step can also be accomplished by the N -acetylglucosamine kinase (GlcNAc kinase/also known as NAGK; [ 40 , 41 ]; indicated in orange in Figure 1 ). The main substrate of this enzyme is usually GlcNAc, as supported, for example, by the corresponding k m -values for the two substrates ManNAc and GlcNAc [ 40 , 42 ].
After a few more steps (for a complete overview of all steps see [ 8 , 43 ]), cytidine 5′-monophospho- N -acetylneuraminic acid (CMP-Neu5Ac; [ 44 , 45 ]) is synthesized. CMP-Neu5Ac acts as substrate for sialyltransferases [ 46 ] and its bioavailability regulates their expression [ 47 ]. Additionally, it feedback-inhibits the activity of the epimerase ([ 48 ]; indicated by the red arrow in Figure 1 ). The allosteric site is located in the epimerase domain between the amino acids 255 and 303 (hGNE1) [ 14 , 43 , 49 , 50 ].
The amino acid side chains that are involved in substrate binding or in the formation and stabilization of the active site can be seen in Figure 2 Aa,Ab (GNE-epimerase domain), Figure 2 Ba,Bb (GNE-kinase domain), and Figure 2 Ca,Cb (GlcNAc kinase) [sequences in 2Aa,Ba,Ca: amino acids involved are marked with a diamond ♦]. In the epimerase domain, these are R19, A20, D21, S23, K24, P27, M29, H49, G111, D112, R113, H132, E134, G136, D143, D144, R147, G182, D187, H220, D225, N253, V282, F287, S301, S302, C303, R306, E307 and R321 [ 43 , 50 , 51 , 52 , 53 ]. Please note: Since we show the amino acid sequence of hGNE1, the isoform examined in this study, in Figure 2 , we also use the amino acid numbering based on this “old” variant. In the kinase domain, these are D413, R420, G476, R477, T489, N516, D517, G545, E566, H569, C579, C581, C586, and E588 [ 43 , 51 , 52 , 54 ]. In the GlcNAc-kinase, these are N36, W38, S76, G77, D107, T127, G128, S129, N130, C131, C143, G145, W146, G147, D152, A156, L201, Y205, A214, C217, R218, S271, V272, K274, and S275 [ 55 , 56 ].
GNEM is a distal myopathy with a worldwide predicted prevalence of 1 to 9 patients per 1 million people [ 8 ] that first affects the tibialis anterior, the biceps femoris short head, and the adductor muscles [ 57 , 58 ] leading to certain gait problems and a typical foot-drop [ 59 , 60 ]. After an average of 12 to 15 years after disease onset, most of the patients will be dependent on a wheelchair [ 61 , 62 ]. Other hallmarks of GNEM are the finding of rimmed vacuoles in affected muscles [ 60 , 63 ], an onset in early adulthood [ 62 , 64 ], and a quite slow progression of the disease [ 8 , 65 ]. GNEM-triggered inflammatory changes are not typical features of this disease [ 60 , 63 , 66 ], although there are confirmed exceptions to this statement [ 67 , 68 , 69 ].
Muscles/Muscle groups, which are least affected, are the quadriceps [ 60 ]—especially the vastus lateralis [ 57 , 58 ]—as well as the muscles in the face [ 8 , 59 , 63 ] and the deltoid muscle [ 60 ]. An influence on the heart and especially on cardiomyocytes is still under debate. While mouse models suggest an influence on cardiac muscle cells [ 70 , 71 ], patient data-based studies do not find direct correlations between GNEM and cardiomyopathy [ 61 , 64 , 72 ].
One therapeutic approach aims to compensate for potential hyposialylation by adding precursors of individual metabolites of the sialic acid pathway or other heavily sialylated proteins. This approach also led to positive effects in mouse models [ 8 , 70 , 73 , 74 , 75 , 76 , 77 ]. Unfortunately, the direct transferability of the results of the animal experiments did not turn out to be that easy [ 8 , 78 ]. Overall, although some trials are quite promising, the disease is not yet curable.
Figure 2. Localization of potential glycation sites in the proteins of interest: the two domains of the human GNE, mRNA variant 2 (hGNE1) and the N -acetylglucosamine kinase. Amino acid sequences of the GNE epimerase ( Aa ), GNE kinase domain ( Ba ), and of the N -acetylglucosamine kinase ( Ca ). Secondary structure elements are highlighted by an orange (sheet) or yellow (helix) background color. Lysines (red), arginines (green) and cysteines (blue) are also color-coded to indicate potential glycation sites. A diamond ♦ over an amino acid indicates whether it is within the active site. Lysines, arginines and cysteines found on the surface of the proteins are represented in Ac , Ad , Bc , Bd , Cc , and Cd . Interactions between the substrate and the active-site amino acids are indicated by green-dashed lines in Ab , Bb and Cb . All visualizations (PDB-IDs: 4ZHT (GNE epimerase domain; 3D structure published in [ 53 ]), 2YHW (GNE kinase domain; 3D structure published in [ 54 ]), 2CH5 ( N -acetylglucosamine-kinase; 3D structure published in [ 56 ])) were created with iCn3D [ 79 , 80 ].
Figure 2. Localization of potential glycation sites in the proteins of interest: the two domains of the human GNE, mRNA variant 2 (hGNE1) and the N -acetylglucosamine kinase. Amino acid sequences of the GNE epimerase ( Aa ), GNE kinase domain ( Ba ), and of the N -acetylglucosamine kinase ( Ca ). Secondary structure elements are highlighted by an orange (sheet) or yellow (helix) background color. Lysines (red), arginines (green) and cysteines (blue) are also color-coded to indicate potential glycation sites. A diamond ♦ over an amino acid indicates whether it is within the active site. Lysines, arginines and cysteines found on the surface of the proteins are represented in Ac , Ad , Bc , Bd , Cc , and Cd . Interactions between the substrate and the active-site amino acids are indicated by green-dashed lines in Ab , Bb and Cb . All visualizations (PDB-IDs: 4ZHT (GNE epimerase domain; 3D structure published in [ 53 ]), 2YHW (GNE kinase domain; 3D structure published in [ 54 ]), 2CH5 ( N -acetylglucosamine-kinase; 3D structure published in [ 56 ])) were created with iCn3D [ 79 , 80 ].
A particular sticking point of this disease, especially in the diagnosis, is the comparatively late onset of the disease. Other muscle disorders as Duchenne muscular dystrophy (DMD), Emery-Dreifuss muscular dystrophy (EDMD), or Facioscapulohumeral muscular dystrophy (FSHD) have an onset in early or late childhood [
81
]. This suggests that age-related effects may play a role in this disease. One hallmark of molecular aging is glycation. Glycation describes an enzyme-independent process of a post-translational modification (PTM) of proteins; in particular, of the amino acid side chains lysine, which has a primary amino group, arginine with its guanidine group [
82
], cysteine with its sulfhydryl group [
83
], or of other substances with a preferably terminal amino group [
84
].
To simplify the identification of potential glycation sites in the sequences of the GNE-epimerase domain, GNE-kinase domain, and GlcNAc kinase, we used a specific color code for arginines, cysteines, and lysines (
Figure 2
Aa,Ba,Ca). The same color code was also used in our three-dimensional representations of the enzymes—shown once in the ribbon (
Figure 2
Ac,Bc,Cc) and once in the molecular surface variant (
Figure 2
Ad,Bd,Cd). In particular, the amino acids that are part of the active site can strongly affect the activity of an enzyme—e.g., if they are mutated or otherwise modified, as they may be critical for stabilization of the binding site or for interaction with the substrate through hydrogen bonds. The functions of arginines, cysteines, and lysines that are part of the active site are listed in
Table 1
.
Since it is already known that mutations at some of the positions of these amino acids lead to reduced enzyme activities [ 50 , 51 , 53 , 55 ], it seems very likely that glycations of these amino acids would also have an impact on enzyme activity. To complete this picture, it is important to mention that the activity of the GNE can be influenced by phosphorylation [ 85 ] and O -GlcNAcylation [ 86 ].
The first step in glycation is a condensation between the amino group and a glycation agent, which can be, for example, a certain type of sugar [ 87 ], a derivate of sugar [ 88 ], di-carbonyls such as glyoxal (GO) or methylglyoxal (MGO) [ 89 , 90 ], or ascorbic acid [ 91 ]. A Schiff base adduct is formed, which can be converted into an Amadori product by an Amadori rearrangement [ 92 ]. This reaction can be followed by further steps—e.g., dehydration, enolizations, or oxidations [ 84 , 87 , 93 ]—leading to a multitude of possible advanced glycation endproducts (AGEs) [ 90 , 94 ]. The AGEs formed are also dependent on the glycation agent used ([ 95 ]; see also Figure 3 A–C). Additionally, the reactivity of different amino acid side chains with different glycation agents varies [ 96 ].
The level of AGEs increases steadily over the course of life [ 97 , 98 , 99 ], which could possibly also have an influence on the symptomatic onset of GNEM. This hypothesis can be supported by the fact that there are already examples in which it has been shown that post-translational modifications caused by MGO lead to a decrease in the activity of an enzyme [ 100 , 101 ].
Table 1. Lysines, Arginines and Cysteines involved in the active site—Functions, Mutations, and Activity.
Table 1. Lysines, Arginines and Cysteines involved in the active site—Functions, Mutations, and Activity.
Residues Function So-Far Known Mutations in Patients In Vitro—Loss of Activity Due to Mutations (Compared to WT) UDP- N -acetylglucosamine 2-epimerase (hGNE1, mRNA variant 2) K24 Involved in forming the vicinity of the active site [ 52 ] n.d.a. n.d.a. R19 UDP binding [ 52 ] n.d.a. n.d.a. R113 Involved in forming the vicinity of the active site [ 52 ] n.d.a. R113A: completely inactive [ 53 ] R147 Involved in forming the vicinity of the active site [ 52 ] n.d.a. n.d.a. R306 Involved in forming the vicinity of the active site [ 50 ] R306Q [ 102 ] n.d.a. R321 Interaction with the phosphate of UDP [ 53 ] R321C [ 103 ] n.d.a. C303 Hydrophobic interactions, but probably no specific function in the enzymatic reaction [ 50 ] C303V [ 104 ] C303X [ 9 ] C303V: epimerase 80%, kinase 60% C303X: epimerase 0%, kinase 0% [ 50 ] N -acetylmannosamine kinase (hGNE1, mRNA variant 2) Residues Function So-Far Known Mutations in Patients In Vitro—Loss of Activity Due to Mutations (Compared to WT) R420 Interaction with the phosphate oxygens [ 51 , 52 ] R420X [ 105 ] R420Q [ 106 ] → patient not yet suffering from myopathy R420M: epimerase activity comparable to WT; kinase activity drastically reduced [ 51 ] R477 ManNAc binding [ 54 ] n.d.a. n.d.a. C579 Zinc binding [ 54 ] C579Y [ 12 ] n.d.a. C581 Zinc binding [ 54 ] C581R [ 7 ] n.d.a. C586 Zinc binding [ 54 ] C586X [ 7 ] n.d.a. N -acetylglucosamine kinase Residues Function In Vitro—Loss of Activity Due to Mutations (Compared to WT) K274 Nucleotide binding [ 56 ] n.d.a. R218 Nucleotide binding [ 56 ] n.d.a. C131 Phosphate transfer from ATP to the hydroxyl groups of GlcNAc [ 55 ] C131S: overall activity reduced (approx.. 10% activity remaining [ 55 ]) C143 Phosphate transfer from ATP to the hydroxyl groups of GlcNAc [ 55 ] C143S: overall activity reduced (approx.. 20% activity remaining [ 55 ]); 75% of WT activity [ 107 ] C217 Nucleotide binding [ 56 ] C217S: overall activity reduced (approx.. 30% activity remaining [ 55 ])
n.d.a.: no data available.
Figure 3. Structural formulas showing different advanced glycation end products (AGEs). Structural formulas of advanced glycation end products (AGEs) formed from lysine [ 95 , 108 , 109 ] ( A ), arginine [ 95 , 110 , 111 , 112 ] ( B ), or cysteine [ 83 , 95 , 113 ] ( C ) and glyoxal (GO; black) or methylglyoxal (MGO; blue).
Figure 3. Structural formulas showing different advanced glycation end products (AGEs). Structural formulas of advanced glycation end products (AGEs) formed from lysine [ 95 , 108 , 109 ] ( A ), arginine [ 95 , 110 , 111 , 112 ] ( B ), or cysteine [ 83 , 95 , 113 ] ( C ) and glyoxal (GO; black) or methylglyoxal (MGO; blue).
The aforementioned di-carbonyl substances can occur naturally as a breakdown product of glycolysis, amino acid, and fatty acid degradation [ 114 , 115 , 116 ]. In addition, they can arise as a byproduct of the glycation process itself via the so-called Namiki pathway [ 84 , 117 ] or by autoxidation of glucose via the Wolff pathway [ 84 , 118 , 119 , 120 ]. They are also ingested through food: MGO and GO, e.g., by consuming coffee and wine [ 121 ] and Vitamin C through fruits and vegetables [ 122 ].
One of the most well-studied AGEs is carboxymethyllysine (CML; Figure 3 A), whose formation is based primarily on a reaction between lysine and glyoxal [ 108 , 123 , 124 ]. Furthermore, most anti-AGE antibodies preferentially recognize CML [ 125 ]. In our study, we also used an antibody against CML as a marker for the glycation level of our proteins—the epimerase and the kinase domain of the GNE and the GlcNAc kinase.
In this study, we attempted to find an explanation for the late onset of GNEM by relating it to PTMs, focusing specifically on glycation. Therefore, we investigated the extent of the influence of MGO- or GO-triggered glycation on the activity of the individual domains of the GNE (hGNE1) and on the GlcNAc kinase. For this purpose, all three enzymes were expressed separately from each other, purified, treated with increasing concentrations of one of the glycation agents, and then analyzed for their activity.
Furthermore, we examined the expression of the GNE—as a whole protein—and the GlcNAc kinase in undifferentiated but MGO- or GO-treated C2C12 cells. These cells belong to a murine skeletal muscle cell line. In addition, the effect of the glycation agents on cell viability was investigated by a MTT assay.
2. Materials and Methods
2.1. Cell Culture and MGO/GO-Treatment
Murine C2C12 myoblasts were cultured in DMEM (Dulbecco’s Modified Eagle’s Medium; 11960044; Gibco/Thermo Fisher Scientific; Waltham, MA, USA) supplemented with 10% FBS (Fetal Bovine Serum; A5256801; Gibco/Thermo Fisher Scientific; Waltham, MA, USA), 1% penicillin-streptomycin (P/S; 10,000 units/mL (P) and 10,000 µg/mL (S); 15140122; Gibco/Thermo Fisher Scientific; Waltham, MA, USA) and 1% L-glutamine (L-Gln; 200 mM; A2916801; Gibco/Thermo Fisher Scientific; Waltham, MA, USA) at 37 °C in a humidified atmosphere with 5% CO
2
. The C2C12 cell line was kindly provided to us by the Poserns Lab (Martin-Luther-University Halle-Wittenberg, Institute for Physiological Chemistry; Halle (Saale), Germany). Growth medium was changed every 48 h.
To assess the effect of MGO and GO on C2C12 myoblasts, the cells were seeded at a density of 9000 cells/cm
2
; in a 10 cm (Ø) dish and incubated at 37 °C in a humidified atmosphere with 5% CO
2
. After one day, the cells were cultured in starvation medium (DMEM + 1% FBS + 1% P/S + 1% L-Gln) with MGO or GO (0.2 mM, 0.5 mM, or 2 mM). Following another day, the cells were divided into two pellets, one for protein isolation and one for RNA isolation.
2.2. RNA Extraction and RT-qPCR
Total RNA was isolated using the Quick-RNA Miniprep Kit (R1054; Zymo Research; Irvine, CA, USA). cDNA was synthesized, using 2 µg of total RNA and SuperScript™ II reverse transcriptase (18064022; 2000 units; Thermo Fisher Scientific; Waltham, MA, USA), following the manufacturer’s instructions. RT-qPCR was performed using qPCR SybrMaster (PCR-372S; Jena Bioscience; Jena, Germany) and the CFX Connect™ Real-Time PCR Detection System (1855201; Bio-Rad; Hercules, CA, USA).
The following primers were used:
Gene Name Direction Sequence
RPL26 forward GGTCTATGCCCATTCGGAAGG
RPL26 reverse TCGTTCGATGTAGATGACGTACT
GAPDH forward CCTGGAGAAACCTGCCAAGTATG
GAPDH reverse AGAGTGGGAGTTGCTGTTGAAGTC
Isoform 1 (short) forward GGCGTCCGGGTTCTACGCA
Isoform 2 (long) forward GGAAACACACGCGCATCTCCAC
Isoform 1 and 2 reverse AATGGTCCCGCTGACCTCGC
GNE1 forward GGTGGACAATGACGGCAACTGT
GNE1 reverse CAGTTCGTGCTGGTGGATGATC
GlcNAc kinase forward GGTAGTATGGCCGCGCTTTA
GlcNAc kinase reverse GGTGTGCAATCCAGTAGGCT
Cq values were normalized to the housekeeping gene RPL26, and relative gene expression was calculated using the ΔΔCq-method.
2.3. Protein Isolation from Cell Culture
For protein isolation, cells were washed with PBS and lysed using RIPA buffer containing protease inhibitor cocktail (Sigma Aldrich; St. Louis, MO, USA), 1 mM NaVO 4 , and 1 mM PMSF. Following 30 min incubation on ice, total protein was isolated by centrifugation at 14,000× g , 4 °C for 5 min and quantified using the Pierce™ BCA Protein Assay Kit (23225; Thermo Fisher Scientific; Waltham, MA, USA).
2.4. MTT Assay
C2C12 myoblasts were seeded at a density of 3 × 10 3 cells in a 96-well cell culture plate and treated with six different concentrations of MGO (0 mM, 0.1 mM, 0.2 mM, 0.5 mM, 0.7 mM, and 1 mM) and GO (0 mM, 0.5 mM, 1 mM, 1.5 mM, 2 mM, and 2.5 mM) for 24 h in DMEM containing 1% FBS. Thiazolylblue-tetrazolimbromide (M5655; Sigma-Aldrich; St. Louis, MO, USA) was added to the cells according to the manufacturer’s instructions and incubated for 4 h.
2.5. Protein Expression in E.coli and Purification
The GNE domains of human GNE/MNK were expressed according to a protocol published by the Chen Group [ 53 ]. The gene encoding the UDP-GlcNAc 2-epimerase domain with an N-terminal His6-tag was bought from Biocat in a pET21a(+) vector. The plasmid was codon optimized to be expressed in Escherichia coli BL21 (DE3) cells. The transformed BL21 (DE3) cells were stored until use as glycerol stocks (5%).
Starting from this glycerol stock, an over-day culture was grown in 5 mL LB medium with 100 mg/L ampicillin, for 8 h at 37 °C and 220 rpm. From the over-day culture, an overnight culture was grown in 15 ml LB medium with 100 mg/L ampicillin, at 37 °C and 220 rpm. With 3.5 mL overnight cultures 4 × 500 mL LB medium with 100 mg/L ampicillin in 2 L flasks were inoculated. This was grown at 37 °C and 180 rpm to an OD600 of 1.9. Then all cultures were pooled, and 700 mL were diluted in 1.3 l LB medium with 100 mg/L ampicillin (at 4 °C). This was redistributed to four 2 L flasks (4 × 500 mL), grown to an OD600 of 0.7 and induced with IPTG (50 µM). Subsequently, the cells were kept for 42 h at 8 °C and 120 rpm. Then, they were grown for 24 h at 16 °C and 180 rpm. The cells were harvested by centrifugation with 4000×
g
for 15 min at 4 °C, and the cell pellet was re-suspended in resuspension buffer (50 mM Tris-HCl, pH 8.0, 500 mM NaCl).
Afterwards, the cells were lysed by using a high shear fluid laboratory homogenizer at 18 kPa (LM10; Microfluidics International Corporation; Newton, MA, USA) and the cell lysate was centrifuged with 20,000×
g
for 25 min at 4 °C. The clarified supernatant was filtered, and the protein was purified via Ni-NTA chromatography on 2 × 5 mL His60 Ni Superflow column (635657; Takara Bio Inc./Clontech; Kusatsu, Japan) using a Chromatography System (Bio-Rad NGC Discover 10; Bio-Rad Laboratories; Hercules, CA, USA). Resuspension buffer and elution buffer (50 mM Tris-HCl pH 8.0, 500 mM NaCl, 500 mM Imidazole) were used in a linear gradient over 300 mL.
Fractions of the protein peak were pooled and concentrated to 10 mL using a Vivaspin 20 (VS2001; Sartorius; Göttingen, Germany) with a molecular weight cut of 10 kDa. The sample was then buffer exchanged to 50 mM Tris-HCl pH 8.0, 100 mM NaCl, 5% glycerol and 0.2 mM TCEP using a HiPrep 26/10 Desalting column (GE17-5087-01; Sigma-Aldrich; St. Louis, MO, USA) and the aforementioned chromatography system. Fractions containing the GNE protein were pooled. 20 mL with a concentration of about 7 mg/mL were obtained.
To avoid confusion with the proteins from cell culture, these proteins will be referred to hereinafter as Protein-Ecoli and the proteins from cell culture as Protein-CC .
2.6. Glycation of the Proteins ( Protein-Ecoli )
In order to investigate the concentration dependence of glycation of methylglyoxal (MGO; 40% in H 2 O; Sigma Aldrich; St. Louis, MO, USA) and glyoxal (GO; 40% in H 2 O; Sigma Aldrich; St. Louis, MO, USA), 6 µg each of N -acetylmannosamine kinase and N -acetyl-glucosamine kinase or 4.8 µg of the UDP- N -acetylglucosamine 2 epimerase were mixed with ascending concentrations of the reagents—0.5 mM, 2 mM, and 5 mM—and incubated for 1 h at 37 °C.
2.7. Western Blot Analysis (Protein-CC and Protein-Ecoli )
Protein-CC:
Equal amounts of protein were mixed with 5× SDS-loading dye (containing 50 mM DTT) and separated on a 4–12% Tris-Glycin gradient gel (Invitrogen by Thermo Fisher; Waltham, MA, USA).
Protein-Ecoli:
The glycated proteins were mixed with 5× SDS-loading dye (containing 50 mM DTT) and separated on a 10–20% Tris-Glycin gradient gel (XP10205BOX; Invitrogen by ThermoFisher; Waltham, MA, USA).
Proteins were transferred on a nitrocellulose-membrane and stained with Ponceau S as loading control. Membranes were blocked with 5% skimmed milk in TBS-Tween (TBS-T) for 1 h at RT. The membranes were then incubated with the primary antibodies: mouse IgG-anti-carboxymethyl lysine (CML26; dilution: 1:10,000 (Protein-CC) or 1:2000 (Protein-Ecoli); ab125145; abcam; Cambridge, UK) or MG-H1 (1H7G5; dilution: 1:1000; NBP2-62810; Novus Biologicals/Bio-Techne; Minneapolis, MN, USA) overnight at 4 °C. Afterwards, the membranes were washed three times with TBS-T. Each washing step lasts 10 min. Following that, the membranes were incubated with the secondary antibody—goat anti-mouse IgG H&L HRP (dilution 1:10,000; ab6789; abcam; Cambridge, UK)—for 1 h at RT. Thereafter, the membranes were again washed 3 times for 10 min each with TBS-T and the Western blot detection reagent from Amersham (cytiva, Marlborough, MA, USA) was used. The ChemiDoc MP imaging system from Bio-Rad Laboratories (Hercules, CA, USA) was used for visualization. Intensities were quantified by ImageLab Software from Bio-Rad Laboratories (Hercules, CA, USA).
2.8. Epimerase Activity Assay ( Protein-Ecoli )
An UDP Glo™ Glycosyltransferase Assay (V6961; Promega Corporation; Madison, WI, USA) was performed to determine UDP- N -acetyl-glucosamine 2-epimerase activity. For this purpose, 747 µg epimerase were incubated at 37 °C with different MGO/GO concentrations (0.5 mM, 2 mM, and 5 mM) for 1 h in a volume of 3 µL. The total volume of the reaction mixture of 52.5 µL was prepared, consisting of 5 µM UDP-GlcNAc, 0.05% BSA, and glycated epimerase in buffer. This mix was incubated for 1 h at 37 °C. Afterwards, 25 µL UDP-Detection Reagent™ were added and incubated at room temperature for 1 h. Afterwards, the luminescence was detected by ClarioStar™ (BMG Labtech GmbH, Ortenberg, Germany).
2.9. Kinase Activity Assay ( Protein-Ecoli )
The N -acetylmannosamine kinase activity and the N -acetylglucosamine kinase activity were determined by a coupled enzyme assay (based on the assays described by [ 19 , 126 ]).
Our enzyme assay used differently glycated GNE-kinase and GlcNAc kinase samples. For this, 3 µg each of the GNE-kinase domain and the GlcNAc kinase were incubated with ascending concentrations of MGO and GO—0.5 mM, 2 mM, and 5 mM—for 1 h at 37 °C. Each of the enzyme samples had a total volume of 2.5 µL.
Afterwards, a reaction mixture with a total volume of 623.5 µL was prepared, consisting of one of each of the different enzyme samples, 62.6 mM Tris, 20.3 mM MgCl
2
, 9.6 mM ATP, 4.8 mM ManNAc, 4.8 mM phosphoenolpyruvate, 1.4 mM NADH, 6 µL Lactic dehydrogenase (600–1000 U/mL)/Pyruvat kinase solution (900–1400 U/mL) (P0294; Sigma Aldrich; St. Louis, MO, USA), and 7.7 mM sodiumphosphatebuffer.
This reaction mixture was incubated at 37 °C until further use. At time points 0 min and 45 min in the case of the ManNAc kinase, and 0 min and 180 min in the case of the GlcNAc kinase, 25 µL of this mixture was removed and added to 75 µL of an EDTA solution (10 mM). The absorbance at the wavelength of 340 nm reflects the NADH concentration. The ClarioStar™ (BMG Labtech GmbH, Ortenberg, Germany) was used to determine the absorbance.
2.10. Structural Comparison
A structural comparison between GNE-kinase and GlcNAc kinase was performed using the VAST+ algorithm (vector alignment search tool; [ 127 , 128 , 129 ]).
In order to do this, we entered the PDB ID of the GNE-kinase (2YHW) into the search field of the Website of the National Center of Biotechnology Information [ 130 ], called up the entry listed under Protein/Structure, and then clicked on the “VAST+” button (similar structures). Afterwards, we entered the PDB ID of the GlcNAc kinase (2CH5) into the search field of the result list.
2.11. Statistical Analysis
For statistical analysis of the epimerase and the kinase activity assays, a two-way analysis of variance (ANOVA) was performed (alpha = 0.05; OriginPro 2019 (OriginLab Corporation; Northampton, MA, USA)). One factor (“way”) was the choice of glycation agent—MGO or GO—and the other the concentration used—0.5 mM, 2 mM, or 5 mM. This was followed by a Tukey post hoc-Test. Based on the determined p -values, asterisks were used to classify the significance levels: p ≤ 0.05: *, 0.005 < p ≤ 0.01: **, and p ≤ 0.005: ***.
3. Results
3.1. Expression and Glycation of the UDP-N-Acetylglucosamine 2-Epimerase, the N-Acetylmannosamine kinase, and the N-Acetylglucosamine Kinase
As it is possible that molecular aging is an important component in the progression and onset of GNEM, this aspect will be the focus of the following experiments. Molecular aging was therefore simulated by glycating the proteins/protein domains of interest using different physiological glycation agents. Afterwards, their individual activities were determined by different assays further explained in the next result section.
First, the proteins/protein domains were expressed in
Escherichia coli
BL21 with a 6xHis-tag added to their N-terminal site. This His-tag was used for purification over Ni-NTA-columns (details can be found in the Material and Methods section). Afterwards, the purified proteins were incubated with ascending concentrations of the glycation agents methylglyoxal (MGO) and glyoxal (GO) and the glycation success was verified by western blots using an antibody specific for glycated lysine side chains (anti-CML; see
Figure 4
,
Supplementary Table S1
and the
Supplementary Figures S1–S3
(showing the uncut Western Blots)).
With ascending concentrations of MGO and GO, the level of relative glycation normalized to Ponceau increases. Across both GNE domains, the signal of CMLs detected was stronger when using the glycation agent GO than MGO.
Looking at the GlcNAc kinase, it is striking that the amount of CMLs and thus the glycation success seems to be at the same level for both glycation agents. Overall, the proteins/protein domains of interest were successfully glycated by both glycation agents.
3.2. Glycation of the GNE-Domains Interferes with Their Enzymatic Activity—Activity of the GlcNAc Kinase Is Not Affected by Glycation
Having shown that the proteins/protein domains of interest were successfully glycated, their activity should now be determined. The aim is to investigate whether glycation can influence enzyme activity, to be able to assess whether the late onset of GNEM might be due to age-related effects.
The first step of the GNE-epimerase activity assay is based on the GNE-epimerase domain reaction, where UDP-
N
-acetylglucosamine (UDP-GlcNAc) is converted under addition of water to
N
-acetylmannosamine (ManNAc) and UDP (see
Figure 5
A). Afterwards, the generated UDP is converted to ATP by adding UDP-Glo-Reagent and light is generated in the form of luminescence (based on the Promega glycosyltransferase assay; details can be found in the Material and Methods section). The amount of light produced was used to back-calculate the UDP concentration. This is possible because the UDP concentration and the amount of light produced are proportionally coupled. The determined UDP concentration was then used as an indicator for enzyme activity. Higher UDP concentrations indicate higher enzyme activities.
The boxplot showing the determined UDP concentrations under the different conditions can be seen in
Figure 5
B. All boxplot-related data, including mean and standard deviation, can be found in
Supplementary Table S2
. All samples showed significant differences (
p
< 0.005; student’s
t
-test; all results can be seen in
Supplementary Table S5
) towards the negative control (see
Figure 5
B). The negative control consists of water, instead of any enzyme. The positive control consists of the non-glycated enzyme. With the exception of the sample that was treated with 0.5 mM MGO, all other samples showed significant differences towards the positive control (
p
< 0.05; student’s
t
-test), indicating reduced enzyme activities—lower UDP-concentrations—compared to the non-glycated enzyme.
Two-factor ANOVA showed that the concentration of the glycation agent is a significant factor for the activity ( p -value: 1.43E-03; see also Supplementary Table S3 ) and the choice of the glycation agent per se not ( p -value: 1.96E-01). The interaction between concentration and glycation agent is again significant ( p -value: 3.58E-03), meaning that the result obtained through different concentrations depends on the used glycation agent.
The subsequent Tukey post hoc-Test identified significant differences between the conditions 0.5 mM MGO and 2 mM MGO, between the conditions 0.5 mM MGO and 0.5 mM GO, and between the concentrations 0.5 mM and 5 mM, regardless of the glycation substance used (for the p -values see Supplementary Table S4 ).
To ensure that the glycation agents do not influence the activity assay itself, the experiment was repeated without the GNE-epimerase domain, but with 0.25 nmol UDP (see
Figure 5
C). The assay enzymes were exposed to one of the two glycation agents in the same amount as in the normal activity assay (same volume; always assuming the highest concentration used). No influences on the activity of the assay enzymes were found under these conditions (
p
-value: 5.35E-01 (control and MGO);
p
-value: 9.07E-01 (control and GO)). This indicates that the reduced UDP concentrations measured with differentially glycated GNE-epimerase domains were a result of a reduced GNE-epimerase domain enzyme activity and not a result of the glycation agents reacting with the assay itself.
In summary, it can be stated that the activity of the GNE-epimerase domain can be influenced by glycation, with a remaining activity of 60% ± 8% after treatment with MGO (5 mM) and 63% ± 5% after treatment with GO (5 mM) compared to the non-glycated protein, which activity was set to 100%. The determination of the activity is based on the UDP consumption (see Supplementary Table S2 ). This also shows that regardless of the glycation agent used, the same level of activity is achieved when comparing the highest glycation conditions.
The activities of the GNE-kinase domain and of the GlcNAc kinase were determined by a coupled enzyme assay ([ 19 , 126 ]; see Figure 6 A). This assay is based on the fact that both kinases can phosphorylate ManNAc to ManNAc-6-phosphate, although ManNAc is not the main substrate of GlcNAc kinase [ 40 , 42 ]. The ADP, which remains after the release of the phosphate from the ATP, is then further used in the pyruvate kinase reaction. The product of that reaction, pyruvate, is further converted to lactate. Concomitantly, the coenzyme NADH is converted to NAD + . The decrease in the NADH concentration can be measured by determining the absorbance at 340 nm. The level of NADH consumption per minute can be seen as a measure of enzyme activity. Higher NADH consumption per minute indicates higher enzyme activities.
The determined NADH consumption per minute for the GNE-kinase domain can be seen in Figure 6 B and for the GlcNAc kinase in Figure 6 C (the boxplot-related data can be found in the Supplementary Tables S6 and S10 ). The GlcNAc kinase, even non-glycated, shows a lower NADH consumption rate per minute than the GNE-kinase domain—only 17% compared to the GNE-kinase domain.
Concerning the GNE-kinase domain, the positive control—again consisting of non-glycated protein—and the samples treated with the lowest concentrations of the glycation agents showed significant differences towards the negative control (
p
< 0.05; student’s
t
-test; see
Figure 6
B and
Supplementary Table S8
). All other samples showed such low NADH consumptions that they no longer show any significant differences from the negative control. With the exception of the treatment with 0.5 mM GO, all samples showed a significant difference from the non-glycated sample (pos. control;
p
< 0.005; see also
Supplementary Table S8
). The overall trend related to the NADH consumption per min is that higher concentrations of the glycation agent leads to lower consumption rates.
The two-factor ANOVA showed that the concentration of the glycation agent and the glycation agent per se are significant factors ( p < 0.005; see also Supplementary Table S7 ) and the interaction between them is not ( p -value: 1.22 × 10 −1 ).
The subsequent Tukey post hoc-Test identified many significant differences between the different conditions, which can all be seen in Figure 6 B with the corresponding p -values in Supplementary Table S9 .
Concerning the GlcNAc kinase, all samples differ significantly from the negative control ( p < 0.01; see Figure 6 C and Supplementary Table S13 ) and show no significant difference from the positive control. Additionally, all other statistical tests do not reveal any other significant effects (see Supplementary Tables S10 and S11 ). This is quite surprising, as it states that glycation does not affect the enzymatic activity of this kinase, despite previous results on the GNE-kinase domain suggesting otherwise.
Again, no influence of the glycation agents on the enzymes of the assay could be determined (see Figure 6 D; p -value: 4.23 × 10 −1 (control and MGO); p -value: 6.52 × 10 −1 (control and GO)). We exposed the assay enzymes to the same amounts of the two glycation agents as in the normal activity assay (same volume; always assuming the highest concentration used).
3.3. Expression of the UDP-N-Acetylglucosamine 2-Epimerase/N-Acetylmannosamine Kinase, and the N-Acetylglucosamine Kinase in MGO/GO-Treated Undifferentiated C2C12 Cells
We also investigated the effect of MGO and GO on undifferentiated C2C12-cells, a murine skeletal muscle cell line. This should help to obtain a first impression of the effect of glycation on the muscle type that is most affected by the disease. Phase-contrast images of C2C12 cells treated with different concentrations of the glycation agents were then analyzed to find out which concentrations appear to be quite well tolerated. An MTT assay was then performed to determine the effect of the glycation agents on cell viability. Based on the data from the MTT assay, the TC
50
-value was calculated whenever possible. Finally, the effect of MGO and GO on mRNA expression of GNE and GlcNAc kinase was determined using quantitative PCR (qPCR).
Looking at the phase-contrast images revealed that the cells tolerated higher concentrations of GO than of MGO. Accordingly, we found no morphological abnormalities in the cell cultures at a maximum concentration of 0.2 mM MGO and 0.5 mM GO (see
Figure 7
A and
Supplementary Figure S4
(showing the unprocessed cell culture images)). This can be confirmed by the results of the MTT assay (see
Figure 7
B; results and
p
-values can be found in
Supplementary Tables S14 and S15
), where we determined a TC
50
-value for MGO of 0.81 mM. With regard to GO, we decided against calculating this value based on the underlying data basis, since we did not exceed the 50% cell viability mark with the concentrations examined. Nevertheless, it is clear that the TC
50
-value of GO with respect to C2C12 myoblasts must be higher than the TC
50
-value of MGO.
The western blots showed the same trend as previously observed when examining the proteins/protein domains individually—that with ascending concentrations of MGO and GO, the level of relative glycation increases (see Figure 7 D). This also stays true after normalization to Ponceau (see supplementary Figure S5 ).
The qPCR showed that the mRNA expression of the GlcNAc kinase was significantly reduced after treatment with 0.5 mM GO ( p -value: 4.56 × 10 −2 ; see Figure 7 C and Supplementary Table S16 ). The expression of the GNE showed no significant changes independent of the concentration or type of the glycation agent (all p -values can be found in Supplementary Table S17 ).
Overall, these investigations showed that too high concentrations of glycation agents, especially of MGO, lead to a reduced cell viability. At non-toxic concentrations, GO/MGO-derived glycation products could be successfully detected in the cells/cell lysates; increasing concentrations led to increasing amounts of glycation products. The mRNA expression of GlcNAc kinase in C2C12 cells was affected by the addition of GO. However, the mRNA expression of GNE was not affected by either of the two glycation agents investigated.
3.4. Structural Comparison of the UDP-N-Acetylglucosamine 2-Epimerase/N-Acetyl-mannosamine kinase and the N-Acetylglucosamine Kinase
To understand similarities and differences between GNE-kinase and GlcNAc kinase, a structural comparison of both was performed using the VAST+ algorithm (vector alignment search tool; [ 127 , 128 , 129 ]; see Figure 8 ). The root mean square deviation (RMSD) of the aligned residues between both kinases was 3.17 Å. Furthermore, a sequence accordance of 21% was found (displayed by white capital letters with a red background in Figure 8 A; or by a red color in the three-dimensional image alignment in Figure 8 B), and 219 residues could be aligned in 3D space (displayed by blue capital letters in Figure 8 A; or by a blue color in Figure 8 B). Regions in a gray color ( Figure 8 B) or with lowercase letters with a gray background represent unaligned amino acids ( Figure 8 A). In addition, a diamond ♦ marks the amino acid side chains involved in the formation of the active site ( Figure 8 A).
Three amino acid side chains can be identified whose 3D structure can be aligned against each other, which are identical, and which are part of the respective active sites. An enclosed rectangle with a Roman numeral marks these amino acid side chains in the amino acid sequence in
Figure 8
A. The amino acid side chain marked by I corresponds to the GNE amino acid at position 476 and to the GlcNAc kinase amino acid at position 77, which was in both cases a glycine. The amino acid side chain marked with III was also a glycine, which was found at position 545 in the GNE and at position 128 in the GlcNAc kinase. Furthermore, this glycine is part of the ATP binding motifs DXGGT and GTG (see yellow rectangles in
Figure 8
A; [
52
,
131
]). The amino acid aspartic acid is located at position II in the sequence. This corresponds to amino acid position 517 in GNE and position 107 in GlcNAc kinase.
The nearly conserved ATP binding motifs in both kinases appear to represent the greatest structural similarity. However, this is not a surprise since both require ATP to transfer the phosphate group to their respective substrate.
The functions, pathogenicity predictions based on polymorphism phenotyping (PolyPhen), statements concerning disease association, genetic locations, and the database of single polymorphisms (dbSNP) IDs [ 132 ] of the amino acids at the positions I to III can be found in the table displayed in Figure 8 C (everything, except for the function, was based on [ 133 ]).
Figure 8. Structural comparison of the GNE-kinase domain (hGNE1) and the GlcNAc-kinase. ( A ) Amino acid comparison of GNE-kinase domain (orange) and GlcNAc kinase (blue). ( B ) Three-dimensional structural comparison of the two kinases. Both were based on the vector alignment search tool VAST+ [ 127 , 128 , 129 ]. A blue color represent amino acids that are aligned in 3D space, a gray color represent unaligned amino acids, and a red color represent identical amino acids. A diamond ♦ over an amino acid indicates whether it is within the active site. The three amino acids, which can be aligned, which are identical, and which are part of the active site are marked by Roman numerals from I to III. The amino acid marked with III—glycine—is part of the ATP-binding motifs DXGGT and GTG [ 52 , 131 ]. All other functions of the marked amino acids can be found in the table in ( C ). Most of the information given here was based on data found on https://www.uniprot.org , (accessed on 20 December 2022) [ 133 ].
Figure 8. Structural comparison of the GNE-kinase domain (hGNE1) and the GlcNAc-kinase. ( A ) Amino acid comparison of GNE-kinase domain (orange) and GlcNAc kinase (blue). ( B ) Three-dimensional structural comparison of the two kinases. Both were based on the vector alignment search tool VAST+ [ 127 , 128 , 129 ]. A blue color represent amino acids that are aligned in 3D space, a gray color represent unaligned amino acids, and a red color represent identical amino acids. A diamond ♦ over an amino acid indicates whether it is within the active site. The three amino acids, which can be aligned, which are identical, and which are part of the active site are marked by Roman numerals from I to III. The amino acid marked with III—glycine—is part of the ATP-binding motifs DXGGT and GTG [ 52 , 131 ]. All other functions of the marked amino acids can be found in the table in ( C ). Most of the information given here was based on data found on https://www.uniprot.org , (accessed on 20 December 2022) [ 133 ].
4. Discussion and Outlook
All proteins/protein domains of interest—the GNE-epimerase domain, the GNE-kinase domain, and the GlcNAc kinase—could be successfully expressed in
E. coli
, purified via their 6xHis-tag, and post-translational modified by the two glycation agents methylglyoxal (MGO) and glyoxal (GO). Afterwards, different activity assays were performed to investigate the effect of glycation on the activity of the enzymes. In addition, we also examined the expression of GNE and the GlcNAc-kinase in undifferentiated, MGO/GO-treated C2C12 cells, a murine skeletal muscle cell line.
The choice of a His-tag needs to be discussed, since it seems also possible that under certain conditions histidine side chains could be modified [ 134 , 135 ]. However, it seems that the histidine modifications described in these studies are based on oxidation and not on glycation, and require at least certain amounts of Cu(II) [ 135 ], so a His-tag seems like a safe choice from this standpoint. Furthermore, such a tag has already been used successfully in another study in connection with GNE [ 53 ]. However, the His-tag itself could also have an impact on the protein and its activity, e.g., due to steric hindrances or due to electrostatic interferences that result in impeded binding of the substrate to the active site [ 136 , 137 ]. Still, one could try introducing removable tags, such as the GST-tag (Glutathione S -Transferase-tag; [ 138 ], and see if the purification success stays the same or maybe even improves. Then, His-tag-based influences [ 139 ] could be excluded.
The stronger CML signal when examining the GO-treated GNE domains as opposed to the MGO-treated ones can be explained by the fact that a fairly favorable pathway for the formation of CMLs is the reaction between lysine side chains and GO (see Figure 3 A; [ 95 , 124 ]). In contrast, the reaction between lysine side chains and MGO leads to the formation of carboxyethyllysines (CELs) (indicated in blue in Figure 3 A; [ 95 , 109 ]). It is therefore quite interesting that a putative specific antibody against carboxymethyllysines (CMLs) is also able to detect MGO-derived modifications on our proteins/protein domains of interest (see Figure 4 ). However, there are already some publications that document cross-reactions of anti-CML antibodies with CELs [ 140 ], respectively, with MGO-derived AGEs [ 86 , 141 ]. Further, it seems quite surprising that although the GNE-epimerase domain has almost twice as many lysines as the GNE-kinase domain, the relative glycation normalized to Ponceau of the kinase domain is more than twice as high compared to the epimerase domain and not the other way around. This could perhaps be a first indication of a higher responsiveness/vulnerability of the kinase to glycation.
Based on the elevated MGO/GO-levels in diabetic patients [ 142 , 143 ], it might be interesting to investigate whether there are patients who suffer from both diseases—GNEM and diabetes mellitus (type I) and whether these patients develop the disease earlier (statistically) than patients suffering from GNEM alone.
One-step further, one could also split up all so far known mutations, into the groups:
Mutation introduces a new potential glycation site,
Mutation has no effect on the number of potential glycation sites (both amino acids lead to a potential glycation site),
Mutation deletes a potential glycation site.
This could then be used, for example, to examine whether different MGO/GO blood levels can be detected in the individual groups.
Our preliminary analysis of the mutations listed on UniProt revealed 19 mutations that lead to a reduction in a potential glycation site (see
Supplementary Table S18A
). These mutations were mainly found in the epimerase domain and 31% of them are predicted to be benign. In addition, five mutations were found in which one amino acid causing a potential glycation site was exchanged for another, resulting in a new potential glycation site (see
Supplementary Table S18B
). Interestingly, in all five cases, an arginine was exchanged for a cysteine. Again, these mutations were predominantly found in the epimerase domain and are mostly damaging or pathogenic; the one found in the kinase domain was probably benign. Ten mutations were found that added an additional potential glycation site, 20% in the epimerase domain and 80% in the kinase domain. These mutations were mainly malignant (70%), 20% uncertain, and 10% benign. This may lead one to hypothesize that adding a potential glycation site is more likely to result in a malignant mutation—greater impact on the protein—than removing a potential glycation site. However, this needs to be verified further, e.g., in in vitro experiments on mutated versions of the protein. In addition, the conclusions/hypotheses of this preliminary mutation analysis can be linked to the other results in this study. Therefore, it seems fitting that adding an extra glycation site would have such a big impact on the kinase domain, which we have previously shown to be more responsive to glycation than the epimerase domain.
Furthermore, there are genetic mutations within one family that result in different individual risks for disease progression and onset [ 12 , 103 , 144 ]. Since no genetic differences can be associated with the interindividual variability in the development of the disease, a possible difference in their lifestyles including different/other exposure of GNE to glycation agents can be considered. This could possibly explain the very different courses of the different mutations.
It is already known that mutations in the GNE gene lead to the development of GNEM. Besides the introduction/deletion of glycation sites, mutations can also lead to changes at different structural levels of the protein [ 50 , 52 ] or to alterations in the interaction of substrate and protein [ 52 ]. Our experiments should help to see whether age might also affect the onset and progression of GNEM.
Based on our experiments, which showed reduced activities for the glycated GNEM, one could hypothesize that glycation, in addition to the effects that mutations already have on the enzyme activity [
50
,
51
], causes the activity to drop to such a level that it can no longer be compensated for (
Figure 9
). This hypothesis assumes a mutated
GNE
gene causes a mutated GNE enzyme that appears to work adequately for a certain period of time/the activity of the enzyme is sufficient for this period. Further, we would assume a constant decrease in activity, which is due to an increasing accumulation of PTMs on the enzyme, therefore assuming that these PTMs would also have a negative effect on the activity of the enzyme (proven in this study). This would lead to reaching and exceeding the tilting point, which in turn leads to the onset of the disease.
In the case of one aforementioned diabetes mellitus and GNEM patient, the higher MGO/GO levels could increase the likelihood of reaching the required number of PTMs faster; scheme in Figure 9 : the slope of the “activity triangle” increases, causing the tilting point to shift further to the left ( Figure 9 ; towards younger years).
Nevertheless, the whole hypothesis has yet to be verified, for example, by comparing the activity of mutated enzymes with the activity of mutated and glycated enzymes, or by a study that initially deals with whether a glycated GNE can be detected at all—in cell culture and in vivo—to rule out that it is just an artefact that does not exist in reality.
Only the individual domains of the GNE were examined in this study because the purification of the GNE as whole is still quite challenging. One critical point seems to be the removal of chaperone proteins [
145
]. Furthermore, our approach enables us to better estimate the individual effects of glycation of the two domains of the GNE. The overall effect of glycation on the protein still stays unknown, and it is also uncertain whether all the glycation sites that can be glycated when treated individually, are also accessible in the overall protein in such a way that glycation is also possible at these sites. What remains significant, however, is the fact that glycation of the individual domains leads to reduced enzyme activities; the effect on the GNE-kinase domain seems to be stronger than on the GNE-epimerase domain. In a next step, these experiments could be repeated on the overall protein.
Further, it would also be interesting to investigate the downstream effects of a glycated GNE in subsequent cell culture experiments. For example, one could check whether influences in sialylation are detectable. The result could then be compared with the assumption that hyposialylation play a role in GNEMs pathophysiology [ 16 , 17 , 18 ].
Furthermore, PTMs such as phosphorylation or O -GlcNAcylation were not considered here, although it has already been shown that these can also have an effect on activity [ 85 , 86 ]. However, O -GlcNAcylation and phosphorylation represent a special type of PTMs; they are enzymatic modifications [ 146 , 147 ]. Therefore, at least in the part of the study where only the protein was treated with the glycation agent, we exclude an influence of these types of PTMs on the activity of the GNE, since the enzymes required for them are missing.
In addition, however, it is quite possible that the glycation reagents react with the amino acid side chains of the protein in a different way than previously described in this study (see, e.g., Figure 3 A), thereby generating a different type of PTM. As an example, lysine side chains could also be acylated by α-dicarbonyls as GO leading, e.g., to N 6 -glycoloyllysine (GALA; [ 148 , 149 ]). The extent to which acylation occurs in our proteins/protein domains of interest and what impact acylation can have on protein activity needs to be investigated in future studies.
Another interesting point was that the activity of the GlcNAc kinase, which, at least from just looking at its reaction schemes, appears to have the potential to stand in for the GNE kinase when needed, was not affected by GO or MGO and so seems to be resistant towards glycation—at least at the concentrations tested.
However, since there are amino acids in the sequence of the GlcNAc kinase that can be glycated (see
Figure 2
Ca and
Table 1
) as well as structural similarities to the GNE kinase, other reasons must be found why this kinase appears to be resistant to glycation—under the given conditions. The different glycation resistance found in the two kinases could also just be an artefact due to the individual examination of the GNE kinase domain. Thus, it is possible that the GNE kinase exhibits the same glycation resistance as the GlcNAc kinase when examined as whole enzyme, together with the epimerase domain. A possible steric shielding of glycation sites by the epimerase domain could be a reason for this. All of this shows once again how important it would be to study the protein as a whole.
Another cause for the different behavior of the GlcNAc kinase could be that the investigated substrate ManNAc is not its main substrate [
40
,
42
]. It was already shown that the choice and availability of the substrate have an influence on the GlcNAc kinase activity, so only GlcNAc protects the GlcNAc kinase against cysteine modifiers and not ManNAc (MalNEt + GlcNAc: 70% ± 4% (remaining activity) whereas MalNEt + ManNAc: 2% ± 1% (remaining activity); [
42
]). This suggests that the binding and stabilization of ManNAc in the active site of the GlcNAc kinase differs from GlcNAc, and maybe the interaction partners/amino acids involved are less sensitive towards glycation. Therefore, it might be interesting to repeat the GlcNAc activity assay with GlcNAc as substrate and MGO/GO as the glycation agent so that one can compare the enzyme activity found there with the activity found with ManNAc as substrate.
In the case that the GlcNAc kinase also shows a resistance to glycation with GlcNAc as substrate, it might be interesting to see how this might help in the treatment of GNEM. However, the biggest problem with seeing GlcNAc kinase as a possible replacement/substitute for the GNE-kinase is that the protein is not expressed in human skeletal muscle [
150
], which would make it impossible to function as a bypass in what are likely to be the most affected cells. On the other hand, reactivating GlcNAc kinase protein expression could be an interesting target in obtaining a functioning bypass for a non-/not-sufficient-working GNE-kinase domain. The RNA is at least expressed in the corresponding muscle cells [
150
,
151
]. Having said that, one should not disregard that GlcNAc kinase expression seems to play a role in certain types of human cancer [
152
].
Furthermore, it might also be interesting to investigate whether glycation can be reversed and thus the activity of the enzyme can be restored or at least increased back to a certain level (the pre-onset level). Fructosamine-3-kinase (FN3K; [ 153 ]) is such a protein that is able to de-stabilize fructosamines—glycation products, based on the reaction between glucose and an amino group—through phosphorylation and thus ultimately leads to their cleavage from the protein [ 154 ]. Therefore, it would be interesting to see if a correlation between FN3K and GNEM could be found—as it exists, for example, in relation to diabetes mellitus [ 155 , 156 ]. A recent study investigating the effect of ex vivo intravitreal FN3K injections on AGE-based cataracts seems to be quite promising as a potential new treatment of certain types of cataracts [ 157 ]. Therefore, it might be good to see if glucose-derived glycation products play a role in GNEM and whether activating the FN3K in muscle cells—maybe it might be possible to inject FN3K-solutions directly into the muscle (i.m.)—would remove these glycations, and so would raise the activity of the GNE back to the pre-onset level.
Based on the aim to reduce or prevent glycations, one could also perform a correlation analysis of enzymes of the glyoxalase system and GNEM. The glyoxalase system is a system that can convert MGO into D -lactic acid [ 158 , 159 ]. Therefore, maybe upregulations of glyoxalase I could help to prevent the GNE from being glycated by MGO, which is a quite ubiquitous molecule in the human body, be it through ingestion through diet, or as byproduct of glycolysis, amino acid, and fatty acid degradation [ 114 , 115 , 116 , 158 ]. However, higher expression of glyoxalase I seems to be correlated with psychiatric problems such as anxiety [ 160 , 161 ], something to keep in mind, if such a study should ever be tested as a GNEM treatment.
Altogether, our study showed that glycations with the glycation agents MGO and GO have a negative effect on the activity of the GNE-epimerase and GNE-kinase domain, but not on the GlcNAc kinase. Furthermore, GlcNAc kinase expression can be altered by GO in C2C12 cells, but not by MGO. However, none of the glycation agents tested altered the expression of the GNE.
Supplementary Materials
The following supporting information can be downloaded at:
https://www.mdpi.com/article/10.3390/biom13030422/s1
; Supplementary Table S1: Anti-CML Western blot-band intensities normalized to Ponceau; Supplementary Figure S1: Western blots—GNE-epimerase domain; Supplementary Figure S2: Western blots—GNE-kinase domain; Supplementary Figure S3: Western blots—GlcNAc Kinase; Supplementary Table S2: Data—UDP-
N
-acetyl-glucosamine 2-epimerase activity assay; Supplementary Table S3: Two-Way analysis of variance (ANOVA) of the UDP-
N
-acetylglucosamine 2-epimerase activity assay; Supplementary Table S4: Tukey post hoc-test of the UDP-
N
-acetyl-glucosamine 2-epimerase activity assay; Supplementary Table S5: Student’s
t
-test of the UDP-
N
-acetylglucosamine 2-epimerase activity assay; Supplementary Table S6: Data—
N
-acetylmannosamine kinase activity assay; Supplementary Table S7: Two-Way analysis of variance (ANOVA) of the
N
-acetylmannosamine kinase activity assay; Supplementary Table S8: Tukey post hoc-test of the
N
-acetylmannosamine kinase activity assay—NADH consumption; Supplementary Table S9: Student’s
t
-test of the
N
-acetylmannosamine kinase activity assay—NADH consumption; Supplementary Table S10:
N
-acetylglucosamine kinase activity assay—NADH consumption; Supplementary Table S11: Two-Way analysis of variance (ANOVA) of the
N
-acetylglucosamine kinase activity assay; Supplementary Table S12: Tukey post hoc-test of the
N
-acetylglucosamine kinase activity assay—NADH consumption; Supplementary Table S13: Student’s
t
-test of the
N
-acetylglucosamine kinase activity assay—NADH consumption; Supplementary Figure S4: Unprocessed C2C12 cell culture images; Supplementary Figure S5: Western Blots C2C12 cell culture; Supplementary Table S14: Results from the MTT-Assay; Supplementary Table S15:
p
-values MTT-Assay; Supplementary Table S16: Results from the qPCR; Supplementary Table S17:
p
-values qPCR—GlcNAc kinase and GNE; Supplementary Table S18: UniProt-based analysis of mutations and their effect on potential glycation sites.
Author Contributions
Conceptualization, K.B.; Data curation, V.H., R.R. and C.N.; Formal analysis, V.H. and A.G.; Funding acquisition, C.P.R.H. and R.H.; Investigation, V.H., J.L.G.L., R.R. and C.N.; Methodology, K.W. and M.-B.N.; Project administration, K.B. and A.G.; Resources, C.P.R.H., K.W. and A.G.; Software, A.C. and A.G.; Supervision, C.P.R.H. and R.H.; Validation, K.B., R.H. and A.G.; Visualization, V.H. and A.G.; Writing—original draft, V.H. and A.G.; Writing—review and editing, V.H. and A.G. All authors have read and agreed to the published version of the manuscript.
Funding
Funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)—Project ID 431232613-SFB 1449 (C.P.R.H.); Deutsche Forschungsgemeinschaft: ProMoAg-RTG 2155; and by the Deutsche Forschungsgemeinschaft: 460683975 (ProDGNE).
Institutional Review Board Statement
Not applicable.
Informed Consent Statement
Not applicable.
Data Availability Statement
All data can be found in this article and its supplement material .
Acknowledgments
We thank the group of Guido Posern (Martin-Luther-University Halle-Wittenberg, Institute for Physiological Chemistry) for kindly providing the C2C12 cells.
Conflicts of Interest
The authors declare no conflict of interest.
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Figure 1. Schematic representation of the sialic acid biosynthetic pathway.
Figure 1. Schematic representation of the sialic acid biosynthetic pathway.
Figure 4.
Investigation of the glycation success of the two GNE-domains and the GlcNAc kinase. The glycation success on each protein/protein domain was investigated through western blots by using an anti-CML antibody specifically against glycated lysines—or more precisely against carboxy-methyl-lysines. (
A
) shows the glycation of the UPD-
N
-acetylglucosamine 2-epimerase by methylglyoxal (MGO;
Aa
) or glyoxal (GO;
Ab
). Correspondingly, (
B
) shows the glycation of
N
-acetylmannosamine kinase by MGO (
Ba
) or GO (
Bb
) and (
C
) that of
N
-acetylglucosamine kinase by MGO (
Ca
) or GO (
Cb
). For each protein/protein domain, a representative Ponceau stain, a representative Western blot, and a bar graph with the anti-CML band intensities normalized to Ponceau (n = 2) were shown. At a concentration of 0 mM, buffer was added instead of a glycation agent. The relative band intensities were written directly above or underneath each band.
Figure 4. Investigation of the glycation success of the two GNE-domains and the GlcNAc kinase. The glycation success on each protein/protein domain was investigated through western blots by using an anti-CML antibody specifically against glycated lysines—or more precisely against carboxy-methyl-lysines. ( A ) shows the glycation of the UPD- N -acetylglucosamine 2-epimerase by methylglyoxal (MGO; Aa ) or glyoxal (GO; Ab ). Correspondingly, ( B ) shows the glycation of N -acetylmannosamine kinase by MGO ( Ba ) or GO ( Bb ) and ( C ) that of N -acetylglucosamine kinase by MGO ( Ca ) or GO ( Cb ). For each protein/protein domain, a representative Ponceau stain, a representative Western blot, and a bar graph with the anti-CML band intensities normalized to Ponceau (n = 2) were shown. At a concentration of 0 mM, buffer was added instead of a glycation agent. The relative band intensities were written directly above or underneath each band.
Figure 5.
Investigation of the influence of glycation on the activity of the GNE-epimerase domain by a luminescence-based assay. (
A
) Scheme of the enzyme activity test with all the relevant reactions. (
B
) Boxplot showing the determined UDP concentration (n = 5; to minimize technical noise, three technical replicates were made for each biological replicate and these values were then averaged → N = 3). (
C
) Bar graph showing whether the glycation agent affects the functionality of the assay (n = 3; N = 3). No GNE-epimerase domain was added in this part, only the assay substances, UDP and the glycation agent (MGO or GO). The abbreviation “a.u.” stands for arbitrary unit. The median was included in all quantile calculations and is represented by a line in the boxplots. The mean is indicated by x’s. Outliers are marked with circles. The boxes below the boxplots show the student’s
t
-test results for each condition. Grey asterisks indicate the results versus the negative control and black asterisks versus the positive control.
p
≤ 0.05: *, 0.005 <
p
≤ 0.01: **, and
p
≤ 0.005: ***.
Figure 5. Investigation of the influence of glycation on the activity of the GNE-epimerase domain by a luminescence-based assay. ( A ) Scheme of the enzyme activity test with all the relevant reactions. ( B ) Boxplot showing the determined UDP concentration (n = 5; to minimize technical noise, three technical replicates were made for each biological replicate and these values were then averaged → N = 3). ( C ) Bar graph showing whether the glycation agent affects the functionality of the assay (n = 3; N = 3). No GNE-epimerase domain was added in this part, only the assay substances, UDP and the glycation agent (MGO or GO). The abbreviation “a.u.” stands for arbitrary unit. The median was included in all quantile calculations and is represented by a line in the boxplots. The mean is indicated by x’s. Outliers are marked with circles. The boxes below the boxplots show the student’s t -test results for each condition. Grey asterisks indicate the results versus the negative control and black asterisks versus the positive control. p ≤ 0.05: *, 0.005 < p ≤ 0.01: **, and p ≤ 0.005: ***.
Figure 6.
Investigation of the influence of glycation on the activity of the GNE-kinase domain and of the GlcNAc kinase by a coupled enzyme assay. (
A
) Scheme of the enzyme activity test with all the relevant reactions. (
B
) Boxplot showing the determined NADH consumption per minute of the GNE-kinase domain (n = 5). (
C
) Boxplot showing the determined NADH consumption per minute of the GlcNAc kinase domain (n = 5). (
D
) Bar graph showing whether the glycation agent affects the functionality of the assay (n = 3). The abbreviation “a.u.” stands for arbitrary unit. The median was included in all quantile calculations and is represented by a line in the boxplots. The mean is indicated by x’s. Outliers are marked with circles. The boxes below the boxplots show the student’s
t
-test results for each condition. Grey asterisks indicate the results versus the negative control and black asterisks versus the positive control.
p
≤ 0.05: *, 0.005 <
p
≤ 0.01: **, and
p
≤ 0.005: ***.
Figure 6. Investigation of the influence of glycation on the activity of the GNE-kinase domain and of the GlcNAc kinase by a coupled enzyme assay. ( A ) Scheme of the enzyme activity test with all the relevant reactions. ( B ) Boxplot showing the determined NADH consumption per minute of the GNE-kinase domain (n = 5). ( C ) Boxplot showing the determined NADH consumption per minute of the GlcNAc kinase domain (n = 5). ( D ) Bar graph showing whether the glycation agent affects the functionality of the assay (n = 3). The abbreviation “a.u.” stands for arbitrary unit. The median was included in all quantile calculations and is represented by a line in the boxplots. The mean is indicated by x’s. Outliers are marked with circles. The boxes below the boxplots show the student’s t -test results for each condition. Grey asterisks indicate the results versus the negative control and black asterisks versus the positive control. p ≤ 0.05: *, 0.005 < p ≤ 0.01: **, and p ≤ 0.005: ***.
Figure 7.
Investigation of the effect of the two glycation agents, MGO and GO, on C2C12-cells with a special focus on the expression of the GNE and the GlcNAc kinase. (
A
) Representative phase contrast images of C2C12 cells, which were treated with different concentrations of the two glycation agents (partly improved in contrast and brightness (the unprocessed images can be found in
supplementary Figure S4
)). The cells in (
Aa
) were not treated with either MGO or GO, the cells in (
Ab
) were treated with 0.2 mM MGO, the cells in (
Ac
) with 0.2 mM GO, and the cells in (
Ad
) with 0.5 mM GO. Furthermore, (
B
) shows the influences of MGO (blue) and GO (green) on the cell viability of the C2C12 cells, determined by an MTT assay (n = 3), and (
C
) on the mRNA expression of the GNE and the GlcNAc kinase determined by qPCR (n = 4). (
D
) Representative Ponceau stains and western blots showing GO- and MGO-derived glycation products (n = 4). GO-derived glycation products were detected by using an anti-CML antibody and MGO-derived glycation products by using an MG-H1-antibody (immunogen: N
α
-acetyl-N
δ
-(5-hydro-5-methyl)-4-imidazolone). The band intensities were determined as the sum of all intensities per lane. Relative band intensities were written directly under each column.
p
≤ 0.05: * and
p
≤ 0.005: ***.
Figure 7. Investigation of the effect of the two glycation agents, MGO and GO, on C2C12-cells with a special focus on the expression of the GNE and the GlcNAc kinase. ( A ) Representative phase contrast images of C2C12 cells, which were treated with different concentrations of the two glycation agents (partly improved in contrast and brightness (the unprocessed images can be found in supplementary Figure S4 )). The cells in ( Aa ) were not treated with either MGO or GO, the cells in ( Ab ) were treated with 0.2 mM MGO, the cells in ( Ac ) with 0.2 mM GO, and the cells in ( Ad ) with 0.5 mM GO. Furthermore, ( B ) shows the influences of MGO (blue) and GO (green) on the cell viability of the C2C12 cells, determined by an MTT assay (n = 3), and ( C ) on the mRNA expression of the GNE and the GlcNAc kinase determined by qPCR (n = 4). ( D ) Representative Ponceau stains and western blots showing GO- and MGO-derived glycation products (n = 4). GO-derived glycation products were detected by using an anti-CML antibody and MGO-derived glycation products by using an MG-H1-antibody (immunogen: N α -acetyl-N δ -(5-hydro-5-methyl)-4-imidazolone). The band intensities were determined as the sum of all intensities per lane. Relative band intensities were written directly under each column. p ≤ 0.05: * and p ≤ 0.005: ***.
Figure 9. Schematic explaining the main hypothesis of the article—how age can influence the late onset of GNEM.
Figure 9. Schematic explaining the main hypothesis of the article—how age can influence the late onset of GNEM.
| https://www.mdpi.com/2218-273X/13/3/422 |
Sustainability | Free Full-Text | A Case Study on Sustainable Quality Assurance in Higher Education
In contemporary academia, accreditation stands as a vital process for universities to uphold their reputation and deliver quality education to students. Key Performance Indicators (KPIs) significantly contribute to this process by enabling institutions to assess their performance in crucial areas, such as student outcomes, faculty engagement, and research effectiveness. To achieve sustainable accreditation, universities necessitate a comprehensive data management system capable of handling extensive data and generating pertinent insights. High-quality education remains paramount for academic institutions to equip students with essential professional skills, thereby enabling societal economic advancement. A sustainable quality management system is an innovative approach emphasizing continuous improvement and long-term planning to enhance an organization’s overall performance and maintain a competitive edge within the sector. This paper presents a case study on sustainable quality assurance in higher education, underscoring the importance of KPIs in accreditation and the need for a robust data management system to ensure sustainability. Additionally, it highlights the significance of delivering high-quality education and the role of a sustainable quality management system in realizing this objective.
A Case Study on Sustainable Quality Assurance in Higher Education
Software Engineering and Disruptive Innovation (SEDI), College of Computer and Information Sciences, Prince Sultan University, Riyadh 11586, Saudi Arabia
Author to whom correspondence should be addressed.
Sustainability 2023 , 15 (10), 8136; https://doi.org/10.3390/su15108136
Received: 17 April 2023 / Revised: 14 May 2023 / Accepted: 16 May 2023 / Published: 17 May 2023
(This article belongs to the Special Issue Education for Sustainable Development: Toward Quality and Inclusive Education for All )
Abstract
:
In contemporary academia, accreditation stands as a vital process for universities to uphold their reputation and deliver quality education to students. Key Performance Indicators (KPIs) significantly contribute to this process by enabling institutions to assess their performance in crucial areas, such as student outcomes, faculty engagement, and research effectiveness. To achieve sustainable accreditation, universities necessitate a comprehensive data management system capable of handling extensive data and generating pertinent insights. High-quality education remains paramount for academic institutions to equip students with essential professional skills, thereby enabling societal economic advancement. A sustainable quality management system is an innovative approach emphasizing continuous improvement and long-term planning to enhance an organization’s overall performance and maintain a competitive edge within the sector. This paper presents a case study on sustainable quality assurance in higher education, underscoring the importance of KPIs in accreditation and the need for a robust data management system to ensure sustainability. Additionally, it highlights the significance of delivering high-quality education and the role of a sustainable quality management system in realizing this objective.
Keywords:
sustainable quality practices
;
quality assurance
;
higher education
;
quality management system
1. Introduction
The concept of quality has experienced a remarkable transformation over time, developing from abstract notions to practical techniques and well-defined procedures [
1
]. Quality can be characterized in various ways, such as value, adherence to requirements, suitability for use, and meeting or exceeding customer expectations [
1
]. Researchers and practitioners concur that quality is a crucial determinant of an organization’s long-term success. Al-Tarawneh and Mubaslat [
2
] posit that quality represents an ongoing process of improvement, resulting in consistent and enduring performance. Quality encompasses not only the product or service but also the organization’s reputation and its quality management practices.
In today’s fiercely competitive business landscape, quality serves as a key differentiator for organizations aiming to distinguish themselves from their counterparts [
3
4
].
Higher education institutions (HEIs) must implement high-quality services to differentiate themselves from competitors and ensure long-term viability [
4
]. To enhance the quality of services and procedures in higher education, an array of quality tools, methods, and models have been adopted. Total Quality Management (TQM), Quality Function Deployment (QFD), and, more recently, Lean Six Sigma (LSS), are examples of these approaches. While these techniques were initially developed for use in the private sector, they have since been successfully applied in public sector and not-for-profit organizations to improve efficiency, reduce costs, and enhance service quality [
5
]. HEIs have reaped substantial benefits from employing these tools and methods, such as cost savings, increased productivity, streamlined procedures, and improved customer satisfaction. However, conventional quality practices are expected to evolve to maintain their effectiveness. Elshennawy [
6
] suggests that quality professionals must adapt to a new era of advanced technology and innovation. Consequently, these professionals and their organizations are expected to refine quality-related practices and procedures by incorporating state-of-the-art technological tools, media, and strategies suitable for both manufacturing and service industries.
The primary objective of employing IT in university management of quality assurance (QA) is to enhance applicants’ satisfaction with the educational process at HEIs through the utilization of software systems [ 7 ]. It is evident that this sector requires the application of sophisticated ICT [ 8 ]. The use of ICT enables more efficient and straightforward execution of tasks such as collecting, processing, and analyzing data necessary for monitoring quality and its adequate presentation.
Effective data exchange can be hindered by the incompatibility between software products developed by different developers [
9
]. Consequently, an increasing number of HEIs are opting to purchase or develop an integrated management system that facilitates the synchronization of all aspects of higher education quality assurance. Therefore, choosing an appropriate quality management system for the educational process is a pressing concern. This issue can be addressed by evaluating current automated educational process management systems, identifying their strengths and weaknesses, and assessing the outcomes of their implementation [
10
]. HEIs either employ pre-made software packages or develop their own systems to tackle the aforementioned challenges. Factors to consider when selecting a system include the HEI units subject to automation, the types of procedures to be automated, and the system components and structure.
Establishing a sustainable data warehouse for accreditation KPIs can assist higher education institutions in streamlining the data collection and analysis process while reducing costs and enhancing accuracy. This study presents a case study on a sustainable data warehouse for accreditation KPIs in higher education, emphasizing best practices, benefits, challenges, and future opportunities.
2. Literature Review
The importance of higher education institutions to meet the standards and requirements to achieve accreditation has increased significantly in recent years. Accreditation is the process of evaluating educational institutions and programs to ensure that they meet certain standards and requirements set by accrediting bodies [ 11 ]. Accreditation Key Performance Indicators (KPIs) are critical for higher education institutions to measure and demonstrate their compliance with these standards and requirements, as well as to improve the quality of education that they provide [ 12 ].
Educational establishments have been challenged to present themselves to the public in the most favorable light possible due to increased competition and the desire to attract students. The procedures for accreditation and quality assurance necessitate the collection, processing, and evaluation of a substantial amount of data. A significant advantage comes from having the appropriate software applications to support this procedure. However, there are no such commercial applications at this time. This is due to their limited use and the unique organization of quality systems in various educational establishments, which refers to various methodologies for evaluating various educational objects and subjects, procedures, and participants.
Different software tools are used by different educational establishments to support different activities and stages of the quality assurance procedures, either partially or completely. This includes applications for data processing and report generation, data aggregation and visualization, and various combinations of commercial and university applications for data collection, processing, and analysis for various educational subjects and objects.
Awino and Agolla [
13
] published a University of Botswana case study exploring sustainable quality assurance measurement for universities. The study offers a perspective on measurement-based assessment of learning at the university level, drawing on rich literature that informs what constitutes quality assurance in higher education. The study aims to develop a sustainable quality assurance framework that can be used to measure and improve the quality of education at the University of Botswana. The framework is designed to be flexible and adaptable to the changing needs of the university and to provide a basis for continuous improvement in the quality of education. The study highlights the importance of quality assurance in higher education and the need for universities to develop sustainable quality assurance frameworks that can be used to measure and improve the quality of education over time.
Holmab et al. [
14
] conducted a comparative analysis of quality assurance in education for sustainable development (ESD) in Nordic countries and China at both the policy and implementation levels. Their findings, which are worth paying attention to, were based on two stages of research. The first stage involved analyzing literature on the subject, while the second stage consisted of conducting a special survey in two provinces of China. The study aimed to identify opportunities for improving ESD in these regions by applying quality assurance methods. By examining the similarities and differences between the approaches taken in Nordic countries and China, the research sheds light on how ESD can be effectively implemented and improved in different contexts. Overall, the study provides valuable insights into the challenges and opportunities of implementing ESD and quality assurance practices in diverse settings.
Amalia et al. [
15
] provide a description of a conceptual model of an Internal Quality Assurance System, which includes the fundamental functional requirements and scenarios. The model can be modified to meet the particular requirements of educational establishments and utilized in the initial stages of software application design and development. Estil [
16
] presented their program-based quality assurance model with a decision support system design and development work. It is a web application for evaluating university programs that meet the quality standards of the Philippine Accrediting Association of Schools, Colleges and Universities (PAASCU) and the Philippine Association of Colleges and Universities Commission on Accreditation (PACUCOA), two accreditation bodies in the Philippines. The application stores, processes, and analyzes the information it collects to support the educational institution’s management process and the preparation of accreditation-related documents.
In Indonesia, a program for evaluating academic quality was developed in 2013 [
17
]. It demonstrates Malcolm Baldrige University’s accomplishments in terms of established quality standards. A service-oriented architecture model is used in both the design and the implementation, with a focus on business intelligence. The application makes use of services to collect, integrate, and extract data from a distributed information island. Alzoabi et al. present a model of a system for assessing a university’s educational quality [
18
]. It is based on relevant indicators for the three main pillars of the education process: content, delivery, and assessment. Additionally, a Delivery Performance Indicator has been developed for performance evaluation.
An application has been developed by Shandong University to guarantee the quality of education [
19
]. The management of teaching, the management of student learning, and the visualization of data throughout the learning process are the three main aspects of the learning process that are distinguished. The application aggregates a variety of data, allowing for the identification of learning process flaws and the implementation of enhancements. Odessa Polytechnic University researchers are working in the same direction [
20
]. They have created a decision support system that takes information from student surveys. It includes modules for defining deviations from recommended values and obtaining values for unobservable learning process characteristics. This makes it possible to identify the current state of the learning process and offer appropriate suggestions for its enhancement.
Gora et al. [
21
] used a Partial Least Squares Structural Equation Modeling (PLS-SEM) approach to provide empirical evidence of the impact of quality assurance in higher education on students’ knowledge, skills, competencies, and employability in the context of sustainability. The study collected survey data from students’ perspectives to test hypotheses regarding the relationship between key factors underlying management and quality assurance in higher education. The study’s methodology is a quantitative research approach that uses statistical analysis to test the hypotheses and provide empirical evidence of the impact of quality assurance in higher education on students’ outcomes. They tested hypotheses regarding the relationship between the key factors underlying management and quality assurance in higher education. The study’s findings suggest that the quality of the educational process, infrastructure and technical equipment, practical activities, and students’ research activities influence the knowledge/competencies/skills acquired by the students. Therefore, higher education institutions can use these findings to improve the quality of their educational process, infrastructure, practical activities, and research activities to enhance students’ outcomes.
In Saudi Arabia, the higher education governance structure falls under the Ministry of Education and Education and Training Evaluation Commission (ETEC) [ 22 ]. Both entities require a set of data that are relevant to their needs. Having such a system made it easy to regularly send these data electronically, which is a sustainable way of dealing with such requests. The ETEC has several tasks, such as setting national standards for the evaluation of education and evaluating the performance of educational institutions.
The purpose of this article is to provide an overview of sustainable data warehousing for accreditation KPIs in higher education institutions. The article aims to help institutions in building an efficient and sustainable data warehouse to collect, analyze, and report the data needed for accreditation KPIs. The article also provides best practices and recommendations for the implementation of a sustainable data warehouse and highlights some of the challenges institutions may face during the implementation process.
3. Data and Quality Assurance
Any organization’s decision making process must be efficient and accurate in order to be considered successful. Depending on the nature and type of the organization—whether manufacturing or service—data can come from a variety of sources. Up until the last ten years, it was difficult for some European HEIs to access data. Bonaccorsi et al. [
23
], for instance, looked into the lack of data in 12 higher education institutions in 12 European nations and offered methods for gathering and validating data from various national sources. In some of the countries studied, national statistical services collected data centrally from individual higher education institutions, while, in others, data were collected directly from individual universities. This revealed data transparency issues. Additionally, the authors identified issues with the uniformity and quality of the data, which have an impact on the data’s veracity.
Collecting and analyzing accreditation KPI data can be challenging for higher education institutions [ 24 ]. The data are often scattered across various systems, and it can be difficult to ensure data accuracy and consistency. There are also challenges in managing data security, privacy, and access permissions, especially when dealing with sensitive information. Additionally, institutions often struggle with limited resources and budget constraints for data management and reporting.
Jacob [
25
] indicates that there are four types of data analytics: diagnostic, descriptive, prescriptive, and predictive. The most common method used in descriptive analytics is to keep track of known or suspected correlations. To find bottlenecks, diagnostic analytics use metrics such as quality process cycle times. Metrics that are concerned with predicting the future include trend analysis and the application of trend rules to SPC data. Advanced analytics are prescriptive. They usually include some degree of autonomous behavior, indicate failure, and specify what actions should be taken to address or alter the outcome. When machine learning and/or artificial intelligence (ML/AI) are utilized, analytics processes that are descriptive, diagnostic, and predictive in nature can be carried out using conventional data in traditional quality settings.
Due to the difficulty of measuring and analyzing a large amount of data, many HEIs face significant difficulties in making strategic decisions [ 26 ]. Nguyen, Gardner, and Sheridan [ 27 ] indicate that data analytics helps higher education institutions (HEIs) understand the important educational processes that help them perform better. The creators expressed that there are three significant ways of dissecting information in HEIs:
Learning Analytics: The learners and the learning processes are the focus of these analytics. To improve learning outcomes, this method collects learners’ profiles and the teaching materials used and conducts descriptive analysis on them.
Academic Analytics: Through the use of descriptive and predictive analyses, this method provides faculty members with a clear understanding of the most significant practices for enhancing learning and teaching methods.
Data Mining for Education: To gain a deeper comprehension of students and educational systems, this strategy makes use of analytics to transform unstructured data into useful information.
Instead of being used as a stand-alone, unintegrated system within the organization, the quality management system must be operated at the enterprise level. Because quality is connected to every operational and managerial aspect of every process in the value chain [
25
], this is regarded as the center of value chain creation within any organization. In order to achieve the autonomy required to shift the high-value staff focus from mechanics of execution to innovation and improvement in traditional quality practices, Jacob [
25
] stated that these processes should be synchronized and software automated before being connected. The author stated that, despite the observed progress in adoption, only slightly more than 10% of organizations adopt an integrated system. Due to the fragmented core processes that exist in today’s organizations, there has been a delay in adopting the high-quality technology that enables systems to become autonomous, a requirement for the adoption of an integrated system. As a result, organizations should align their quality processes in order for the software to automate them. All of an organization’s quality processes can be connected to other systems and operations once they have been standardized and automated. Such a connection would boost collective analytics and learnings to continuously enhance system autonomy.
The system’s central repository of data is used to monitor quality indicators and generate reports at the university or organizational unit level. The integration of existing data from individual organizational unit databases is one of the system’s main functions. The ability to record data for which there is currently no electronic record is yet another important feature. At the university level, the functionality for extracting, transforming, and loading a central data warehouse is implemented by a subsystem for the integration of existing data. Data about students, teaching staff, programs, and courses are all stored in the data warehouse. In addition, the results of student surveys are stored in the data on teaching staff for evaluation of teaching quality. Programming apparatuses in light of the utilization of business knowledge are utilized for the examination and showing of this information.
Several quality indicators are coming from several surveys. Automated and streamlining these surveys in existing systems help a great deal in making the data ready when needed. These steps are essential in any digital transformation or automation of quality aspects. Placing these surveys in the right system with a clear process that ensures the right response rate is achieved is a very important aspect of these efforts’ success. Prince Sultan University has more than nine surveys related to students, faculty, services, etc. These systems were placed in the existing system with a suitable mechanism to enforce a certain response rate.
4. Data Warehouse and Quality Assurance
Data warehousing is a crucial process that involves collecting and storing data from various sources in a centralized repository. This repository is designed to support the analysis and reporting of data, making it an essential tool for higher education institutions seeking to improve their accreditation KPIs.
A sustainable data warehouse for accreditation KPIs can help institutions collect, analyze, and report data efficiently and accurately. This is achieved through the key components of data integration, data modeling and architecture, data quality management, data governance, and reporting and analysis. These components ensure that the data collected and reported are consistent, accurate, and reliable.
To build a sustainable data warehouse for accreditation KPIs, it is essential to follow best practices. These include creating a clear data governance policy, implementing data security measures, establishing a data quality management program, ensuring data accuracy and consistency, and providing tools for reporting and analysis. By following these best practices, institutions can ensure that their data warehouse is effective and reliable, leading to improved accreditation KPIs and overall success.
There are three main layers to the traditional Business Intelligence architecture, which is based on data warehouses: the information source layer; the processing, storage, and movement of data layer; and the reporting and visualization layer. All of the system’s data sources are included in the data source layer. The Extract Transform Load (ETL) layer is in charge of extracting data from the data sources, cleansing and loading it into a staging area or other location, and finally loading it into the data warehouse. Data are presented to the decision maker in a variety of formats in the presentation layer to aid in data comprehension and decision making.
A fundamental shift in the orientation of analytics functions, particularly Institutional Research (IR), is the transformation of data into insight that drives action in more prospective and prescriptive ways. IR will be asked to guide the maturation of data use across the entire campus as analytics permeate the community. Fortunately, institutional researchers are uniquely qualified to do so because of their combination of analytical skills and a thorough understanding of their institution’s history and culture. Through the use of data analytics, IR will facilitate organizational transformation and build networks of data analysts throughout the institution.
Despite this, colleges and universities do not care about the volume of data or the variety of analysis tools unless the conditions are right for their effective use. A solid foundation of data based on accuracy, timeliness, relevance, integration, and security can be very beneficial to institutions. In order for decision makers to gain insights in close to real time, the steps of acquiring, processing, and analyzing data must be completed quickly. A lack of integration is a major obstacle to providing insight that is accurate, timely, and pertinent. Differences in storage, definition, structure (or lack thereof), and intended use are just a few of the obstacles that must be overcome when combining data from various sources. In a time when unstructured data, which can be extremely rich, account for 90% of enterprise data, connecting them to other data sources frequently entails finding ways to extract value from them [
28
]. As a result, effective integration becomes an even more crucial step in the process of generating dynamic data and insights.
In order to securely acquire, process, and analyze data from a variety of sources, the appropriate infrastructure is required. Over half (57%) of respondents to the most recent survey conducted by the Higher Education Data Warehousing Forum regarding the most pressing issues that its members face selected data governance as the most pressing issue. Technology was mentioned in six of the top twelve categories. Data quality accounted for 45%, metadata and data definitions for 42%, predictive analytics for 35%, data visualization for 34%, integration for 33%, and self-service for 30% [ 29 ].
Campuses must reorient their cultures toward a collaborative model of data-informed decision making in order to make investments in high-quality data, insights, and the infrastructure that supports them. In the absence of a culture of analytics, efforts to embed analytics may raise concerns about reducing quality, removing choice, tracking students, cutting programs and jobs, and destroying the identity of the institution. Data analytics must be integrated into a future vision that is centered on student success and institutional sustainability [
30
], and leadership must promote the use of data. Campuses willing to invest in their culture and infrastructure—two essential elements for safely and effectively harnessing the analytics revolution—will reap significant benefits.
5. PSU Case Study
This study utilized a case study research approach to investigate the implementation of a sustainable quality assurance system at Prince Sultan University (PSU). According to Yin [
31
], a case study research approach is appropriate for investigating a phenomenon within its real-life context and when the boundaries between the phenomenon and its context are unclear. In this study, the case study approach enabled an in-depth analysis of the development and implementation process of the quality assurance system within the specific context of PSU, including the roles of the Information Technology Center (ITC) and the Deanship of Quality Assurance (DQAD).
The close collaboration between ITC and DQAD was essential to the success of the implementation. This study documents the process of the implementation, reflecting on the experience and challenges faced throughout the process. The case study approach allowed for a comprehensive investigation of the implementation process and provided insights into the factors that contributed to the success of the quality assurance system at PSU.
The methodology followed at Prince Sultan University to establish a sustainable university data warehouse for accreditation KPIs calculations that will provide valuable insights and support data-driven decision making is as follows:
Define the scope of the data warehouse: Determine the data sources that will be included in the data warehouse, the types of data that will be collected, and the specific KPIs that will be calculated. These include existing systems and suggested systems, such as Student Information System, (SIS), Library Information System, and survey engine.
Identify the data integration requirements: Determine the data integration requirements for the data warehouse. This includes identifying the software and systems that will be integrated with the data warehouse, as well as the processes that will be used to extract, transform, and load the data. We mainly focus on building an integration layer, such as web services and APIs.
Develop a data model: Develop a data model for the data warehouse. This includes defining the tables, columns, and relationships that will be used to store and organize the data. We mainly focus on ETL (Extract, Transform, Load) to deal with data.
Design the data warehouse architecture: Determine the architecture for the data warehouse. This includes deciding on the hardware and software components that will be used, as well as the network infrastructure that will be required.
Implement the data warehouse: Begin building the data warehouse by setting up the hardware and software components, creating the necessary databases and tables, and implementing the data integration processes. We employ facts and dimensions in the data warehouse to ensure consistency. A fact is a piece of quantitative data that is kept in fact tables and has a foreign key relationship with several dimension tables. Facts and dimensions work together to explain the items in a fact table.
Populate the data warehouse: Once the data warehouse is set up, begin populating it with data from the various sources identified in Step 1. This may involve extracting data from existing systems, cleaning and formatting the data, and loading them into the data warehouse.
Test the data warehouse: Conduct thorough testing and validation of the data warehouse to ensure that it is functioning as expected. This may involve running queries and reports to verify that the data are accurate and that the KPI calculations are working correctly.
Train users: Provide training to users who will be working with the data warehouse. This may include training on how to access and query the data, as well as training on how to interpret the KPIs that are calculated.
Visualize the KPIs: We use Microsoft Power BI to visualize KPIs at different levels. Each level has its dashboard. Levels are institutional, college, department, and graduate programs. Dashboards contain actual KPIs, targets, and benchmarks.
Maintain and update the data warehouse: Once the data warehouse is operational, it is important to maintain it and keep it up to date. This may involve adding new data sources, updating the data model, and modifying the KPI calculations as needed.
The project started at the beginning of September 2018. The start was about studying all related KPIs and their data sources. After identifying different levels of KPIs, namely strategic, institutional, and program KPIs, and after identifying these KPIs’ levels, a wiki website was developed to document these KPIs, their data sources, and their calculation methods. The KPIs’ details were documented using the KPI card approach.
After documenting the needed KPIs, the next task is to map out the sources of the data. The sources of data were different by nature. Some of these data are transactional and can be extracted from existing systems. The included systems are Student Information System (SIS), Human Resource Management System (HRMS), Faculty Portal, Student Portal, Learning Management System (LMS), and Library Management System. Figure 1 shows these systems.
The SIS automatically pulls information about courses, registrations, and other information. These data were extracted using web services that were built on top of the system at a specific time, which was referred to as the consensus date. In a similar manner, data about faculty members and their ranks are retrieved from the HRMS. Research data, professional development, and community service are available to faculty members through the faculty portal. To streamline the collection of data, the portal is integrated with the Scopus database.
Other types of data are primarily collected through surveys. The team decided to automate the surveys and build a clear mechanism to ensure obtaining the needed response rate, which is a very common issue with surveys. After optimizing and automating these needed surveys, they were placed in existing systems to streamline the process of collecting and validating the data. Course Evaluation Survey (CES) is automated in SIS and is conducted every semester. The response rate is always more than 90%. Other surveys that are automated in SIS are Midway Survey and Program Exit Survey. Faculty and employee satisfaction surveys were automated to be part of HRMS. All other surveys related to students are placed in the student portal, such as the Alumni survey.
After mapping these data sources and automating the surveys, a conceptual diagram was designed to capture the architecture of the system. The team decided to adopt the best practices in building such a system. A data warehouse approach was built with all related methods, such as Extract, Transform, Load (ETL), Staging, Data Cubes, Data Marts, etc. For the visualization of the data and building Dashboards, Microsoft PowerBI was chosen. Several Dashboards were built for different purposes, such as Strategic, Institutional, College, and Programs dashboards.
Figure 2
shows a conceptual diagram of the data warehouse.
6. Digital Transformation and Quality Assurance
The QA objectives and criteria for education and the evaluation of teaching quality have changed because of the digital era [ 32 ]. QA in teaching and learning undergoes a digital transformation as a result, taking on new aspects. These changes include the following features:
Goals—from a single set to more varied objectives: Talents with a wider range of skills are required in the digital age. This forces a shift in emphasis from students’ knowledge acquisition to well-rounded development, including capacity building and value nurturing, as well as away from the prior standard QA aims in education.
Functions—from rating to early warning: The typical method of quality assurance (QA) in education involves assessing how well instruction is delivered and how well students are learning, and then optimizing the subsequent QA activities. QA in education is now able to gather and evaluate real-time data on student learning, teaching delivery, course implementation, and other topics because of big data and AI prediction technology. These, in turn, provide timely presentations of how teaching and learning are progressing and trend analysis of the entire process. Hence, they serve as a function for early warning.
Objects—from scattered to integrated: Following the digital revolution, QA teaching and learning objects switch from structured data analytics of a single information system to unstructured data comprehensive analytics across information systems and enterprises. Information is dispersed, links lack any meaningful relationship, and many departments only pay attention to their respective areas of responsibility in the original QA system. A QA system that has been digitally altered, however, does not face these problems because it integrates all QA components in a methodical way.
Coverage of standards—from partial and one-sided to complete and all-sided: The standards for QA in teaching and learning have changed from targeting only some instructional stages and certain aspects of instructional objectives to covering the entire educational process and all dimensions of instructional objectives as quality goals take on more dimensions and measuring and statistics are digitalized.
Teaching quality assessment—from periodic to normalized, and from sampling to total size: According to the traditional method of quality assurance in education, only a sample of the students, teachers, courses, and academic programs are evaluated, often once every two semesters. This results in insufficient influence on instruction due to inefficient assessment feedback time management and inaccurate assessment results. The data-driven intelligent teaching assessment, in contrast, increases the efficiency of measuring, assessing, and providing feedback, enabling standardized and full-size quality assessment.
Teaching quality assessment flow—from closed to open: Data were sent between several assessors under the former assessment procedure, which had limited transparency and efficiency at a high expense. The idea of data sharing and the support of digital technology has allowed for the inclusion of more items and stakeholders in the digital age. Many stakeholders can use the same database for assessments. Additionally, this facilitates communication and cooperation between university departments and outside organizations as well as within the university. It also increases the openness, transparency, and participation of the evaluation process.
Figure 3 illustrates how consolidating data onto a single platform and automating data collection processes can have a positive impact on educational environments. By enabling the blend of learning and bridging communication gaps, educational services can be provided more efficiently. Reflective monitoring of Key Performance Indicators (KPIs) through dashboards and alerts can also help to improve the quality of education.
When faculty information, student information, and learning management systems are systematized, they can jointly contribute to the achievement of UN Sustainable Development Goal 4, which is focused on quality education. Additionally, when combined with the Library system, these systems can enable the same content to be delivered, accessed, and assessed for all genders. The automated assessment system can also eliminate biases, which is aligned with UN Sustainable Development Goal 5.
These systems are designed to communicate with each other and provide real-time information regarding various KPIs. This allows for quick decision making in response to any component that needs to be addressed. Furthermore, these systems can provide access to valuable resources for students and individuals in need, which aligns with UN Sustainable Development Goal 9.
Building a single system capable of performing all tasks at the same time presents many challenges, which requires a re-evaluation of the entire education system. To address this, a Publisher–Subscriber architecture that uses web services allows different systems (both proprietary and open source) to communicate with each other. Agile methodologies can be used to construct these systems, enabling in-time fixes and actions to be taken.
By using these quality systems, educational support can be provided to all genders, and the qualification of instructors can be improved. This aligns with the goals of a 21st-century education that is agile, reflective, and responsive. These quality systems can become the foundation of 21st-century education, enabling us to accelerate development and achieve milestones, which aligns with UN Sustainable Development Goal 17.
In summary, the integration of various systems and processes can have a positive impact on education, enabling more efficient services, better communication, and improved decision making. By aligning with UN Sustainable Development Goals, these quality systems can help to improve education for all genders and enable a more agile and responsive education system.
7. Reflections on Lessons Learned
The case study conducted at PSU has yielded valuable insights into the implementation of continuous improvement processes in higher education institutions. These findings can serve as a practical guide for institutions looking to adopt similar strategies. To ensure the successful automation of processes, it is crucial to develop a comprehensive implementation plan. The DevOps model is an effective approach to automation, starting with the most critical component and continuously improving the system using the Agile methodology.
It is advisable to consolidate the data collection process and avoid implementing new systems for existing ones, if possible. The Publisher–Subscriber model is recommended to ensure data unification and system security. By following these recommendations, higher education institutions can streamline their processes and achieve greater efficiency and effectiveness.
Furthermore, the researchers have made a noteworthy observation that this model has successfully avoided employee resistance to data sharing. This is because employees remain the owners of the data, which has resulted in a more cooperative and collaborative work environment. Additionally, this model has also eliminated duplication of effort, which has led to increased efficiency and productivity.
To ensure that the system is entirely fault-proof, it is recommended to make incremental changes to the process rather than changing it all at once. This approach will allow for a more thorough and comprehensive review of the system, which will ultimately result in a more robust and reliable system.
However, the case study has identified several challenges that need to be addressed. These challenges include a lack of cooperation from system heads and staff, budgeting issues, the consolidation of different systems, the unification of data, and changing requirements from education officials and accreditation bodies.
To overcome these challenges, it is recommended to follow a DevOps model for development and integration, a Publisher–Subscriber model for data sharing, an XML-based common data language for communication, incremental system development, and incremental policy implementation based on feedback. By adopting these strategies, organizations can ensure that their systems are efficient, reliable, and meet the changing needs of their stakeholders.
In conclusion, it is essential to adopt a proactive approach to address the challenges faced by organizations in the development and integration of their systems. By following the recommended strategies, organizations can overcome these challenges and ensure that their systems are fault-proof, efficient, and meet the needs of their stakeholders.
8. Conclusions
The development of a software system for quality assurance in higher education poses significant challenges. Accreditation agencies establish indicators and quality criteria for qualitative and quantitative evaluations, complicating the process for educational institutions to adhere to such standards. Nonetheless, institutions can create their own internal quality systems to comply with these requirements. Employing software tools to automate quality assurance processes proves essential in achieving this aim. To simplify compliance with these standards and indicators, we advocate for abstraction and operation at a higher level, facilitating adaptation to changes in the standards and indicators.
This paper examined Prince Sultan University’s experience constructing its quality assurance system and the lessons gleaned throughout the process. Drawing from our successful implementation of automation concepts at PSU, we endorse the adoption of modern software development methods, such as agile methodology, for the development of a comprehensive system. We further propose implementing development incrementally and employing DevOps methodology for system integration. For data consolidation, we strongly recommend utilizing a Publisher–Subscriber-based model, which allows for rapid integration, a common data language, secure access, and reduced resistance from existing employees. By adhering to these recommendations, educational institutions can develop a robust quality assurance system that meets accreditation standards and ensures the delivery of high-quality education.
Author Contributions
Conceptualization, M.A. and Y.J.; investigation, M.A. and Y.J.; writing—original draft preparation, M.A. and Y.J.; writing—review and editing, M.A. and Y.J.; project administration, M.A. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
Not applicable.
Informed Consent Statement
Informed consent was obtained from all subjects involved in the study.
Data Availability Statement
Not applicable.
Acknowledgments
The authors would like to acknowledge the support of Prince Sultan University for paying the Article Processing Charges (APC) of this publication.
Conflicts of Interest
The authors declare no conflict of interest.
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Figure 1. Prince Sultan University data sources.
Figure 1. Prince Sultan University data sources.
Figure 2. Prince Sultan University data warehouse.
Figure 2. Prince Sultan University data warehouse.
Figure 3. Effect on SDG with taken actions.
Figure 3. Effect on SDG with taken actions.
| https://www.mdpi.com/2071-1050/15/10/8136/xml |
Debate: High Speed 2 - 10th Jul 2019 - Victoria Prentis extracts
Wed 10th Jul 2019 - Commons - High Speed 2 debate Victoria Prentis contributions to the 10th July 2019 High Speed 2 debate
High Speed 2 Debate
Full Debate: Read Full Debate
Department: HM Treasury
High Speed 2
Victoria Prentis Excerpts
Wednesday 10th July 2019
(3 years, 11 months ago)
Westminster Hall
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Victoria Prentis (Banbury) (Con)- Hansard- Copy Link-
With that in mind, Mr Hosie, I endorse wholeheartedly everything said by the first three speakers, and particularly my right hon. Friend the Member for South Northamptonshire (Andrea Leadsom), who truly eviscerated the business case for HS2. I politely disagree with the right hon. Member for Birmingham, Hodge Hill (Liam Byrne). I do not feel that £100 billion is worth some jobs in Birmingham; there may be ways to assist with employment in Birmingham other than by spending £100 billion of taxpayers’ money. [ Interruption.]I do not have time to go through all his arguments in detail, but I look forward to talking to him firmly about it later.
I will make two brief points. The first is romantic, which I make no apology for. We love our area. It is fair to say that some objections to HS2 are a form of—
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Sir Patrick McLoughlin- Hansard- Copy Link-- Excerpts
Nimbyism.
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Victoria Prentis- Hansard- Copy Link-
Nimbyism, as the former Secretary of State says.
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Craig Tracey- Hansard- Copy Link-- Excerpts
Will my hon. Friend give way?
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Victoria Prentis- Hansard- Copy Link-
No, I will carry on, if I may; I have no time.
I reject the nimbyism argument. We are building far more houses in my constituency than in the right hon. Member for Birmingham, Hodge Hill’s, finishing three a day at the moment. We embraced the Oxford-Birmingham canal in the 1790s, we embraced the M40 30 years ago and we broadly welcome east-west rail in our area. We are not against large national infrastructure projects, but we object to large national infrastructure projects with no real benefit, for us or for the nation as a whole. We feel that strongly.
As a former civil servant, the rational argument, as opposed to the romantic one, is that the process to set up HS2 causes me real pain and worry. Frankly, the Committee corridor deals done at the time of the Select Committee stink. They set neighbour against neighbour on purpose, and it was not a pleasant experience to watch. There has been a continual lack of engagement and transparency from HS2. I have a list of questions to which I have repeatedly demanded answers, and it shows no sign of taking me seriously or engaging with me. My right hon. Friend the Member for Chesham and Amersham (Dame Cheryl Gillan) had a very interesting wake-up call when she made a freedom of information request to find out what it felt about her personally. I have not yet grown a thick enough skin to make a freedom of information request about my name and HS2, and I know that my right hon. Friend the Member for South Northamptonshire has not, either.
It is disgusting that taxpayers’ money is being spent on an organisation that behaves this badly. In short, HS2 is a white elephant that is trampling over the dreams and aspirations of my constituents and I cannot support it.
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Ms Ghani- Hansard- Copy Link-- Excerpts
I know that NDAs are a particularly sore point for the Labour party right now, but we regularly engage with local authorities, sharing work at the early design stage with them, which is why they use NDAs, especially during the planning phase. They are used to protect commercially sensitive and personal information. I will take the point about using taxpayers’ money on the chin. We need to ensure that we are always using taxpayers’ money properly and transparently. We always hold HS2’s feet to the fire on all of those issues. I am happy to put all of this in writing, and to answer in writing any further questions that the hon. Gentleman has.
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Victoria Prentis- Hansard- Copy Link-
I do not want the Minister to be in any doubt that worries about NDAs come from only one side of the House. On the Conservative Benches, we are equally concerned about the governance of HS2. NDAs are a real concern to us in getting to the bottom of what is going on.
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Ms Ghani- Hansard- Copy Link-- Excerpts
As I mentioned, NDAs are used to deal with commercially sensitive or personal information. This is a large project involving a large chain of people and companies. We will put into the public domain any information that we can. We will respond to all queries from Members of Parliament within the allotted time.
Arguments have been made for and against HS2. I want to explain why this Government are committed to HS2. Every time the House has voted on this project, the Government have always won with a stomping majority. Our current infrastructure is 150 years old. It is an overstretched Victorian network. Passenger numbers have doubled in the past 20 years, and on key routes in the west coast inter-city corridor they are set to triple.
We have an overused and overcrowded railway, which is also one of the oldest. With HS2 in place, we can deal with the pressures on express trains, freight trains andslower local commuter services, which are already operating at peak capacity. That is just one of the reasons why HS2 is crucial: to solve our chronic capacity problems. I was intrigued by the argument that there will not be as many passengers using our railway network in the future. I hope this Government will not make the argument for people to stand still, but will encourage people to go out for social and work reasons.
HS2 is a new dedicated railway for fast inter-city express services, no longer encumbered by the inevitable inefficiencies associated with mixed-use lines, which will also free up huge capacity on the existing railway for more local trains, including for services to places such as Milton Keynes. In fact, 70% of the jobs created across our economy will be outside London, bringing prosperity to the north and the midlands, just as the first railways did, and not only to the cities on the high-speed line. HS2 trains will call at over 25 stations across the UK, from London to Scotland. It has already created 9,000 jobs and 200 apprenticeships. We expect that to rise to 30,000 jobs at peak construction, including over 2,000 new apprentices, many of whom will be trained at the national colleges in Doncaster and Birmingham.
| https://www.parallelparliament.co.uk/mp/victoria-prentis/debate/2019-07-10/commons/westminster-hall/high-speed-2 |
Coordination of SnCl3− ligands to {Cp*M}2+ (M = Rh, Ir) | Request PDF
Request PDF | On Mar 1, 2014, P.A. Abramov and others published Coordination of SnCl3− ligands to {Cp*M}2+ (M = Rh, Ir) | Find, read and cite all the research you need on ResearchGate
Coordination of SnCl3− ligands to {Cp*M}2+ (M = Rh, Ir)
March 2014
Journal of Organometallic Chemistry 754:32–38
DOI: 10.1016/j.jorganchem.2013.12.043
The geometries, electronic structures and donor-acceptor interactions of the geometric isomers of complexes PtH(PH3)2(L) (L=SnF3, SnF2Cl, SnBr3, and SnI3) have been investigated with electronic structure methods such as QTAIM, ETS-NOCV, and NBO, at the PBEPBE level of theory. Similarly to trichlorostannate, which was characterized before, the trihalostannate fragments act as strong σ-donor and weak π-acceptor ligands upon coordination. Based on structural parameters, their trans influences increase in the order of SnF3 < SnF2Cl < SnCl3 < SnBr3 < SnI3.
Organometallic half-sandwich Cp*Rh/Ir complexes are useful model complexes in which one hemisphere of the coordination shell is blocked by a π-bound negatively charged six-electron donor substituted cyclopentadienyl ring. The different ligands can be accommodated in the remainder of the coordination sphere to form a variety of complexes. A range of organometallic Rh/Ir pentamethylcyclopentadienyl complexes has been synthesized1, 2, 3, 4, 5, 6 and characterized as potential catalysts,⁷ anticancer agents8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 and elegant supramolecular architectures. This chapter provides an introduction to representative Cp*Rh/Ir complexes bearing various ligands with B, C, N, O, P, S and/or H donor atoms.
Relativistic effects and electron delocalization in transition metal complexes complicate the interpretation of their NMR parameters. It is very important to understand impact of such effects on structure-property relationships. Here we report a computational study of structure and NMR parameters of a series of bimetallic complex anions [Cp*M(SnCl3)nCl3-n]⁻, where M = Rh, Ir, n = 1, 2, 3. AIM and NBO analysis of chemical bonding was performed. Properties of Sn-M bonds determine large relativistic contributions for ¹¹⁹Sn NMR parameters. The difference in ¹¹⁹Sn NMR shifts between similar Ir and Rh complexes is defined mostly by large relativistic spin-orbit (SO) effects. We discuss Heavy-Atom-on-Vicinal-Heavy-Atom (HAVHA) effects. Finite nuclear model and exchange-correlation response kernel were tested in combination with various DFT functionals.
Attempts to prepare hexafluoroacetylacetonate (hfac) piano stool complexes of pentamethylcyclopentadienyl Cp* iridium and rhodium led to a surprising array of unexpected products. The desired complex, Cp*M(hfac)Cl, was obtained following the reaction of sodium hexafluoroacetylacetonate (hfacNa) with [Cp*MCl2]2 in dichloromethane. Variations of this synthetic method resulted in twelve unique crystallographically identified products, eleven of which contain the hfac ligand or a trifluoroacetylacetonate (TFA) ligand, either coordinated to the metal or as a non-coordinating anion. Five dinuclear Cp* iridium hydroxo-bridged products with various fluorinated non-coordinating anions were obtained. The most intriguing two complexes are trinuclear Cp*IrIII hydroxo-bridged clusters that have, at their core, an Ir3NaO4 cubane structure. Attempts to devise rational syntheses of the hydroxo-bridged cluster compounds were not successful. Generation of the TFA moieties likely occurred following degradation of Cp*Ir(hfac)Cl. The reaction between [Cp*MCl2]2 and 1,1,1-trifluoroacetylacetonate (tfac) proceeded as expected to give Cp*M(tfac)Cl with no observed side product formation, indicating that the metal-coordinated tfac moiety is significantly more stable than the metal-coordinated hfac moiety.
Mono‐ and bis(trichlorostannyl) complexes [MCl(SnCl3)(η⁵‐C5Me5){P(OR)3}] (1, 2) and [M(SnCl3)2(η⁵‐C5Me5){P(OR)3}] (3, 4) (M = Rh, Ir; R = Me, Et) were prepared by allowing chloro compounds MCl2(η⁵‐C5Me5)[P(OR)3] to react with anhydrous SnCl2 in refluxing 1,2‐dichloroethane. Treatment of trichlorostannyl complexes of iridium 2 and 4 with NaBH4 in ethanol afforded hydride‐trihydridestannyl derivatives [IrH(SnH3)(η⁵‐C5Me5){P(OR)3}] (5) and bis(trihydridestannyl) [Ir(SnH3)2(η⁵‐C5Me5){P(OR)3}] (6), the reaction of which with methylpropiolate HC≡CCOOMe led to trivinylstannyl derivatives [IrH{Sn[C(COOMe)=CH2]3}(η⁵‐C5Me5){P(OMe)3}] (7 a) and [Ir{Sn[CH=C(H)COOMe]3}2(η⁵‐C5Me5){P(OMe)3}] (8 a). The complexes were characterised spectroscopically (IR and ¹H, ³¹P, ¹³C, ¹¹⁹Sn NMR) and by X‐ray crystal structure determination of [Ir(SnCl3)2(η⁵‐C5Me5){P(OMe)3}] (4 a).
The coordinating properties of the trichlorostannate ligand in hydrido platinum trichlorostannato and platinum bis-trichlorostannato complexes, containing various phosphine ligands, have been elucidated by means of charge decomposition analysis, the Ziegler-Rauk Energy Decomposition with the Natural Orbitals for Chemical Valence, Domain-Averaged Fermi Hole, and natural bond orbital methods. Trichlorostannate has been found to be a strong σ-donor and a weak π-acceptor ligand with coordination properties not far from those of the cyano ligand. For back-bonding, the tin-chlorine σ∗ orbitals are mostly responsible. In contrast to previous assumptions, the 5d orbitals of tin play no role at all in the interaction with the platinum center. QTAIM calculations suggest, that the platinum-tin interaction should be interpreted as donor-acceptor, rather than covalent type. Trichlorostannate has been found to have weaker trans influence in comparison to the cyano ligand. © 2017 Wiley Periodicals, Inc.
Hydrogen selenide in M–Se and C–Se bond formation. [Cp*3Ir3Se2]2+ clusters: New synthesis, molecular and electronic structure and related studies
Reaction of [Cp*IrCl2](2) with in situ generated H2Se at 140 degrees C gives triangular cluster [Cp*3Ir(3)Se(2)](2+) which was isolated and characterized as new [Cp*3Ir(3)Se(2)](BF4)(2) (1) salt by X-ray, ESI-MS, Se-77 NMR techniques, and by theoretical calculations. The same reaction in the presence of CH2O gives two Se-containing products - [Cp*3Ir(3)(mu(3)-Se)(2)][ZnCl3(MeOH)](2)center dot MeOH (2) and (SeMe3)[ZnCl4] (3). Both complexes were characterized by X-ray diffractometry and Se-77 NMR. Cyclic voltammetry of [Cp*3M(3)Se(2)](2+) (M = Rh, Ir) is reported. Two consecutive two-electron reversible reductions have been identified for [Cp*3Rh(3)Se(2)](2+). [Cp*3Ir(3)Se(2)](2+) undergoes only a single-step two electron quasi reversible reduction. Quantum-chemical calculations show the presence of Ir-Ir bonds inside the trinuclear cluster core.
Novel oxidation resulting from the reaction of tin(II) chloride with Ir2(CO)2(μ-S)(μ-Ph2PCH 2PPh2)2: Structure of Ir2(CO)2(SnCl3) 2(μ-S)(μ-Ph2PCH2PPh2) 2
| https://www.researchgate.net/publication/259993903_Coordination_of_SnCl3-_ligands_to_CpM2_M_Rh_Ir |
eCFR :: 12 CFR 217.133 -- Cleared transactions.
eCFR
Title 12
Displaying title 12, up to date as of 5/30/2023. Title 12 was last amended 5/22/2023.
Title 12 —Banks and Banking
Risk-Weighted Assets for General Credit Risk
§ 217.133
Table of Contents
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Citation: 12 CFR 217.133 copy
URL: https://www.ecfr.gov/current/title-12/chapter-II/subchapter-A/part-217/subpart-E/subject-group-ECFR3295710cb15f6cd/section-217.133 copy
Agency :
Federal Reserve System
Part 217
Authority:
12 U.S.C. 248(a),321–338a, 481–486, 1462a, 1467a, 1818, 1828, 1831n, 1831o, 1831p-1, 1831w, 1835, 1844(b), 1851, 3904, 3906–3909, 4808, 5365, 5368, 5371, 5371 note, and sec. 4012,Pub. L. 116–136, 134 Stat. 281.
Source:
Reg. Q,78 FR 62157,62285, Oct. 11, 2013, unless otherwise noted.
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( a ) General requirements—
( 1 ) Clearing member clients.A Board-regulated institution that is a clearing member client must use the methodologies described inparagraph (b)of this section to calculate risk-weighted assets for a cleared transaction.
( 2 ) Clearing members.A Board-regulated institution that is a clearing member must use the methodologies described inparagraph (c)of this section to calculate its risk-weighted assets for a cleared transaction andparagraph (d)of this section to calculate its risk-weighted assets for its default fund contribution to a CCP.
( b ) Clearing member client Board-regulated institutions—
( 1 ) Risk-weighted assets for cleared transactions.
( i )To determine the risk-weighted asset amount for a cleared transaction, a Board-regulated institution that is a clearing member client must multiply the trade exposure amount for the cleared transaction, calculated in accordance withparagraph (b)(2)of this section, by the risk weight appropriate for the cleared transaction, determined in accordance withparagraph (b)(3)of this section.
( ii )A clearing member client Board-regulated institution's total risk-weighted assets for cleared transactions is the sum of the risk-weighted asset amounts for all of its cleared transactions.
( 2 ) Trade exposure amount.
( i )For a cleared transaction that is a derivative contract or a netting set of derivative contracts, trade exposure amount equals the EAD for the derivative contract or netting set of derivative contracts calculated using the methodology used to calculate EAD for derivative contracts set forth in§ 217.132(c)or(d), plus the fair value of the collateral posted by the clearing member client Board-regulated institution and held by the CCP or a clearing member in a manner that is not bankruptcy remote. When the Board-regulated institution calculates EAD for the cleared transaction using the methodology in§ 217.132(d), EAD equals EAD unstressed.
( ii )For a cleared transaction that is a repo-style transaction or netting set of repo-style transactions, trade exposure amount equals the EAD for the repo-style transaction calculated using the methodology set forth in§ 217.132(b)(2)or(3)or(d), plus the fair value of the collateral posted by the clearing member client Board-regulated institution and held by the CCP or a clearing member in a manner that is not bankruptcy remote. When the Board-regulated institution calculates EAD for the cleared transaction under§ 217.132(d), EAD equals EAD unstressed.
( 3 ) Cleared transaction risk weights.
( i )For a cleared transaction with a QCCP, a clearing member client Board-regulated institution must apply a risk weight of:
( A )2 percent if the collateral posted by the Board-regulated institution to the QCCP or clearing member is subject to an arrangement that prevents any loss to the clearing member client Board-regulated institution due to the joint default or a concurrent insolvency, liquidation, or receivership proceeding of the clearing member and any other clearing member clients of the clearing member; and the clearing member client Board-regulated institution has conducted sufficient legal review to conclude with a well-founded basis (and maintains sufficient written documentation of that legal review) that in the event of a legal challenge (including one resulting from an event of default or from liquidation, insolvency, or receivership proceedings) the relevant court and administrative authorities would find the arrangements to be legal, valid, binding, and enforceable under the law of the relevant jurisdictions.
( B )4 percent, if the requirements ofparagraph (b)(3)(i)(A)of this section are not met.
( ii )For a cleared transaction with a CCP that is not a QCCP, a clearing member client Board-regulated institution must apply the risk weight applicable to the CCP undersubpart D of this part.
( 4 ) Collateral.
( i )Notwithstanding any other requirement of this section, collateral posted by a clearing member client Board-regulated institution that is held by a custodian (in its capacity as a custodian) in a manner that is bankruptcy remote from the CCP, clearing member, and other clearing member clients of the clearing member, is not subject to a capital requirement under this section.
( ii )A clearing member client Board-regulated institution must calculate a risk-weighted asset amount for any collateral provided to a CCP, clearing member or a custodian in connection with a cleared transaction in accordance with requirements undersubparts EorF of this part, as applicable.
( c ) Clearing member Board-regulated institution—
( 1 ) Risk-weighted assets for cleared transactions.
( i )To determine the risk-weighted asset amount for a cleared transaction, a clearing member Board-regulated institution must multiply the trade exposure amount for the cleared transaction, calculated in accordance withparagraph (c)(2)of this section by the risk weight appropriate for the cleared transaction, determined in accordance withparagraph (c)(3)of this section.
( ii )A clearing member Board-regulated institution's total risk-weighted assets for cleared transactions is the sum of the risk-weighted asset amounts for all of its cleared transactions.
( i )For a cleared transaction that is a derivative contract or a netting set of derivative contracts, trade exposure amount equals the EAD calculated using the methodology used to calculate EAD for derivative contracts set forth in§ 217.132(c)or(d), plus the fair value of the collateral posted by the clearing member Board-regulated institution and held by the CCP in a manner that is not bankruptcy remote. When the clearing member Board-regulated institution calculates EAD for the cleared transaction using the methodology in§ 217.132(d), EAD equals EAD unstressed.
( ii )For a cleared transaction that is a repo-style transaction or netting set of repo-style transactions, trade exposure amount equals the EAD calculated under§ 217.132(b)(2)or(3)or(d), plus the fair value of the collateral posted by the clearing member Board-regulated institution and held by the CCP in a manner that is not bankruptcy remote. When the clearing member Board-regulated institution calculates EAD for the cleared transaction under§ 217.132(d), EAD equals EAD unstressed.
( 3 ) Cleared transaction risk weights.
( i )A clearing member Board-regulated institution must apply a risk weight of 2 percent to the trade exposure amount for a cleared transaction with a QCCP.
( ii )For a cleared transaction with a CCP that is not a QCCP, a clearing member Board-regulated institution must apply the risk weight applicable to the CCP according tosubpart D of this part.
( iii )Notwithstandingparagraphs (c)(3)(i)and(ii)of this section, a clearing member Board-regulated institution may apply a risk weight of zero percent to the trade exposure amount for a cleared transaction with a QCCP where the clearing member Board-regulated institution is acting as a financial intermediary on behalf of a clearing member client, the transaction offsets another transaction that satisfies the requirements set forth in§ 217.3(a), and the clearing member Board-regulated institution is not obligated to reimburse the clearing member client in the event of the QCCP default.
( 4 ) Collateral.
( i )Notwithstanding any other requirement of this section, collateral posted by a clearing member Board-regulated institution that is held by a custodian (in its capacity as a custodian) in a manner that is bankruptcy remote from the CCP, clearing member, and other clearing member clients of the clearing member, is not subject to a capital requirement under this section.
( ii )A clearing member Board-regulated institution must calculate a risk-weighted asset amount for any collateral provided to a CCP, clearing member or a custodian in connection with a cleared transaction in accordance with requirements undersubparts EorF of this part, as applicable.
( d ) Default fund contributions—
( 1 ) General requirement.A clearing member Board-regulated institution must determine the risk-weighted asset amount for a default fund contribution to a CCP at least quarterly, or more frequently if, in the opinion of the Board-regulated institution or the Board, there is a material change in the financial condition of the CCP.
( 2 ) Risk-weighted asset amount for default fund contributions to nonqualifying CCPs.A clearing member Board-regulated institution's risk-weighted asset amount for default fund contributions to CCPs that are not QCCPs equals the sum of such default fund contributions multiplied by 1,250 percent, or an amount determined by the Board, based on factors such as size, structure, and membership characteristics of the CCP and riskiness of its transactions, in cases where such default fund contributions may be unlimited.
( 3 ) Risk-weighted asset amount for default fund contributions to QCCPs.A clearing member Board-regulated institution's risk-weighted asset amount for default fund contributions to QCCPs equals the sum of its capital requirement, K CMfor each QCCP, as calculated under the methodology set forth inparagraph (d)(4)of this section, multiplied by 12.5.
( 4 ) Capital requirement for default fund contributions to a QCCP.A clearing member Board-regulated institution's capital requirement for its default fund contribution to a QCCP ( K CM) is equal to:
( 5 ) Hypothetical capital requirement of a QCCP.Where a QCCP has provided its K CCP, a Board-regulated institution must rely on such disclosed figure instead of calculating K CCPunder thisparagraph (d)(5), unless the Board-regulated institution determines that a more conservative figure is appropriate based on the nature, structure, or characteristics of the QCCP. The hypothetical capital requirement of a QCCP ( K CCP), as determined by the Board-regulated institution, is equal to:
K CCP= Σ CMi EAD i* 1.6 percent
Where:
CM iis each clearing member of the QCCP; and
EAD iis the exposure amount of the QCCP to each clearing member of the QCCP, as determined underparagraph (d)(6)of this section.
( 6 ) EAD of a QCCP to a clearing member.
( i )The EAD of a QCCP to a clearing member is equal to the sum of the EAD for derivative contracts determined underparagraph (d)(6)(ii)of this section and the EAD for repo-style transactions determined underparagraph (d)(6)(iii)of this section.
( iii )With respect to any repo-style transactions between the QCCP and a clearing member that are cleared transactions, EAD is equal to:
EAD i= max{ EBRM i− IM i− DF i;0}
Where:
EBRM iis the exposure amount of the QCCP to each clearing member for all repo-style transactions between the QCCP and the clearing member, as determined under§ 217.132(b)(2)and without recognition of the initial margin collateral posted by the clearing member to the QCCP with respect to the repo-style transactions or the prefunded default fund contribution of the clearing member institution to the QCCP;
IM iis the initial margin collateral posted by each clearing member to the QCCP with respect to the repo-style transactions; and
DF iis the prefunded default fund contribution of each clearing member to the QCCP that is not already deducted inparagraph (d)(6)(ii)of this section.
( iv )EAD must be calculated separately for each clearing member's sub-client accounts and sub-house account ( i.e.,for the clearing member's proprietary activities). If the clearing member's collateral and its client's collateral are held in the same default fund contribution account, then the EAD of that account is the sum of the EAD for the client-related transactions within the account and the EAD of the house-related transactions within the account. For purposes of determining such EADs, the independent collateral of the clearing member and its client must be allocated in proportion to the respective total amount of independent collateral posted by the clearing member to the QCCP.
( v )If any account or sub-account contains both derivative contracts and repo-style transactions, the EAD of that account is the sum of the EAD for the derivative contracts within the account and the EAD of the repo-style transactions within the account. If independent collateral is held for an account containing both derivative contracts and repo-style transactions, then such collateral must be allocated to the derivative contracts and repo-style transactions in proportion to the respective product specific exposure amounts, calculated, excluding the effects of collateral, according to§ 217.132(b)for repo-style transactions and to§ 217.132(c)(5)for derivative contracts.
( vi )Notwithstanding any other provision ofparagraph (d)of this section, with the prior approval of the Board, a Board-regulated institution may determine the risk-weighted asset amount for a default fund contribution to a QCCP according to§ 217.35(d)(3)(ii).
[Reg. Q,78 FR 62157,62285, Oct. 11, 2013, as amended at80 FR 41421, July 15, 2015;84 FR 35269, July 22, 2019;85 FR 4426, Jan. 24, 2020;85 FR 57962, Sept. 17, 2020]
| https://www.ecfr.gov/current/title-12/chapter-II/subchapter-A/part-217/subpart-E/subject-group-ECFR3295710cb15f6cd/section-217.133 |
Genes | Free Full-Text | Aberrant Splicing Events Associated to CDH23 Noncanonical Splice Site Mutations in a Proband with Atypical Usher Syndrome 1
Aims: The aim of this study was the genetic diagnosis by next generation sequencing (NGS) of a patient diagnosed with Usher syndrome type 2 and the functional evaluation of the identified genetic variants to establish a phenotype& ndash;genotype correlation. Methods: Whole exome sequencing (WES) analysis identified two heterozygous intronic variants in CDH23, a gene responsible of Usher syndrome type 1. Evaluation of the putative splicing effects was performed in vivo, in whole blood samples, and in vitro, by transfection of midigene constructs in HEK293T cells. Results: Two intronic variants were identified in intron 45 of CDH23& mdash;one novel, c.6050-15G& gt;A, and the other, c.6050-9G& gt;A, already reported as a noncanonical splice site (NCSS) mutation& mdash;with partial functional characterization. In vivo and in vitro analyses showed aberrant transcripts by the addition of 13 and 7 nucleotides to exon 46, respectively. Transcript degradation by nonsense mediated decay (NMD) in blood cells could only be prevented by cycloheximide treatment. Midigene constructs showed that the two variants contributed to exon skipping and generated aberrantly spliced transcripts. Conclusions: A combination of in vivo and in vitro assays provided a comprehensive view of the physiological effects of NCSS variants, which in this case led to a clinical reassignment of the proband as affected with atypical USH1 syndrome.
Aberrant Splicing Events Associated to CDH23 Noncanonical Splice Site Mutations in a Proband with Atypical Usher Syndrome 1
Sofía Jiménez-Ochoa 1,2 ,
Juan José Rodríguez-Ezcurra 3,† ,
Gemma Marfany 1,2,4,5,† and
Roser Gonzàlez-Duarte 1,*,†
1
DBGen Ocular Genomics, 08028 Barcelona, Spain
2
Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, Avda.Diagonal 643, 08028 Barcelona, Spain
3
Barraquer—Centro de Oftalmología Barcelona, 08021 Barcelona, Spain
4
Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER), 08025 Barcelona, Spain
5
Institut de Biomedicina de la Universitat de Barcelona-Institut de Recerca Sant Joan de Deu (IBUB-IRSJD), 08028 Barcelona, Spain
Author to whom correspondence should be addressed.
These authors are equally contributors.
Genes 2019 , 10 (10), 732; https://doi.org/10.3390/genes10100732
Received: 4 September 2019 / Revised: 17 September 2019 / Accepted: 19 September 2019 / Published: 21 September 2019
Abstract
:
Aims: The aim of this study was the genetic diagnosis by next generation sequencing (NGS) of a patient diagnosed with Usher syndrome type 2 and the functional evaluation of the identified genetic variants to establish a phenotype–genotype correlation. Methods: Whole exome sequencing (WES) analysis identified two heterozygous intronic variants in
CDH23
, a gene responsible of Usher syndrome type 1. Evaluation of the putative splicing effects was performed in vivo, in whole blood samples, and in vitro, by transfection of midigene constructs in HEK293T cells. Results: Two intronic variants were identified in intron 45 of
CDH23
—one novel, c.6050-15G>A, and the other, c.6050-9G>A, already reported as a noncanonical splice site (NCSS) mutation—with partial functional characterization. In vivo and in vitro analyses showed aberrant transcripts by the addition of 13 and 7 nucleotides to exon 46, respectively. Transcript degradation by nonsense mediated decay (NMD) in blood cells could only be prevented by cycloheximide treatment. Midigene constructs showed that the two variants contributed to exon skipping and generated aberrantly spliced transcripts. Conclusions: A combination of in vivo and in vitro assays provided a comprehensive view of the physiological effects of NCSS variants, which in this case led to a clinical reassignment of the proband as affected with atypical USH1 syndrome.
Keywords:
Usher syndrome
;
CDH23
;
splice site variants
;
functional analysis
;
phenotypic effects
1. Introduction
Usher syndrome (USH) is a group of inherited autosomal recessive disorders characterized by partial or total progressive hearing and vision loss. All Usher disease forms are clinically and genetically heterogeneous and constitute the most common cause of combined deafness and blindness [ 1 ]. Sensorineural hearing impairment is caused by abnormalities of the inner ear, and vision loss occurs as photoreceptor cells in the retina deteriorate progressively, leading to retinitis pigmentosa (RP) [ 2 ].
Three major clinical USH subtypes are distinguished: Type I (USH1), Type II (USH2), and Type III (USH3), on the basis of the severity of the clinical traits [ 1 , 3 ]. USH1 represents the most severe form, showing extensive genetic and allelic heterogeneity, and is characterized by severe to profound congenital deafness, variable vestibular areflexia, and adolescent onset retinitis pigmentosa [ 4 ]. To date, six genes have been identified as causative of USH1: MYO7A, USH1C, CDH23, PCDH15, USH1G , and CIB2 . Of those, the major gene associated with USH1 is MYO7A , which accounts for up to 70% of cases [ 5 , 6 , 7 ]. Usher Type II (USH2) is associated with moderate to severe hearing loss, absence of vestibular dysfunction, and later onset retinal degeneration. Three USH2 causative genes have been identified. Of these, the USH2A gene explains the majority of cases (85–86%) whereas GPR98 (USH2C) and DFNB31 (USH2D) account for the remainder (15–14%) [ 7 , 8 ]. Usher Type III, mainly caused by mutations in CLRN1 (USH3A), shows progressive hearing loss, variable onset of RP, and vestibular response. USH3 is rare, except in the Finnish population and among Ashkenazi Jews [ 9 ].
CDH23 , a member of the cadherin superfamily, maps to chromosome 10, encompasses more than 290 kb and 69 exons, and encodes a 3.354 amino acid protein. Cadherin family genes encode integral membrane proteins that mediate calcium-dependent cell–cell adhesion. CDH23 plays an essential role in maintaining normal retinal and cochlear function. A total of 360 different CDH23 mutations have been described to date, revealing an interesting genotype–phenotype correlation [ 10 , 11 , 12 ]. Protein truncating mutations in CDH23 due to nonsense, frameshift, or splice site pathogenic variants cause USH1, whereas missense mutations in the same gene usually are causative of non-syndromic deafness [ 12 ]. In addition, a missense mutation c.4136G > T has been associated to familial and sporadic pituitary adenomas [ 13 ]. Notably, more than 40 (>10%) of the reported pathogenic mutations in CDH23 alter the splicing pattern of the gene (an updated list of CDH23 splicing mutations is shown in Table 1 ).
In rare diseases, most pathogenic variants that disrupt splicing alter canonical donor or acceptor consensus splice sites (DS and AS, respectively), but other variants located at the flanking regions, in the so-called noncanonical splice sites (NCSS), are also emerging as causative of aberrant splicing events. NCSS variants, whether pathogenic or not, are usually detected either by direct sequencing of gene exons or after target gene and next-generation sequencing. Most intronic NCSS variants are located either at positions +3 to +6 downstream DSs, or −14 to −3 upstream ADs, including the polypyrimidine tract) [
15
], and are often classified as either variants of unknown significance (VUS) or non-disease-causing variants [
16
]. Although
in silico
algorithms can be used to assess the possible effect of the identified changes in splicing, the results of such tests are only predictive, and the precise effect of the specific mutation should be verified in functional studies. Among the potential molecular consequences of the NCSS variants, the production of aberrant transcripts due to exon skipping and/or frameshift would result in nonsense-mediated decay of transcripts bearing a premature stop codon. In fact, it has been estimated that about one third of disease-associated mutations alter pre-mRNA splicing [
17
], thus underscoring the importance of in vivo/in vitro splice assays to test and verify the pathogenicity of these types of nucleotide variants.
Here, we report the identification and in vivo characterization of a novel NCSS mutation in CDH23 (c.6050-15G>A) in double heterozygous combination with a previously reported NCSS in the same intron c.6050-9G>A mutation [ 18 ] by direct RT-PCR from fresh whole blood samples. This useful method allows the rapid and direct evaluation of the effect of VUS variants in the splicing of genes that are expressed in this accessible tissue. In addition, the effects on splicing of each allele have been individually assessed and further confirmed by in vitro splicing assays.
2. Materials and Methods
2.1. Clinical Diagnosis
An adult female patient was clinically diagnosed with Usher syndrome on the basis of ophthalmic studies that included visual acuity, visual field, fundus ophthalmoscopy, electroretinography, pure-tone audiometry, and vestibular evaluation. Because of the absence of vestibular dysfunction, the patient was preliminarily classified as USH2 type, pending confirmation by genetic diagnosis. Consent for genetic testing was obtained from the patient and family.
2.2. Samples
Peripheral blood DNA from patient and available relatives (parents and unaffected brother) were obtained using the QIAamp DNA Blood Maxi Kit (Qiagen, Hilden, Germany). After approval from the Bioethics Committee of the Universitat de Barcelona (Institutional Review Board IRB_00003099, 2016), written informed consents from all the individuals were obtained following the tenets of the Declaration of Helsinki prior to donation of blood samples. The DNA from the patient was analyzed by whole exome sequencing (WES). Variants identified in any gene associated with USH were carefully prioritized by allele frequency in gnomAD and our cohort of controls, as well as the predicted molecular phenotypic effect. Only
CDH23
showed two variants located in either exonic sequences or adjacent to the splicing sites, one of them being a reported causative mutation. The two
CDH23
variants were confirmed by Sanger sequencing. Cosegregation analysis in the family was performed by specific PCR followed by Sanger sequencing.
2.3. In Silico Analysis of the Effect of Variants in Splicing
The potential effect of the non-canonical splice variants c.6050-15G>A and c.6050-9G>A on the splicing of CDH23 was assessed comparing the wild-type and mutated sequences using four different algorithms (SpliceSite Finder, MaxEntScan, NNSPLICE, and GeneSplicer) via Alamut Genova Software, http:///www.interactive-biosoftware ).
2.4. In Vivo Splicing Analysis of CDH23 Transcripts in the Patient
After previous confirmation that
CDH23
was expressed in blood, samples from the patient and control were used to analyze the splicing pattern of exons 45-46-47 by RT-PCR. Cycloheximide was added to fresh blood samples to avoid nonsense-mediated decay of aberrant out-of-frame transcripts. Duplicate samples were obtained to compare untreated versus treated samples (cycloheximide at 100 µg/ml, incubation for 4 h at RT). After 4 h, RNAlater solution (ThermoFisher Scientific, Waltham, MA, USA) was added to both treated and untreated duplicates, following the manufacturer’s instructions. Total RNA was extracted using RiboPure-Blood Kit (Life Technologies, now ThermoFisher Scientific, Waltham, MA, USA) according to the manufacturer’s instructions. First, cDNA strand was synthesized using the qScript cDNA Synthesis Kit (QIAGEN, Hilden, Germany). For the analysis of splicing events, first-strand cDNA templates were used to amplify the region of interest (exons 45-46-47 of
CDH23
) with specific primers (Exon45F: 5′-CCTCTCACGGTGCTCAATGG-3′, Exon47R: 5′-CAAAGGCGTCCTCCTGGTTG-3′). The amplification reaction consisted of 40 cycles (94 °C for 30 s, 62 °C for 30 s, and 72 °C for 30 s). PCR products were visualized on 1.5% agarose gels stained with SYBR Safe DNA Gel Stain (ThermoFisher Scientific, Waltham, MA, USA) and sequenced. RT-PCR products were also subcloned into pGEM-T-Easy vector (Promega, Madison, WI, USA) and transformed into DH5α cells. Positive clones were analyzed by Sanger sequencing.
2.5. In Vitro Splicing Assays in HEK293T Cells
For individual analysis of each of the
CDH23
variants, (c.6050-15G>A and c.6050-9G>A), genomic fragments of 3751bp that spanned exons 45, 46, and 47 were subcloned into the HIV-tat intron of the pSPL3 expression vector (Addgene, Watertown, MA, USA). HEK293T cells were seeded on 24-well plates (50,000 cells/well) and grown in DMEM (Thermofisher Scientific, Waltham, MA, USA) supplemented with 10% of FBS (fetal bovine serum). After 24 h, the cells were lipofected with constructs bearing either the pSPL3-wtCDH23 midigene (MGC1-WT), pSPL3-mutCDH23 midigene (containing the c.6050-9G>A or c.6050-15G>A variants (MGC1-9A and MGC1-15A, respectively)), or the empty pSPL3 vector. Transfections were performed according to the manufacturer’s instructions (Lipotransfectin, Guillena, Spain). Thirty hours after transfection, cells were treated with cycloheximide (100 ug/ml) for 4 h. After 4 h treatment, untreated and treated cells were collected and lysed and total mRNA was obtained using a High Pure RNA Isolation Kit (Roche Life Sciences, Indianapolis, IN, USA). First, cDNA strand and RT-PCR of the
CDH23
region of interest were performed, as detailed above, for the in vivo analysis of transcripts. Amplified bands were directly excised from the gel, purified, and analyzed by Sanger sequencing.
3. Results
The patient, an adult woman, reported congenital deafness without vestibular dysfunction. She was using hearing aids that allowed limited verbal communication. She reported night blindness since adolescence. Eye fundus examination showed pigment deposits in the medial peripheral area, vascular attenuation, and pallor of the optic nerve (
Figure 1
A, top panels). Tomographic and autofluorescence images revealed normal macular and foveal thickness and a discrete hyperfluorescent ring in the perimacular region (
Figure 1
A, bottom panels). Color vision was normal with altered contrast adaptation. Visual field tests and three dimensional-electroretinogram (3D-ERGs) recordings showed loss of peripheral concentric vision preserving the central 10 degrees (
Figure 1
B). All these traits are associated with retinitis pigmentosa. The ophthalmological examination showed that the clinical phenotype of the patient has remained stable for the last three years. The comparison of the audiometry tests recorded at 5 years old (1995) and 2019 showed stable congenital severe hearing loss (
Figure 1
C). The initial clinical diagnosis was Usher syndrome type II, and genetic diagnosis of the patient and family was required for confirmation.
After WES analysis and prioritization of genetic variants, two nucleotide variants were identified in the
CDH23
gene: c.6050-9G>A (already reported as pathogenic in an Usher syndrome patient [
18
]) and c.6050-15G>A (novel). The two identified genetic variants were validated by Sanger sequencing and confirmed by segregation analysis in the family (
Figure 2
). Mutations in
CDH23
have already been reported as causative of both typical and atypical Usher type I. The typical form is characterized by severe hearing loss, vestibular dysfunction, and retinitis pigmentosa; when one of these traits is not present, the disorder is clinically classified as atypical USH1 [
4
].
The variant c.6050-9G>A had been previously reported to alter the splicing of exon 46, therefore, we surmised that the new variant was also pathogenic and causative of aberrant splicing. To validate this hypothesis, several prediction algorithms (SSF, MaxEnt, NNSPLICE, GeneSplicer) were used to assess the potential splicing effects of the identified variants (c.6050-15G>A and c.6050-9G>A) compared to the wild-type
CDH23
sequence. Notably, only one of these four algorithms (MaxEnt) predicted the position of the wild-type acceptor site (AS), indicating that this sequence is not a consensus AS motif. Furthermore, the two identified genetic variants introduced putative novel acceptor sites, which were predicted even with higher score values than the wild-type sequence (
Table 2
). These in silico results prompted us to check whether the
CDH23
two alleles were indeed pathogenic and altered the splicing pattern.
Considering that most pathogenic variants affecting the noncanonical AS sequence caused either exon skipping or the inclusion of additional nucleotides, the potential effects of these identified intron 45 variants might cause an in-frame skipping of exon 46, or the addition of 7 and 13 nucleotides in exon 46. Both additions would result in a frameshift, leading to premature protein truncation and subsequent transcript degradation by nonsense-mediated decay (NMD). Therefore, total whole blood samples from the proband and control were analyzed after treatment with cycloheximide (CHX) to inhibit NMD.
The variant c.6050-9G >A had been previously reported to alter the splicing of exon 46, therefore, we surmised that the new variant was also pathogenic and causative of aberrant splicing. To validate this hypothesis, several prediction algorithms (SSF, MaxEnt, NNSPLICE, GeneSplicer) were used to assess the potential splicing effects of the identified variants (c.6050-15G>A and c.6050-9G>A) compared to the wild-type
CDH23
sequence. Notably, only one of these four algorithms (MaxEnt) predicted the position of the wild-type acceptor site (AS), indicating that this sequence is not a consensus AS motif. Furthermore, the two identified genetic variants introduced putative novel acceptor sites, which were predicted even with higher score values than the wild-type sequence (
Table 2
). These in silico results prompted us to check whether the
CDH23
two alleles were indeed pathogenic and altered the splicing pattern.
Considering that most pathogenic variants affecting the noncanonical AS sequence caused either exon skipping or the inclusion of additional nucleotides, the potential effects of these identified intron 45 variants might cause an in-frame skipping of exon 46, or the addition of 7 and 13 nucleotides in exon 46. Both additions would result in a frameshift, leading to premature protein truncation and subsequent transcript degradation by nonsense-mediated decay (NMD). Therefore, total whole blood samples from the proband and control were analyzed after treatment with cycloheximide (CHX) to inhibit NMD.
Whole blood RT-PCR amplification of CDH23 45 to 47 exons ( Figure 3 A) produced one clear band corresponding to the wild-type transcript in the control ( Figure 3 A, lane 3). In contrast, two different products were amplified in the proband ( Figure 3 A, lanes 1 and 2), which became more evident after cycloheximide treatment—a shortest band that showed the size expected for exon 46 skipping ( Figure 3 A, band B) and a slower migrating band whose size was similar to that of the control ( Figure 3 A, band A). Direct sequencing of the PCR bands produced overlapping sequences from the splicing junction ( Figure S1 ). Therefore, the PCR bands from CHX-treated samples were separately cloned and sequenced, confirming that the two variants did indeed produce aberrant transcripts ( Figure S1 ). The G>A transition variant (c.6050-15G>A) generated a novel 15 bp upstream AS motif (AGCA) in intron 45, resulting in an addition of 13 bp in exon 46. This frameshift mutation would generate a truncated protein of 2029 amino acids (p.Gly2017Alafs*16). Aside from this, the variant c.6050-9G>A also created a novel acceptor site of exon 46, resulting in the frameshift addition of 7 bp in exon 46, in accordance with previous data [ 18 ]. These results confirmed the presence of nonsense-mediated decay (NMD) of the two aberrant transcripts, as they could only be amplified in cycloheximide-treated samples ( Figure 3 B, lanes 1 and 2). Of note, we also obtained amplification of wild-type spliced isoform in both cycloheximide-treated and -untreated samples from the proband, indicating that, at least in blood, some CDH23 transcripts included the correct splicing of exon 46, suggesting that some amount of wild-type protein could still be produced.
In order to assess the contribution of each allele to the splicing isoforms observed in the patient, we performed in vitro exon-trapping assays. Wild-type (WT) or mutant midigene
CDH23
constructs were generated (MGC1-WT, MGC1-15A, MGC1-9A) and tested in transiently transfected HEK293T cells (
Figure 3
B). Midigenes contain the genomic context of the genetic variant, and in this case genomic fragments spanning from exon 45 to exon 47 were amplified from the proband DNA and cloned in a suitable exon-trapping vector (pSPL3), widely used for these type of assays. Endogenous
CDH23
expression in HEK293T cells was previously ruled out by RT-PCR analysis using specific
CDH23
primers. To avoid nonsense-mediated mRNA decay, cells were incubated with cycloheximide (details in the Materials and Methods section) (
Figure 3
C). The empty pSPL3 vector was used as negative control.
Sanger sequence analysis of the RT-PCR bands derived from MGC1-WT, MGC1-15A, or MGC1-9A transfected cells revealed two bands of different sizes. The shortest band corresponded to the transcript with skipping of exon 46 (
Figure 3
C, Δex46 band). On the other hand, the largest band (
Figure 3
C, bands 2 and 3) from cells transfected with MGC1-15A and MGC1-9A produced, respectively, the expected 780 bp and 774 bp transcripts containing the 13 bp and 7 bp added to exon 46, in accordance to the in vivo results (sequences in
Figure 3
D). However, compared to the in vivo analysis, NMD of frameshift transcripts was not clearly detected in transfected cells (the same results in CHX-treated and untreated cells), neither were we able to detect the wild-type transcript encompassing exons 45-46-47 in cells transfected with MGC1-15A and MGC1-9A.
4. Discussion
In order to secure the clinical diagnosis and provide an accurate prognosis for people affected with Usher syndrome, it is essential to identify the causative gene and assess the functional consequences of the nucleotide variants, particularly intronic variants, which can modulate the phenotypic severity depending on the combination of alleles. The phenotypic impact of non-coding variants in some diseases has already been illustrated by mutations in
ABCA4,
the major gene of Stargardt disease, where the functional analysis of NCSS and deep intronic variants have been crucial for the molecular diagnosis of unsolved cases and drawing genotype–phenotype correlations [
19
,
20
,
21
].
In this study, we identified two
CDH23
noncanonical splice site (NCSS) variants in an Usher syndrome patient, one of them being novel (c.6050-15G>A). Many mutations altering the splicing of
CDH23
, both in canonical and noncanonical splice sites, were reported, associated with an ample range of phenotypic severity of USH1 (a complete list of intronic
CDH23
mutations can be found in
Table 1
). The pathogenicity of the two identified NCSS variants in our proband was confirmed after analysis of the
CDH23
splicing pattern in vivo and in vitro. Canonical splice site mutations usually resulted in exon skipping, while the associated molecular effects of NCSS variants depended on the sequence alteration, the genomic context, and tissue-specific splicing factors [
15
]. In this work, bioinformatic analysis of the two
CDH23
NCSS variants predicted a shift in the AS splice site, and suggested their potential pathogenic effect. It is remarkable that the two nucleotide variants identified were located in the same intronic sequence and shifted the AS position, suggesting that the intron 45 AS is not a strong splicing motif, in accordance with the fact that most prediction algorithms miss the canonical WT AS.
The in vivo functional analysis of both
CDH23
intron 45 variants (c.6050-9G>A and c.6050-15G>A) showed not only the production of aberrantly spliced products (thus confirming the pathogenicity of the NCSS variants), but also the presence of relatively low levels of WT transcript (exons 45-46-47). Variable proportions of mutant and normal transcripts have been reported to be tissue-dependent in atypical Usher syndrome type I patients [
22
], and thus the splicing of
CDH23
is likely to show different regulation in whole blood and cochlea or retina, consequently explaining the milder phenotype (non-progressive RP and no vestibular dysfunction) of the proband, altogether leading to the reassignation of the clinical entity from USH2 into atypical USH1.
The in vivo functional assays in whole blood of the proband confirmed the NMD of aberrantly spliced products of c.6050-9G>A and c.6050-15G>A
CDH23
variants, as expected for frameshift-causing mutations, since they could only be detected after cycloheximide treatment. In addition to the aberrant inclusion of extra nucleotides, the functional in vitro assays with
CDH23
midigene constructs were used to confirm the contribution of each individual mutation to the skipping of exon 46. Our results in transfected cells also supported the weakness of the WT AS of exon 46, since the control WT construct mainly produced the exon 46-skipped form, and very low levels of the correctly spliced transcript could be detected. In fact, the transcript with exon 46 skipping was in frame and may be of physiological value. Of note, exon 46 skipping has also been reported in patients carrying a mutation in the NCSS of the DS of exon 45 [
14
]. We believe that the combination of in vivo and in vitro assays, as those performed in our work, gives a more complete view of the physiological consequences of NCSS variants. NMD-mediated degradation of aberrant transcripts has only been detected using in vivo assays, whereas the individual contribution of each allele to altered splicing events could be evaluated by single construct transfections in vitro. Indeed, in vivo transcriptional analysis is restricted to cases where the gene of interest is expressed in whole blood or amenable tissues. Nonetheless, it is also worth considering that the relative amounts of differently spliced forms might shift in specific organs/tissues, such as the retina or inner ear. In fact, a tissue-specific splicing effect in the inner ear vs retina of a NCSS
MYO7A
(another Usher type I causative gene) mutation (c.5742+5G>A) has been reported in a mouse animal model [
23
], overall supporting the complexity of the phenotypic spectrum of the NCSS mutations.
Supplementary Materials
The following are available online at https://www.mdpi.com/2073-4425/10/10/732/s1 , Figure S1: Sanger sequencing of the CDH23 transcripts detected in vivo.
Author Contributions
Conceptualization, R.V., G.M., and R.G.D.; methodology, R.V., M.d.C.-M., and S.J.-O.; formal analysis, J.J.R.-E.; investigation, R.V. and G.M.; writing—original draft preparation, R.V., J.J.R.-E., G.M., and R.G.D.; writing—review and editing, R.V., G.M., and R.G.D.
Funding
This activity was sponsored by DBGen Ocular Genomics and by grants SAF2016-80937-R (Ministerio de Economía y Competitividad/FEDER), 2017SGR-0738 (Generalitat de Catalunya) to G.M. and R.G.D.
Acknowledgments
The authors are grateful to the patient and her family for their continued support to this genetic study.
Conflicts of Interest
The authors hereby declare that there is no competing interest.
References
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Figure 1. Clinical findings of patient 96DBG1 diagnosed with Usher syndrome. ( A ) Eye fundus of the right eye (RE) and left eye (LE) at 29 years of age, showing pigment peripheral deposits, vascular attenuation, and pallor of the optic nerve. Autofluorescent images show a hyperfluorescent ring in the perimacular region. ( B ) Multifocal electroretinogram (ERG) plots of the right (RE) and left (LE) eyes with the three-dimensional (3D) representation showing concentric visual loss with preserved vison in the central 10 degrees area. ( C ) Audiometry scores of tests performed at 5 years old (dotted lines) and at 29 years old (straight lines), right ear—red, and left ear—blue.
Figure 1. Clinical findings of patient 96DBG1 diagnosed with Usher syndrome. ( A ) Eye fundus of the right eye (RE) and left eye (LE) at 29 years of age, showing pigment peripheral deposits, vascular attenuation, and pallor of the optic nerve. Autofluorescent images show a hyperfluorescent ring in the perimacular region. ( B ) Multifocal electroretinogram (ERG) plots of the right (RE) and left (LE) eyes with the three-dimensional (3D) representation showing concentric visual loss with preserved vison in the central 10 degrees area. ( C ) Audiometry scores of tests performed at 5 years old (dotted lines) and at 29 years old (straight lines), right ear—red, and left ear—blue.
Figure 2. Pedigree of family 96DBG with the segregation analysis of CDH23 variants.
Figure 2. Pedigree of family 96DBG with the segregation analysis of CDH23 variants.
Figure 3.
In vivo and in vitro splicing analysis of the identified
CDH23
alleles. (
A
) Analysis of the
CDH23
CDH23
transcripts in addition to the wild-type transcript. Lane 1—patient sample (−CHX), Lane 2—patient sample (+CHX), Lane 3—control sample (−CHX), Lane 4—negative control. The band of 563 bp corresponded to the transcript with an in-frame skipping of exon 46. The band around 760–780 bp corresponded to the wild-type as well as to the aberrant transcripts with additional +7 and +13 nucleotides. Subsequent Sanger sequencing of cloned individual bands confirmed the insertion of 7 bp and 13 bp (774 pb, 780 pb bands) corresponding to each mutant allele. Transcripts bearing premature stop codon due to frameshift were only amplified in cycloheximide-treated blood samples (+CHX). (
B
) Schematic representation of the studied genomic region of
CDH23
gene and the midigene construct for in vitro splicing assays (MGC1). The position of each mutation is indicated. The genomic region encompassing exons 45, 46, and 47 was cloned between the splice donor (SD) and acceptor (SA) sites within the pSPL3 vector. (
C
) In vitro splicing assays in HEK293T cells transfected with either the wildtype (WT) or mutant
CDH23
midigenes (MGC1-WT, MGC1-15A, and MGC1-9A, respectively) with or without cycloheximide treatment (+CHX). All constructs (MGC1-WT, MGC1-15A, and MGC1-9A) produced skipping of exon 46. CHX treatment in cells transfected with the mutant constructs increased the relative amplification of the aberrantly spliced transcripts. (
D
) Sanger sequence analysis of each transcript band confirmed the wild-type splicing event in cells transfected with MGC1-WT, in contrast to the addition of +13 and +7 nucleotides in exon 46 in cells transfected with MGC1-15A and MGC1-9A, respectively.
Figure 3. In vivo and in vitro splicing analysis of the identified CDH23 alleles. ( A ) Analysis of the CDH23 mRNAs of whole blood samples (treated and untreated with cycloheximide, CHX) from patient and control by RT-PCR, showing the presence of aberrantly spliced CDH23 transcripts in addition to the wild-type transcript. Lane 1—patient sample (−CHX), Lane 2—patient sample (+CHX), Lane 3—control sample (−CHX), Lane 4—negative control. The band of 563 bp corresponded to the transcript with an in-frame skipping of exon 46. The band around 760–780 bp corresponded to the wild-type as well as to the aberrant transcripts with additional +7 and +13 nucleotides. Subsequent Sanger sequencing of cloned individual bands confirmed the insertion of 7 bp and 13 bp (774 pb, 780 pb bands) corresponding to each mutant allele. Transcripts bearing premature stop codon due to frameshift were only amplified in cycloheximide-treated blood samples (+CHX). ( B ) Schematic representation of the studied genomic region of CDH23 gene and the midigene construct for in vitro splicing assays (MGC1). The position of each mutation is indicated. The genomic region encompassing exons 45, 46, and 47 was cloned between the splice donor (SD) and acceptor (SA) sites within the pSPL3 vector. ( C ) In vitro splicing assays in HEK293T cells transfected with either the wildtype (WT) or mutant CDH23 midigenes (MGC1-WT, MGC1-15A, and MGC1-9A, respectively) with or without cycloheximide treatment (+CHX). All constructs (MGC1-WT, MGC1-15A, and MGC1-9A) produced skipping of exon 46. CHX treatment in cells transfected with the mutant constructs increased the relative amplification of the aberrantly spliced transcripts. ( D ) Sanger sequence analysis of each transcript band confirmed the wild-type splicing event in cells transfected with MGC1-WT, in contrast to the addition of +13 and +7 nucleotides in exon 46 in cells transfected with MGC1-15A and MGC1-9A, respectively.
Table 1. Splicing mutations described in the CDH23 gene, with their nucleotide position and associated phenotype (from the Human Gene Mutation Database, updated with mutations in [ 14 ], highlighting the mutations in intron IVS45 and those identified in this work (in red)).
Table 1. Splicing mutations described in the CDH23 gene, with their nucleotide position and associated phenotype (from the Human Gene Mutation Database, updated with mutations in [ 14 ], highlighting the mutations in intron IVS45 and those identified in this work (in red)).
Mutation GRCh37/hg19 Intron Disease c.145+6T>G 73206158 IVS-2 Usher syndrome 1 c.288+1G>C 73269982 IVS-3 Usher syndrome 1 c.336+1G>A 73270759 IVS-4 Usher syndrome 1d c.429+4G>A 73270973 IVS-5 Non-syndromic autosomal recessive deafness c.1134+1G>A 73377151 IVS-10 Usher syndrome 1 c.1135-1G>T 73403617 IVS-10 Hearing loss c.1987-2A>C 73447402 IVS-17 Usher syndrome 1 c.2176+1G>C 73450342 IVS-19 Deafness, non-syndromic, autosomal recessive c.2177-2A>G 73453902 IVS-19 Usher syndrome 1 c.2289+1G>A 73454017 IVS-20 Usher syndrome 1d c.2289+6T>G 73454022 IVS-20 Hearing loss, non-syndromic c.2398-1G>T 73461778 IVS-21 Retinal disease c.2587+1G>T 73461969 IVS-22 Usher syndrome 1 c.3580-1G>T 73490225 IVS-29 Usher syndrome 1 c.4104+4A>T 73492136 IVS-31 Usher syndrome 1 c.4105-4_4105-2delGCAinsTCT 73493993 IVS-31 Usher syndrome c.4489-2A>C 73500577 IVS-35 Usher syndrome c.4846-3C>G 73537434 IVS-37 Hearing loss, autosomal recessive c.5068-2A>T 73537944 IVS-38 Usher syndrome 1 c.5187+2T>C 73538067 IVS-39 Usher syndrome 1 c.5368+1G>A 73539205 IVS-40 Usher syndrome 1 c.5820+5G>A 73545500 IVS-43 Sector retinitis pigmentosa and hearing loss c.5821-2A>G 73548695 IVS-43 Usher syndrome 1 c.5923+1G>A 73548800 IVS-44 Usher syndrome c.5924-2A>C 73550043 IVS-44 Hearing loss c.6049G>A 73550170 E-44 NCSS IVS-45 Usher syndrome 1 c.6049+1G>A 73550171 IVS-45 Usher syndrome 1 c.6050-1G>C 73550888 IVS-45 Usher syndrome 1 c.6050-9G>A 73550880 IVS-45 Usher syndrome 1 c.6050-15>A 73550874 IVS-45 Usher syndrome 1 c.6712+1G>A 73553398 IVS-47 Usher syndrome 1 c.6829+1G>A 73556978 IVS-48 Usher syndrome 1 c.6829+2T>C 73556979 IVS-48 Usher syndrome 1 c.6830-2_6830delAGC 73558109 IVS-48 Usher syndrome 1d c.7225-2A>G 73559247 IVS-50 Usher syndrome 1 c.7362+5G>A 73559391 IVS-51 Usher syndrome 1 c.7482+1G>A 73560513 IVS-52 Usher syndrome c.7660+1G>T 73562833 IVS-53 Usher syndrome 1 c.7660+5G>A 73562837 IVS-53 Hearing loss c.8064+2T>C 73565756 IVS-55 Usher syndrome 1 c.8722+1delG 73567765 IVS-59 Usher syndrome 1 c.9199-4G>A 73571264 IVS-62 Usher syndrome 1 c.9278+5G>C 73571352 IVS-63 Usher syndrome 1 c.9510+19_9510+25delGGCATCA 73572385 IVS-66 Usher syndrome 1 c.9510+1G>A 73572367 IVS-66 Usher syndrome 1
Table 2. In silico analysis using the Alamut program showing the splicing predictor scores and the in vivo and in vitro functional effects of mutations c.6050-9G>A and c.6050-15G>A (our data).
Table 2. In silico analysis using the Alamut program showing the splicing predictor scores and the in vivo and in vitro functional effects of mutations c.6050-9G>A and c.6050-15G>A (our data).
NR: not recognized, WT: wild-type. In red- altered splicing scores and aberrant splicing events .
| https://www.mdpi.com/2073-4425/10/10/732/htm |
Diagnostics | Free Full-Text | Cardiovascular Adaptations to Four Months Training in Middle-Aged Amateur Long-Distance Skiers
Cross-country skiing has a positive effect on health. However, without an individual, thoughtful, and professional plan, it can cause irreversible health problems from overload and injury. The impact of exercise on results is well understood within the group of professional athletes. However, this remains unknown within the group of amateur cross-country skiers and marathon runners& mdash;in particular, the impact of the summer preparation period in which training loads performed in the oxygen zone combined with resistance training dominate. The aim of this study was to assess changes in the cardiovascular capacity and body mass composition of male cross-country skiers in the preparation period of their macrocycle. Variables were analyzed using basic descriptive statistics: mean and standard deviation (SD). To compare the results from both measurements (initial and final) the paired Wilcoxon test was used. A statistically significant increase was noted in maximum oxygen uptake and maximum minute ventilation, and a decrease in body fat content, maximum lactate concentration and lactate threshold, and heart rate on anaerobic threshold. Research indicated that in the amateur group increases similar to those in top competitors were achieved in the parameters tested, but the initial level was often significantly lower.
Cardiovascular Adaptations to Four Months Training in Middle-Aged Amateur Long-Distance Skiers
by Natalia Grzebisz
Vistula School of Hospitality, Faculty of Dietetics, 02-787 Warsaw, Poland
Diagnostics 2020 , 10 (7), 442; https://doi.org/10.3390/diagnostics10070442
Received: 16 June 2020 / Revised: 26 June 2020 / Accepted: 28 June 2020 / Published: 30 June 2020
(This article belongs to the Special Issue Diagnostic Challenges in Sports Cardiology )
Abstract
:
Cross-country skiing has a positive effect on health. However, without an individual, thoughtful, and professional plan, it can cause irreversible health problems from overload and injury. The impact of exercise on results is well understood within the group of professional athletes. However, this remains unknown within the group of amateur cross-country skiers and marathon runners—in particular, the impact of the summer preparation period in which training loads performed in the oxygen zone combined with resistance training dominate. The aim of this study was to assess changes in the cardiovascular capacity and body mass composition of male cross-country skiers in the preparation period of their macrocycle. Variables were analyzed using basic descriptive statistics: mean and standard deviation (SD). To compare the results from both measurements (initial and final) the paired Wilcoxon test was used. A statistically significant increase was noted in maximum oxygen uptake and maximum minute ventilation, and a decrease in body fat content, maximum lactate concentration and lactate threshold, and heart rate on anaerobic threshold. Research indicated that in the amateur group increases similar to those in top competitors were achieved in the parameters tested, but the initial level was often significantly lower.
Keywords:
cardiovascular capacity
;
cross-country skiing amateur
;
heart
Graphical Abstract
1. Introduction
Monitoring of physical effort in competitive sport is a key element in the training process used by trainers, physiologists, and doctors. It also allows to assess the health and capacity of amateurs. In particular, the determination of cardiovascular capacity parameters establishes the initial level before training, allows to assess the progress made and to predict the negative impact of excessive physical exertion. This applies in particular to endurance efforts such as long-distance cross-country skiing. It requires many years of physical activity and the use of periodization of training, for example, to avoid overloading and its negative impact on health.
The parameter used to assess exercise capacity in endurance athletes is the maximum oxygen uptake (VO
2max
). Its level and change during many years of training is very well described in the literature when it comes to professional athletes. However, there are no reports on the impact of physical effort on the level and change of VO
2max
in amateur long-distance skiing, which significantly differs in terms of requirements from other sports.
In recent years long-distance skiing (especially the Ski Classics series) has gained the attention of scientists, but the research has been focused on elite skiers [ 1 ]. To my knowledge, this paper is the very first on amateur long-distance skiers and their cardiovascular capacity.
The majority of popular long-distance races (30 up to 220 km) are easy in terms of track profile (flat sections and slight climbs, easy downhills), but this type of effort is long-term and characterized by near-threshold intensity. It requires not only efficiency, but also good technique [ 2 ].
Cross-country skiing is one of the most demanding sports. In addition to the high energy demand, the specificity of the effort is also important. It involves all body muscles, especially the upper parts [ 3 , 4 ].
This discipline has a positive effect on health. Scientists emphasize the role of systematic physical activity in improving the cardiovascular risk profile and body weight composition in middle-aged men. In the population low body mass index and high body fat percentage are associated with increased mortality. Therefore, qualitative and not quantitative changes in the body are important. In addition, body fat content should be within the reference ranges. This may bring greater cardiovascular benefits than a decrease in body mass index with a decrease in muscle mass [ 5 ].
However, without an individual, thoughtful, and professional plan, it can cause irreversible health problems from overload and injury. This is why it is so important to be aware of the body and to control the impact of training. An additional advantage of monitoring is a better adaptation of the training plan and the prevention of fatigue and overtraining. The monitoring process should apply to both athletes and amateurs. Both groups exert submaximal and maximum effort during competition, but professional athletes have a coaching team that checks for negative changes in the body [ 6 ].
Amateurs have to take care of this themselves, in terms of physiotherapy, physiological monitoring, biochemistry, diet, supplementation, training loads, as well as monitoring progress. Their work and private lives also have a significant impact on these changes. The impact of exercise on results is well understood within the group of professional athletes. However, it remains unknown within the group of amateur cross-country skiers and marathon runners—in particular, the impact of the summer preparation period, in which training loads performed in the oxygen zone combined with resistance training dominate. The use of roller skis is also unique, as it not only involves almost all muscles in the body but also relieves the joints [
7
].
The aim of this study was to assess changes in the cardiovascular capacity of cross-country skiers in the preparation period of their macrocycle (the annual cycle of preparations of athletes).
2.1. Subjects
The study was conducted in accordance with the guidelines of Good Clinical Practice and the Helsinki Declaration. The study was approved by the Bioethics Committee at the Faculty of Human Nutrition and Consumption at Warsaw University of Life Sciences (SGGW) (Nr. 38p/2018, approved on 22 January 2019). All subjects and parents gave their written consent before any testing. The research group consisted of 16 well-trained amateur skiers (mean age 37.5 +/− SD years, and 37.9 in the second test). The competitors worked professionally in a big city and could spend up to 90 min daily for physical training. There were no data on cardiovascular risk factors and changes in response to training for this group.
The research was carried out at the end of the transitional period in May and after the preparation period in September. The criteria for inclusion in the study were: consent to participate in the study, possession of current medical approval, and completion of at least three long-distance races in the last season. Exclusion criteria were: lack of consent for participation in the study, poor health (any disease occurrence), or lack of medical consent.
2.2. Anthropometric Measurements
Body weight was measured on the Tanita MC-980 MA Plus Body Composition Analyzer, consisting of an eight-point touch electrode system. The test was carried out just before the incremental exercise tests began. The following were determined: body weight, water content, minerals, vitamins, fat content in the body (% and kg) and slim mass muscle (muscle mass in % and kg), WHR (waist-to-hip ratio), and BMI (body mass index). All measurements were carried out at Sportslab Sports Diagnostics Center in Warsaw, Poland.
2.3. Measurement of Aerobic Capacity (VO 2max Test)
To assess the aerobic capacity expressed by the level of maximum oxygen uptake (VO 2max ) a time trial test was used with gradually increasing intensity. This test was performed on a treadmill using HP Cosmos CPET equipment and Cosmed Quark/k4B2. The test started at a speed of 6 km/h and a 0% treadmill inclination. Then every 3 min, the speed was increased by 1 km/h, and the inclination by 1%. The test was continued until the subjective feeling of exhaustion by the competitor (to refuse). The frequency of heart contractions at rest and during exercise was recorded using the Garmin ANT+ heart rate monitor. The paper presents the maximum results of the test below. Dr. Müller Super GL Analyser was used to measure lactate concentrations. All measurements were carried out at Sportslab Sports Diagnostics Center in Warsaw, Poland.
2.4. Training Loads
For four months, the skiers performed a systematic endurance and strength effort. It consisted of running, resistance training in the gym, cycling, and, above all, targeted training, which was on roller skis. Individual exercise zones were designated for each person during the first exercise studies.
Figure 1 , Figure 2 and Figure 3 summarize the comprehensive efforts (running, cycling, swimming, general development exercises) and targeted training (ski imitation, roller skis, Ercolina, which is the machine for strengthening the arms and upper body, and special exercises). These data contain information about the intensity and volume of hourly training during the test period. The intensity was pre-rated in five exercise zones: I, II-aerobic, AT (anaerobic threshold)-mixed, anaerobic-Submaximal (Submax), and maximal (Max).
2.5. Statistics
Variables were analyzed using basic descriptive statistics: arithmetic mean and standard deviation (SD). To compare the results from both measurements (initial and final) the paired Wilcoxon test was used, taking a materiality level of 0.05. The value of 0.05 was assumed as the significance level (denoted by * p < 0.05, * p < 0.01, *** p < 0.001).
3. Results
A comparison of the results of the body weight and exercise parameters of the first and second tests is presented in Table 1 . Statistically significant changes were recorded in the: percentages of body fat mass, body fat mass (kg), VO 2max (relative) (mL/kg/min), maximum lactate concentration (mmol/L), maximum ventilation (L/min), lactate concentration (on the threshold) AT (mmol/L), and breathing rate on AT (bpm). The other parameters did not show statistically significant changes (see Table 1 ).
4. Discussion
The main findings of this study are: (1) a statistically significant change in relative VO
2max
(
p
= 0.008), similar to that in elite cross-country skiing; (2) a change in body fat mass (in absolute terms as well as in %); (3) a change in maximum ventilation.
In the study, the largest statistically significant change was recorded in relative VO
2max
(
p
= 0.008). This corresponded to an increase of 2.1 mL/kg/min, which was 4.3% on a percentage basis. There are a lack of publications on the impact of a training program (especially roller ski training) on performance parameters in amateur long-distance skiing that could be used to compare these changes. However, we can compare the results to research on other endurance disciplines, e.g., triathlon. A group of 32 participants followed a training program lasting five months with the goal to finish the Half-Ironman competition (which is a long-distance event, similar in hours of effort to 90 km of skiing) [
8
]. The program significantly increased the maximal oxygen consumption of participants (45.9 ± 8.2 to 48.6 ± 7.5 mL/kg/min,
p
= 0.002) and the difference between tests was 5.9%. In elite cross-country skiing the change in relative VO
2max
was slightly lower (3.1 ± 4.5%) in response to loads in the preparation mesocycle [
9
].
These results confirm that regular physical activity increases the values of VO
2max
, which is the main indicator of the fitness level. Many other studies have also confirmed the positive effects of regular training on VO
2max
for people over 30 years of age. These effects were greater in the cases of people who led sedentary lifestyles, as well as in cases of introducing HIIT (high intensity interval training) to the training program [
10
]. Furthermore, high-intensity exercise may reduce by up to 50% the decline in VO
2max
in young and middle-aged men if the activity is maintained long term. It is worth noting that age-related loss of VO
2max
is 10% [
11
]. Researchers indicated that in the elite the changes occurred between the early, middle, and late preparation phases of the macrocycle with minor changes in the competitive season [
12
]. It can be assumed that this period of preparation in amateurs also significantly affects health-related changes in the body.
It is worth emphasizing that studies did not show significant differences between the results of the time-to-exhaustion test in running and roller skiing. Elite cross-country skiers did not elicit higher VO
2max
during roller ski skating than during running, and this relationship did not change during the pre-season training period. This may be a monitoring tip for trainers and physiologists, for whom the use of roller skis on a treadmill is limited or impossible.
Several studies have demonstrated that male and female world-class skiers are among the endurance athletes with the highest VO
2max
. Accordingly, world-class performance has been associated with maximal values above 70 and 80 mL/kg/min, or 4.0 and 6.0 L/min, in female and male skiers, respectively [
13
]. Values of VO
2max
[
14
] in a group of athletes (55.46 mL/kg/min) were significantly greater than in a group of nonathletes (37.78 mL/kg/min), and, in particular, aerobic athletes (like runners, cyclists, and skiers, excluding sprinters) showed higher values than anaerobic athletes (like sprinters and heavy weightlifters) (58.88 mL/kg/min vs. 52.04 mL/kg/min).
Increasing the VO 2max , lowering the fat content, and increasing the ventilation are evidences of good adaptation to the effort and an increase in the cardiovascular efficiency [ 15 ]. Minute ventilation and lung diffusion capacity are factors related to the functioning of the respiratory system affecting the value of VO 2max . In people with good physical fitness it is about 110–130 L/min, in sportsmen 150–160 L/min, and in some cases up to 200–210 L/min [ 16 ]. Its increase, as in these studies, indicates an improvement in exercise capacity and better oxygenation of the body during maximum effort.
Higher maximum values have been recorded [ 17 ]. The winners of Marcialonga, Vasaloppet, and Birkebeinerrennet (which are the three most prestigious long-distance ski races) also presented higher values [ 18 ]. Of course, it is not surprising, if we take into consideration the generally higher sports level of subjects and professional training. Elite skiers train mostly around 20–25 h per week during the preparation period from May to October [ 3 ]. In this study amateur skiers trained a mean of 41.7 h per month, which is 10.4 h per week.
As a result, amateurs show lower maximum values for minute ventilation. Therefore, the tendency and increase in response to training should be evaluated. It also indicates a positive adaptation of the cardiovascular system to effort.
Statistically significant differences were also shown in cases of the percentage and kilogram reductions of body fat. Studies have shown that this factor significantly affects VO 2max [ 19 ]. In other studies it was noted that skiers should aim to achieve a body composition with a high percentage of lean mass and a low percentage of fat mass. A focus on trunk mass through increased muscle mass appears to be important, especially for amateur and long-distance skiing, where double-poling is the most common technique [ 20 , 21 ]. Another research suggested that large amounts of lean body mass, especially in the arms, seem to be of great importance for cross-country skiing performance [ 22 ]. Elite male cross-country skiers have approximately 10.5% body fat [ 23 ]. In this research the level was higher: 15.3 ± 2.6 in the first test, and 14.6 ± 3.0 in the second. The level was similar to young non-athletes [ 24 ] but BMI was similar to athletes. Interestingly, the parameters were much better than those obtained in [ 8 ], where body fat mass in % was 23.4 ± 7.5 in the first test (before the training program) and 23.6 ± 7.0 in the second, after a six-month triathlon training program. BMI was 25.0 ± 2.7 and 24.7 ± 2.4, respectively.
In this study, a statistically significant decrease in body fat mass was recorded. Similar trends were also seen in pilot studies [ 25 ]. It was proven that a decrease in body fat mass can improve exercise capacity and results [ 26 ]. Optimal body fat for men in endurance disciplines is around 8–10% (during the competitive period) [ 27 ]. In [ 28 ] it was recommended that cross-country skiers should have 7% to 12% fat mass in the body. A reduction of body fat below 4%, however, can affect the body’s regenerative capacity and adversely affect the immune system. A value of >10% of body fat translates into poorer sports results because of, among other factors, higher than optimal body weight. By lowering body weight accordingly, by reducing body fat, we increase the level of oxygen intake per kilogram of body weight. Higher oxygen availability translates into better exercise options [ 27 ].
In addition, researchers highlighted the link between high body fat content and mortality. Reducing body fat instead of total weight seems to benefit the cardiovascular system more than a decrease in body mass index [
29
]. The results of these studies indicated the health impact of physical activity on the health of amateurs. A further decline may positively affect the effort and health of these amateurs but should not fall below 8%. Researchers suggested that a low lean mass index can be a strong indicator of mortality in men [
30
,
31
]. Reducing body fat and engaging in physical activity are important factors in improving the cardiovascular risk profile in middle-aged men. Achieving the correct body fat content can bring many health benefits for male amateur cross-country skiers.
The mean race intensity in the Vassaloppet race was 82% of maximal heart rate (HR) and did not differ between performance groups, even though elite skiers skied ∼15% faster than amateurs. The research showed that the amateur group contributed a longer effort in zones two and three, in comparison with elite cross-country skiers [ 32 ]. This emphasizes the role of aerobic and mixed possibilities in amateur efforts.
An increase in heart rate on lactate threshold (HR AT) was recorded in these studies. This indicates a positive adaptation to effort in response to a four-month workout. Delaying the transition from exercise in an aerobic to an anaerobic zone has a positive effect on exercise capacity. Shifting the lactate curve to the right results in a greater use of fat stores than of muscle glycogen, of which reserves in the body are limited.
During endurance training, the exercise load at the anaerobic threshold level is considered to be the most effective in relatively long exercises. Subsequent crossing of the lactate threshold during increasing work load allows you to extend your effort. When lactate increases, hydrogen ions are also released, which is the main cause of fatigue. A decrease in lactate concentration at the anaerobic threshold and in the maximum concentration will indicate correct adaptation to exercise. The optimal training of a long-distance skier should mainly approach the maximum oxygen consumption–VO
2max
with the least accumulation of lactic acid in the blood [
33
]. Lowering the concentration of lactic acid and minimizing the effects of its secretion at higher speeds are important matters of training for long-distance runners. It is also worth noting that lactate shows a high correlation with other indicators, e.g., VO
2max
[
34
].
The correct response to exercise was recorded in these studies. This was indicated by a decrease in lactate concentration at the threshold and in maximum values. However, it should be emphasized that a decrease in lactate concentration may also be an indicator of fatigue. A low-carbohydrate diet may be another factor affecting its lower values. Both of these factors will reduce the body’s exercise capacity.
5. Conclusions
The study indicates that a four-month comprehensive training for amateur long-distance skiers with the use of roller skis has a positive effect on the cardiovascular system. In addition, reducing body fat can be an important factor in protecting against heart disease in middle-aged men. A statistically significant increase was noted in maximum oxygen uptake and maximum minute ventilation, and a decrease in body fat content, maximum lactate concentration and lactate threshold, and heart rate on AT. Research indicated that in the amateur group increases similar to those in top competitors were achieved in the parameters tested, but the initial level was often significantly lower. Future research may focus on the analysis of a larger research group, include control groups, and focus especially on upper body training.
Funding
References
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Figure 1. Monthly summary of comprehensive loads in hours.
Figure 1. Monthly summary of comprehensive loads in hours.
Figure 2. Monthly summary of targeted loads in hours.
Figure 2. Monthly summary of targeted loads in hours.
Figure 3. Summary of training hours.
Table 1. Comparison of the results of the first and second tests.
Table 1. Comparison of the results of the first and second tests.
Parameter Mean (Standard Deviation) Result 1 Result 2 p –Value Height (cm) 182.2 (6.0) 182.2 (5.8) 1.000 Body weight (kg) 78.8 (6.3) 78.4 (6.0) 0.333 BMI (kg/height 2 ) 23.7 (1.3) 23.6 (1.2) 0.191 % body fat mass 15.3 (2.6) 14.6 (3.0) 0.038 Body fat mass (kg) 12.1 (2.6) 11.4 (2.7) 0.023 Test duration (s) 1566.7 (130.4) 1592.7 (133.5) 0.267 Running speed (maximum km/h) 14.0 (0.7) 14.2 (0.8) 0.181 VO 2max (relative) (mL/kg/min) 49.0 (4.5) 51.1 (4.6) 0.008 VO 2max (absolute) (L/min) 3.9 (0.4) 4.0 (0.5) 0.054 Maximum heart rate (heartbeats per minute) 183.9 (9.8) 182.3 (10.1) 0.195 Maximum lactate concentration (mmol/L) 12.5 (2.8) 10.8 (2.5) 0.013 Maximum ventilation (L/min) 147.3 (20.5) 151.2 (22.2) 0.038 The frequency of maximum breathing (number of breaths/min) 59.7 (12.4) 60.4 (10.6) 0.410 Running speed anaerobic threshold (AT) (km/h) 11.1 (0.7) 11.2 (0.7) 0.575 Oxygen uptake–VO 2 (relative) on AT (mL/kg/min) 44.8 (3.8) 44.9 (3.6) 0.934 Oxygen uptake–VO 2 (absolute) on AT (L/min) 3.6 (0.4) 3.5 (0.4) 0.609 Heart rate on AT (number of breaths per min) 170.4 (7.7) 168.1 (10.4) 0.073 Lactate concentration (on the threshold) AT (mmol/L) 4.9 (1.3) 4.0 (0.9) 0.017 AT ventilation (L/min) 108.9 (17.9) 112.2 (18.6) 0.229 Heart rate on AT (bpm) 40.09 (6.2) 43.4 (7.1) 0.024
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The Collateral Benefit of COVID-19 Mitigation Strategies on Influenza | American Board of Family Medicine
The Collateral Benefit of COVID-19 Mitigation Strategies on Influenza
Abstract
Introduction:The ongoing COVID-19 pandemic initiated the implementation of numerous disease mitigation strategies aimed to prevent transmission of the SARS-CoV-2. Given the similarity in mode of transmission, we posit that these strategies have also had a collateral benefit in minimizing the transmission of influenza during the 2020 to 2021 season in California.
Methods:Five years of data including incidence of influenza-like illness (ILI), influenza hospitalization, and mortality related to influenza in California were analyzed.
Results:In each of these parameters, there was a marked decrease in influenza activity, suggesting the additional benefit of COVID-19 mitigation strategies on influenza prevention.
Discussion:Further study is recommended to determine which specific variables had greater impact on transmission of respiratory viruses, and therefore can be utilized to prevent future outbreaks of respiratory illness.
California
COVID-19
Influenza
Pandemics
Introduction
A state of emergency was declared in California on March 4, 2020, after the first reported death of a California resident due to COVID-19. This began the implementation of several COVID-19 mitigation strategies to prevent transmission of the disease. This included the cancellation of large events, restaurant closures, mask wearing mandates, and travel bans, among others. These measures have had a profound effect on the course of pandemic, which has led many to infer the impact of these mitigation strategies on the transmission of other respiratory illnesses, such as influenza. 1
Both influenza and SARS-CoV-2 are transmitted through respiratory droplets, most often through coughing or sneezing. For this reason, masks are an effective tool to mitigate respiratory virus transmission. Although there is controversy about the effectiveness of masks, numerous studies have shown that in general, mask-wearing has a protective effect against the transmission of respiratory viruses. 2Moreover, other social distancing strategies, such as school closures and travel bans, have obvious benefit in the reduction of both SARS-CoV-2 and influenza transmission.
Influenza makes a good candidate for study because of its year-to-year variability and distinct seasonality, which is driven mainly by climate. A complex interaction between alternating subtypes and antigenic drift determines yearly variation in subtypes and corresponding disease severity. 3Flu seasonality is typically defined by a significant increase in activity during the winter months. Despite its consistency, the dynamic seasonality of influenza is poorly understood. Emerging research suggests that the underlying factors contributing to influenza's cyclic epidemic cycle relates to seasonal variations in host health, temperature, and air travel which has a large spike during the winter months. 3
Despite the widespread availability of a vaccine in the country, the disease burden of influenza continues to weigh heavily on the US. The CDC estimates that in the 2019 to 2020 season, influenza infected 35,000,000 Americans, caused 380,000 hospitalizations, and 20,000 deaths. 4Furthermore, the estimated average total economic burden on the US was $11.2 billion as of 2018. 5As the winter months of 2020 approached, both citizens and health care providers braced for the combined burden of both the new coronavirus and the seasonal flu. However, the anticipated peak of the flu season never came, perhaps preventing a catastrophic inundation of the US health care system.
In this study, we propose that the COVID-19 mitigation strategies employed in the state of California had a collateral benefit on preventing influenza infection and disease.
Methods
Data and figures were taken from the California Influenza Surveillance Program of the California Department of Public Health (CDPH), which publishes a weekly influenza surveillance report. The report from week 20 (May 16-May 22) of 2021 was used for this study. We analyzed values for influenza-like illness visits among patients seen by California sentinel providers, influenza-related hospital admissions, and deaths coded as influenza over the last 5 years (2016 to 2021). The start and end points coincide with the typical beginning and end of the flu season in California (Fall-Summer). These data were then analyzed for trends coinciding with each year's flu season. These 3 parameters serve as an appropriate proxy for influenza activity, as they cover a wide range of disease severity (ie, outpatient, inpatient, death).
Eighty-five sentinel providers participated in the influenza surveillance report, as of week 20 (May 16 – May 22) of 2021. Influenza-like illness (ILI) was defined as any illness presenting with fever (≥100 or 37.8), cough and/or sore throat, and the absence of a known cause other than influenza.
Data from Kaiser Permanente facilities in Northern California were also used to track rates of influenza hospital admission over the last 5 years. Admission diagnosis including keywords: “flu,” “influenza,” “pneumonia,” and other similar words were used to identify pneumonia and influenza related admissions (P&I admissions). The total number of P&I admissions was divided by the total number of hospital admissions occurring in the same period (2016 to 2021) to estimate the percentage of P&I admissions. In addition, the CDPH notes that admissions due to pregnancy, labor and delivery, birth, and outpatient procedures were excluded from the denominator.
Influenza mortality data were obtained from death certificates. The CDPH defined influenza-related death as any death field on a death certificate that included influenza. The total number of death certificates mentioning influenza was then divided by the total number of all cause deaths during the same time period (2016 to 2021). The CDPH notes that influenza-coded deaths are not necessarily laboratory-confirmed and thus are an underestimate of all influenza-associated deaths. 6
Vaccination data over the last 5 years were also analyzed to determine how changes in vaccination coverage may have affected trends in the incidence of influenza. Data were collected from the CDC National Center for Immunization and Respiratory Diseases (NCIRD) FluVaxView, which is publicly available at no cost on the agency website. We acknowledge that our interpretations do not reflect the views of the US Government, Department of Health and Human Services, or Centers for Disease Control and Prevention. Data for patients age 6 years and older were included, as this is the recommended age for flu vaccination. End-of-season rates of vaccination coverage was estimated using May as an end point, when the flu season typically ends in America. Percent coverage was determined by dividing the number of documented seasonal influenza vaccinations over the total number of respondents. 7Only vaccination data for seasonal influenza were used. H1N1 vaccination data were omitted as it does not follow the same seasonality as influenza A and is therefore not relevant to this study.
Results
Figure 1illustrates a dramatic decline in percentage of influenza-like illness (ILI) visits among patients seen by California sentinel providers between 2016 and 2021. Influenza season occurs in the fall and winter months, peaking typically in February, as is shown in the figure. In the 2020 flu season, however, the rise of ILI ends at a comparatively low peak in February 2021 and subsequent decline in following months. A similar trend is observed in hospitalization due to influenza. In comparison to previous flu seasons, 2020/2021 saw only twenty-eight ICU hospitalizations, 6 ICU admissions, and 2 deaths among persons diagnosed with influenza on admission. 6
Figure 1.
Percentage of influenza-like illness visits among patients seen by California sentinel providers, 2016 to 2021. Source: California Influenza Surveillance Program's weekly report (week 20: May 16, 2021 – May 22, 2021). Eight-five sentinel providers provided data to the study. Numerators and denominators were not publicly available. Seasonal baseline was calculated using a regression model applied to 5 years of data before the COVID-19 pandemic.
Figure 2illustrates the timeline of the implementation of COVID-19 mitigation strategies in California. Spanning from early March 2020 to June 2021, both state and local governments gradually implemented various mitigation measures. 8In comparingFigures 1and2, it is evident that these implemented measures correlate with the relatively low incidence of influenza at each time point.
Download figure
Figure 2.
Timeline of California COVID-19 mitigation policies. Source: CalMatters. Major events in the implementation of COVID-19 mitigation strategies are mapped onto a timeline overlapping with the 2020/2021 flu season. Although policies continued to change afterward, the end of California's Blueprint for Safer Economy Program was used as an endpoint since it coincides with the end of a typical flu season.
Figure 3shows the percentage of influenza-coded deaths occurring in California from 2016 to 2021. The 2020/2021 flu season also shows a dramatic decrease in influenza-associated mortality. During week 20, no influenza-coded deaths were reported. The 2020/2021 season in total included only fifty influenza-coded deaths. Thirty-three (66%) of influenza-coded deaths occurring in the 2020/2021 season were persons aged 65 or older. 9
Figure 3.
Percentage of influenza-coded deaths occurring in California among California residents, 2016 to 2021. Source: California Influenza Surveillance Program's weekly report (week 20: May 16, 2021 – May 22, 2021). Numerators and denominators were not available. Influenza-coded deaths were coded as deaths in California which included influenza in the cause of death field on the death certificate. This sum was then divided by the total number of deaths in California in the same time period to achieve the values shown in the figure. California Department of Public Health (CDPH) notes that influenza-coded deaths are not necessarily laboratory-confirmed cases of influenza, and therefore these values underestimate the true number of influenza-associated deaths.
Figure 4.
End-of-season influenza vaccination coverage in persons ≥ 6 months, California. Source: CDC National Center for Immunization and Respiratory Diseases (NCIRD) FluVaxView. Sample size in each year was as follows: 2016 to 2017: 8010, 2017 to 2018: 10,838, 2018 to 2019: 9857, 2019 to 2020: 7935, 2020 to 2021: 9129).
We also analyzed California influenza vaccination coverage in persons aged 6 months and older over the last 5 years. These data shown inFigure 4were collected from the CDC National Center for Immunization and Respiratory Diseases (NCIRD) FluVaxView. These values represent estimated end-of-season rates of vaccination using May as an endpoint, when the flu season typically ends in America. 7
Discussion
A significant downward trend was observed in the number of influenza cases, number of hospitalizations due to influenza, and mortality due to influenza in 2020-21. We think that COVID mitigation strategies could have contributed to the decrease in incidence of influenza in California. The decline in influenza cases during the pandemic is not limited to California. In Taiwan, a similar study concluded that disease prevention measures, hospital preparedness and response, and public awareness and compliance in response to COVID-19 provided collateral benefits of significant reduction of severe influenza, S. Pneumoniae, and deaths due to pneumonia. 10Studies show a disruption in many respiratory viruses, including influenza, during the COVID-19 pandemic in the United States as a whole. Similar trends are seen in decline of laboratory-confirmed influenza hospitalization, as well as reduced diversity of subclades relative to previous years. 11
There is evidence to suggest that relaxation of COVID-19 mitigation strategies led to late outbreaks of influenza, which had been previously controlled. In Cambodia, influenza season typically occurs from May to July, however much like California, influenza circulation was much lower than previous years. Sovann et al. found that in Cambodia, where COVID-19 restrictions had been eased in June and July 2020, an outbreak of influenza occurred in August 2020, which is atypically late in the season. 12This further supports the link between influenza and COVID-19 mitigation strategies.
1 limitation of this study is that in the calculation of percentage of ILI, hospitalization, and mortality due to influenza, the denominator (total number of patients) was likely affected by the pandemic. Although the CDC report did not include these numbers, it is possible that both office visits and hospital utilization may have decreased in response to limited health care access and hospital capacity during this time. This may account for part of the decrease in ILI and influenza hospitalization. Similarly, all-cause mortality increased in 2020 due to COVID-19, which may have skewed the percent mortality due to influenza in that year. It is unclear, however, whether these limitations wholly account for the dramatic decline in influenza that occurred in 2020. In addition, the hospitalizations due to influenza in Kaiser Northern California hospitals included “pneumonia” admissions. This skews the data because pneumonia has multiple etiologies that do not relate to influenza.
We also explored the possibility that the COVID-19 pandemic changed vaccination behavior. The CDC's report on the subject concluded that 35% of respondents reported that they were more likely to receive the influenza vaccine because of the COVID-19 pandemic. By contrast, 11% of respondents reported being less likely to receive the influenza vaccine because of the pandemic. 13As shown by the end of the flu season in May 2021 there appeared to be no significant change in vaccination status from the previous year. 7Therefore, these differences are unlikely to account for the decline in influenza in 2020/2021.
Acknowledgments
We thank the California Department of Public Health and California Influenza Surveillance Program for their data and figures. We would also like to thank the physicians who participated in their surveys, which allowed us to conduct this study.
Notes
This article was externally peer reviewed.
Funding:None.
Conflict of interest:None.
To see this article online, please go to:http://jabfm.org/content/35/4/680.full.
Received for publication November 1, 2021.
Revision received January 25, 2022.
Accepted for publication January 27, 2022.
References
1.
Governor Newsom declares state of emergency to help state prepare for broader spread of COVID-19 | California Governor . California Governor . https://www.gov.ca.gov/2020/03/04/governor-newsom-declares-state-of-emergency-to-help-state-prepare-for-broader-spread-of-covid-19/. Published 2020 . Accessed July 16, 20 .
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Liang M ,
Gao L ,
Cheng C ,
et al
. Efficacy of face mask in preventing respiratory virus transmission: a systematic review and meta-analysis . Travel Med Infect Dis 2020 ; 36 : 101751 .
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Lofgren E ,
Fefferman NH ,
Naumov YN ,
Gorski J ,
Naumova EN
. Influenza seasonality: underlying causes and modeling theories . J Virol 2007 ; 81 : 5429 – 36 .
4.
Disease burden of influenza . Centers for Disease Control and Prevention . Available from: https://www.cdc.gov/flu/about/burden/index.html . Published June 11, 2021 . Accessed July 16, 2021 .
5.
Putri WCWS ,
Muscatello DJ ,
Stockwell MS ,
Newall AT
. Economic burden of seasonal influenza in the United States . Vaccine 2018 ; Jun 22 36 : 3960 – 6 . Epub 2018 May 22 .
6.
Influenza and Other Respiratory Viruses Weekly Report: Highlights (Week 20: May 16, 2021 – May 22, 2021) .; 2021 : 2 – 3 .
7.
Fluvaxview . Centers for Disease Control and Prevention . Available from: https://www.cdc.gov/flu/fluvaxview/index.htm . Published October 22, 2021 . Accessed January 24, 2022 .
8.
Procter R
. Remember when? timeline marks key events in California's year-long pandemic grind . CalMatters . Available from: https://calmatters.org/health/coronavirus/2021/03/timeline-california-pandemic-year-key-points/ . Published March 4, 2021 . Accessed January 21, 2022 .
9.
California Influenza Surveillance Program . Influenza and Other Respiratory Viruses Weekly Report: Highlights (Week 20: May 16, 2021 – May 22, 2021) .; 2021 : 6 .
10.
Chan KS ,
Liang FW ,
Tang HJ ,
Toh HS ,
Yu WL
. Collateral benefits on other respiratory infections during fighting COVID-19 . Med Clin (Barc) 2020 ; 155 : 249 – 53 .
11.
Olsen SJ ,
Winn AK ,
Budd AP ,
et al
. Changes in influenza and other respiratory virus activity during the COVID-19 pandemic—United States, 2020-2021 . MMWR Morb Mortal Wkly Rep 2021 ; 70 : 1013 – 9 . Published 2021 Jul 23 .
12.
Sovann LY ,
Sar B ,
Kab V ,
et al
. An influenza A (H3N2) virus outbreak in the Kingdom of Cambodia during the COVID-19 pandemic of 2020 . Int J Infect Dis 2021 ; 103 : 352 – 7 .
13.
Lindley MC ,
Srivastav A ,
Hendrich M
. Early-season influenza vaccination uptake and intent among adults–United States , September 2020 .
| https://www.jabfm.org/node/14088.full.print |
Reflections for Police Officer Robert J. Bilodeau, New York City Police Department, New York
Police Officer Robert Bilodeau was shot and killed while investigating suspicious behavior. Officer Bilodeau and his partner were...
Police Officer Robert J. Bilodeau
New York City Police Department, New York
End of WatchTuesday, February 12, 1980
Reflections for Police Officer Robert J. Bilodeau
Bilodeau remains as the only officer in NYPD history to have received the Medal of Honor twice.Posted Saturday, 20 June 2020By Detective Richard"Bo" DietlOn February 12, 1980, I responded to a 10-13, officer needing assistance, and found Officer Bobby Bilodeau, a Street Crime Unit cop, dying of a gunshot wound after a running gun battle with drug dealers in upper Manhattan. His family was awarded the NYPD Medal of Honor, posthumously; it was his second.Bilodeau remains as the only officer in NYPD history to have received the medal twice.Less than a year earlier, on April 5, 1979, Bobby had had his throat slashed by a passerby while acting as a decoy a few blocks south of the New York Port Authority Bus Terminal.He survived, but it took 63 stitches to close his throat; he nearly died.It took him just three weeks to come back on the job after his throat was slashed.He told me that he had needed to come back because he needed to protect people who weren’t able to protect themselves. For him, being a cop, and being part of the all-volunteer Street Crime Unit wasn’t just his job; it was his calling.I thought of Bobby, now dead over 40 years, the other day as I heard New York City Police Commissioner Dermot Shea speak of disbanding the 600 officer Anti-Crime Unit, the successor to the Street Crime Unit where Bobby had served.Reportedly, Commissioner Shea decided to disband the Anti-Crime Unit because it was disproportionately involved with so many shootings and civilian complaints. (One review of shooting statistics claimed 31% of all NYPD killings came from the roughly 6% of the force on the Anti-Crime Unit. ACU also reportedly had a disproportionately high percentage of civilian complaints.)But Shea’s dodgy, top-side, assumption about that data set is that a uniformed officer responding to crimes in a radio mobile patrol (RMP) car will have the same policing experience as a plainclothes ACU cop actively seeking out crimes in progress.The disproportionate stats NYPD critics cite to eliminate the ACU result from the unit’s aggressive, proactive, peripatetic, daily policing in some of the city’s highest crime neighborhoods, "looking for the worst people in the worst neighborhoods during the worst hours," as one John Jay instructor put it. Anti-crime cops might have 10, 20 or even 30 encounters with suspects or victims to each uniformed officer’s single encounter.Nearly 50 years ago my old boss, David Durk, the crusading, media-savvy, politically-connected, NYPD commander whose disclosures, along with those of the famous Frank Serpico, led to the creation of the Knapp Commission, acknowledged to me that it was about 10% of cops — aggressive, risk-taking, go-getters like Bobby Bilodeau and I were —who made about 90% of the arrests.That realization ultimately led to the creation of the Street Crime Unit in 1971.Street Crimes’ unofficial slogan, adopted after I left, was "We Own the Night."Commissioner Shea’s radical and misguided move to eliminate the Anti-Crime Unit will diminish the extraordinary performance of a few cops to align it with those of the many; to make great, heroic, risk-taking, go-getter, cops just "so-so," mail-it-in civil-service drones who seek to fall into the middle of the bell curve of performance rather than to be among the best.The result will be that crime — especially violent crimes in high-crime neighborhoods —will spike and people, overwhelmingly people of color, will die.The NYPD won’t "Own the Night," the criminals and gang-bangers will.And the people in the high crime neighborhoods where ACU operated most will suffer most as their sons, daughters, husbands and wives suffer the criminal pathology of the few that only policing can stop.Great cops like Bobby Bilodeau would have had no part of it.Neither should Commissioner Shea.Let’s hope he sees the folly of his mistake before too many people have to die.Richard"Bo" Dietl, the founder and CEO of Beau Dietl & Associates was an NYPD police officer and detective from 1970 to 1985. As a member of the Street Crime Unit and the Anti-Crime Unit, he was mugged over 500 times as a decoy, hospitalized over 30 times, and effected over 1,600 felony arrests. He never resorted to deadly force
42 years in Heaven. Your plaque on the wall at Randall’s Island served as a constant reminder of your ultimate sacrifice and the inherent dangers of being a Street Crime Cop doing God’s Work. Continue to Rest In Peace Nighthawk.
RIP Officer Bilodeau.
Rest easy
To the family, friends and colleagues of Officer Bilodeau: I proudly mailed my NO PAROLE letter today. I am sorry for your loss. It’s so unfair that you have to keep reliving your pain, with each new parole board hearing! To Officer Bilodeau: Thank You for your service to our country; your sacrifice for your community. You are not forgotten!God Bless You All
I was a State Court Officer working AR 3 when I first met him.He was a great guy a cops, cop. Him and Mario took me under their wing.He is truly missed.Harry Dobson Ret ADW NYCDOCFebruary 21, 2018
After your neck was slashed there came a day that we were sitting at my kitchen table. My wife looked at your neck and didn't say anything. When I got home later she asked why you didn't retire on 3/4 s. I told her that you were a cop. She then tried to convince me to change careers also. I gave her the same answer. A year later you were still doing your job as a "Cop". It's what we do. RIP Bob, you are missed.
Thirty-eight years-never forgotten!R.I.P.- Bobby.
TPF/SCUNYPD
I would see your Memorial plaque hanging in the Street Crime Unit. Heard great things about you. A True Warrior. Proud to say I worked in SCU with Warriors like you..Rest in Peace
Det. Ray WinzNYPD
HI ROBERT I'M NOT GOING TO GIVE A SPEECH THIS YEAR, JUST WANT TO SAY I STILL MISS YOU AND LOVE YOU.
POLICE OFFICER JOSEPH BALLENEWARK, NEW JERSEY, RETIRED
RIP Officer and thank you for your service. You are not forgotten. God. bless you and your family
Police Officer (retired)New York Police Department
Thank you for your service my brother. Heros are few, cowards are many. Continue to rest in peace and know that your actions are for ever appreciated by your brothers and sisters in the N.Y.P.D. God bless you and your family. ALL BLUE LIVES MATTER.
Lt. Ray FloresN.Y.P.D. (ret.)
HI Robert!It's now 35 yrs. since that punk took your life.Wish I could say things are getting better but their not. We're still being executed while trying to protect the hopeless.Take care. talk to you next year.Joseph Balle
P/O JOSEPH BALLENEWARK N.J. PD. RET.
i REMEMBER THIS TRAGEDY WHILE i WAS IN THE POLICE ACADEMY. I ALWAYS REMEMBERED HIS NAME AND LOOKED IT UP THIS DAY.REST IN PEACE
Retired P.O. Al CarratureN.Y.P.D Retired
Miss you Robert. you will never be forgotten.
HI ROBERTI'M DOING MY BEST TO CONTROL MY TEMPER THIS YEAR AND NOT COMPLAIN BUT I CAN'T. THEY STILL TREAT POLICE OFFICERS LIKE CRIMINALS, ESPECIALLY WHEN A SHOOTING IS INVOLVED. THE THOUGHT OF THAT PUNK THAT KILLED YOU REALLY DRIVES ME CRAZY.KEEP ASKING THE HEAD RABBI UP THERE TO CUT THE MEN IN BLUE SOME SLACK.YAKE CARE BUDDY, STILL MISS YOU AND LOVE YOU A LOT..
P.O. JOSEPH BALLENEWARK,NJ RET.
He was in my classes at JJC and he was a fellow Episcopalian.
Keith C. Edwards
Bobby33 years-not forgotten!RIP
TPF/SCUNYPD
Hi Robert,It will be 33 years to the day tomorrow that the punk took your life! I got tired of seeing, as I'm sure others have a shadow box of you being portrayed on The Officer Down Memorial Board. I dropped a little note to the current PC (Kelly) who through his staff (Lt. Peter McCaffrey) was able to get your picture posted. Still miss you very much and keep an eye out for the thin blue line!
PO Joseph Balle'NEWARK,NJ RET.
Your heroism and service is honored today, the 32nd anniversary of your death. Your memory lives and you continue to inspire. Thank you for your service. My cherished son Larry Lasater was a fellow police officer murdered in the line of duty on April 24, 2005 while serving as a Pittsburg, CA police officer.Time never dimishes respect and your memory will always be honored and revered. I pray for solace for all those who love and remember you for I know both the pain and pride are forever. Your family is in my heart's embrace. Joseph, thanks for shariing a brother/friend's devotion through your reflectionsRest In Peace
Phyllis LoyaMom of fallen California Officer Larry Lasater, Pittsburg PD, eow 4/24/05
HI ROBERT!I'LL TRY NOT TO COMPLAIN TO MUCH BUT HERE GOES. NOW INSTED OF GIVING MEDALS TO OUR MARINES FOR LEAKING ON THE ENEMY THEY COURT-MARTIAL THEM.POLICE IN- VOLVED IN SHOOTINGS ARE GUILTY UNTIL PROVEN INNOCENT. ALL THE PUNKS LIKE THE ONE WHO KILLED YOU ARE NOW PORTRAYED AS UPSTANDING PEOPLEWITH THE POTENTIAL OF BECOMING EVERYTHING FROM ASTRONAUTS TO BRAIN SURGEONS, THEY SHOW ALL THESE PUNKS WITH GRADUATE CAPS AND GOWNS OR IN BOYSCOUT UNIFORMS.THE THIN BLUE LINE IS GETTING THINER BECAUSE ALL THEGOOD MEN CAN NOT TAKE ALL THE B/S ANYMORE.KEEP AN EYE OUT FOR ALL OUR BROTHERS.MISS YOU AS ALWAYS,BROTHER JOE BALLE
P.O. JOSEPH R. BALLENEWARK,NJ RET.
HI ROBERT!SORRY I'M A WEEK LATE BUT YOU KNOW HOW THAT GOES.AS YOU CAN SEE OUR BROTHER ANS SISTER'S ARE BEING SHOT LIKE IT'S THE OPENING DAY OF DEER SEASON. NOT COMPLAINING BUT ASK YOUR CO IF HE COULD LIGHTEN UP JUST A LITTLE.IT'S BEEN 31 YEARS SINCE YOU MADE THE ALTIMATE SACRIFICE AND YOUR STILL MY HERO AND THE ONLY BROTHER I KNOW WHO RECEIVED TWO MEDALS OF HONOR AND TOUCHED SO MANY LIVES.KEEP AN EYE ON THE THIN BLUE LINE THEY NEED ALL THE HELP THEY CAN MUSTER.MISS YOUBROTHER JOE BALLE
JOSEPH BALLE NEWARK RET.
TPF/SCU
30 years-gone but not forgotten
Brother LEONYPD
| https://www.odmp.org/officer/reflections/1858-police-officer-robert-j-bilodeau |
MARTIN G MONDRY MD, NPI 1881670552 - Anesthesiology in Foley, AL
Martin Mondry an anesthesiologist in 1613 N Mckenzie St Foley, Al 36535. Taxonomy code 207L00000X with license number 33096 (WI) and 26 years of experience. Provider is enrolled in PECOS Medicare. Accepted Insurance: Medicaid and Medicare
Anesthesiology in Foley, AL
NPI Profile
NPI Record
Similar Providers
Table of Contents
NPI Profile Information Primary Taxonomy Accepted Insurance PECOS Enrollment and Medicare Participation Status Hospital Affiliations Secondary Taxonomies NPI Validation Other Providers Same Location
Individual Male Years of Experience 26 Anesthesiology PECOS Enrolled Accepts Medicare Approved Payment
About MARTIN G MONDRY MD
Martin Mondry
is an anesthesiologist established in Foley, Alabama
and his medical specialization is Anesthesiology
with more than 26 years of experience. The NPI number of this provider is 1881670552
and was assigned on December 2005. The practitioner's primary taxonomy code is
207L00000X
with license number 33096 (WI). The provider is registered as an individual and his NPI record was last updated 10 years ago.
NPI 1881670552
Provider Name MARTIN G MONDRY MD
Location Address 1613 N MCKENZIE ST FOLEY, AL 36535
Location Phone (770) 874-5439
Mailing Address 5665 NEW NORTHSIDE DR NW SUITE 320 ATLANTA, GA 30328
Gender Male
NPI Entity Type Individual
Medical School Name OTHER
Graduation Year 1998
Is Sole Proprietor? Yes
Enumeration Date 12-15-2005
Last Update Date 03-22-2013
An anesthesiologist like Martin Mondry manages the care of surgical patients and pain relief through drug administration that reduces or eliminates pain during an operation, medical procedure or during labor and delivery of babies. During surgical procedures anesthesiologists are responsible for adjusting the amount of anesthetic, monitoring the patient's heart rate, body temperature, blood pressure and breathing.Martin Mondry is
enrolled in PECOS
and is eligible to order or refer health care services for Medicare patients. The provider is eligible to order or refer: Part B Clinical Laboratory and Imaging, Durable Medical Equipment (DME), a Home Health Agency (HHA) and Power Mobility Devices.
Martin Mondry is registered with Medicare
and accepts claims assignment
, this means the provider accepts Medicare's approved amount for the cost of rendered services as full payment. Participating providers may not charge Medicare beneficiaries more than Medicare's approved amount for their services. Medicare beneficiaries still have to pay a coinsurance or copayment amount for a visit or service. According to Medicare claims data he has hospital affiliations with West Florida Hospital.
Primary Taxonomy
The primary taxonomy code defines the provider type, classification, and specialization. There could be only one primary taxonomy code per NPI record. For individual NPIs the license data is associated to the taxonomy code.
Taxonomy Code 207L00000X
Classification Anesthesiology
Type Allopathic & Osteopathic Physicians
License No. 33096
License State WI
Taxonomy Description An anesthesiologist is trained to provide pain relief and maintenance, or restoration, of a stable condition during and immediately following an operation or an obstetric or diagnostic procedure. The anesthesiologist assesses the risk of the patient undergoing surgery and optimizes the patient's condition prior to, during and after surgery. In addition to these management responsibilities, the anesthesiologist provides medical management and consultation in pain management and critical care medicine. Anesthesiologists diagnose and treat acute, long-standing and cancer pain problems; diagnose and treat patients with critical illnesses or severe injuries; direct resuscitation in the care of patients with cardiac or respiratory emergencies, including the need for artificial ventilation; and supervise post-anesthesia recovery.
Accepted Insurance
The NPI profile data indicates this provider might be enrolled and accepting health plans from the following insurance companies or healthcare programs:
Medicaid
Medicare
*Please verify directly with this provider to make sure your insurance plan is currently accepted.
Business Address
1613 N MCKENZIE ST
FOLEY, AL
ZIP 36535
Phone: (770) 874-5439
Fax: (770) 874-5483
Get Directions
Mailing Address
5665 NEW NORTHSIDE DR NW
SUITE 320
ATLANTA, GA
ZIP 30328
Phone: (770) 874-5400
Fax: (770) 874-5483
Location Map
PECOS Enrollment and Medicare Participation Status
What is PECOS?
PECOS is the Medicare Provider, Enrollment, Chain and Ownership System. PECOS is Medicare's enrollment and revalidation system and it is the primary source of information about verified Medicare professionals. A NPI number is necessary to register in PECOS. Providers must enroll in PECOS to avoid denied claims.
Registered in PECOS? Yes
PECOS PAC ID 6204737604
PECOS Enrollment ID I20071218000282
Accepts Medicare Assignment? Yes
"What does it mean "accepts medicare assignment"? When a provider accepts Medicare assignment, the provider agrees to be paid directly by Medicare and to accept the payment amount approved by Medicare. Additionally, the provider agrees to not bill patients for more than the Medicare deductible and coinsurance amounts. A provider who doesn't accept assignment may charge you up to 15% over the Medicare-approved amount. This is known as the limiting charge. You may have to pay this amount, or it may be covered by another insurer.
Eligible order / refer Part B Clinical Laboratory and Imaging Yes
Eligible order / refer Durable Medical Equipment Yes
Eligible order / refer Home Health Agency (HHA) Yes
Eligible order / refer Power Mobility Devices Yes
Hospital Affiliations
Medicare hospital affiliation is identified through self-reporting data, inpatient, outpatient, physician and ancillary service claims linked by the Medicare claims NPI number and place of service code. Additionally, to further determine provider hospital affiliation the clinician must have provided services to at least three patients on three different dates in the last 12 months. Martin Mondry is affiliated with the following medical facilities:
Hospital Name
Address
Phone
Hospital Type
CMS Certification Number (CCN)
Overall Rating
WEST FLORIDA HOSPITAL
8383 N DAVIS HWY
PENSACOLA, FL 32514
(850) 494-4000
Acute Care Hospitals
100231
Secondary Taxonomies
The secondary taxonomy codes define the provider type, classification, and specialization. For individual NPIs the license data is associated to each taxonomy code.
No. Taxonomy Code Type Classification Specialization License No. State Primary
1 207P00000X Allopathic & Osteopathic Physicians Emergency Medicine MD.30804 AL No
Taxonomy Description: an emergency physician focuses on the immediate decision making and action necessary to prevent death or any further disability both in the pre-hospital setting by directing emergency medical technicians and in the emergency department. The emergency physician provides immediate recognition, evaluation, care, stabilization and disposition of a generally diversified population of adult and pediatric patients in response to acute illness and injury.
Additional Identifiers
Additional identifier(s) currently or formerly used as an identifier for the provider. The codes may include UPIN, NSC, OSCAR, DEA, Medicaid State or PIN identification numbers.
Identifier
Type / Code
Identifier State
Identifier Issuer
31895500
MEDICAID (05)
WI
P00082072
OTHER (01)
WI
RAILROAD
F49387
MEDICARE UPIN (02)
NPI Validation Check Digit Calculation
The following table explains the step by step NPI number validation process using the ISO standard Luhn algorithm.
Start with the original NPI number, the last digit is the check digit and is not used in the calculation.
1 8 8 1 6 7 0 5 5 2
Step 1: Double the value of the alternate digits, beginning with the rightmost digit.
2 8 16 1 12 7 0 5 10
Step 2: Add all the doubled and unaffected individual digits from step 1 plus the constant number 24.
2 + 8 + 1 + 6 + 1 + 1 + 2 + 7 + 0 + 5 + 1 + 0 + 24 = 58
Step 3: Subtract the total obtained in step 2 from the next higher number ending in zero, the result is the check digit.
60 - 58 = 2 2
The NPI number 1881670552 is valid because the calculated check digit 2
using the Luhn validation algorithm matches the last digit of the original NPI number.
Other Providers at the Same Location
The following 20 providers are registered at the same or nearby location.
NPI
Name / Type
Taxonomy
Address
1306843305
ETHER BUNNY INC
Organization
Anesthesiology
1613 N MCKENZIE ST
FOLEY, AL 36535
(251) 965-5393
1366432007
SHAWN T. GUFFIN M.D.
Individual
Anesthesiology
1613 N MCKENZIE ST
FOLEY, AL 36535
(251) 965-5393
1235111964
DR. RALPH H EWING JR. M.D.
Individual
Radiology (Diagnostic Radiology)
1613 N MCKENZIE ST
FOLEY, AL 36535
(251) 949-3513
1124000856
SOUTH BALDWIN DIAGNOSTIC IMAGING ASSOCIATES, P.C.
Organization
Specialist
1613 N MCKENZIE ST
FOLEY, AL 36535
(251) 949-1513
1730146069
MARK R CONNELL M.D.
Individual
Radiology (Diagnostic Radiology)
1613 N MCKENZIE ST
FOLEY, AL 36535
(251) 476-5443
1902055924
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(PDF) Functional Characterization of a Lipoprotein-Encoding Operon in Campylobacter jejuni
PDF | Bacterial lipoproteins have important functions in bacterial pathogenesis and physiology. In Campylobacter jejuni, a major foodborne pathogen... | Find, read and cite all the research you need on ResearchGate
Functional Characterization of a Lipoprotein-Encoding Operon in Campylobacter jejuni
May 2011
PLoS ONE 6(5):e20084
DOI: 10.1371/journal.pone.0020084
CC BY 4.0
Authors:
Zhangqi Shen
Iowa State University
Abstract and Figures
Bacterial lipoproteins have important functions in bacterial pathogenesis and physiology. In Campylobacter jejuni, a major foodborne pathogen causing gastroenteritis in humans, the majority of lipoproteins have not been functionally characterized. Previously, we showed by DNA microarray that CmeR, a transcriptional regulator repressing the expression of the multidrug efflux pump CmeABC, modulates the expression of a three-gene operon (cj0089, cj0090, and cj0091) encoding a cluster of lipoproteins in C. jejuni.
In this work, we characterized the function and regulation of the cj0089-cj0090-cj0091 operon. In contrast to the repression of cmeABC, CmeR activates the expression of the lipoprotein genes and the regulation is confirmed by immunoblotting using anti-Cj0089 and anti-Cj0091 antibodies. Gel mobility shift assay showed that CmeR directly binds to the promoter of the lipoprotein operon, but the binding is much weaker compared with the promoter of cmeABC. Analysis of different cellular fractions indicated that Cj0089 was associated with the inner membrane, while Cj0091 was located on the outer membrane. Inactivation of cj0091, but not cj0089, significantly reduced the adherence of C. jejuni to INT 407 cells in vitro, indicating that Cj0091 has a function in adherence. When inoculated into chickens, the Cj0091 mutant also showed a defect in early colonization of the intestinal tract, suggesting that Cj0091 contributes to Campylobacter colonization in vivo. It was also shown that Cj0091 was produced and immunogenic in chickens that were naturally infected by C. jejuni.
These results indicate that the lipoprotein operon is subject to direct regulation by CmeR and that Cj0091 functions as an adhesion mechanism in C. jejuni and contributes to Campylobacter colonization of the intestinal tract in animal hosts.
Localization of Cj0089 and Cj0091 in C. jejuni. The cytosol fraction (lane 1), periplasmic fraction (lane 2), inner membrane fraction (lane 3), and outer membrane fraction (lane 4) were separated by SDS-PAGE and probed with anti-rCmeB (panel I), anti-rCj0089 (panel II), anti-rMOMP (panel III), and anti-rCj0091 (panel IV), respectively. doi:10.1371/journal.pone.0020084.g004 …
Generation of deletional and insertional mutations in cj0089 and cj0091. (A) Schematic diagram of the locations of deletional and insertional mutations. The genes are indicated by boxed arrows. The locations of the Kan R insertion are indicated as solid arrows. (B) PCR confirmation of the insertions in Cj89 2 and Cj91 2. Lanes 1, cj0089 in wild-type strain; lane 2, cj0089 in Cj89 2 ; lane 3, cj0091 in wild-type strain; and lane 4, cj0091 in cj91 2. (C) Immunoblotting analysis of protein production in various constructs. Wild-type (lane 1), Cj89 2 (lane 2), and Cj91 2 (lane 3) were separated by SDS-PAGE and probed with anti-rCj0089 (panel I), anti-rCj0091 (panel II), and anti-rMOMP (panel III). MOMP, a 45-kDa outer membrane protein, was used as a loading control. doi:10.1371/journal.pone.0020084.g005 …
Adherence of C. jejuni strain NCTC 11168 and the mutants to INT 407 cells. Strain NCTC 11168, Cj89 2 , and Cj91 2 were inoculated onto monolayers of INT 407 cells and the percentages of adherent bacterial cells were calculated by viable plate counts. Each experiment was conducted in quadruplicate and repeated for 3 times. Bars and error bars indicate the mean 6 standard deviation. * indicates significant differences in colonization levels at P,0.05 level as determined by Student's t-test. doi:10.1371/journal.pone.0020084.g006 …
Colonization of C. jejuni strain NCTC 11168 and its mutants in chickens. Approximately 10 7 CFU of each of NCTC 11168 (solid squares), Cj89 2 (open circles), Cj91 2 (solid triangles), Comp91 (solid diamonds) were inoculated into 3-day-old chickens. Cecal contents were collected on 3, 6, and 10 days post inoculation (DPI) and enumerated by plate counts. Each symbol represents the colonization level in a single bird. The mean for each group is depicted by a horizontal bar. The detection limit of the plating method is about 100 CFU/g of feces. An asterisk indicates significant differences in colonization levels at P,0.05 as determined by Student's t-test. doi:10.1371/journal.pone.0020084.g007 …
Immunoblotting detection of natural anti-Cj0091 antibodies in chickens. Strips of nitrocellulose membranes with rCj0091 were reacted with 4 chicken sera (lanes 2-5) that contained Campylobacter-specific maternal antibodies derived from natural infections and one chicken serum (lane 6) that was negative for antiCampylobacter antibodies. Anti-rCj0091 was applied as a positive control (lane 1). doi:10.1371/journal.pone.0020084.g008 …
Functional Characterization of a Lipoprotein-Encoding
Operon in
Campylobacter jejuni
Mayumi Oakland
¤a
, Byeonghwa Jeon
¤b
, Orhan Sahin, Zhangqi Shen, Qijing Zhang *
Department of Veterinary Microbiology and Preventive Medicine, Iowa State University, Ames, Iowa, United States of America
Abstract
Background:
Bacterial lipoproteins have important functions in bacterial pathogenesis and physiology. In Campylobacter
jejuni , a major foodborne pathogen causing gastroenteritis in humans, the majority of lipoproteins have not been
functionally characterized. Previously, we showed by DNA microarray that CmeR, a transcriptional regulator repressing the
expression of the multidrug efflux pump CmeABC, modulates the expression of a three-gene operon ( cj0089 , cj0090 , and
cj0091 ) encoding a cluster of lipoproteins in C. jejuni .
Methodology/Principal Findings:
In this work, we characterized the function and regulation of the cj0089 - cj0090 - cj0091
operon. In contrast to the repression of cmeABC , CmeR activates the expression of the lipoprotein genes and the regulation
is confirmed by immunoblotting using anti-Cj0089 and anti-Cj0091 antibodies. Gel mobility shift assay showed that CmeR
directly binds to the promoter of the lipoprotein operon, but the binding is much weaker compared with the promoter of
cmeABC . Analysis of different cellular fractions indicated that Cj0089 was associated with the inner membrane, while Cj0091
was located on the outer membrane. Inactivation of cj0091 , but not cj0089 , significantly reduced the adherence of C. jejuni
to INT 407 cells in vitro , indicating that Cj0091 has a function in adherence. When inoculated into chickens, the Cj0091
mutant also showed a defect in early colonization of the intestinal tract, suggesting that Cj0091 contributes to
Campylobacter colonization in vivo . It was also shown that Cj0091 was produced and immunogenic in chickens that were
naturally infected by C. jejuni .
Conclusion/Significance:
These results indicate that the lipoprotein operon is subject to direct regulation by CmeR and that
Cj0091 functions as an adhesion mechanism in C. jejuni and contributes to Campylobacter colonization of the intestinal tract
in animal hosts.
Citation: Oakland M, Jeon B, Sahin O, Shen Z, Zhang Q (2011) Functional Characterization of a Lipoprotein-Encoding Operon in Campylobacter jejuni . PLoS
ONE 6(5): e20084. doi:10.1371/journal.pone.0020084
Editor: Michael Hensel, University of Osnabrueck, Germany
Received January 14, 2011; Accepted April 18, 2011; Published May 23, 2011
Copyright: ß 2011 Oakland et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This study was supported by National Institutes of Health (www.nih.gov/) grant RO1DK063008 and the Food Safety Research and Respons e Network
(http://www.fsrrn.net/), funded by the United States Department of Agriculture National Research Initiative. The funders had no role in study desi gn, data
collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: [email protected]
¤a Current address: Department of Microbiology, University of Iowa, Iowa City, Iowa, United States of America
¤b Current address: Department of Pathology and Microbiology, Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, Pr ince Edward
Island, Canada
Introduction
Campylobacter jejuni is a Gram-negative, curved or spirally shaped
bacterium with a single, polar, unsheathed flagellum at one or
both ends [1]. It is a commensal organism existing in the intestinal
tracts of a variety of wild and domestic animals, especially in birds.
C. jejuni is a leading cause of acute diarrhea in humans worldwide
[2]. The typical symptoms of Campylobacter infections in humans
include watery to bloody diarrhea, abdominal pain, fever, and
presence of leukocytes and red blood cells in feces [3]. Campylobacter
infections can also develop to Guillain-Barre ´ syndrome (GBS), an
autoimmune-mediated neurodegenerative disorder which causes
acute neuromuscular paralysis [4]. The most significant source
of Campylobacter infections for humans is the consumption of
undercooked chicken.
The pathogenic process of C. jejuni in humans has not been well
understood, but can be divided into several stages [5]. Once
ingested by the host, C. jejuni survives the stresses in the stomach
and small intestine. Upon reaching to the large intestinal tract, C.
jejuni colonizes mucus layer and adheres to the intestinal cell
surface of the host gastrointestinal tract. The organism produces a
cytolethal distending toxin (CDT) and possibly other toxins, but
their role in pathogenesis is not clear [6]. Once adhered to the host
intestinal epithelial cells, C. jejuni may invade into and proliferate
within the host cells. The invasion and proliferation of the
organism inside host cells are considered the cause of cell damage
and induce host inflammatory responses, which result in diarrhea
with fecal leukocytes [7]. Occasionally C. jejuni can spread to
extraintestinal sites, such as liver, gallbladder, pancreas, uterus,
and fetal tissues [3,7].
The known put ative viru lence factor s involved in Campyl obacter
pathogen esis includ e flagella, l ipooligo saccharid e (LOS), CDT,
and outer me mbrane pro teins [7]. Fl agella aid Campylo bacter to
move throu gh the mucus lay er and cont ribute to col onization
PLoS ONE | www.plosone.org 1 May 2011 | Volume 6 | Issue 5 | e20084
and invasio n [8]. LOS is inv olved in adher ence to host cel ls and
serves as an endo toxin that indu ces host intest inal inflamm atory
responses [7]. In addition, molecular mimicry of LOS to human
ganglios ides is consi dered a key f actor in the de velopmen t of
GBS [9]. CDT causes cell cycle arrest and host DNA damage,
which induce host inflammatory responses [10]. The outer
membrane proteins of Campylobacter are involved i n interact ions
with hosts and play important roles in adherence and
coloniza tion. CadF, a 3 7-kDa surfac e protein, b inds to
fibronectins located at cell-to-cell contact regions in the
gastrointestinal epithelium. CadF is required for Campylobacter
coloniza tion of chick ens [11,12] . PEB1 is a peri plasmic pr otein
homologou s to a solute -binding com ponent of am ino acid ABC
transporters [13]. PEB1 is important for C. jejuni adherence to
human cells and colonization in the intestinal tract of mice [14].
The major ou ter membra ne protein (M OMP), a 45-k Da porin,
adheres in vitro to human intestinal cell membranes and
fibronectin [15], but whether it is involved in in vivo adheren ce
is unknown . CmeABC func tions as an ef flux pump to ex trude a
variety of substrates such as antibiotics, ions, SDS, and bile salts
[16–18]. I n addition, C meABC media tes bile resi stance and i s
required f or C. jejuni colonization in the gastrointestinal tract of
chickens [16].
Bacterial lipopro teins have diverse funct ions including cell
adhesion, transpo rt, nutrient acquisiti on, mating, and serum
resistance as well as stimulat ion of inflammatory/immun e
responses in host cel ls [19]. C. jejuni has multiple memb rane
lipoproteins pred icted from the genomic sequences [19]. At
present, only four of these li poproteins, JlpA [20] and Ca pA [21],
CjaA [22], and FlpA [23] have be en functionally char acterized in
C. jejuni . JlpA, a surface-exposed, l oosely cell-associa ted lipopro-
tein, is involved in th e interaction of C. jejuni with the sur face-
exposed heat shock pr otein 90 a (Hsp90 a ) of hos t cells and
triggers signal tran sduction, leading to th e activation of
components (NF- k B and p38 MAP kinase) in volved in host
proinflammatory re sponses to infection s [24]. CapA is also
involved in Campylob acter adherence to host ep ithelial cells and
colonization in gas trointestinal tract of chi cken [21]. CjaA is an
inner-membrane as sociated lipoprotein , and has been shown that
immunization of chick ens with avirulent Sa lmonella strain
expressing CjaA red uced the colonizati on of the intestinal trac t
by C. jejuni [22]. FlpA is a pu tative outer membrane -associated
lipoprotein, which med iates adherence to ch icken and human
epithelial cells as well as chicken co lonization via binding to
fibronectin [23,25 ].
In a previous study co mparing the global gene expr ession
profiles of in vitro grow n NCTC 11168 and its iso genic CmeR
mutant using DNA micro array [26], we found that C meR, which
is a transcriptional re pressor for the multidrug efflux pump
CmeABC [27], functi ons as a pleiotropic regu lator modulating
the expression of mul tiple genes in C. jeju ni NCTC 11168 [26]. In
total, 28 genes show ed $ 2-fold changes in expr ession in the
CmeR-deletion mutan t compared with the wil d-type strain.
Among the CmeR-regu lated targets were cj 0089 and cj0091
encoding putative l ipoproteins. cj0089 an d cj0091 , along with
cj0090 (also encoding a puta tive lipoprotein) appe ar to be
organized into an op eron, but their deta iled regulatory
mechanisms and the rol e in Campylobacter pa thophysiology remain
unknown. Consideri ng the fact that bact erial lipoproteins hav e
important functions and the majority of l ipoproteins in C. jeju ni
have not been characte rized, we conducted bo th in vitro and in vivo
experiments to eluc idate the regulation of the lipoprotein-
encoding operon an d the functions of th e encoded products in
Campylobacter adherence and colonization.
Results
Genomic organization and co-transcription of cj0089,
cj0090, and cj0091
The three genes encoding the cluster of lipoproteins are
tandemly positioned in the chromosome of C. jejuni NCTC
11168 (Figure 1A). cj0089 and cj0090 are separated by 9
nucleotides, while cj0090 and cj0091 are separated by 23
nucleotides. No predicted stem-loop structures exist between the
ORFs. According to the prediction by Petersen et al . [28], there is
a putative RpoD promoter located upstream of cj0089 . The
TATA-box of this promoter is located 40 nucleotides upstream of
the cj0089 translational initiation codon (data not shown). No
promoter was predicted immediately upstream of cj0090 or
cj0091. To determine whether cj0089, cj0090, and cj0091 are
co-transcribed, RT-PCR was performed on the C. jejuni strain
using primers cj89int-F and cj91int-R (Tables 1 and 2), which span
the three ORFs (Figure 1A). A 1194-bp expected product was
amplified in the PCR reaction with the RNA and RT, while no
product was obtained in the reaction without RT, indicating that
cj0089 , cj0090 , and cj0091 are con-transcribed and likely organized
into an operon (Figure 1B). The operon is flanked by an upstream
gene encoding an anaerobic C4-dicarboxylate transporter ( dcuA )
and a downstream gene ( cj0092 ) encoding a hypothetical protein.
There is a potential Rho-independent transcriptional terminator
forming a 23-nucleotide stem-loop structure located immediately
downstream of dcuA (Figure 1A). Another stem-loop structure is
present downstream of cj0091 (Figure 1A). These sequence
features further support the notion that the three lipoprotein
genes form an operon.
Predicted features of the putative lipoproteins
Analysis of the predicted amino acid sequences indicated that
cj0089 , cj0090 , and cj0091 encode putative lipoproteins because
each of them has a typical N-terminal lipoprotein signal peptide.
LipoP algorithm [29] predicted a signal peptidase II cleavage site
at LFLTA Q C for Cj0089, at FLLSA Q C for Cj0090, and at
LLFSG Q C for Cj0091. Cj0089 (453 amino acids), Cj0090 (122
amino acids), and Cj0091 (207 amino acids) each has a calculated
molecular mass of 51.28 kDa, 13.92 kDa, and 22.32 kDa,
respectively. The molecular masses of the mature lipoproteins,
after cleavage of the signal peptides, are predicted to be 49.4 kDa,
12.29 kDa, and 20.51 kDa, respectively. BLASTP searches
against the public non-redundant protein database (http://www.
ncbi.nlm.nih.gov/) showed that Cj0089 bears similarity (78–89%)
to tetratricopeptide TPR-2 repeat proteins found in Shewanella spp.
The functions of these tetratricopeptide TPR-2 repeat proteins
have not been characterized. Cj0089 also has a 27.4% identity to
HP0018, a hypothetical protein in Helicobacter pylori . Cj0091 is
33.5% identical to HP1457 (hypothetical protein) and has a
conserved domain similar to the collagen-binding surface adhesin,
SpaP (antigen I/II family) of Yersinia pestis biovar Orientalis [30],
where its function has not been determined empirically. Cj0090
has a 46% identity to a Helicobacter pylori protein (HP0444;
hypothetical protein). In this study, we choose to focus on
characterization of Cj0089 and Cj0091.
Production of rCj0089 and rCj0091 and their specific
antibodies
The coding sequences of cj0089 and cj0091 , excluding their
signal peptides, were separately cloned into pQE-30 vector,
expressed in E. coli JM109, and the proteins purified by affinity
chromatography. Using the purified proteins, rabbit polyclo-
nal antibodies against rCj0089 and rCj0091 were produced. The
Surface Lipoproteins of Campylobacter
PLoS ONE | www.plosone.org 2 May 2011 | Volume 6 | Issue 5 | e20084
Figure 1. Genomic organization and co-transcription of
cj0089
,
cj0090
, and
cj0091
. (A) The genes are depicted by boxed arrows. The
locations of the primers used for RT-PCR were indicated by arrows. Predicted stem-loop encoding regions are shown by vertical oval arrows. (B) RT-
PCR was performed to determine the co-transcription of cj0089 , cj0090 , and cj0091 using primers, cj89int-F and cj91int-R. Lane 1, no RT control; lane 2,
RNA with RT and DNA polymerase; lane 3, Positive control (DNA was used as the template).
doi:10.1371/journal.pone.0020084.g001
Table 1. Bacterial strains and plasmids used in this study.
Plasmid or strain Relevant characteristics Source
Strains
C. jejuni
NCTC 11168 Wild type [57]
Cj89- 11168 derivative, cj0089::Kan
r
This study
Cj91- 11168 derivative, cj0091::Kan
ract
This study
Comp91 Cj91- complemented with pUOA18-Comp91 This study
E. coli
DH5 a F- W 80lacZ D M15 D (lacZYA-argF)U169re cA1endA1hsdR17 (r
k
2
, m
k +
)phoAsupE44thi-1gyrA96relA1 l
2
Invitrogen
JN109 endA1 recA gyrA96 thi hsdR17 (r
k
2
, m
k +
)r e l A 1 s u p E 4 4 D (lac-proAB)[FreaD36proABlacI
q
Z D M15] Promega
Plasmids
pUC19 E. coli cloning vector [58]
pUC19-89 pUC19 containing full-length cj0089, Amp
r
This study
pUC19-89K pUC19-89 derivative carrying cj0089::Kan
r
This study
pUC19-91 pUC19 containing full-length cj0091, Amp
r
This study
pUC19-91K pUC19-89 derivative carrying cj0091::Kan
r
This study
pRY112 E. coli-C. jejuni shuttle vector, Cm
r
[52]
pRY112-Comp91 pRY11 2 conta ining c onta ining t he pro moter r egion o f cmeABC and fu ll-le ngth Cj 0091 This study
pUOA18 E. coli-C. jejuni shuttle vector, Cm
r
[53]
pUOA18-Comp91 pUOA1 8 conta inin g conta ining t he pro moter r egio n of cmeABC and full-length Cj0091 This stu dy
pMW10 E. coli-C. jejuni shuttle vector with promoterless E. coli lacZ gene, Kan
r
[51]
doi:10.1371/journal.pone.0020084.t001
Surface Lipoproteins of Campylobacter
PLoS ONE | www.plosone.org 3 May 2011 | Volume 6 | Issue 5 | e20084
anti-Cj0089 antibody recognized a protein with a molecular mass
of 49 kDa in NCTC 11168. On the other hand, anti-Cj0091
recognized a protein with a molecular mass of approximately
18 kDa, slightly smaller than the calculated mass of Cj0091
(20.51 kDa) (data not shown). These immunoblotting results
indicated that both lipoproteins were produced in C. jejuni when
grown in MH broth.
Regulation of cj0089 and cj0091 by CmeR
In a previous DNA microarray study by our research group
[26], it was found that cj0089 and cj0091 were down-regulated in
the cmeR mutant, suggesting that CmeR activates the expression of
the lipoprotein genes. To confirm the previous finding at the
protein level, the expression levels of Cj0089 and Cj0091 in the
wild-type strain and in the cmeR mutant were analyzed by
immunoblotting using anti-rCj0089 and anti-rCj0091 antibodies.
The same amount of total proteins was loaded in each lane and
additionally MOMP (a major outer membrane protein present in
all C. jejuni isolates) was used as in internal control for protein
loading in each lane. The immuoblotting results clearly showed
that the production of Cj0089 and Cj0091 in the cmeR mutant was
decreased compared with that in the wild-type (Figure 2).
According to the densitometric analysis of immunoblots using
AlphaEase H software (Alpha Innotech), the band intensity of
Cj0089 was 2.98 fold higher in the wild-type than that in the c meR
mutant, and the band intensity of Cj0091 was 1.92 fold higher in
the wild-type than that in the cmeR mutant. The immunoblotting
data further confirmed the results of the DNA microarray and
real-time RT-PCR [26].
To determine if CmeR directly or indirectly regulates the
lipoprotein operon, a gel mobility shift assay (EMSA) was per formed
using rCmeR and the promoter sequence ups tream of cj0089 . The
promoter DNA was amplified with primer s Pcj89-F1 and Pcj89-R1
(Table 2). rCmeR bound to the promoter region of the lipoprotein
operon (Figure 3). However, the binding was signif icantly weaker
compared with that of the cmeABC promoter, suggesting that CmeR
has a low affinity to the lipoprotein promoter. Regardless, the
finding from EMSA suggests th at this lipoprotein operon is su bject
to direct regulation by CmeR.
Cj0089 and Cj0091 are membrane-associated proteins
In order to determine the cellular localization of Cj0089 and
Cj0091, C. jejuni strain NCTC 11168 was fractionated to isolate
proteins from the cytosol, periplasm, inner membrane, and outer
membrane. The fractions were examined by immunoblotting with
anti-rCj0089 and anti-rCj0091 antibodies (Figure 4). Cj0089 was
detected predominantly in the inner membrane fraction while
Cj0091 was found in both the inner and outer membrane
fractions, but the majority of Cj0091 was in the outer membrane.
Antisera against rCmeB, an inner membrane drug transporter of
multidrug efflux pump CmeABC [16], and against the recombi-
Table 2. Primer sequences used in this study.
Primers Sequences
cj0089-F5 5 9 -GAGgcatgcCCGACTTTGTTAGGTGCAGTGCAA-3 9 ( Sph I)
cj0089-R5 5 9 -GCAgagctcGCTGGAATTCTAAGGGCTTGATAGTCCT-3 9 ( Sac I)
cj89-U2 5 9 -GCTccatggTGCCTTATCTTGACGCATTAAAACACG-3 9 ( Nco I)
cj89-L2 5 9 -CAGccatggGGGAAGCTTCTTTTG CAAATTTAAATATAAATGG-3 9 ( Nco I)
cj0091-F2 5 9 -GTGCGTtctagaAGAGGTTTACCAAAAAGTA-3 9 ( Xba I)
cj0091-R2 5 9 -CTTTTGGgagctcATCAAATTCCTTAGCATTCGTA-3 9 ( Sac I)
cj0089F 5 9 -AGTggatccTGCCTTTTTTTAACAGCTTGTG-3 9 ( BamH I)
cj0089R 5 9 -GAGgagctcTTATTTTTCCATGATAGCAAC-3 9 (Sac I)
cj0091-F1 5 9 -AGTggatccTGTGCGCAAACAGCTTATACAGATGGAAAG-3 9 ( BamH I)
cj0091-R1 5 9 -GAGgagctcTTACCAAGTAACTGAT TTACTAGAACCGGTTTTATC-
3 9 ( Sac I)
Pcj89-F1 5 9 -AGGCTTTGTATTAGCTCCTATGCTTAT-3 9
Pcj89-R1 5 9 -CAAGCAATACCTGAAAAAATCAACCCAA-3 9
Cj89int-F 5 9 -TTTAAAATAAATATGCCTGCAATGA-3 9
Cj89int-R 5 9 -GCGATACCAATGTCCCTTTTT-3 9
KanNco-F 5 9 -CTTATCAATATATccatggAATGGGCAAAGCAT-3 9 ( Nco I)
KanNco-R 5 9 -GATAGAAccatggATAATGCTAAGACAATCACTAAA-3 9 ( Nco I)
Comp91-F2 5 9 -CAAccgcggATGATTTTAGATTAGAAATTAAAGCAA-3 9 ( Sac I)
Comp91-R2 5 9 -GCCCgagctcAACACTTGAGCTAAAA-3 9 ( Sac II)
Comp91-F3 5 9 -GCTtctagaTGGAATCAATAGCTCCAAAGCTTAA-3 9 ( Xba I)
*The restriction sites in the sequences are indicated by lower cases. The
corresponding restriction enzymes for the restriction sites were indicated in
parenthesis.
doi:10.1371/journal.pone.0020084.t002
Figure 2. Effect of c
meR
mutation on the expression of Cj0089
and Cj0091 as determined by immunoblotting. Whole cell lysates
of strains NCTC 11168 (lane 1) and the cmeR mutant (lane 2) were
separated by SDS-PAGE and probed with anti-rCj0089 (panel I), anti-
rCj0091 (panel II), and anti-rMOMP (panel III). MOMP, a 45-kDa outer
membrane protein, was used as an internal control for protein loading.
doi:10.1371/journal.pone.0020084.g002
Figure 3. Binding of rCmeR to the promoter DNA of the
lipoprotein operon as determined by EMSA. The positive control
DNA (promoter of cmeABC ; lanes 1 to 3), negative control DNA (coding
sequence of cmeB; lanes 4 to 6), and the promoter DNA of the
lipoprotein operon (lanes 7 to 9) are included in the same gel. In the
reactions, a fixed amount of DIG-labeled DNA (0.02 pmol) was
incubated with 0 (lanes 1, 4, and 7), 20 (lanes 2, 5, and 8), or 40 ng
(lanes 3, 6, and 9) of rCmeR, respectively. The position of the DIG-
labeled DNA (D) and DNA-rCmeR complex (D/P) are indicated.
doi:10.1371/journal.pone.0020084.g003
Surface Lipoproteins of Campylobacter
PLoS ONE | www.plosone.org 4 May 2011 | Volume 6 | Issue 5 | e20084
nant major outer membrane protein (MOMP) [31], were used as
controls for the membrane fractions. CmeB is exclusively detected
in the inner membrane fraction; however, MOMP was detected in
both outer membrane and inner membrane fractions, with the
majority of MOMP was being in the outer membrane fraction
(Figure 4). The results from the controls suggested that the inner
membrane fraction contained some outer membrane proteins,
while the outer membrane fraction was pure. Based on the blotting
results and in reference to the controls, it was concluded that
Cj0089 is associated with the inner membrane, while Cj0091 is
associated with outer membrane of C. jejuni .
Cj0089 and Cj0091 were inactivated in the insertional
mutants
To study the functions of the lipoproteins, insertional mutants of
cj0089 and cj0091 were generated (Figure 5A). Correct insertion
and orientation of the Kan
R
cassette in Cj89
2
and Cj91
2
were
confirmed by PCR (Figure 5B). The disruptions of cj0089 and
cj0091 were also confirmed by immunoblotting using anti-rCj0089
and anti-rCj0091 (Figure 5C). In Cj89
2
, the expression level of
cj0091 was significantly decreased, but was not abolished
(Figure 5C, panel II, lane 2), indicating that the insertion in
cj0089 caused a partial polar effect on cj0091 .
Figure 4. Localization of Cj0089 and Cj0091 in
C. jejuni
. The
cytosol fraction (lane 1), periplasmic fraction (lane 2), inner membrane
fraction (lane 3), and outer membrane fraction (lane 4) were separated
by SDS-PAGE and probed with anti-rCmeB (panel I), anti-rCj0089 (panel
II), anti-rMOMP (panel III), and anti-rCj0091 (panel IV), respectively.
doi:10.1371/journal.pone.0020084.g004
Figure 5. Generation of deletional and insertional mutations in
cj0089
and
cj0091
. (A) Schematic diagram of the locations of deletional and
insertional mutations. The genes are indicated by boxed arrows. The locations of the Kan
R
insertion are indicated as solid arrows. (B) PCR confirmation
of the insertions in Cj89
2
and Cj91
2
. Lanes 1, cj0089 in wild-type strain; lane 2, cj0089 in Cj89
2
; lane 3, cj0091 in wild-type strain; and lane 4, cj0091 in
cj91
2
. (C) Immunoblotting analysis of protein production in various constructs. Wild-type (lane 1), Cj89
2
(lane 2), and Cj91
2
(lane 3) were separated by
SDS-PAGE and probed with anti-rCj0089 (panel I), anti-rCj0091 (panel II), and anti-rMOMP (panel III). MOMP, a 45-kDa outer membrane protein, was
used as a loading control.
doi:10.1371/journal.pone.0020084.g005
Surface Lipoproteins of Campylobacter
PLoS ONE | www.plosone.org 5 May 2011 | Volume 6 | Issue 5 | e20084
Cj0091 is required for Campylobacter adherence to INT
407 cells in vitro
Since the results indicated that Cj0091 is an outer membrane-
associated protein and has a domain homologous to SpaP involved
in surface adherence, it is possible that Cj0091 is involved in the
interaction between C. jejuni and host cells. To examine this
possibility, the ability of NCTC 11168 wild type strain and the two
isogenic mutants, Cj89
2
and Cj91
2
, to adhere to the monolayers
of human intestinal cell line INT 407 was measured (Figure 6).
Cj91
2
showed a 4.3-fold reduction in adherence compared with
the wild-type strain (P , 0.05). Cj89
2
had a 1.3-fold reduction in
adherence compared to the wild-type; however, the difference was
not significant (p . 0.05). The adherence ability of the comple-
mented strain of Cj91
2
, Comp91, to INT 407 cell line was
restored partially to the wild-type level (Figure 6). To rule out the
possibility that the observed phenotype of Cj91
2
was due to its
increased sensitivity to Triton X-100 (used in the adhesion assay to
dissociate bacteria from the INT 407 cells), both the wild-type and
Cj91
2
strains were treated with 1% Triton X-100 for 20 min and
then the treated bacteria were plated onto MH agar plates for
CFU counts. The result indicated that both strains were equally
resistant to the treatment with Triton X-100 (result not shown).
These findings indicate that Cj0091, but not Cj0089 has a
significant role in Campylobacter adherence to INT 407 cells.
Cj0091 is involved in intestinal colonization in chicken
To test whether Cj0089 and Cj0091 had a role in chicken
colonization, the wild-type strain 11168, its isogenic mutants
Cj89
2
and Cj91
2
, and Comp91 were separately inoculated into
four groups of chickens. At necropsy, cecal contents were collected
on DPI 3, 6, and 9 from 5 chickens from each group and cultured
for enumeration of Campylobacter using selective plate counting. On
DPI 3 and 6, the mean level of colonization by Cj91
2
was
substantially lower (reduced approximately 2.8 and 2.7 log
10
units,
respectively) than that of the wild-type strain (Figure 7). The
differences were statistically significant (p , 0.05). However, on
DPI 10 no significant differences in colonization between the wild-
type and Cj91
2
were observed. The level of colonization was
restored to the wild-type level in the complemented strain,
Comp91 (Figure 7). Throughout the experiment, no differences
in colonization were observed between the wild-type and Cj89
2
(Figure 7). The colonization reduction seen with Cj91
2
was not
attributable to the difference in in vitro growth rates or motility
because growth and motility of the mutants were equally
comparable to those of the wild-type strain (data not shown).
Together, these results indicate that Cj0091, but not Cj0089,
contributes to the establishment of colonization during the early
stages of C. jejuni infection in the intestinal tract of chickens.
Cj0091 is expressed and immunogenic in chickens
The contribution of Cj0091 to adherence and in vivo
colonization prompted us to determine if Cj0091 was produced
and immunogenic in chickens naturally infected by Campylobacter .
For this purpose, rCj0091 was used as antigen in immunoblotting
and was probed with chicken sera collected from 5 individual
Figure 6. Adherence of
C. jejuni
strain NCTC 11168 and the
mutants to INT 407 cells. Strain NCTC 11168, Cj89
2
, and Cj91
2
were
inoculated onto monolayers of INT 407 cells and the percentages of
adherent bacterial cells were calculated by viable plate counts. Each
experiment was conducted in quadruplicate and repeated for 3 times.
Bars and error bars indicate the mean 6 standard deviation. * indicates
significant differences in colonization levels at P , 0.05 level as
determined by Student’s t-test.
doi:10.1371/journal.pone.0020084.g006
Figure 7. Colonization of
C. jejuni
strain NCTC 11168 and its mutants in chickens. Approximately 10
7
CFU of each of NCTC 11168 (solid
squares), Cj89
2
(open circles), Cj91
2
(solid triangles), Comp91 (solid diamonds) were inoculated into 3-day-old chickens. Cecal contents were
collected on 3, 6, and 10 days post inoculation (DPI) and enumerated by plate counts. Each symbol represents the colonization level in a single bird.
The mean for each group is depicted by a horizontal bar. The detection limit of the plating method is about 100 CFU/g of feces. An asterisk indicates
significant differences in colonization levels at P , 0.05 as determined by Student’s t-test.
doi:10.1371/journal.pone.0020084.g007
Surface Lipoproteins of Campylobacter
PLoS ONE | www.plosone.org 6 May 2011 | Volume 6 | Issue 5 | e20084
chickens, among which 4 contained natural maternal antibodies
against C. jejuni and the other one was a negative control
( Campylobacter -free and no anti- Campylobacter maternal antibodies)
[32]. As shown in Figure 8, the 21-kDa rCj0091 was detected by
the 4 sera, in which high level of C. jejuni -specific maternal
antibodies (IgG) were present, but not by the serum in which the
C. jejuni -specific maternal antibodies were absent (Figure 8). These
findings strongly suggest that Cj0091 was produced and
immunogenic during the colonization of chickens by C. jejuni .
Discussion
In this study, we characterized an operon encoding three
lipoproteins, Cj0089, Cj0090, and Cj0091. It was confirmed that
this operon is activated and directly regulated by CmeR, a
pleiotropic regulator modulating the expression of multiple genes
with diverse functions in Campylobacter [26]. We also demonstrated
that Cj0091, but not Cj0089, plays an important role in mediating
Campylobacter adherence to INT 407 cells and in Campylobacter
colonization of the gastrointestinal tract of chickens, especially in
the early stage of the infection. These findings identify a new
adhesion mechanism in C. jejuni and provide new insights into the
pathogenesis of C. jejuni .
Homology searches us ing BLASTP showed th at Cj0089 is
similar to the tetratri copeptide TPR-2 repeat pr otein of Shewanella
spp. (78–89% homology; E-val ue = 4e-19 to 4e-16). The tetra-
tricopeptide rep eat (TPR) is a structu ral motif, which media tes
protein-protein in teractions. TPR-cont aining proteins hav e
diverse functions s uch as regulation of the cell cycle, pr otein
transport, the regu lation of transcripti on, splicing events, and
protein folding [33,34 ]. Proteins containing the TP R motif have
been found in vari ous organisms includin g bacteria, yeast, pl ants,
insects, and animals [33,34]. At present the function of Cj008 9 is
unknown, and the fu nction of Cj0090 has ye t to be determined.
Since cj0089 , cj0090 ,a n d cj0091 form an operon , it is possible
that the three encod ed products have a fun ctional link. This
possibility remains to be de fined in future studies . Cj0091 has a
conserved domain hom ologous to the collagen -binding surface
adhesin, SpaP (antige n I/II family) of Y. pesti s biovar Orientalis.
spaP was first identifi ed in Streptococcus m utans as a gene encoding
antigen I/II [35] an d is also known as P1 [36] . The antigen P1,
encoded by spaP, plays a role in adher ence of S. mutans to the
salivary pellicle of tooth surf aces or to other microorganisms
[37,38]. At this stage, i t is unknown if Cj0091 binds to col lagen or
has functions similar to those of SpaP in S. mutant .I ts h o u l db e
mentioned that Cj008 9 and Cj0091 are putat ive lipoproteins as
supported by bioinf ormatics analyses an d membrane associati on
experiments, and fu rther studies such as palmitoyl ation assay
using [
3
H]-palmitate are ne eded to prove that they ar e truly
modified by lipids.
In this study we confirmed the regulation of the putative
lipoprotein operon by CmeR (Figures 2 and 3). Based on the result
of EMSA, CmeR directly interacts with the promoter DNA
(Figure 3). However, the interaction is much weaker compared
with the cmeABC promoter, suggesting that CmeR is a secondary
regulator of the lipoprotein operon. This notion is supported by
the fact that the fold change in expression of the lipoprotein genes
was moderate as determined by microarray, real-time RT PCR,
and immunoblotting. Analysis of the upstream sequence of cj0089
did not identify the typical inverted repeat found in the promoter
region of cmeABC recognized by CmeR [27]. Since CmeR serves
as an activator for the lipoprotein operon, which is in contrast to
the regulation of cmeABC (repressed by CmeR), the binding site for
CmeR in front of the lipoprotein operon could be different from
the one upstream cmeABC . This possibility awaits further
inverstigation.
The contribution of Cj0091 to Campylobacter adherence was
investigated using the human intestinal epithelial cell line INT 407
(Figure 6). So far, adhesins characterized in C. jejuni include PEB1
[14], CadF [11], MOMP [15], JlpA [20], CapA [21], FlpA [23],
and Cj1349c [23]. PEB1 is a periplasmic protein, homologous to
the periplasmic solute-binding protein component of amino acid
ABC transporters [13]. An important function of PEB1 is that it
binds to aspartate and glutamate, which are important sources of
carbon and energy for Campylobacter [13,39]. CadF, a surface
protein, is involved in the binding of C. jejuni to fibronectin in the
host gastrointestinal epithelium and stimulation of the host cell
signal transduction pathway [11,40]. MOMP, a trimeric outer
membrane protein [41,42], is involved in pore-forming activity
[43], and assists outer membrane structural organization and
stabilization [44]. Although one study suggested MOMP could be
involved in adherence [15], the exact role of MOMP in the
interaction between Campylobacter and host cells is unknown. JlpA is
a lipoprotein and is involved in interaction with host cells in vitro
[20]. Besides functioning as an adhesin, JlpA interacts with
surface-exposed heat shock protein 90 a (Hsp90 a ) on host cells,
triggering signaling pathways and leading to the activation of NF-
k B and p38 MAP kinase [24]. CapA, which is an autotransporter,
is involved in the colonization of the chicken gut and plays a role
in adherence to human epithelial cells [21]. FlpA contains Fn type
III domains, and is involved in interaction with host cells in vitro
and in vivo via binding to fibronectin [23,25]. Cj1349c has been
shown to be involved in adherence to chicken liver epithelial cells
[23]. Thus, C. jejuni appears to possess multiple adhesins and the
Figure 8. Immunoblotting detection of natural anti-Cj0091
antibodies in chickens. Strips of nitrocellulose membranes with
rCj0091 were reacted with 4 chicken sera (lanes 2–5) that contained
Campylobacter -specific maternal antibodies derive d from natural
infections and one chicken serum (lane 6) that was negative for anti-
Campylobacter antibodies. Anti-rCj0091 was applied as a positive
control (lane 1).
doi:10.1371/journal.pone.0020084.g008
Surface Lipoproteins of Campylobacter
PLoS ONE | www.plosone.org 7 May 2011 | Volume 6 | Issue 5 | e20084
partial reduction of adherence seen with Cj91
2
may be explained
by the complementary effects of other adhesins.
Although we showed that Cj0091 is an outer membrane
associated protein (Figure 4), it has yet to be determined whether
this protein is located on the outer surface or is facing the
periplasmic space. Controlled protease treatments did not yield
conclusive result on the surface exposure of Cj0091 (data not
shown). Therefore, it is uncertain how Cj0091 contributes to
Campylobacter adherence to human epithelial cells. More advanced
technologies (such as immunogold labeling and electron micros-
copy) may be used in future work to ascertain the exact location of
Cj0091 on the outer membrane. It should be pointed out that not
all adhesins are true outer surface exposed proteins. For example,
PEB1 and CjaA are reported adhesins of Campylobacter and are
mainly localized in the periplasmic space or inner membrane, but
these proteins are shown to be secreted or attached on the outer
surface, functioning as adhesins [22,55]. Thus, even if Cj0091
faces inward on the outer membrane, this would still not exclude
its role as an adhesin.
C. jejuni mainly colonizes in cecal and cloacal crypts in chickens
[45,46]. Unlike the colonization in mammals, such as mice, swine,
rabbits, monkeys, and humans, where the organism commonly
invades the host intestinal epithelial cells, C. jejuni does not usually
invade the intestinal epithelium of chickens [47–49]. Thus, surface
colonization is an important feature of Campylobacter infection in
chickens. Ceca of chickens are blind-ended sacs filled with small
food particles, fluid, and microorganisms. Cecal contents are
constantly moving and periodically evacuated [50]. Thus, cecum is
not a stagnant environment and Campylobacter must possess
mechanisms for persistent colonization in this niche. Interestingly,
the differences in colonization between the wild-type and Cj91
2
were only seen at the early stage (before DPI 10) of infection
(Figure 7). We speculate that this may reflect the possibility that
Cj0091 is only required for the initial adherence and optimal
establishment of infection, or that adaptation of the Cj91
2
mutant
occurs in the intestinal tract, overcoming the early defect in
colonization. Although it has been reported that Campylobacter does
not directly interact with intestinal epithelial cells, but rather
resides in the mucus layer of the crypts moving freely and rapidly
in chickens [46], it is highly likely that adherence to the
gastrointestinal mucosal cell surface is still required for successful
colonization in chickens [7]. Indeed, independent studies have
shown that CapA, CadF, PEB1, and FlpA are each required for
Campylobacter colonization in chickens [12,14,21,23].
It was demonstrated in this study that Cj0089 is an inner
membrane protein (Figure 4). Disruption of cj0089 did not result in
significant changes in in vitro adherence and in vivo colonization
(Figures 6 and 7), suggesting that Cj0089 is not essential for
Campylobacter growth in the intestinal tract. Alternatively, it may
suggest that Cj0089 shares redundant function(s) with other genes
in C. jejuni . Although cj0089 and cj0091 are located in the same
operon and both are regulated by CmeR, they may have different
functions in Campylobacter biology. Interestingly, mutation of cj0089
reduced, but did not abolish, the expression of cj0091 due to a
polar effect (Figure 5). The partial reduction in Cj0091 expression
did not cause an apparent phenotypic change, suggesting that
partial production of Cj0091 is sufficient for adherence and
colonization at the wild-type level.
Another interesting finding in this study is that Cj0091 is
abundant in C. jejuni in vitro and is apparently immunogenic in
chickens (Figure 8). To date, no commercial vaccines against
Campylobacter are available for use in humans or poultry, but some
promising candidates have been evaluated for potential develop-
ment of vaccine products [5,22]. The fact that the Campylobacter is
commensal in poultry and that it shows high genetic and antigenic
diversity among different strains make the development of an
effective vaccine quite difficult. One of the promising vaccine
candidates is an attenuated Salmonella strain carrying the C. jejuni
CjaA antigen [22]. CjaA is a highly immunogenic protein that is
well conserved among different Campylobacter serotypes and induces
protective immune responses in chickens [22]. Cj0091 is also
highly conserved among the 4 sequenced strains of C. jejuni ( $ 99%
amino acid identity). This fact plus the findings from this study
suggest that Cj0091 may be used as a potential vaccine candidate
in the control of C. jejuni colonization in chickens. This possibility
will be examined in future studies.
Materials and Methods
Bacterial strains, plasmids, and culture conditions
The various bacterial strains, mutants, and plasmids used in this
study are listed in Table 1. Campylobacter strains were routinely
grown in Mueller-Hinton (MH) broth (Difco, Detroit, MI) or agar
at 42 u C with an atmosphere of 5% O
2,
10% CO
2
, and 85% N
2
.
Escherichia coli strains were grown is Luria-Bertani (LB) broth
(Difco) or agar at 37 u C with shaking at 250 rpm. Media were
supplemented with ampicillin (Amp) (100 m g/ml), kanamycin
(Km) (50 m g/ml), or chrolamphenicol (Cm) (4 m g/ml for Campylo-
bacter ,2 0 m g/ml for E. coli ) as needed.
PCR
All primers used for PCR are listed in Table 2. PCR
amplification was performed in a volume of 100 m l containing
200 m M of each deoxynucleoside triphosphate, 200 nM primers,
2.5 mM MgSO
4
, 100 ng of template DNA and 5 U of Taq DNA
polymerase (Promega, Madison, WI) or pfu Turbo DNA polymer-
ase (Stratagene, La Jolla, CA). Cycling conditions varied de-
pending on the estimated melting temperatures of the primers and
the expected size of the products. PCR products were purified with
a QIAquick PCR purification kit (QIAGEN, Valencia, CA). For
reverse transcriptase PCR (RT-PCR), total RNA was isolated
from C. jejuni NCTC 11168 using the RNeasy minikit (QIAGEN).
Isolated total RNAs were treated with RNase-free DNase
(QIAGEN) to remove contaminating genomic DNA, and this
was followed by quantification and qualification of the RNA using
a NanoDrop microscale spectrophotometer (NanoDrop Technol-
ogies, Wilmington, DE). RT-PCR was conducted using the
SuperScript
TM
III One-Step RT-PCR system with Platinum H
Taq DNA Polymerase (Invitrogen, Carlsbad, CA). Cycling
conditions for the RT-PCR were as follows: synthesis of cDNA
at 50 u C for 30 min; denaturation at 94 u C for 2 min, followed by
40 cycles of 94 u C for 15 s, 55 u C for 30 s and 72 u C for 2 min 30 s;
and a final extension at 72 u C for 10 min. The negative control was
a RT-PCR mixture with the Taq polymerase (Promega) without
the RT step, while the positive control was a reaction with
genomic DNA as the template.
Production of rCmeR
F ull-length recombinant CmeR was produced in E. coli as
described previously [26,27] with some modifications. Specifically,
by serine using site-directed mutagenesis to increase the stability of
purified CmeR. The mutagenesis was performed using the
QuikChange II site-directed mutagenesis kit (Stratagene). Com-
plimentary primers CmeRC1-F (5 9 -GAAATTTTAGATGA) and
CmeRC1-R (5 9 -GATGAAAGTGTTTTTTACTTATGTCAT-
CTAAAATTTC-3 9 ) were used to generate the C69S mutation,
while primers CmeRC2-F (5 9 -CTTGCTGTTCTTTTTAGCAC-
Surface Lipoproteins of Campylobacter
TATGTTAAAAGAACC-3 9 ) and CmeRC2-R (5 9 -GGTTCTTT-
TAACATAGTGCTAAAAAGAACAGCAAG-3 9 ) were used to
generate the C166S mutation. The reaction was performed in a
50 m l mixture containing 5 m lo f1 0 6 reaction buffer, 50 ng of
purified pQE11168CmeR plasmid ( cmeR cloned into pQE30) [27],
1 m l of each of the 10 m M primers (CmeRC1-F, CmeRC1-R,
CmeRC2-F, and CmeRC2-R), 1 m l of dNTP mix, 1 m l of PfuUltra
HF DNA polymerase (2.5 U/ m l) and ddH
2
O. The temperature
cycling used for synthesis and amplification started with 1 cycle at
95 u C for 30 s and then followed by 18 cycles (95 u C for 30 s, 55 u C
for 1 min, and 68 u C for 4 min). The reaction was then cooled on
I restriction enzyme (10 U/ m l) was added directly to the
amplification reaction, which was then gently mixed and
incubated at 37 u C for 1 hour. Then, the Dpn I-treated DNA
was transformed into competent E. coli JM109 cells. Positive
colonies were selected on LB Agar plate containing ampicillin
(100 m g/ml). The mutated plasmids were isolated and the desired
mutations were confirmed by DNA sequencing. The rCmeR
carrying the C69S and C166S changes were produced, purified
and used for DNA binding assay as described previously [26].
Deletional mutation of cj0089
An isogenic cj0089 mutant was constructed by deletional
mutagenesis in C. jejuni strain NCTC 11168. To construct the
cj0089 mutant, primers cj0089-F5 and cj0089-R5 (Table 2) were used
to amplify the 1915-bp fragment containing the entire open reading
frame (ORF) of cj0089 (1362 bp) and its flanking sequences from C.
jejuni strain NCTC 11168 chromosomal DNA. The PCR product was
digested with Sph Ia n d Sac I and cloned into pUC19 (Invitrogen) to
form pUC19-89. Inverse PCR was performed using pfu Turbo DNA
polymerase (Stratagene) on pUC19-89 using primers cj89-U2 and
cj89-L2 (Table 2), which resulted in a 460-bp deletion within cj0089 .A
kanamycin-resistance (Kan
R
pfu Turbo DNA polymerase (Stratagene ), was inserted into the
amplified product to obtain p UC19-89K. The suicide vector,
pUC19-89K, was introduced into C. jejuni NCTC 11168 by
electroporation. Transformants were selected on MH agar containing
Km (50 m g/ml). Disruption of cj0089 by deletion of the partial ORF
and insertion of the Kan
R
gene with the correct orientation was
confirmed by PCR, and the cj0089 mutant was named Cj89
2
.
Insertional mutation of cj0091
An isogenic cj0091 mutant was constructed by insertional
mutagenesis in C. jejuni NCTC 11168. The 1724-bp fragment
containing the entire ORF of cj0091 (624 bp) and its flanking
sequences was amplified using primers cj0091-F2 and cj0091-R2
(Table 2) from C. jejuni NCTC 11168 chromosomal DNA. The
PCR product was digested with Sac I and Xba I and cloned into
pUC19, forming pUC19-91. pUC19-91 was digested with Cla I
followed by Klenow treatment (Takara, Shiga, Japan) to form
blunt ends. The Kan
R
Turbo DNA polymerase (Stratagene), was inserted into the Cla I-
digested and Klenow-treated pUC19-91 to obtain pUC19-91K.
The suicide vector, pUC19-91K, was introduced into C. jejuni
NCTC 11168 by electroporation. Transformants were selected on
MH agar containing 50 m g of Km per ml. PCR was performed to
confirm the disruption of cj0091 by the Kan
R
gene with the right
orientation, and the cj0091 mutant was named Cj91
2
.
Complementation of Cj91
2
To construct the complement of Cj91
2
, primers 91comp-F2
and 91comp-R2 (Table 2) were first used to amplify the 744-bp
fragment containing the entire ORF of cj0091 (624 bp) and its
flanking sequences from C. jejuni strain NCTC 11168 chromo-
somal DNA. The PCR product was digested with Sac I and Sac II
and cloned into pRY112 [52], containing the promoter region of
cmeABC to form pRY112-Comp91. Primers 91comp-F3 and
promoter region of cmeABC and entire ORF of Cj0091 from
pRY112-comp91. The amplified product was digested with Sac I
and Xba I and cloned into pUOA18 [53] to form pUOA18-
Comp91. The vector, pUOA18-Comp91, was introduced into
Cj91
2
by conjugation. Transformants were selected on MH agar
containing 50 m g of Km per ml and 4 m g of Cm per ml. PCR and
immunoblotting were performed to confirm the complementation
of Cj91
2
, and the complement of Cj91
2
was named Comp91.
Expression and purification of recombinant Cj0089 and
Cj0091
6 x histidine (His)-tagged recombinant Cj0089 and Cj0091
(rCj0089 and rCj0091, respectively) were produced in E. coli using
the pQE-30 vector of the QIAexpress System (QIAGEN). A 1323-
bp sequence (not including the N-terminal lipoprotein signal
peptide sequence) of cj0089 (1362 bp) was amplified using primers
cj0089F and cj0089R (Table 2). A 567-bp fragment (without the
was also amplified using primers cj0091-F1 and cj0091-R1
(Table 2). The amplified products containing restriction sites at
the 5 9 -ends (Table 2) were purified and digested with appropriate
restriction enzymes and separately ligated into pQE-30 vectors.
The predicted lipoprotein signal peptides of Cj0089 and Cj0091
were not included in the recombinant products. Thus, the
recombinant products represented the mature proteins in C. jejuni .
Cloning, expression and purification of rCj0089 and rCj0091 were
performed using the procedures provided by the QIAexpress
system. The purified proteins were washed with 1 x PBS
(containing 10 mM benzamidine) to remove imidazole and were
concentrated using Ultracel H YM-30 (for Cj0089) and Ultracel-
H YM-10 (for Cj0091) Centrifugal Filter Units (Millipore, Billerica,
MA).
Production of rabbit antisera
A polyclonal rabbit antiserum against rCj0089 was generated in
our laboratory. A New Zealand white rabbit was immunized three
times with rCj0089 at a 2-week interval between the injections.
Each immunization used 100 m g of rCj0089 emulsified in
incomplete Freund’s adjuvant. The animal was sacrificed 21days
after the last injection to collect the antisera against rCj0089.
Polyclonal antiserum against rCj0091 was generated in two rabbits
were stored at 2 80 u C for further use.
Electrophoretic mobility shift assays (EMSA)
To determine whether CmeR directly bind s to the operator
region of cj0089 , EMSA, as descr ibed by Alekshun et al. [54], was
performed with slight modificatio ns. The 179-bp promoter region of
cj0089 was amplified using primers Pcj89 -F1 and Pcj89-R1
(Table 2). The amplified product was then labeled at the 3 9 end
with digoxigenin-11-ddUT P (DIG-11-ddUTP) using the DIG
Oligonucleotide 3 9 -En d Labeling kit (Roche Molecular Biomedi -
cals, Indianapolis, IN). The DIG-11 -ddUTP-labeled DNA
(0.02 pmol) was incubated with different amounts of rCmeR (0,
20, and 40 ng) in 20 m l binding buffer containing 20 mM HEPES
(pH 7.6), 1 mM EDTA, 10 mM (NH
4
)
2
SO
4
, 5 mM dithopthreitol,
0.2% Tween-20, 30 mM KCl, and 50 ng of poly(dI-dC). The
reaction mixtures were incubat ed at room temperature for 30 min,
Surface Lipoproteins of Campylobacter
followed by electrophores is on a nondenaturing 6% (w/ v)
polyacrylamide gel in a 0.5 x TBE buffer (44.5 mM Tris,
44.5 mM boric acid, 1 mM EDTA, pH 8.0) at 200 V for 45 min.
The DNA was transferred from the gel to a positively charged nylon
membrane using a vacuum blotter. Alkaline phosph atase-conjugat-
ed anti-DIG antibody and the chemiluminesc ent substrate CDP-
star (Roche Molecular Biochemica ls) were sequentially applied to
the membrane. The chemilumi nescence signals on the blots were
captured using a digital im aging system (ChemiIma ger
TM
5500 from
Alpha Innotech, San Leandro, CA). The promoter DNA of cmeABC
and the intragenic fragment of cmeB were used as the pos itive and
negative controls, respectiv ely, as described in a previous study [2 7].
Preparation of cell fractions
The cell fractions of cytoplasm, periplasm, inn er membrane, and
outer membrane were obta ined using the method descr ibed by
Leon-Kempid et al. [55], with slight modif ications. In total, 500 ml
of an overnight culture of C. jejuni strain NC TC 11168 were
harvested by centrifugation at 5000 x g for 30 min, and the cell
pellet was resuspended in 20 ml of the ST buffer (20% w/v sucrose,
30 mM Tris-HCl, pH 8.0) at room temperature. EDTA was added
suspension was incubated for 10 min at room temperature with
shaking. The cells were then centrifuged at 8000 x g for 10 min at
room temperature to collect the cell pellet. The supernatant was
discarded. The pellet was resuspended and stirre d in ice-cold
10 mM Tris-HCl (pH 7.5) at 4 u C for 10 min followed by
centrifugation at 15,000 x g at 4 u C for 15 min. The supernatant
was concentrated by 10% TCA and kep t as the periplasmic fraction .
The pellet was again resuspended in 5 ml of ice-cold 10 mM Tris-
HCl (pH 7.5), followed by sonication (Virsonic, an SP Industries
Company, Warminster, PA) by three bursts of 30 s at 6 m m
amplitude and centrifugati on at 13,000 x g at 4 u C for 15 min. The
pellet was discarded. The supernat ant was ultracentrifuged at
100,000 x g at 4 u C for 1 hour. The supernatant was then
transferred to a new tube an d again centrifuged at 10 0,000 x g at
4 u C for 1 hour. The supernatant was concentrated by 10% TCA,
corresponding to the cytoplasmic frac tion. The pellet collected was
the total membrane fraction. The isolation of inn er and outer
membrane was performed using the method of Carlon e et al. [56].
The pellet of membrane fraction was washed thre e times with ice-
cold 10 mM Tris-HCl (pH 7.5) and resuspended in 0.2 ml of
10 mM HEPES buffer (pH 7.4). An equal volume of sarkosol buffer
(2% sodium N-lauroylsarkosi ne; SIGMA) was added and incubated
mixed occasionally. The inner me mbrane proteins were solubili zed
at this step. The mixture was cent rifuged at 15,600 x g for 30 min at
4 u C. The supernatant was kept as the soluble inner membrane
fraction. The pellet was washed with 0.5 ml of 10 mM HEPES
buffer followed by resuspension in 200 m l of 10 mM HEPES buffer.
This fraction was the outer membrane fraction . The fractions were
analyzed by SDS-PAGE and imm unoblotting.
Adhesion assays
Adhesion assays were performed according to the method
described by Jin et al. [20], with some modifications. INT 407
cells (ATCC CCL-6) were grown in Minimum Essential Medium
(MEM) (GIBCO, Invitrogen) conta ining 10% fetal bovine serum
(FBS), 100 m g/ml streptomycin, and 100 units/ ml penicillin G
(GIBCO, Invitrogen) at 37 u C under the atmosp here of 5% CO
2
.
Once the INT 407 cells became confluent, the monolayers were
trypsinized and approximately 1 6 10
5
cells/well in MEM with 10%
FBS without antibiotic s were applied to each well of a 24-wel l tissue
culture plate, which was incubated at 37 u C for 18 h under the
2
. The monolayers were washed twice with
1 x PBS. Overnight fresh cultures of NCTC 11168, Cj89
2
,C j 9 1
2
,
and Comp91 were added to wells containing mono layers in 1 ml of
MEM with 10% FBS at an INT 407 cells-to-bacteria ratio of 1:100,
and incubated at 37 u C under the atmosphere of 5% CO
2
for 3 h.
The monolayers were washed five times with 1 x PBS. The washed
monolayers were then lysed wit h 0.2 ml of 1% (w/v) Triton X-100
in PBS for 15 min. The Campylobacter cells were enumerated by plate
counting on MH agar plates. All assays were repeated three times
and were done in quadruplicate.
Motility assay
Bacterial strains were grown overnight and their OD
600
was
adjusted to ca. 0.5. A single stab inoculation was made in the
incubated at 42 u C for 48 hours. The swarming diameters of the
strains were measured at the widest portion of the swarm halo.
Colonization in chicken
To examine whether the mutations of cj0089 and cj0091
affected C. jejuni colonization in chickens, 3-day-old commercial
broilers (Ross x Cobb), purchased from a commercial hatchery,
were inoculated via oral gavage with approximately 10
7
CFU of
NCTC 11168, Cj89
2
, Cj91
2
, or Comp91 (each group consists of
15 birds). At necropsy, cecal samples were collected from 5 birds
from each group at 3, 6, and 10 days post inoculation (DPI),
homogenized, serially diluted in 1 x PBS, and plated on MH plates
containing Campylobacter -specific selective agents and growth
supplements (SR084E and SR117E; Oxoid). After two-day
incubation at 42 u C under microaerophilic conditions, the
Campylobacter colonies were counted.
Ethics Statement
All animals were handled in strict accordance with the
recommendations in the Guide for the Care and Use of
Laboratory Animals of the National Institutes of Health. The
animal use protocol was approved by the Institutional Animal
Care and Use Committee of Iowa State University (A3236-01). All
efforts were made to minimize suffering of animals.
Acknowledgments
We thank Baoqing Guo, Feng Shi, Ewen Barton, and Jing Han for
providing technical assistance.
Author Contributions
Conceived and designed the experiments: MO BJ OS QZ. Performed the
experiments: MO BJ OS ZS. Analyzed the data: MO BJ OS ZS QZ.
Contributed reagents/materials/analysis tools: MO BJ OS ZS QZ. Wrote
the paper: MO QZ.
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Surface Lipoproteins of Campylobacter
PLoS ONE | www.plosone.org 11 May 2011 | Volume 6 | Issue 5 | e20084
... Finally, we found several proteins that, according to the KEEG database analysis, could not be assigned to any of the aforementioned functional groups but were identified with high confidence. Two were PflA (C8J_1462; paralyzed flagella), the element of the C. jejuni flagellar motor, and an inner membrane-anchored lipoprotein of an unknown function (C8J_0082)
[52]
[53][54]. Modeling of the C8J_1462 and C8J_0082 revealed that both contains cysteine residues implicated in the formation of bridges (44-57, 537-565, 766-779 and 39-71, respectively). For the list of the remaining proteins associated with less significant q-values, refer to Supplementary Table S1. ...
... The Cj0089 gene of C. jejuni NCTC 11168 was described by Oakland et al. as a part of the cj0089-cj0090-cj0091 operon activated by CmeR. All proteins encoded by this operon are membrane-located lipoproteins with an undefined function involved in chicken colonization
[52]
. ...
Interplay between DsbA1, DsbA2 and C8J_1298 Periplasmic Oxidoreductases of Campylobacter jejuni and Their Impact on Bacterial Physiology and Pathogenesis
Article
Full-text available
INT J MOL SCI
Anna Marta Banaś
Katarzyna Marta Bocian-Ostrzycka
Stanislaw Dunin-Horkawicz
Elżbieta Katarzyna Jagusztyn-Krynicka
The bacterial proteins of the Dsb family catalyze the formation of disulfide bridges between cysteine residues that stabilize protein structures and ensure their proper functioning. Here, we report the detailed analysis of the Dsb pathway of Campylobacter jejuni. The oxidizing Dsb system of this pathogen is unique because it consists of two monomeric DsbAs (DsbA1 and DsbA2) and one dimeric bifunctional protein (C8J_1298). Previously, we showed that DsbA1 and C8J_1298 are redundant. Here, we unraveled the interaction between the two monomeric DsbAs by in vitro and in vivo experiments and by solving their structures and found that both monomeric DsbAs are dispensable proteins. Their structures confirmed that they are homologs of EcDsbL. The slight differences seen in the surface charge of the proteins do not affect the interaction with their redox partner. Comparative proteomics showed that several respiratory proteins, as well as periplasmic transport proteins, are targets of the Dsb system. Some of these, both donors and electron acceptors, are essential elements of the C. jejuni respiratory process under oxygen-limiting conditions in the host intestine. The data presented provide detailed information on the function of the C. jejuni Dsb system, identifying it as a potential target for novel antibacterial molecules.
... There was increased expression (3.564x) of omp50, a hypothetical outer membrane porin. Cme genes (e.g., cmeB (1.567) and cmeA (1.314)) coding for a Cme efflux pump proteins were upregulated except for cmeC [64,
65]
. A transmembrane protein (AA01_00144/Cj0268c) required for adhesion and colonisation in vitro [66,67] was elevated (2.881). ...
... The genes coding for fibronectin-binding adhesion proteins (flpA (2.909) and fbpA (2.160)) with possible roles in colonization [68] had elevated expression during the invasion. Two additional lipoprotein-coding genes were overexpressed (AA01_01303/Cj0090) (1.879) and AA01_01302/Cj0091 (2.132), probably playing a role in adhesion and repressed by the CmeR regulator
[65]
. Expression of the gene cj0588 involved in adhesion was also elevated [69]. ...
Virulence Traits of Inpatient Campylobacter jejuni Isolates, and a Transcriptomic Approach to Identify Potential Genes Maintaining Intracellular Survival
Article
Full-text available
Judit K Kovács
Alysia Cox
Bettina Schweitzer
György Schneider
There are still major gaps in our understanding of the bacterial factors that influencethe outcomes of humanCampylobacter jejuniinfection. The aim of this study was to compare thevirulence-associated features of 192 humanC. jejunistrains isolated from hospitalized patients withdiarrhoea (150/192, 78.1%), bloody diarrhoea (23/192, 11.9%), gastroenteritis (3/192, 1.6%), ulcerativecolitis (3/192, 1.5%), and stomach ache (2/192, 1.0%). Traits were analysed with genotypic andphenotypic methods, including PCR and extracellular matrix protein (ECMP) binding, adhesion,and invasion capacities. Results were studied alongside patient symptoms, but no distinct links withthem could be determined. Since the capacity ofC. jejuni to invade host epithelial cells is one of its most enigmatic attributes, a high throughput transcriptomic analysis was performed in the third hour of internalization with a C. jejuni strain originally isolated from bloody diarrhoea. Characteristic groups of genes were significantly upregulated, outlining a survival strategy of internalized C. jejuni comprising genes related (1) to oxidative stress; (2) to a protective sheath formed by the capsule,LOS, N-, and O- glycosylation systems; (3) to dynamic metabolic activity supported by different translocases and the membrane-integrated component of the flagellar apparatus; and (4) to hitherto unknown genes .
View
... There was increased expression (3.564x) of omp50, a hypothetical outer membrane porin. Cme genes (e.g., cmeB (1.567) and cmeA (1.314)) coding for a Cme efflux pump proteins were upregulated except for cmeC [64,
65]
. A transmembrane protein (AA01_00144/Cj0268c) required for adhesion and colonisation in vitro [66,67] was elevated (2.881). ...
... The genes coding for fibronectin-binding adhesion proteins (flpA (2.909) and fbpA (2.160)) with possible roles in colonization [68] had elevated expression during the invasion. Two additional lipoprotein-coding genes were overexpressed (AA01_01303/Cj0090) (1.879) and AA01_01302/Cj0091 (2.132), probably playing a role in adhesion and repressed by the CmeR regulator
[65]
. Expression of the gene cj0588 involved in adhesion was also elevated [69]. ...
Virulence Traits of Inpatient Campylobacter jejuni Isolates, and a Transcriptomic Approach to Identify Potential Genes Maintaining Intracellular Survival
Preprint
Full-text available
Judit K Kovács
Alysia Cox
Bettina Schweitzer
György Schneider
There are still major gaps in our understanding of the bacterial factors that influence the outcomes of human Campylobacter jejuni infection. The aim of this study was to compare the virulence-associated features of 192 human C. jejuni strains isolated from hospitalized patients with diarrhoea (150/192, 78.1%), bloody diarrhoea (23/192, 11.9%), gastroenteritis (3/192, 1.6%), ulcerative colitis (3/192, 1.5%), and stomach ache (2/192, 1.0%). Traits were analysed with genotypic and phenotypic methods, including PCR and extracellular matrix protein (ECMP) binding, adhesion, and invasion capacities. Results were studied alongside patient symptoms, but no distinct links with them could be determined. Since the capacity of C. jejuni to invade host epithelial cells is one of its most enigmatic attributes, a high throughput transcriptomic analysis was performed in the third hour of internalization with a C. jejuni strain originally isolated from bloody diarrhoea. Characteristic groups of genes were significantly upregulated, outlining a survival strategy of internalized C. jejuni comprising genes related (1) to oxidative stress; (2) to a protective sheath formed by the capsule, LOS, N-, and O-glycosylation systems; (3) to dynamic metabolic activity supported by different translocases and the membrane-integrated component of the flagellar apparatus; and (4) to hitherto unknown genes.
... These clinical isolates were observed to contain sequence polymorphisms within the cmeABC promoter region. A recombinant CmeR named rCmeRSS
[37]
with cysteines 69 and 166 replaced with serine was used for EMSA as described previously [12,38]. The Cys-Ser substitution does not affect the binding activity, but significantly improves the stability of recombinant CmeR as the Cys residues are sensitive to oxidation during in vitro binding assay. ...
... To determine if the sequence variations affected the DNA binding activity of CmeR, we generated various forms of recombinant CmeR using site-directed mutagenesis. Plasmid pQECmeRSS
[37]
was used as a template for site directed mutagenesis, which was done using the Stratagene Quik-Change II kit. Site-specific primers (Table 1) were used to produce the amino acid changes in CmeR from isolates CT2:2, M63885, CT9:7, and T37597A. ...
Genetic Basis and Functional Consequences of Differential Expression of the CmeABC Efflux Pump in Campylobacter jejuni Isolates
Article
Full-text available
Jul 2015
PLOS ONE
Tara Grinnage-Pulley
Qijing Zhang
The CmeABC multidrug efflux transporter of Campylobacter jejuni plays a key role in antimicrobial resistance and is suppressed by CmeR, a transcriptional regulator of the TetR family. Overexpression of CmeABC has been observed in laboratory-generated mutants, but it is unknown if this phenotype occurs naturally in C. jejuni isolates and if it has any functional consequences. To answer these questions, expression of cmeABC in natural isolates obtained from broiler chickens, turkeys and humans was examined, and the genetic mechanisms and role of cmeABC differential expression in antimicrobial resistance was determined. Among the 64 C. jejuni isolates examined in this study, 43 and 21 were phenotypically identified as overexpression (OEL) and wild-type expression (WEL) levels. Representative mutations of the cmeABC promoter and/or CmeR-coding sequence were analyzed using electrophoretic mobility shift assays and transcriptional fusion assays. Reduced CmeR binding to the mutated cmeABC promoter sequences or decreased CmeR levels increased cmeABC expression. Several examined amino acid substitutions in CmeR did not affect its binding to the cmeABC promoter, but a mutation that led to C-terminal truncation of CmeR abolished its DNA-binding activity. Interestingly, some OEL isolates harbored no mutations in known regulatory elements, suggesting that cmeABC is also regulated by unidentified mechanisms. Overexpression of cmeABC did not affect the susceptibility of C. jejuni to most tested antimicrobials except for chloramphenicol, but promoted the emergence of ciprofloxacin-resistant mutants under antibiotic selection. These results link CmeABC overexpression in natural C. jejuni isolates to various mutations and indicate that this phenotypic change promotes the emergence of antibiotic-resistant mutants under selection pressure. Thus, differential expression of CmeABC may facilitate Campylobacter adaptation to antibiotic treatments.
... The entire coding region of the kpsS gene was amplified from strain IA3902 by PCR using primers ST101_F and ST101_R ( Table 3). The PCR product was digested with SacI and SacII and cloned into the plasmid construct pRY112-pABC
(54,
55) to generate pRY112-kpsS, in which the kpsS gene was fused to the constitutively expressed promoter of cmeABC. The constructed plasmid was confirmed by PCR. ...
Key Role of Capsular Polysaccharide in the Induction of Systemic Infection and Abortion by Hypervirulent Campylobacter jejuni
Article
Apr 2017
INFECT IMMUN
Orhan Sahin
Samantha A Terhorst
Eric R Burrough
Qijing Zhang
Campylobacter jejuni is a zoonotic pathogen, and a hypervirulent strain, named clone SA, has recently emerged as the predominant cause of ovine abortion in the United States. To induce abortion, orally ingested Campylobacter must translocate across the intestinal epithelium, spread systemically in the circulation, and reach the fetoplacental tissue. Bacterial factors involved in these steps are not well understood. C. jejuni is known to produce capsular polysaccharide (CPS), but the specific role CPS plays in systemic infection and particularly abortion in animals remains to be determined. In this study, we evaluated the role of CPS in bacteremia using a mouse model and in abortion using a pregnant guinea pig model following oral challenge. Compared with C. jejuni NCTC11168 and 81-176, a clone SA isolate (IA3902) resulted in significantly higher bacterial counts and duration of bacteremia in mice. Loss of capsule production via gene-specific mutagenesis in IA3902 led to complete abolishment of bacteremia in mice and abortion in pregnant guinea pigs, while complementation of capsule expression almost fully restored these phenotypes. The capsule mutant strain was also impaired for survival in guinea pig sera and sheep blood. Sequence-based analyses revealed that clone SA possess a unique CPS locus with mosaic structure, which has been stably maintained in all clone SA isolates derived from various hosts and times. These findings establish CPS as a key virulence factor for induction of systemic infection and abortion in pregnant animals and provide a viable candidate for development of vaccines against hypervirulent C. jejuni.
... The recombinant CmeR, named rCmeRSS, was induced and purified from JM109pQECmeRSS ( Table 2) under native conditions as described in the manufacturer's instruction (Qiagen). Construction of this strain was described previously in
Oakland et al. (2011)
. rCmeRSS was purified using the same method as rCosRWT and rCosRC218S. ...
Dual Repression of the Multidrug Efflux Pump CmeABC by CosR and CmeR in Campylobacter jejuni
Yang Mu
Lei Dai
Qijing Zhang
During transmission and intestinal colonization, Campylobacter jejuni, a major foodborne human pathogen, experiences oxidative stress. CosR, a response regulator in C. jejuni, modulates the oxidative stress response and represses expression of the CmeABC multidrug efflux pump. CmeABC, a key component in resistance to toxic compounds including antimicrobials and bile salts, is also under negative regulation by CmeR, a TetR family transcriptional regulator. How CosR and CmeR interact in binding to the cmeABC promoter and how CosR senses oxidative stress are still unknown. To answer these questions, we conducted various experiments utilizing electrophoretic mobility shift assays and transcriptional fusion assays. CosR and CmeR bound independently to two separate sites of the cmeABC promoter, simultaneously repressing cmeABC expression. This dual binding of CosR and CmeR is optimal with a 17 base pair space between the two binding sites as mutations that shortened the distance between the binding sites decreased binding by CmeR and enhanced cmeABC expression. Additionally, the single cysteine residue (C218) of CosR was sensitive to oxidation, which altered the DNA-binding activity of CosR and dissociated CosR from the cmeABC promoter as determined by electrophoretic mobility shift assay. Replacement of C218 with serine rendered CosR insensitive to oxidation, suggesting a potential role of C218 in sensing oxidative stress and providing a possible mechanism for CosR-mediated response to oxidative stress. These findings reveal a dual regulatory role of CosR and CmeR in modulating cmeABC expression and suggest a potential mechanism that may explain overexpression of cmeABC in response to oxidative stress. Differential expression of cmeABC mediated by CmeR and CosR in response to different signals may facilitate adaptation of Campylobacter to various environmental conditions.
... More rational approaches included the use of specific protein antigens either purified, DNA-based or delivered by attenuated Salmonella strains. These include the flagellin subunit FlaA 7,8 , the outer membrane protein MOMP 9 , the adhesin Peb1 10 , the multidrug efflux pump component CmeC 11 , the ferric enterobactin receptor CfrA, the lipoproteins CjaA and CjaC (mediating amino acid transport) 12 , among others [13][14][15][16][17][18]
[19]
. Although target-specific antibody responses were induced in most cases, the response provided either limited protection (FlaA-LTB 20 ; rCmeC 21 ; CjaD 22 Dps 23 ), was targeted against conformationally variable epitopes (MOMP) 24,25 , was not cross-protective (FlaA) 26,27 or the results were highly variable (CjaA or CjaA-TetC) 22,28-31 dependent on the model system or the route of administration. ...
Engineering the Campylobacter jejuni N-glycan to create an effective chicken vaccine
Full-text available
May 2016
Harald Nothaft
Brandi Davis
Yee Ying Lock
Christine Szymanski
Campylobacter jejuni is a predominant cause of human gastroenteritis worldwide. Source-attribution studies indicate that chickens are the main reservoir for infection, thus elimination of C. jejuni from poultry would significantly reduce the burden of human disease. We constructed glycoconjugate vaccines combining the conserved C. jejuni N-glycan with a protein carrier, GlycoTag, or fused to the Escherichia coli lipopolysaccharide-core. Vaccination of chickens with the protein-based or E. coli-displayed glycoconjugate showed up to 10-log reduction in C. jejuni colonization and induced N-glycan-specific IgY responses. Moreover, the live E. coli vaccine was cleared prior to C. jejuni challenge and no selection for resistant campylobacter variants was observed. Analyses of the chicken gut communities revealed that the live vaccine did not alter the composition or complexity of the microbiome, thus representing an effective and low-cost strategy to reduce C. jejuni in chickens and its subsequent entry into the food chain.
... CapA represents a surface-localized lipoprotein of C. jejuni, which mediates adherence to Caco-2 cells and plays an important role in the colonization of the chicken gut (Ashgar et al., 2007). Another protein, Cj0091 is important for the adherence of C. jejuni to INT407 cells (later identified as HeLa contaminated cell line) and also contributes to the colo-nization of chicken
(Oakland et al., 2011)
. In addition, Cj0268c enhances the adherence to Caco2 cells although this protein seems to be localized in the periplasmic space with no access of its C-terminus to the bacterial surface and a directed mutagenesis of gene cj0497 indicated this gene to encode for a potential adhesion protein (Javed et al., 2010;Tareen et al., 2013). ...
Campylobacter jejuni: Cornponents for adherence to and invasion of eukaryotic cells
Article
Full-text available
Mar 2015
BERL MUNCH TIERARZTL
Raimond Lugert
Uwe Groß
Andreas Erich Zautner
Campylobacter (C.) jejuni is the most important reported cause for bacterial diarrhoea. The infection can be accompanied by fever and abdominal cramps and in rare cases the Guillain-Barré syndrome or reactive arthritis can develop as a post-infection complication. Several biological properties of Cjejuni, e. g. motility and chemotaxis, contribute to the biological fitness of the pathogen. For this, deficiencies in the function of these features clearly reduce the pathogenicity of C. jejuni without being a virulence factor per se. Opposing to this, there are two essential requirements to determine the virulence of C. jejuni which represent the adherence to, and the invasion of host cells. Thereby, adherence, as a virulence factor, is mediated by many different bacterial-derived components like proteins but also by several oligo- and polysaccharide structures that are linked to surface proteins but also to the flagella. In addition, several invasion-relevant features of C. jejuni have been detected so far. Whereas some of them are described functionally to modulate cytoskeleton arrangement of the host cell, others are only described as invasion relevant. Indeed, investigations with respect to the pathogenic potential of some adherence- and invasion-relevant components did not give identical results indicating that their relevance might depend on the interplay of the respective C. jejuni strains used in these studies with the corresponding host cells. This review summarizes the C. jejuni components for adherence to and invasion of host cells together with their particular mode of action if known.
Editor name: Stefania Stefani Journal Pre-proof In-silico analyses provide strong statistical evidence for intra-species recombination events of the gyrA and CmeABC Operon loci Contributing to the Continued Emergence of Resistance to Fluoroquinolones in Natural Populations of Campylobacter jejuni
Article
Rusudan Tsiklauri
Ekaterine Gabashvili
Saba Kobakhidze
Mamuka Kotetishvili
Objectives
: The continued emergence of Campylobacter jejuni strains resistant to fluoroquinolones (FQs) has posed a significant threat to global public health, leading frequently to undesirable outcomes of human campylobacteriosis treatment. The molecular genetic mechanisms contributing to the increased retention of resistance to FQs in this species natural populations, especially in antibiotic-free environments, are not clearly understood. This study aimed to determine whether genetic recombination could be such a mechanism.
Methods
: We applied a large array of algorithms, imbedded in the SplitsTree and RDP4 software packages, analyzing the DNA sequences of the chromosomal loci including the gyrA gene and the CmeABC operon to identify events of their genetic recombination between C. jejuni strains.
Results
: The SplitsTree analyses of the above genetic loci resulted in several parallelograms with the bootstrap values being in a range of 94.7-100, with the high fit estimates being 99.3-100. These analyses were further strongly supported by the Phi test results (p ≤ 0.02715) and the RDP4-generated statistics (p ≤ 0.04005). The recombined chromosomal regions, along with the gyrA gene and CmeABC operon loci, were found to contain also the genetic loci that included, but not limited to, the genes encoding for phosphoribosyltransferase, the lipoprotein, the outer membrane motility protein and the radical SAM domain protein.
Conclusion
: These findings strongly suggest that the genetic recombination of the chromosomal regions involving the gyrA, CmeABC and their adjacent loci can be an additional mechanism underlying the constant emergence of epidemiologically successful FQ-resistant strains in C. jejuni natural populations.
Campylobacteriosis
Chapter
Qijing Zhang
Orhan Sahin
Avian species, especially domestic poultry including chickens, turkeys, ducks, and geese, are frequently infected with the members of thermophilic Campylobacter, primarily Campylobacter jejuni and Campylobacter coli. Although thermophilic campylobacters are not significant pathogens for poultry, they are important to food safety and public health, with C. jejuni being responsible for the majority of human campylobacteriosis, followed by C. coli, and rarely by C. lari. Campylobacter has now emerged as a leading bacterial cause of foodborne gastroenteritis in humans around the world. Most of Campylobacter-related illnesses in humans are sporadic and characterized by self-limiting watery and/or bloody diarrhea, abdominal cramps, and possible fever; however, severe conditions may occur in immunocompromised patients, requiring antibiotic treatment. Campylobacter infection is associated with Guillain-Barre syndrome, a postinfectious autoimmune disease characterized by acute and progressive neuromuscular paralysis. The members of the genus Campylobacter are associated with a wide variety of diseases in humans and animals although they are commensals in poultry.
The tetratricopeptide repeat: a structural motif mediating protein‐protein interactions
| https://www.researchgate.net/publication/51177465_Functional_Characterization_of_a_Lipoprotein-Encoding_Operon_in_Campylobacter_jejuni |
IJERPH | Free Full-Text | Impact of Virtual Heartfulness Meditation Program on Stress, Quality of Sleep, and Psychological Wellbeing during the COVID-19 Pandemic: A Mixed-Method Study
Stress and lack of quality sleep affect a large portion of the population around the globe, and the COVID-19 pandemic has genuinely brought attention to these problems. This study aimed to investigate whether using a virtual heart-based meditation program is associated with improved stress levels and quality of sleep among participants from the general population during the COVID-19 pandemic. We recruited 63 participants to receive an 8-week virtually conducted Heartfulness meditation program in a prospective pre–post single-arm intervention study from September 28 to November 22 2020. Perceived Stress Scale (PSS) and Pittsburgh Sleep Quality Index (PSQI) scores were collected at baseline, at 4 weeks, and 8 weeks. Of the 63 participants enrolled in the study, 36 (57%) completed an 8-week Heartfulness meditation program. There was a significant decrease in PSS (mean difference of 6.68 with 95% C.I. 4.89–8.47, p < 0.0001) and in PSQI (mean difference of 2.05 with 95% C.I. 1.03–3.07, p < 0.0001) between week zero and week eight, regardless of Health Care Professional status. The qualitative thematic analysis strongly supported the survey results. A significant reduction in perceived stress score and improvement in sleep quality index was noted at the end of a virtual Heartfulness meditation program. Moreover, Heartfulness meditation practice may help cultivate the quality of empathy, acceptance, and individual peace. We conclude that the effects of virtually accessible Heartfulness meditation practice need to be explored further in larger studies.
Impact of Virtual Heartfulness Meditation Program on Stress, Quality of Sleep, and Psychological Wellbeing during the COVID-19 Pandemic: A Mixed-Method Study
by Kunal Desai 1,* , Pratibha Gupta 2 , Priti Parikh 3 and Alpa Desai 1
Int. J. Environ. Res. Public Health 2021 , 18 (21), 11114; https://doi.org/10.3390/ijerph182111114
Received: 17 September 2021 / Revised: 19 October 2021 / Accepted: 21 October 2021 / Published: 22 October 2021
Abstract
:
Stress and lack of quality sleep affect a large portion of the population around the globe, and the COVID-19 pandemic has genuinely brought attention to these problems. This study aimed to investigate whether using a virtual heart-based meditation program is associated with improved stress levels and quality of sleep among participants from the general population during the COVID-19 pandemic. We recruited 63 participants to receive an 8-week virtually conducted Heartfulness meditation program in a prospective pre–post single-arm intervention study from September 28 to November 22 2020. Perceived Stress Scale (PSS) and Pittsburgh Sleep Quality Index (PSQI) scores were collected at baseline, at 4 weeks, and 8 weeks. Of the 63 participants enrolled in the study, 36 (57%) completed an 8-week Heartfulness meditation program. There was a significant decrease in PSS (mean difference of 6.68 with 95% C.I. 4.89–8.47,
p
< 0.0001) and in PSQI (mean difference of 2.05 with 95% C.I. 1.03–3.07,
p
< 0.0001) between week zero and week eight, regardless of Health Care Professional status. The qualitative thematic analysis strongly supported the survey results. A significant reduction in perceived stress score and improvement in sleep quality index was noted at the end of a virtual Heartfulness meditation program. Moreover, Heartfulness meditation practice may help cultivate the quality of empathy, acceptance, and individual peace. We conclude that the effects of virtually accessible Heartfulness meditation practice need to be explored further in larger studies.
Keywords:
Heartfulness meditation
;
stress
;
sleep
;
pandemic
;
COVID-19
1. Introduction
Stress is a condition or feeling experienced when a person perceives that demands exceed the personal and social resources the individual can mobilize. It can be simplified as a demand-supply mismatch of one’s inner resources and inner or external needs. Stress is triggered by intrinsic or extrinsic factors associated with biological responses. Stress is considered a causative or contributing factor for many health problems, including hypertension, cardiovascular disease, obesity, diabetes, mental health disorders, immune dysfunction, and sleeping disorders, as cited by the previous authors [ 1 , 2 ]. Sleep is one of the single most important factors determining the level of stress and overall health; similar to stress, insufficient sleep or sleep disorders leads to physical and emotional health problems [ 3 ]. Therefore, stress and lack of quality sleep are considered serious public health challenges which our community face despite modern lifestyles, comforts, and technological advances. The COVID-19 pandemic has genuinely brought attention to this preexisting stress problem by making it significantly worse. A recent 2021 survey by the American Psychological Association revealed that 48% of Americans reported an increased level of stress. Approximately 67% reported sleeping more or less than they wanted to since the pandemic started [ 4 ]. The Centers for Disease Control and Prevention (CDC) has recommended several ways to cope with stress, including eating regularly, good sleep hygiene, exercise, relaxation, and meditation [ 5 ].
There are various meditation techniques, but this study focuses on Heartfulness meditation, a simple heart-based meditation practice aimed at attaining a balanced state of mind. The practice comprises a morning session focusing on relaxation and meditation, an evening rejuvenation session that involves removing emotional impressions of the day, and a session at night for a deeper connection with oneself involving a short meditation session before sleep. In addition, trainer-guided sessions are also offered. Meditation programs in general, including Heartfulness meditation, have shown a positive impact on psychological stress and well-being in the participants with specific medical or mental health needs [ 6 , 7 , 8 , 9 ]. However, psychological stress is experienced by a large portion of the population, especially during the COVID-19 pandemic [ 4 ]. Assessing the impact of meditation programs among the general population can be helpful to understand how best to utilize such interventions. There is vast literature assessing the impact of different meditation practices on emotional regulation, health-promoting, and prosocial behaviors. Mindfulness meditation practices have been shown to improve emotional regulation and reduce drug abuse [ 10 ]. Cross-sectional data showed that US adults who practiced mindfulness meditation are more likely to be physically active [ 11 ]. A systemic review and metanalysis of 26 randomized trials support the efficacy of meditation-based interventions for increasing empathy, compassion, and pro-social behaviors [ 12 ]. Limited qualitative data exists regarding Heartfulness meditation practice on the participants’ experiences and perceived changes in their overall attitude towards life and wellbeing. Moreover, the current literature lacks data regarding effectiveness of virtual delivery of meditation programs [ 7 , 13 , 14 ]. This study, therefore, seeks to investigate whether using a virtual heart-based meditation program is associated with improvements in stress levels and quality of sleep among participants from the general population. Moreover, we report participants’ experiences and perceived changes that are crucial in providing better insights and further improving the utilization of such practices.
2. Materials and Methods
2.1. Study Design and Data Collection
This prospective pre–post single-arm intervention study assessed the effect of an 8-week heart-based meditation on the level of stress using the Perceived Stress Scale (PSS) and quality of sleep using the Pittsburgh Sleep Quality Index (PSQI). The participants were surveyed on coronavirus disease 2019 (COVID-19)-related stress, i.e., whether or not they are worried about themselves or anyone in the family catching this infection. All the participants were asked to complete this survey and PSS and PSQI scale survey at baseline, week four, and at the end of the study period of 8 weeks.
Qualitative data on the impact of such meditation practices on overall wellbeing, interaction with others, and stress management were also collected. All participants were offered optional one-to-one virtual interview sessions, which took place within three weeks after the end of the study period that were recorded and transcribed for thematic analysis.
2.2. Recruitment of Participants
The study was open to the public in the United States of America from 28 September–22 November 2020. Participants were adults above 18 years of age willing to participate in the study, have a basic knowledge of the Internet, and able to follow instructions regarding email communications and accessing video conferences. Any person under medical care for depression or other mental health conditions was encouraged not to participate or only participate after discussion with his/her healthcare provider so that the study participation did not interfere with current treatment. The study participants were recruited from different parts of the United States. The information regarding the study was provided to the public through social media platforms such as Facebook using a flyer. Several local universities, healthcare institutions, and corporations were also provided information through personal and professional contacts. The website page was created by Heartfulness research institute with frequently asked questions regarding the research study and a link to a consent form. The research project was explained to willing participants, and any questions were answered before signing any informed consent.
2.3. Intervention
2.3.1. Orientation and Education Sessions
The primary investigator conducted a live virtual orientation session on the aspects of the study and the structure of the meditation protocol before the start of the study. Participants were also briefed about expectations during meditation sessions and were offered the contact details of the trainer for any further questions. They were provided with educational material via email consisting of essential information regarding Heartfulness meditation practice. The primary investigator conducted six live virtual education sessions via PowerPoint presentations every weekend during the first 6 weeks of the study period on these topics in the following order: benefits of meditation, challenges and tips to improve meditation practice, learn rejuvenation technique, learn bedtime prayer meditation, heartfulness practice overview, and formal questions and answers. These sessions were recorded, and links to video recordings were shared with all study participants to review at their convenience if unable to attend live sessions.
2.3.2. Meditation with a Heartfulness Trainer
I.
The participants were recommended to attend a minimum of two out of a total of eight virtual trainer-guided group Heartfulness relaxation and meditation sessions each week. These sessions, conducted by one of the authors and a Heartfulness trainer (KD), included 5–7 min of relaxation followed by 20 min of meditation. Heartfulness meditation practice asks participants to gently focus their attention, with eyes closed on the source of light within the heart. Rather than trying to visualize this, participants were asked to simply tune in to their hearts and be open to any experience that they may have. If their mind wanders, participants were advised to redirect toward the heart gently [
9
].
II.
The participants were also provided instructions on using the phone application called ‘HeartsApp’ on their phones. They could connect as an anonymous seeker with a Heartfulness trainer through the application and meditate without any audiovisual interaction.
2.3.3. Self-Practice
In addition to attending a minimum of two out of a total of eight virtual trainer-guided group Heartfulness relaxation and meditation sessions each week, they were also suggested self-practices to the best of their abilities.
I.
Heartfulness relaxation followed by meditation preferably in the morning or any other convenient time for about 20 min with the same technique as guided group sessions. They may listen to Heartfulness relaxation using online resources on www.heartfulness.org .
II.
The following two self-practices were advised to the participants after completing education sessions for each technique.
Heartfulness Rejuvenation: An evening practice of rejuvenation lasting 15 min was recommended where they imagine that stress and heaviness were leaving the body through the back in the form of smoke or vapor. These heaviness and stress were to be replaced by a flow of purity, lightness, and freshness.
Bedtime Prayer meditation: Participants were recommended to prayerfully contemplate the day’s events for self-introspection and meditate on the source of light within the heart for about 5 min before sleeping.
Participants were also provided with a practice tracker sheet to record attendance in the group meditation sessions, self-practice, and meditation using Hearts App. The practice tracker sheets were asked to be submitted every 2–3 weeks. The investigators recorded group meditation session attendance.
2.3.4. Statistical Analysis
Basic demographic information, including age, gender, and level of physical activity, were collected. Participants were evaluated for their perceived stress and sleep quality using the measurement tools with well-established reliability and validity, such as Perceived Stress Scale (PSS) and the Pittsburgh Sleep Quality Index (PSQI). In order to determine if there were any significant decreases in these variables over the course of the study, each of them was analyzed via a repeated measures ANOVA. The repeated measure was the time (0 weeks, 4 weeks, and 8 weeks). An independent variable was included for whether the respondent was a Health Care Professional (Yes or No) out of concern that they may be experiencing a higher level of stress while working during the COVID-19 pandemic. The presence of an interaction between Time and Health Care Professional was investigated first. A significant interaction would indicate any changes in the response variables over time are not always constant for Health Care Professionals and non-Health Care Professionals. If the interaction term was not significant, it was removed, and the main effects of Time and Health Care Professional were assessed directly. Post hoc multiple comparisons were made using Tukey’s multiple comparison procedure. A level of significance of α = 0.05 was used throughout to assess statistical significance, and SAS version 9.4 (SAS Institute, Inc., Cary, NC, USA) was used for all analyses. The qualitative data on interviews, on the other hand, were analyzed thematically for dominant themes using the constant comparative method.
3. Results
A total of 63 participants were enrolled in the study, of which 36 (57%) completed the entire eight weeks of the Heartfulness meditation program. One participant dropped out due to a COVID-19 infection in the family and another due to personal non-COVID-19-related health issues. The remaining dropped out participants reported a lack of time commitment. Among 36 participants who completed 8 weeks of the program, 31 (86%) were female. While one participant did not complete the demographic information sheet, 11/35 (31%) were healthcare professionals, and 24/35 (69%) were non-healthcare professionals.
3.1. Adherence to Practice
A total of 28 out of 36 participants (77.7%) attended at least two group trainer-guided meditation sessions per week. There is no acceptable minimum adherence level in clinical trials regarding Heartfulness meditation self-practice. If participants practiced any of the suggested self-practices (Meditation, Rejuvenation, and bedtime prayer meditation) four or more times a week, it was considered adherence to suggested self-practice for our study. A total of 18 out of 31 participants (58.1%) adhered to the suggested self-practice regimen. Five participants did not report adherence data regarding self-practice. In addition, on average the participants completed approximately eight HeartsApp meditation sessions across the duration of the program.
Weekly results in the text below and throughout are expressed as (mean ± standard error).
3.2. Survey on COVID-19-Related Stress
There was a significant interaction between Time and Health Care Professional status, so all pairwise comparisons between Time and Health Care Professional status were made. There was a significant decrease in worry about a family member experiencing a COVID-19 infection for non-healthcare professionals between week 0 (6.40 ± 0.45) and week 4 (5.12 ± 0.49) (
p
= 0.0014), as well as between week 0 (6.40 ± 0.45) and week 8 (5.06 ± 0.50) (
p
= 0.0009). There were no significant differences in worry about a family member experiencing a COVID-19 infection for healthcare professionals. There were no significant differences in worry about a family member experiencing a COVID-19 infection between healthcare professionals and non-healthcare professionals at any of the time points. There were no significant differences in worry about participants themselves experiencing a COVID-19 infection for healthcare professionals or non-healthcare professionals.
3.3. Effect on Stress (PSS)
The results of Tukey’s multiple comparison procedure for PSS are given below in Table 1 . There was a significant decrease in perceived stress between week 0 (20.76 ± 0.70) and week 4 (14.97 ± 0.87) for all subjects regardless of Health Care Professional status ( p < 0.0001). As shown in Table 1 , the estimated mean difference was 5.79 points lower at week 4. There was also a significant decrease in perceived stress between week 0 (20.76 ± 0.70) and week 8 (14.09 ± 0.84) for all subjects regardless of Health Care Professional status ( p < 0.0001). The estimated mean difference was 6.68 points lower at week 8. There was insufficient evidence to suggest any difference in perceived stress between week 4 and week 8 ( p -value = 0.53).
3.4. Effect on Sleep Quality (PSQI)
The results of Tukey’s multiple comparison procedure for PSQI are given below in Table 2 . There was a significant decrease in PSQI between week 0 (8.66 ± 0.42) and week 4 (7.11 ± 0.51) for all subjects, regardless of Health Care Professional status ( p = 0.0022). The estimated mean difference was 1.55 points lower at week 4. There was also a significant decrease in PSQI between week 0 (8.66 ± 0.42) and week 8 (6.61 ± 0.50) for all subjects, regardless of Health Care Professional status ( p < 0.0001). The estimated mean difference was 2.05 points lower at week 8. There was insufficient evidence to suggest any difference in PSQI between week 4 and week 8 ( p -value = 0.54).
3.5. Qualitative Thematic Analysis
A total of 21 participants volunteered to participate in an optional interview, of which 17 (80.95%) participants were planning to continue Heartfulness meditation, and 15 (71.43%) participants were either planning to or already recommended these meditation practices to others. The qualitative analysis of narratives describing the impact of Heartfulness meditation on overall wellbeing, interactions with others, and outlook of life identified several themes.
Table 3
describes the major themes along with their description and examples of comments from the participants. Primarily, participants suggested that their attitude changed to be more positive, empathetic, and disciplined. Specifically, in coping with the COVID-19 pandemic, one participant said, “It [Heartfulness meditation practices] made me feel safer, less helpless and more hopeful”. Other comments from participants are shown in
Table 3
.
While specific comments are included in Table 3 , one participant, who took anxiety medication in the past (stopped two years before participating in the study), suggested that Heartfulness meditation practices helped them feel less anxious and less stressed more naturally. Some participants also suggested that these meditation practices alleviated stress and made them calmer and more focused. Moreover, some participants talked about how these meditation practices helped alleviate stress and improve sleep. Below are the specific comments from the participants:
“I have less fatigue because I feel my sleep has improved due to meditation”.
“I think Heartfulness has had an impact on my long intermittent insomnia. When I wake up anywhere between 2:30–5:30 a.m. [now], I feel calm and confident that I will fall back asleep whereas pre-Heartfulness I felt anxious and most often did not fall back asleep”.
Participants also talked about how these practices improved their ability to control emotional reactions and accept their circumstances. Specific comments are included in Table 3 . One participant summed up all the effects and themes and said, “One impact is that when I have been doing the [Heartfulness meditation] sessions, it brings a calming effect to me. Additionally, I think that trickles over into the rest of your life, your interactions with people, and just to being thoughtful and mindful in how I am interacting with people, and I think it’s somewhat generated from the peace within”.
4. Discussion
Stress and lack of quality sleep are the two most essential precursors leading to chronic medical and mental health problems influencing the health of our community. Several studies depict many stress-related health problems related to disasters or public health crises, including mental health problems, substance abuse, suicide, sleep disturbances, and cardiovascular disease [ 15 , 16 ]. In current times, COVID-19 pandemic has disrupted virtually every aspect of daily living and created an unprecedented stressful situation for all of humanity around the globe. Several studies have reported higher levels of stress, anxiety, and depression, among the general population and healthcare workers because of the COVID-19 pandemic since December 2019 [ 17 , 18 , 19 , 20 , 21 ]. This study also highlights the burden of stress and poor sleep quality, affecting healthcare and non-healthcare workers equally during the COVID-19 pandemic. A public health crisis can have both immediate and long-lasting adverse effects on the health and wellbeing of people. Our study using the mixed method, i.e., quantitative and qualitative measures, reports the impact of Heartfulness meditation practice on psychological wellbeing during the COVID-19 pandemic.
Meditation programs are conventionally conducted in in-person settings, and it is conceivable that it may be harder to engage in a virtual environment than in-person sessions. A recent study evaluated the effects of mindfulness training using similar PSS and PSQI measures as our study. They found that virtual mindfulness training was equivalent to in-person mindfulness training to reduce stress during and before the pandemic. However, they did not find evidence that this training improved sleep quality [
13
]. In another study, an 8-week mindfulness-oriented meditation (MOM) course where 75% of the course was conducted virtually showed an improvement in the psychological wellbeing of female teachers during the COVID-19 pandemic [
14
]. A recent study showed that a brief, virtual, Heartfulness meditation program via audio relaxation techniques through a Heartfulness trainer improved sleep quality and loneliness among physicians and advance practice providers [
7
]. Our study showed that following Heartfulness meditation practice, PSS and PSQI improved significantly in the participants from different parts of the United States. About 31% were healthcare professionals, and the entire program was conducted virtually. Based on these observations, we propose that meditation programs offered via virtual platforms can offer a convenient, helpful, and easily accessible tool to a large community at once to help improve the psychological wellbeing of individuals.
This study adds to the existing literature supporting the benefits of Heartfulness practice, as reported by some previous studies showing the benefit of Heartfulness relaxation and meditation to reduce stress, burnout, loneliness, and improves the quality of sleep [
7
,
8
,
9
,
22
]. The exact mechanism of Heartfulness meditation is not well understood. The results of qualitative analysis in our study bring a unique perspective to this aspect as we were able to show that the participant’s subjective experiences strongly supported the results of the survey findings. Thus, these results enhance our understanding of how Heartfulness meditation practice helps reduce stress and improve the quality of sleep. Our qualitative analysis suggests these effects could be because a simple heart-based meditation brought a ‘calming effect’ in our participants, resulting in ‘inner peace’. Such an effect also resulted in inner changes in our participants, including positive thinking, accepting and empathic attitude, and an increase in awareness of one’s own emotions and the needs of others.
We noted a significant decrease in worry about a family member experiencing a COVID infection for non-healthcare professionals but not among healthcare professionals. This difference could have been due to healthcare professionals having a more apprehensive perception of COVID-19 infection and its severity while serving the affected patients. Interestingly, we found no significant change in worry of participants experiencing a COVID-19 infection themselves during the study period even though there was a significant improvement in quality of sleep and level of stress. Regarding this observation, we speculate based on qualitative analysis that Heartfulness meditation practice was likely helpful in cultivating resilience and coping with difficult circumstances in a calmer state of mind, resulting in the reduction in stress.
The guided relaxation that preceded every group meditation session was also very beneficial in reducing stress and anxiety and helped participants practice meditation more effectively. The guided relaxation likely stimulates the parasympathetic pathway in the brain, which helps establish a relaxed state of mind before meditation.
This study has several limitations. The sample size was relatively small. As this was a pretest–posttest design, there was a lack of a control group, and participants in the study self-selected meditation, suggesting the possibility of selection bias. We also cannot exclude the possibility of unknown sources of bias and the personal life circumstances of participants that could have played a role in the changes noticed. Of the 63 enrolled participants, 36 completed the study, indicating a high attrition rate of 43%. Most of the participants dropped out within the first three weeks and reported an inability of time commitment. The dropouts could have served as a control group if we had administered the post-intervention surveys. Similar high attrition rates were observed in previous studies among the intervention group [
7
,
23
,
24
]. An additional perceived limitation could be the use of personal reporting of self-practice of the different meditation techniques and variability in individual adherence. However, we recorded attendance in virtual group meditation sessions conducted by the Heartfulness trainer to accurately analyze adherence with the primary requirement of the program. Another limitation of the study is that our data may not include the effect of the passage of time on perceived stress and sleep quality. However, the surveys and subsequent interviews specified that the focus of interest was their experience with the meditation sessions and practices throughout the study period. Additionally, in survey studies relying on human recollection, the responses may be imprecise. Long-term data about the sustained improvement in sleep quality and reduction in stress need to be explored in future studies.
5. Conclusions
Virtually accessible meditation programs such as Heartfulness practice could be an effective tool to offer to a large community at once. Such a practice could be feasible to incorporate into the current lifestyle of many individuals, regardless of one’s vocation. Our study demonstrated statistical improvements in perceived stress score and sleep quality index in participants undergoing a virtual Heartfulness meditation program. Heartfulness practice may also help enable individuals to cultivate a quality of empathy, acceptance, and individual peace. Promoting healthier lifestyles, including meditation practice, can be an essential preventive measure to combat possible future health problems related to psychological stress. The effects of virtually accessible Heartfulness meditation practice need to be explored further in larger studies.
Author Contributions
Conceptualization, K.D. and P.G.; Methodology, K.D. and P.P.; Validation, K.D., P.G. and P.P.; Formal Analysis, P.P. and K.D.; Investigation, K.D.; Resources, K.D.; Data Curation, A.D.; Writing—Original Draft Preparation, K.D.; Writing—Review and Editing, K.D., P.G. and P.P; Supervision, K.D.; Project Administration, K.D. and A.D.; Funding Acquisition, P.G. All authors have read and agreed to the published version of the manuscript.
Funding
This research was supported by Evans Allen Research Program of National Institute of Food and Agriculture Award # NI201445XXXXG018. Dr. Sri Subramania I. Sritharan PhD P.E., Associate Director for Research, Dr. Pratibha Gupta is the part of this grant, Agricultural Research and Development Program (ARDP), College of Engineering, Science, Technology and Agriculture (CESTA), Central State University, Wilberforce, OH 45384-1004.
Institutional Review Board Statement
The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Institutional Review Board at Wright State University, Dayton, Ohio, USA on 5 September 2020. It was also approved by Central State University, Wilberforce, OH through IRB Reliance Agreement on 22 September 2020.
Informed Consent Statement
Informed consent was obtained from all subjects involved in the study.
Data Availability Statement
Acknowledgments
Authors would like to thank: 1. Sri Subramania I. Sritharan, Research, Agricultural Research and Development Program (ARDP), College of Engineering, Science, Technology and Agriculture (CESTA), Central State University for financial support. 2. Mike Bottomley: Wright State University for providing detailed statistical analysis of the results.
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 data; in the writing of the manuscript, or in the decision to publish the results.
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Table 1. Results of Tukey’s multiple comparison procedure for PSS.
Table 1. Results of Tukey’s multiple comparison procedure for PSS.
Comparison Mean Difference p -Value 95% C.I. Week 0–Week 4 5.79 <0.0001 (3.94, 7.65) Week 0–Week 8 6.68 <0.0001 (4.89, 8.47) Week 4–Week 8 0.89 0.53 (−1.09, 2.86)
Table 2. Results of Tukey’s multiple comparison procedure for PSQI.
Table 2. Results of Tukey’s multiple comparison procedure for PSQI.
Comparison Mean Difference p -Value 95% C.I. Week 0–Week 4 1.55 0.0022 (0.49, 2.61) Week 0–Week 8 2.05 <0.0001 (1.03, 3.07) Week 4–Week 8 0.50 0.54 (−0.62, 1.62)
Table 3. Emerging themes on the impact of the Heartfulness meditation program.
Theme Description Example Comment from Respondents The attitude changed to be more Positive thinking, Empathetic, and Disciplined. The attitude towards others and life changed positively after participating in the study. Participants suggested they became more compassionate, understanding and started thinking positively. They became more disciplined as well. “I feel a bit more patient; I feel a little bit more compassionate, a little bit more open to other people, and less judgmental.” “I find that I am just in general a lot more thankful about very simple things.” “I noticed that I reconnected to some of the human side of things. Because sometimes we can get lost in the process and the thinking about the whole thing, you sort of forget that is actually a person.” Alleviated stress and made calmer and more focused The practice helped alleviate stress, and participants felt more focused and calmer “I found the meditation to be extremely helpful for just staying calm in the storm, but I did not grow up with that sort of understanding.” “I was having a harder time concentrating, especially on projects that required a lot of thought. I really dreaded them because I just had a hard time staying focused. Additionally, that has been a big improvement for me because of the meditation I have been doing. It has helped me a lot and I do not dread those projects.” Ability to control emotional reactions and became more mindful and accepting The practice helped develop the ability to control emotional reactions. Some participants suggested they became more mindful of the situations and accepting “I have been able to listen better. Even if what I am listening to contradicts my own personal views. I listen, I do not react, and I do not respond with the intensity that I want to—instead I accept them and move on.” “I am now mindful of the fact that I am always in a hurry and avoid unplanned interactions with neighbors and friends. So, I am trying to work on slowing down and allowing time for spontaneous phone conversations or physical interactions.” “It was like, if bad things are happening, of course, you are going to feel bad and react badly. Now [after meditation practices] it’s like, I actually have the power in this to stay calm and observe both emotions in my own self, and then things around me and that was just very very helpful.”
| https://www.mdpi.com/1660-4601/18/21/11114 |
BCM-HGSC | Eric Boerwinkle, Ph.D. | page 4
Associate Director, Baylor College of Medicine Human Genome Sequencing Center Contact information [email protected] Other positions Dean, UTHealth School of Public Health M. David Low Chair in Public Health Kozmetsky Family Chair in Human Genetics Professor, Human Genetics Center and Dept. of Epidemiology Research interests The research interests of Dr. Boerwinkle encompass the
Eric Boerwinkle, Ph.D.
Associate Director, Baylor College of Medicine Human Genome Sequencing Center
Contact information
[email protected] (link sends e-mail)
Other positions
Dean, UTHealth School of Public HealthM. David Low Chair in Public HealthKozmetsky Family Chair in Human GeneticsProfessor, Human Genetics Center and Dept. of Epidemiology
Research interests
The research interests of Dr. Boerwinkle encompass the genetic analysis of the common chronic diseases in humans, including coronary artery disease, hypertension, and non-insulin dependent (type II) diabetes.
Dr. Boerwinkle received his B.S. in Biology from the University of Cincinnati in 1980, an M.A. in Statistics (1984), and M.S. and Ph.D. in Human Genetics (1985) from the University of Michigan, Ann Arbor where he served as Senior Research Associate in the Department of Human Genetics from 1985-1986. He joined the University of Texas-Houston Center for Demographic/ Population Genetics in 1986 as a Research Assistant and became Assistant Professor in the same year. In 1991 he joined the Department of Human Genetics at the School of Public Health, University of Texas-Houston Health Science Center as Associate Professor, in 1996 was promoted to Professor, and in 1997, Director of the Human Genetics Center. He became a faculty member of the Institute of Molecular Medicine in 1996 and became Professor and Director of the Research Center for Human Genetics.
Dr. Boerwinkle is a member of the American Diabetes Association and the American Society of Human Genetics. The research interests of Dr. Boerwinkle encompass the genetic analysis of common chronic diseases in humans, including coronary artery disease, hypertension, and non-insulin dependent (type II) diabetes. This work includes localizing genes which contribute to disease risk, identification of potentially functional mutations within these genes, testing these candidate functional mutations in experimental systems, defining the impact of gene variation on the epidemiology of disease, and determining the extent to which these genes interact with environmental factors to contribute to disease risk. Activities include both statistical analysis and laboratory work. A large part of Dr. Boerwinkle's current research effort consist of localizing genes contributing to disease risk using modern genome-wide mapping methods. Success depends on keeping up with the latest genomic technical advances. The laboratory is set-up and operating as a high through-put sequencing and genotyping facility in which speed, accuracy and efficiency are monitored continuously. However, we are constantly seeking out more efficient methods to collect and manage genetic information.
Dr. Boerwinkle and colleagues have completed the world's first genome-wide analyses for a variety of CAD risk factors, including diabetes and hypertension. These investigations have lead to the identification of novel susceptibility genes in both cases. Dr. Boerwinkle is particularly interested in methods for identifying potentially functional mutations within a gene region. This seemingly simple objective is made difficult because the functional mutations are expected to have small effects and are imbedded in a sea of silent genetic variation. Once nearly all of the variation is catalogued directly by DNA sequencing, individuals are genotyped for each variable site. Both novel and traditional statistical methods are applied to relate the array of genetic information to a wealth of phenotypic data. This algorithm generates "candidate functional mutations" that are then tested in an in vitro or mouse model system. Once a functional mutation has been identified, Dr. Boerwinkle's group evaluates the ability of the variable site to predict the onset of disease (e.g. myocardial infarction or stroke) above and beyond traditional risk factors. This work is carried out as part of multiple prospective studies of cardiovascular disease and its risk factors in tens of thousands of individuals representing the major American ethnic groups.
Finally, he is working on experimental designs for studying genotype by environment interaction in humans. In particular, we are working on the extent to which interindividual variation in lipid lowering and anti-hypertensive medications are influenced by genetic factors. The practical objective of the research is to use genetic information to identify individuals at increase risk of disease and to design more efficacious interventions. Genetic studies are defining, at the molecular level, novel mechanisms of disease risk, onset and progression. Dr. Boerwinkle and collaborators address the localization of genes which contribute to disease risk in cardiovascular diseases, hypertension and diabetes. The methodology used involves screening of families having the disease and linking the presence of disease with known markers of the human genome. In this manner, the genomic region in which relevant mutations are located can be mapped and the relevant DNA sequenced. By assessing the structural change the mutation may have caused in the gene product (protein), it is possible to infer how it may affect biological function. In order to determine experimentally whether a mutation is functional, it is necessary to introduce the mutated gene into an animal, usually a mouse, and assess its biological effects on the animal's phenotype.
Dr. Boerwinkle has participated in multiple notable discoveries since joining the Institute. Only two will be highlighted here. First, Dr. Boerwinkle's group has completed the first ever genome-wide search for genes contributing to inter-individual blood pressure levels. This initial effort has lead to the identification of an important gene (an adrenergic receptor) which influences blood pressure levels and the risk to hypertension. This is the first time that such a genome-wide approach has led to the identification of a susceptibility gene to a major cardiovascular disease risk factor. Second, Dr. Boerwinkle has participated in similar efforts to identify genes contributing to the risk of developing non-insulin dependent (type II) diabetes. In this case, however, there were no genes in the region that were suspects for the disease. A team of collaborating investigators have painstakingly characterized the genetic region and identified the mutated gene (in this case a protease). This is the first time that anyone has ever positionally cloned a gene contributing to any common chronic disease. This work is of obvious potential clinical importance. It may lead to improved prediction of those at increased risk of disease and the design of more efficacious intervention strategies. The technologies and information from the human genome project provide new tools for lessening the burden of ill-health. Dr. Boerwinkle's accomplishments in developing an internationally recognized team of investigators targeting the genetics of cardiovascular disease and its risk factors ensures a productive future and further discoveries.
Publications
2021
Lin BM , Grinde KE , Brody JA , Breeze CE , Raffield LM , Mychaleckyj JC , et al. . Whole genome sequence analyses of eGFR in 23,732 people representing multiple ancestries in the NHLBI trans-omics for precision medicine (TOPMed) consortium. EBioMedicine. 2021;63:103157. PubMed DOI Google Scholar Tagged
Wang P , Castellani CA , Yao J , Huan T , Bielak LF , Zhao W , et al. . Epigenome-wide association study of mitochondrial genome copy number. Hum Mol Genet. 2021;31(2):309-319. PubMed DOI Google Scholar Tagged
Bressler J , Davies G , Smith AV , Saba Y , Bis JC , Jian X , et al. . Association of low-frequency and rare coding variants with information processing speed. Transl Psychiatry. 2021;11(1):613. PubMed DOI Google Scholar Tagged
Murdock DR , Venner E , Muzny DM , Metcalf GA , Murugan M , Hadley TD , et al. . Genetic testing in ambulatory cardiology clinics reveals high rate of findings with clinical management implications. Genet Med. 2021;23(12):2404-2414. PubMed DOI Google Scholar Tagged
Seplyarskiy VB , Soldatov RA , Koch E , McGinty RJ , Goldmann JM , Hernandez RD , et al. . Population sequencing data reveal a compendium of mutational processes in the human germ line. Science. 2021;373(6558):1030-1035. PubMed DOI Google Scholar Tagged
Cade BE , Lee J , Sofer T , Wang H , Zhang M , Chen H , et al. . Whole-genome association analyses of sleep-disordered breathing phenotypes in the NHLBI TOPMed program. Genome Med. 2021;13(1):136. PubMed DOI Google Scholar Tagged
Wang H , Noordam R , Cade BE , Schwander K , Winkler TW , Lee J , et al. . Multi-ancestry genome-wide gene-sleep interactions identify novel loci for blood pressure. Mol Psychiatry. 2021;26(11):6293-6304. PubMed DOI Google Scholar Tagged
Li H , Sisoudiya SD , Martin-Giacalone BA , Khayat MM , Dugan-Perez S , Marquez-Do DA , et al. . Germline Cancer Predisposition Variants in Pediatric Rhabdomyosarcoma: A Report From the Children's Oncology Group. J Natl Cancer Inst. 2021;113(7):875-883. PubMed DOI Google Scholar Tagged
Fuentes Lde Las , Sung YJu , Noordam R , Winkler T , Feitosa MF , Schwander K , et al. . Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci. Mol Psychiatry. 2021;26(6):2111-2125. PubMed DOI Google Scholar Tagged
Kwong AM , Blackwell TW , LeFaive J , de Andrade M , Barnard J , Barnes KC , et al. . Robust, flexible, and scalable tests for Hardy-Weinberg equilibrium across diverse ancestries. Genetics. 2021;218(1). PubMed DOI Google Scholar Tagged
Schunk SJ , Kleber ME , Marz W , Pang S , Zewinger S , Triem S , et al. . Genetically determined NLRP3 inflammasome activation associates with systemic inflammation and cardiovascular mortality. Eur Heart J. 2021;42(18):1742-1756. PubMed DOI Google Scholar Tagged
Xu H , Schwander K , Brown MR , Wang W , Waken RJ , Boerwinkle E , et al. . Lifestyle Risk Score: handling missingness of individual lifestyle components in meta-analysis of gene-by-lifestyle interactions. Eur J Hum Genet. 2021;29(5):839-850. PubMed DOI Google Scholar Tagged
Ahluwalia TS , Prins BP , Abdollahi M , Armstrong NJ , Aslibekyan S , Bain L , et al. . Genome-wide association study of circulating interleukin 6 levels identifies novel loci. Hum Mol Genet. 2021;30(5):393-409. PubMed DOI Google Scholar Tagged
Natarajan P , Pampana A , Graham SE , Ruotsalainen SE , Perry JA , de Vries PS , et al. . Chromosome Xq23 is associated with lower atherogenic lipid concentrations and favorable cardiometabolic indices. Nat Commun. 2021;12(1):2182. PubMed DOI Google Scholar Tagged
Yu Z , Grams ME , Ndumele CE , Wagenknecht L , Boerwinkle E , North KE , et al. . Association Between Midlife Obesity and Kidney Function Trajectories: The Atherosclerosis Risk in Communities (ARIC) Study. Am J Kidney Dis. 2021;77(3):376-385. PubMed DOI Google Scholar Tagged
Taliun D , Harris DN , Kessler MD , Carlson J , Szpiech ZA , Torres R , et al. . Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program. Nature. 2021;590(7845):290-299. PubMed DOI Google Scholar Tagged
Jones G , Trajanoska K , Santanasto AJ , Stringa N , Kuo C-L , Atkins JL , et al. . Genome-wide meta-analysis of muscle weakness identifies 15 susceptibility loci in older men and women. Nat Commun. 2021;12(1):654. PubMed DOI Google Scholar Tagged
Dyment DA , O'Donnell-Luria A , Agrawal PB , Akdemir ZCoban , Aleck KA , Antaki D , et al. . Alternative genomic diagnoses for individuals with a clinical diagnosis of Dubowitz syndrome. Am J Med Genet A. 2021;185(1):119-133. PubMed DOI Google Scholar Tagged
Xue D , Bush WS , Renton AE , Marcora EA , Bis JC , Kunkle BW , et al. . Large-scale sequencing studies expand the known genetic architecture of Alzheimer's disease. Alzheimers Dement (Amst). 2021;13(1):e12255. PubMed DOI Google Scholar Tagged
2020
Chen S , Jain M , Jhangiani S , Akdemir ZC , Campeau PM , Klein RF , et al. . Genetic Burden Contributing to Extremely Low or High Bone Mineral Density in a Senior Male Population From the Osteoporotic Fractures in Men Study (MrOS). JBMR Plus. 2020;4(3):e10335. PubMed DOI Google Scholar Tagged
| https://www.hgsc.bcm.edu/people/boerwinkle-e?f%5Bauthor%5D=9871&page=3 |
Quitting smoking helps social life | EurekAlert! Science News
Smoking is bad, it turns out, not only for your physical wellbeing but for your social health, too -- with smokers increasingly edged out to the margins of social circles, according to new research from Harvard and UC San Diego.
Quitting smoking helps social life
Social-network study also finds group effects in smoking cessation
University of California - San Diego
<here is a image 98127954e978e842-0fa470c5711c6591 ? >
IMAGE:A random sample of 1000 subjects in 1971 and 2000. Yellow nodes are smokers (with the node size proportional to number of cigarettes consumed); green nodes are nonsmokers. Orange arrows...view more
Credit: Courtesy James Fowler, UC San Diego.
Putting down cigarettes for good can have unexpected social benefits, according to new research from Harvard and the University of California, San Diego. Smoking is bad, it turns out, not only for your physical wellbeing but for your social health, too - with smokers increasingly edged out to the margins of social circles.
Another significant finding of the study, published in the May 22 issue of the New England Journal of Medicine, is that the decision to quit appears to be taken up almost communally, with whole clusters of spouses, friends, siblings and co-workers giving up the habit at about the same time.
The researchers - Nicholas Christakis of Harvard Medical School and James Fowler of UC San Diego - analyzed changes in smoking behavior from 1971 to 2003 in a large social network of 12,067 densely interconnected people.
The study follows up on research by Fowler and Christakis published last summer, also in the New England Journal of Medicine, finding that obesity is "socially contagious" - spreading from person to person in a social network so that if one becomes obese those closely connected to them have a greater chance of becoming obese themselves.
Using data from the same Framingham Heart Study (which, among other things, was the first to identify the link between smoking and cardiovascular disease), the researchers observed that smoking behaviors are subject to similar social-network effects, at two and three degrees of separation. Except that quitting smoking, they found, spread through the network not only like one domino knocking down the next, which in turn knocks down another, but also like a house of cards collapsing.
Christakis and Fowler note that their findings speak both to the power of relationships and to the efficacy of public-health campaigns to reduce smoking. While smoking remains a leading cause of preventable death, rates in the U.S. have decreased substantially.
"When you look at the entire network over this 30-year period, you see that the average size of each particular cluster of smokers remains roughly the same," Fowler said. "It's just that there are fewer and fewer of these clusters as time goes on."
Observing that "entire pockets of people who might not know each other all quit smoking at once," said Christakis, points to a cultural shift or a change in the zeitgeist. "What appears to happen is that people quit in droves."
Generally, the researchers found, the closer the relationship between contacts, the greater the influence when one person quit smoking. When one spouse quit, for example, the other spouse's chances of continuing to smoke decreased by 67 percent. Among friends, the effect was 36 percent. Among co-workers in small firms, 34 percent. Among siblings, the effect was 25 percent. Neighbors did not seem to be influenced by one another's smoking habits.
Education played a role: Among friends who both had at least one year of college, the effect was 61 percent. The paper concludes that the educated are not only more influential, but also that they are also more easily influenced.
Surprisingly, people quit roughly in tandem, with whole groups becoming nonsmokers. Those who continued to smoke, meanwhile, formed their own "cliques" that, over time, shifted from the center of the social network to the periphery.
"In the early 1970s," said Fowler, "it was completely irrelevant if you smoked. You could be central in your circle and be connected to lots of other people who were similarly central. You could be popular, in other words. By the 2000s, it had become highly relevant: If you smoked, you would, in some sense, be shunned."
The reverse was also true: Once you quit, you tended to move back to a more central position among your contacts.
"We show," Fowler said, "that this not coincidental - there seems to be a causal relationship at work."
All of which points to possible policies for addressing other public-health concerns - like the researchers' previous study case, obesity.
"Network phenomena," they write, "might be exploited to spread positive health behaviors," and targeting groups, not just individuals, might be more effective.
Yet, cautions Fowler, effective doesn't necessarily equate with good. "Stigmatization is effective," he said. "But is it always advisable? Social pressure comes with a cost. We see here that we have stigmatized not only smoking but smokers too. Huddling in a corner with your smoking friends is going to make it that much harder for you to stop. And we also know from other research that social isolation is detrimental to your physical health on several other levels as well."
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Keywords
| https://archive.eurekalert.org/pub_releases/2008-05/uoc--qsh051608.php |
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2017
External press release 16 Mar 2017 CAP-XX adds compact cylindrical supercapacitors CAP-XX, a leading developer of supercapacitors that deliver peak power to support batteries, has launched its first compact cylindrical supercapacitors to provide high performance at low cost for less space-constrained devices.
16 Mar 2017 First shipment of large quantities of graphene quantum dots Dotz Nano, a company that capitalizes on the technological innovation in the Advanced Materials industry, announces the world's largest shipment of Graphene Quantum Dots for commercial use.
15 Mar 2017 London chokes: action pathetic The recent meeting of the SMMT EV Group in London revealed just how far the capital is from a plan let alone adequate action to prevent the 10,000 deaths yearly from vehicle emissions, now the top emissions killer.
15 Mar 2017 Can e-textiles take the next step towards the mass market? Over the past 20 years, e-textiles have progressed from an academic curiosity to an important technology platform generating revenue for companies globally. In particular, the industry saw strong growth for several years up to 2015, with successful launches of many new products from a series of players.
15 Mar 2017 Gelatin actuator for edible robotics A fully edible pneumatic actuator based on gelatin-glycerol composite
15 Mar 2017 Artificial island to provide renewable energy for Europe Central to the plan is the construction of one or more islands, so called Power Link Islands with interconnections to surrounding countries, in the middle of the North Sea.
Full profile interview 15 Mar 2017 Sigfox Sigfox provide a global network for connecting devices over long distances. Now available in 32 countries, Sigfox plan to expand to 28 more within the next 18 months. David Pugh spoke with Thomas Nichols, EVP at Sigfox on the companies roadmap.
14 Mar 2017 New Report from IDTechEx on Transparent Conductive Films (TCF) The transparent conductive film (TCF) industry will leave behind its years of sluggish growth to achieve rapid growth.
14 Mar 2017 So long stiffness: a stretchable plastic electrode The brain is soft and electronics are stiff, which can make combining the two challenging, such as when neuroscientists implant electrodes to measure brain activity and perhaps deliver tiny jolts of electricity for pain relief or other purposes.
14 Mar 2017 Massive Ford EV investment At "Future Powertrain" March 2017, Steve Gill, Director- Powertrain Engineering Ford of Europe Ford Motor Company declared that Ford will spend $4.5 billion on electric vehicles over the coming five years.
14 Mar 2017 Uncompromising on organic solar cells Researchers have developed a semi-transparent organic solar cell that achieves better efficiency and transparency than existing ones.
14 Mar 2017 Triboelectric energy harvesting and storage improved To sustainably power electronics by converting mechanical energy into electricity, energy storage is essential to supply a stable regulated electric output, something traditionally realized by a direct connection between the two components through a rectifier.
14 Mar 2017 Robust robotics for a safer world Robots have come to play important roles in defense and manufacture, but autonomous robots that learn in real time and apply that knowledge in the field remain a work in progress.
External press release 14 Mar 2017 Energy Harvesting Network dissemination event The annual one-day dissemination event organised by the Energy Harvesting Network is being held on 5th April 2017 at Manchester Town Hall.
14 Mar 2017 Prototyping for the Internet of Things: Raspberry Pi To celebrate the end of national pie week in the UK, David Pugh interviewed Roger Thornton, principal hardware engineer at Raspberry Pi following the launch of the Pi ZeroW.
Full profile interview 14 Mar 2017 NGK INSULATORS, LTD. NGK Insulators is a Japanese conglomerate which produces sodium/sulphur batteries for stationary applications. A fire accident in 2011 cost the company $600M but they are now back in the game.
Full profile interview 14 Mar 2017 EDF Technology Analyst Dr Lorenzo Grande interviewed Philippe Stevens from EDF. They have developed a rechargeable Zn/air battery with a specific energy of 450 Wh/kg, as well as an aqueous Li/air battery.
13 Mar 2017 Autonomous cars re-thought Suppliers such as Delphi argue that autonomous cars will sell first to organisations, notably as taxis but, after a delay, they will be bought strongly by private individuals. IDTechEx notes that many cities will ban private cars, autonomous or not
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Background
1 urn:lsid:arphahub.com:pub:F9B2E808-C883-5F47-B276-6D62129E4FF4 urn:lsid:zoobank.org:pub:245B00E9-BFE5-4B4F-B76E-15C30BA74C02 Biodiversity Data Journal BDJ 1314-2836 1314-2828 Pensoft Publishers 10.3897/BDJ.8.e58836 58836 14737 Data Paper (Biosciences) Animalia Zoology & Animal Biology Biodiversity & Conservation Europe Soil invertebrates occurrences in European North-East of Russia Konakova Tatyana [email protected] 1 Kolesnikova Alla 1 Taskaeva Anastasia Anatolevna https://orcid.org/0000-0002-4519-8458 1 1 Institute of Biology of Komi Scientific Centre of theInstitute of Biology of Komi Scientific Centre of the Ural Branch of the Russian Academy of Sciences, Syktyvkar, Russia Institute of Biology of Komi Scientific Centre of theInstitute of Biology of Komi Scientific Centre of the Ural Branch of the Russian Academy of Sciences Syktyvkar Russia
Corresponding author: Tatyana Konakova ( [email protected]
).
Academic editor: Dmitry Schigel 2020 30 11 2020 8 e58836 B5ED5E1F-9C3A-5EAB-85A7-8B9D8C6A6FC1 4310608 21 09 2020 25 11 2020 Tatyana Konakova, Alla Kolesnikova, Anastasia Anatolevna Taskaeva This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Abstract Background
The European North-East of Russia is the territory which includes the Nenets Autonomous District, represented by the East European tundra (from Kanin Peninsula to Vaigach Island), Komi Republic with its taiga ecosystems and the Urals (Northern, SubPolar and Polar). Over 20 years of systematic studies of soil fauna in the studied region has resulted in a huge amount of data being accumulated that can be analysed from different positions. Considering that the representation of Russian soil biota data, especially from European North-East of Russia in the GBIF database is not large, our data are of great interest to the scientific world community. The accumulation of such data will solve questions on national and global scales using large arrays.
This study produced a dataset containing information on occurrences on soil invertebrates ( Lumbricidae
, Chilopoda
, Diplopda, Collembola
, Elateridae
and Staphylinidae
) in the European North-East of Russia. The dataset summarises occurrences noted in natural and disturbed forests, tundra and mountain ecosystems. New information
Data from 196 geo-referenced localities of European North-East of Russia (tundra, taiga and mountains ecosystems) have been collated. A total of 5412 occurrences are included in the resource. The current project surveys 13 species of earthworms, 20 species of millipedes, 246 species of springtails, 446 species of rove beetles and 60 species of click beetles. The diversity of soil invertebrates in the European North-East of Russia has not been fully explored and further exploration will lead to more taxa. Keywords occurrence Lumbricidae Chilopoda Diplopoda Collembola Staphylinidae Elateridae soil tundra taiga mountains North-East of Europe ANNULUS CLOSURE EXPANDABLE DEVICE BASED ON SHAPE-MEMORY MATERIALS AND MEDICAL TEXTILES: SCALE-UP TO PRODUCTION, TESTING AND DEMONSTRATION. 684546 501100000780 European Commission http://doi.org/10.13039/501100000780 Introduction
Soils are increasingly recognised as crucial components of ecosystems and biodiversity ( Wardle et al. 2004
, Bardgett and Wardle 2010
) and they represent unique compartments of terrestrial ecosystems by comprising components of the atmosphere, biosphere, hydrosphere and lithosphere. Soil biodiversity supports many terrestrial ecosystem functions ( Wall et al. 2012
) and delivers important ecosystem services, such as food and fibre production, carbon sequestration and degradation of pollutants. However, the data and information regarding diversity that lives in soil remain insufficiently catalogued and coordinated and this limits our ability to fully assess the key role which soil biodiversity plays in supporting terrestrial systems and ecosystem services ( Ramirez et al. 2015
).
Databases of specific soil-animal groups, for example, Chilobase, Collembola
.org or Lumbricidae
and others, offer complete taxonomical lists of the worldwide known species, partly with bibliographic references to the original descriptions, determination keys etc. Unfortunately, none of these databases collects or offers comprehensive background habitat information and distributional data are often not georeferenced or only available at very large and rough spatial scales. Therefore, they do not provide the data necessary for meta-analyses of detailed species’ spatiotemporal distributions or of species’ ecological niche spaces. However, synthesis of global soil invertebrate data would allow many fundamental questions to be addressed relating to ecology, evolution, ecotoxicology and conservation. For example, basic macroecological patterns, such as effects of elevational and latitudinal gradients on diversity, could be examined with such a dataset. The other special interest is in determining the historical forces driving species biogeography. For many species, the chance of winning the battle against global extinction depends on their ability to both live in a range of environments and the ability to track them. During last 5-10 years, one of the most important questions relating to global distributional patterns of soil animals is related to diversity patterns and the abiotic and biotic factors driving global distributions of native and non-native species. The occurrence dataset in GIBF is the first step to understanding species distribution. These data are able to shed light on the occurrence and distribution pattern of rarely-detected species within a given area of interest. Previously, we have already published data on the occurrence of ground beetles ( Konakova and Kolesnikova 2020
) and sampling datasets of springtails ( Taskaeva 2020a
, Taskaeva 2020b
, Taskaeva 2020c
, Taskaeva and Melekhina 2020
).
In this data paper, we describe this dataset and make it freely available online for future use. General description Purpose
The main goal was to describe a dataset on soil invertebrates ( Collembola
, Lumbricidae
, Myriapoda
, Staphylinidae
and Elateridae
) occurrences in European North-East of Russia. The objectives of this study are (i) to include literature data of observations beginning from 1905 and the last 20 years in the study area, (ii) to provide a basis for analysing spatio-temporal changes in biodiversity and landscape in the study area. Project description Title
Soil invertebrates occurrences in European North-East of Russia Personnel
Tatyana Konakova, Alla Kolesnikova and Anastasia Taskaeva Study area description
The European North-East of Russia (ENER) is the territory which includes the Nenets Autonomous District, represented by the East European tundra (from Kanin Peninsula to Vaigach Island), Komi Republic with its taiga ecosystems and the Urals (Northern, Subpolar and Polar). The study area is also composed of a diverse set of land parcels of different historical use in agriculture and local activity. There are some enterprises producing paper, oil, coal etc.
The largest part of European North-East of Russia is covered by forests. Spruce forests, which are a zonal type of vegetation, dominate. Following the spruce, pine forests also exist in the study area with birch trees being slightly less in number. Forests formed by fir, larch, Siberian cedar and aspen cover much smaller areas and not all territories of the region.
In the Far North of the region, there is a tundra zone. The vegetation cover here is represented by various types of tundra combined with swamps. Moss tundra are common on the coast of the Barents Sea. To the south, spotted shrub-moss and shrub tundra prevail. In river valleys, thickets of high willows have developed.
The Ural Ridge is represented by the slopes of the Polar, Subpolar and Northern Urals. In mountain conditions, vertical distribution of vegetation stands out: mountain-forest, podholtz, mountain-tundra and a belt of cold deserts. The National Park “Yugyd-Va” and Pechoro-Ilych Reserve, being the zones of ecological, faunistic and floristic interest (UNESKO) and belonging to the national inventory of natural heritage, are situated at the Urals.
The climate of the region is temperate continental with local specificities due to the topography
and mixed land-cover. Towards to the north, it is replaced by the Arctic. The northern part lies in the permafrost zone. The average July temperature in the north is +15°C, in the southern part +18°C. The duration of the summer period is 50-60 days in the north and 80-100 days in the south. Winter is the longest period of the year and lasts 5-8 months ( Kolesnikova et al. 2017
). Design description
The study of the soil invertebrates diversity of terrestrial ecosystems in the ENER is aimed to implement a species inventory including records from the 20 last years of research. Soil invertebrates sampling took place mainly during the summer period. Records were mostly observations and preserved specimens, because the studied territory places a high priority on biodiversity conservation and protection. The standard methods of soil zoology were used.
The results of this study were documented in the Institute of Biology of Komi Scientific Centre of the Ural Branch of the Russian Academy of Sciences. Funding
The Ministry of Education and Science of the Russian Federation. Project No АААА-А17-117112850235-2 "Distribution, systematics and spatial organisation of fauna and animals population in taiga and tundra landscapes and ecosystems at the Northeast European Russia" Sampling methods Study extent
We built our database by compiling occurrences of soil invertebrates species, based on an exhaustive search in published and unpublished authors' sources, as well as from museums of the Institute of Biology Komi SC UB RAS, Syktyvkar State University and the personal collection of K.F. Sedykh. Sampling description
Soil and litter dwelling invertebrates were sampled at 196 points evenly distributed over the study area. Three sampling methods were used:
Soil extraction (0-10 cm deep, 5-10 cm diameter for mesofauna and 25×25 cm for macrofauna), followed by the Tullgren funnel method over a 7-day period.
Manual soil sampling.
Pitfall traps or Barber traps were made of plastic pots (10 cm deep, 12 cm diameter), filled with salt water (30% v/v) and formalin (5% v/v) and buried to the rim into the soil.
A count with an entomological net.
Exhauster method
A visual search
All soil invertebrates were identified to the species level using applicable determination keys ( Andersson et al. 2005
, Costa et al. 2010
, Fjellberg 1998
, Fjellberg 2007
, Herman 2001
, Potapov 2001
, Kaprus et al. 2016
, Vsevolodova-Perel 1997
).
On each slide and/or label, the following fields were filled out: “Collection date”, “Locality” (with geographic coordinates), “Habitat”, “Collector name” and “Determined by” (identification). Quality control
The data were collected and identified to species by specialists from the Institute of Biology of Komi Scientific Centre of the Ural Branch of the Russian Academy of Sciences. Some Collembola
, Lumbricidae
, Myriapoda
, Staphylinidae
and Elateridae
specimens were identified by taxonomic specialists from the Severtsov Institute of Ecology and Evolution of the Russian Academy of Sciences, Moscow State Pedagogical University, Institute for Problems of Ecology and Mineral Wealth Use of Tatarstan Academy of Science, Tembotov Institute of Ecology of Mountain Territories of Russian Academy of Science, Institute of the Industrial Ecology Problems of the North, Zoological Institute of Russian Academy of Sciences and the Zoological Museum of Moscow University. Step description
In each biotope, 20-30 soil samples were collected. Barber traps were made of plastic pots (10 cm deep, 12 cm diameter), filled with salt water (30% v/v) and formalin (5% v/v) and buried to the rim into the soil. Individuals, that could not be identified in the field, were stored in 95% ethanol for later identification using binocular loupes. Collembola
were then slide-mounted on cavity slides and identified to the species level using applicable determination keys ( Fjellberg 1998
, Fjellberg 2007
, Kaprus et al. 2016
, Potapov 2001
). On each slide, the following fields were filled out: “Collection date”, “Locality” (with geographic coordinates), “Habitat”, “Collector name” and “Determined by” (identification). Some parts of the springtails were kept in alcohol. Geographic coverage Description
The study was carried out in the European part of Russia (Fig. 1
). This dataset comprises data for 50 localities of Collembola
, 104 – of Lumbricidae
, 79 – Myriapoda
, 88 – Staphylinidae
and 84 – Elateridae
(Figs 2
, 3
, 4
, 5
, 6
). Amongst the reviewed groups, earthworms, millipedes, rove beetles and click beetles are better studied in the taiga zone. However, it is worth noting that the majority of springtail records are from tundra (Fig. 7
). Coordinates
56.4 and 70.37 Latitude; 44.06 and 65.29 Longitude. Taxonomic coverage Description
All invertebrates were identified to species.
European North-East of Russia localities, included in the dataset, account for over 246 springtail species. In the world, there are more than 8.6 thousand species of springtails, but due to the description of new taxa, this number is constantly increasing ( Zhang et al. 2018
). The number of Collembola
species in tundra localities ranges from 10 to 105 (mean = 52.2, s.d. = 28.3), in taiga - from 9 to 80 (mean = 41.5, s.d. = 20.8) and in mountains ecosystems – from 12 to 62 (mean = 42.1, s.d. = 19.5, Fig. 8
). Most of the species in the dataset are recorded from tundra as well as the majority of localities studied here. Altogether, these species account for 2,326 unique geo-referenced occurrence records.
European North-East of Russia localities included in the dataset account for over 13 species of earthworms. The world earthworm fauna contains 3.7 thousand species ( Hendrix et al. 2008
), while only 50 species are known for Russia ( Vsevolodova-Perel 1997
). The lowest values of species richness occurred across the boreal/subarctic regions, which was expected, based on aboveground biodiversity patterns ( Phillips et al. 2019
). This low earthworm diversity could be due to these regions typically being outside of the optimal temperature range (12-20˚C) for earthworms ( Reynolds 1994
). The number of earthworms species in tundra localities varies frrom 1 to 5 (mean = 1.8, s.d. = 0.2), in taiga – 1-10 (mean = 3.6, s.d. = 0.3) and the Urals – from 1 to 10 (mean = 4.2, s.d. = 0.6, Fig. 9
). In East European tundra, D. octaedra
and E. nordenskioldi nordenskioldi
are well distributed and have a number of adaptations to their existence in harsh northern conditions ( Makarova and Kolesnikova 2019
). L. rubellus
is met very seldom and two species are found only in anthropogenic soils ( Kolesnikova et al. 2019
). It is noticed that, in the Urals, the average number of species of worms is higher than in the taiga and tundra ecosystems (Fig. 4), since here, in addition to the typical inhabitants of taiga and tundra landscapes, there are endemics Perelia diplotetratheca
and Eisenia atlavinitea
. Altogether, these species account for 329 unique geo-referenced occurrence records.
More than 3100 species of Chilopoda
( Edgecombe et al. 2010
) and more than 11000 species of Diplopoda
( Enghoff et al. 2015
) are known in the world fauna. We reveal 20 species of millipedes for European North-East of Russia.The largest number of species is noticed in the taiga zone, where its value ranges from 1 to 10 (mean = 4, s.d. = 0.5). In tundra, it varies from 1 to 4 (mean = 1.2, s.d. = 0.1) and, in mountains, only 1-2 (mean = 1.1, s.d. = 0.1) species are encountered (Fig. 10
). This trend is natural as the Lithobius curtipes
is the dominant species. Altogether, these species account for 202 unique geo-referenced occurrence records.
Staphilinids are one of the most extensive and diverse families amongst beetles with about 1500 genera and more than 60000 species known in the world fauna and at least 4000 species in Russia ( Herman 2001
). European North-East of Russia localities, included in the dataset, account for over 446 species of rove beetles, that is only 11% of the Staphilinids diversity of Russia. The number of species per locality ranges from 1 to 76 (mean = 13.1, s.d. = 3) in tundra, from 1-140 (mean = 23.6, s.d. = 4.3) in taiga and from 2 to 58 (mean = 26.4, s.d. = 5.3) in mountains (Fig. 11
). In tundra landscapes, the cold-resistant Omaliinae
and Aleocharinae
prevail. The slight excess of the average species richness in the Urals mountains compared to the taiga zone is explained by the high-altitude zone of the mountains, where species of boreal and arctic fauna inhabiting the mountain-forest and mountain-tundra belts, as well as the Ural-Siberian species, such as Tachinus bicuspidatus
, are registered. Altogether, these species account for 1829 unique geo-referenced occurrence records.
The world fauna of click beetles includes more than 10000 species ( Costa et al. 2010
). Amongst them, only 350 species are known for Russia ( Prosvirov 2013
). Our data include 60 species, i.e. more than 17% of their diversity of Russia. Elateridae
are also better studied in the taiga zone, where the species richness ranges from 1 to 39 species (mean = 9.5, s.d. = 1.6). In the tundra ecosystems, the number of species is minimal and varies from 1 to 14 species (mean = 3.1, s.d. = 0.9). The fauna is presented by small representatives of the genera Hypnoidus
and Oedostethus. Actually, only one species Hypnoidus rivularis
is constantly found. It is numerous and inhabits a wide variety of types of tundra: shrubs, grains, moss-lichen and willow ( Medvedev 2005
). The average number of species in the Urals is slightly higher than in the taiga, due to inhabitants of mountain ecosystems, such as Selatosomus gloriosus
(Fig. 12
). Altogether, these species account for 727 unique geo-referenced occurrence records. Taxa included Rank Scientific Name phylum Annelida class Clitellata order Crassiclitellata family Lumbricidae phylum Arthropoda class Chilopoda class Diplopoda order Collembola order Coleoptera family Staphylinidae family Elateridae Temporal coverage Notes
Data sources provided the dates when the species was detected for the first time in a given region of the 5412 records included in the dataset. The earliest first record dates back to 1905 and the most recent event occurred in 2019. Collection data Collection name
Soil invertebrates occurrences in European North-East of Russia Specimen preservation method
alcohol, formalin, dried Usage licence Usage licence
Other IP rights notes
This work is licensed under a Creative Commons Attribution Non Commercial (CC-BY-NC) 4.0 Licence. Data resources Data package title
Soil invertebrates occurrences in European North-East of Russia Resource link http://ib.komisc.ru:8088/ipt/resource?r=inv Alternative identifiers https://www.gbif.org/dataset/a3f7d0d8-d9e1-42ae-b1f7-d1fc445b931d
; https://doi.org/10.15468/5a8ydf Number of data sets
1 Data set 1. Data set name
Soil invertebrates occurrences in European North-East of Russia Data format
Darwin Core Download URL http://ib.komisc.ru:8088/ipt/resource?r=inv Description
The current project surveys 13 species of earthworms, 20 species of millipedes, 246 species of springtails, 446 species of rove beetles and 60 species of click beetles. A total of 5412 occurrences are included in the resource ( Konakova et al. 2020
). The earliest first record dates back to 1905 and the most recent event occurred in 2019. Data set 1. Column label Column description occurrenceID An identifier for the Occurrence (as opposed to a particular digital record of theoccurrence). recordedBy A person, group or organisation responsible for recording the original Occurrence. verbatimLocality Original description of the place of the find. year The four-digit year in which the Event occurred, according to the Common Era Calendar. decimalLongitude The geographic longitude (in decimal degrees, using the spatial reference system given in geodeticDatum) of the geographic centre of a Location. decimalLatitude The geographic latitude (in decimal degrees, using the spatial reference system given in geodeticDatum) of the geographic centre of a Location. stateProvince Administrative-territorial unit of the country (oblast, okrug or republic) county The name of the country or major administrative unit in which the Location occurs. associatedReferences A list (concatenated and separated) of identifiers (publication, bibliographic reference, global unique identifier, URI) of literature associated with the Occurrence. basisOfRecord Recommended best practice is to use the standard label of one of the Darwin Core classes. georeferencedBy A list (concatenated and separated) of names of people, groups or organisations who determined the georeference (spatial representation) for the Location. geodeticDatum The ellipsoid, geodetic datum or spatial reference system (SRS) upon which the geographic coordinates given in decimalLatitude and decimalLongitude are based. kingdom The full scientific name of the kingdom in which the taxon is classified. phylum The full scientific name of the phylum in which the taxon is classified. class The full scientific name of the class in which the taxon is classified. order The full scientific name of the oder in which the taxon is classified. family The full scientific name of the family in which the taxon is classified. genus The full scientific name of the genus in which the taxon is classified. scientificNameAuthorship The authorship information for the scientificName formatted according to the conventions of the applicable nomenclaturalCode. scientificName The full scientific name, with authorship and date information, if known. When forming part of an Identification, this should be the name in the lowest level taxonomic rank that can be determined. This term should not contain identification qualifications, which should instead be supplied in the IdentificationQualifier term. Acknowledgements
We are grateful to Alexey Medevedev whose data on the click beetles are used and also to employees of Institute of Biology for their help in field material collecting. Author contributions
Tatyana Konakova prepared the dataset, wrote the metadata description and manuscript
Alla Kolesnikova identified earthworms, millipedes, rove beetles species and wrote the manuscript
Anastasia Taskaeva identified springtail species and wrote the manuscript. References Andersson G Meidell B Budd G Scheller U 2005 Nationalnyckeln till Sveriges flora och fauna. Mangfotingar. Myriapoda ArtDatabanken, SLU Uppsala 351 91-88506-56-8 Bardgett Richard Wardle David 2010 Aboveground-Belowground Linkages: Biotic Interactions, Ecosystem Processes, and Global Change. Oxford University Press Oxford 320 Costa C Lawrence J Rosa S 2010 Elateridae Leach, 1815. Kristensen N Beutel R Handbook of Zoology. Arthropoda : Insecta . Coleoptera , Beetles. Vol. 2. Morphology and Systematics ( Elateroidea , Bostrichiformia , Cucujiformia partim) Vol. 2 Walter de Gruyter GmbH & Co KG, Berlin/New York 75-103 Edgecombe D G Zapparoli M Bonato L 2010 Chilopoda – taxonomic overview Minelli A Anatomy, Taxonomy, Biology. The Myriapoda Vol. 1 36-463 Enghoff H Golovatch S I Short M Stoev P Wesener T 2015 Diplopoda — taxonomic overview Minelli A Anatomy, Taxonomy, Biology. The Myriapoda . Vol. 2 363-453 10.1163/9789004188273_017 Fjellberg A 1998 The Collembola of Fennoscandia and Denmark. Part 1. Poduromorpha Fauna Entomologica Scandinavica 35 Brill 184 9004112413 Fjellberg A 2007 The Collembola of Fennoscandia and Denmark. Part 2. Entomobryomorpha and Symphypleona . Fauna Entomologica Scandinavica Vol. 42 Brill 273 10: 9004157700 10.1163/ej.9789004157705.i-265 Hendrix P Callaham M Drake J 2008 Pandora’s box contained bait: the global problem of introduced earthworms Annual Review of Ecology Evolution and Systematics 39 563 613 10.1146/annurev.ecolsys.39.110707.173426. Herman L 2001 Catalog of the Staphylinidae ( Insecta : Coleoptera ) I-VII Bulletin of the American Museum of Natural History 4218 Kaprus I Weiner W Paśnik G. 2016 Collembola of the genus Protaphorura Absolon, 1901 ( Onychiuridae ) in the Eastern Palearctic: morphology, distribution, identification key ZooKeys 620 119 150 10.3897/zookeys.620.9372 Kolesnikova A A Dolgin M M Konakova T N 2017 Ground beetles ( Coleoptera , Carabidae ). Fauna of the European North-East of Russia Vol. 8 Institute of Biology of Komi Scientific Centre of the Ural Branch of the Russian Academy of Sciences Syktyvkar 340 Russian 978-5-9909731-5-2 Kolesnikova A A Baturina M A Shadrin D M Konakova T N Taskaeva A A 2019 New records of Lumbricidae and Collembola in anthropogenic soils of East European tundra ZooKeys 885 15 25 10.3897/zookeys.885.37279 Konakova T Kolesnikova A 2020 Carabidae of the European North-East of Russia. v1.2. Occurrence. Institute of Biology of Komi Scientific Centre of the Ural Branch of the Russian Academy of Sciences via GBIF.org https://www.gbif.org/dataset/b2b5f706-2758-4b90-90a1-c62764786cdf 10.15468/zlidpp Konakova T Kolesnikova A. Taskaeva A 2020 Soil invertebrates occurrences in European North-East of Russia. Version 1.9. Occurrence dataset Institute of Biology of Komi Scientific Centre of the Ural Branch of the Russian Academy of Sciences via GBIF.org 10.15468/5a8ydf Makarova O L Kolesnikova A A 2019 Earthworms ( Oligochaeta , Lumbricidae ) in the tundra of Eastern Europe Biology Bulletin 46 5 438 449 10.1134/S1062359019050078 Medvedev A A 2005 Click beetles Fauna of the European North-East of Russia Vol. VIII Institute of Biology of Komi Scientific Centre of the Ural Branch of the Russian Academy of Sciences 158 Russian 5-02-025945-4 Phillips Helen Guerra Carlos Bartz Marie Briones Maria 2019 Global distribution of earthworm diversity Science 366 480 485 10.1126/science.aax4851 Potapov M 2001 Synopses on Palaearctic Collembola . Isotomidae . Vol. 3 Senckenberg Museum of Natural History Görlitz 603 Prosvirov A S 2013 To the knowledge of the fauna of click-beetles ( Coleoptera : Elateridae ) of south of European Russia and the Caucasus Caucasian Entomological Bulletin 9 2 253 259 Russian 10.23885/1814-3326-2013-9-2-253-259 Ramirez Kelly Döring Markus Eisenhauer Nico Gardi Ciro 2015 Toward a global platform for linking soil biodiversity data Frontiers in Ecology and Evolution 3 91 https://doaj.org/article/ef8543982c8840fba2ce48e48be74313 10.3389/fevo.2015.00091 Reynolds J 1994 Earthworms of the world Global Biodiversity 4 11 16 Taskaeva A 2020 Collembola of Kolguev, Malozemelskaya tundra and Delta Pechora. Version 1.2. Sampling event Institute of Biology of Komi Scientific Centre of the Ural Branch of the Russian Academy of Sciences via GBIF.org 10.15468/52pvpz Taskaeva A 2020 Collembola of Padimeiskie lakes territory on the Bolshezemelskaya tundra (European North-East Russia). Version 1.1. Sampling event dataset Institute of Biology of Komi Scientific Centre of the Ural Branch of the Russian Academy of Sciences via GBIF.org 10.15468/pfwjw9 Taskaeva A 2020 Collembola of the Chernaya river basin. Version 1.2. Sampling event dataset Institute of Biology of Komi Scientific Centre of the Ural Branch of the Russian Academy of Sciences via GBIF.org 10.15468/mivwrm Taskaeva A Melekhina E 2020 Collembola of oil polluted soils of Usinsk district (Komi Republic). Sampling event Institute of Biology of Komi Scientific Centre of the Ural Branch of the Russian Academy of Sciences via GBIF.org 10.15468/dceqct Vsevolodova-Perel T S 1997 The earthworms of the fauna of Russia. Nauka Moscow 102 Russian 5-02-5215-9 Wall Diana Bardgett Richard Behan-Pelletier Valerie Herrick Jeffrey Jones Hefin Ritz Karl Six Johan Strong Donald Putten Wim H. van der 2012 Soil ecology and ecosystem services Oxford University Press Oxford 464 9780199575923 10.1093/acprof:oso/9780199575923.001.0001 Wardle David Bardgett Richard D Klironomos John N Setälä Heikki Putten Wim H Van Der Wall Diana H 2004 Ecological linkages between aboveground and belowground biota Science 304 1629 1633 10.1126/science.1094875 Zhang B Chen C Matteos E Scheu S Schaefer I 2018 Cryptic species in Lepidocyrtus lanuginosus ( Collembola : Entomobryidae ) are sorted by habitat type Pedobiologia 68 12 19 10.1016/j.pedobi.2018.03.001 5F63515D-1978-5E35-9365-5DF36A906535 10.3897/BDJ.8.e58836.figure1 4310610 Figure 1.
Sampling localities for soil invertebrates in the European North-East of Russia included in the dataset ( https://www.gbif.org/dataset/a3f7d0d8-d9e1-42ae-b1f7-d1fc445b931d
). https://binary.pensoft.net/fig/447153 F12368EB-4780-5D69-9BFE-690BDB6FD920 10.3897/BDJ.8.e58836.figure2 4310618 Figure 2.
Sampling sites of Collembola
in North-East Europe are included in the dataset. https://binary.pensoft.net/fig/447191 883FA3E1-D5BA-5787-AF9E-EA282528A4FD 10.3897/BDJ.8.e58836.figure3 4310620 Figure 3.
Sampling sites of Lumbricidae
in North-East Europe are included in the dataset. https://binary.pensoft.net/fig/447193 25FB15F7-6B0F-56DB-A77B-3CD8BB5E69C2 10.3897/BDJ.8.e58836.figure4 4310622 Figure 4.
Sampling sites of Myriapoda
in North-East Europe are included in the dataset. https://binary.pensoft.net/fig/447194 06C00E18-1BA2-5D49-9EA6-605049516346 10.3897/BDJ.8.e58836.figure5 4310624 Figure 5.
Sampling sites of Staphylinidae
in North-East Europe are included in the dataset. https://binary.pensoft.net/fig/447202 0BDB7F3C-8965-5BBB-844D-FE0358D0B7DC 10.3897/BDJ.8.e58836.figure6 4310626 Figure 6.
Sampling sites of Elateridae
in North-East Europe are included in the dataset. https://binary.pensoft.net/fig/447203 801F178F-AD85-53AD-A1CA-C55E48298287 10.3897/BDJ.8.e58836.figure7 4310628 Figure 7.
Number of records included in the datasets for each typology of habitat. https://binary.pensoft.net/fig/447206 82813024-FF64-5593-A76F-406AF73DA3F8 10.3897/BDJ.8.e58836.figure8 4310630 Figure 8.
Springtail species richness in localities of the European North-East of Russia dataset. https://binary.pensoft.net/fig/447211 4A829331-0F5B-57B5-9705-600A953EB601 10.3897/BDJ.8.e58836.figure9 4310632 Figure 9.
Earthworms species richness in localities of the European North-East of Russia dataset https://binary.pensoft.net/fig/447213 954406A5-F94D-5A5B-BE13-F370E6EF5C03 10.3897/BDJ.8.e58836.figure10 4310612 Figure 10.
Millipedes species richness in localities of the European North-East of Russia dataset. https://binary.pensoft.net/fig/447215 011F991F-A3C5-5C03-8EE1-C9E7523E6F8D 10.3897/BDJ.8.e58836.figure11 4310614 Figure 11.
Rove beetles species richness in localities of the European North-East of Russia dataset. https://binary.pensoft.net/fig/447217 0BCFE8A9-B72B-5B26-BC45-5A9D4B606F47 10.3897/BDJ.8.e58836.figure12 4310616 Figure 12.
Click beetles species richness in localities of the European North-East of Russia dataset. https://binary.pensoft.net/fig/447219
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<article-categories >
<subj-group subj-group-type =" heading " >
<subject > Data Paper (Biosciences)
</subject >
</subj-group >
<subj-group subj-group-type =" heading " > ... </subj-group >
<subj-group subj-group-type =" Taxon classification " >
<subject > Animalia </subject >
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<subject > Zoology & Animal Biology </subject >
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<subject > Europe </subject >
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<article-title >
Soil invertebrates occurrences in European North-East of Russia
</article-title >
<article-title > ... </article-title >
</title-group >
<title-group > ... </title-group >
<contrib-group content-type =" authors " >
<contrib contrib-type =" author "
corresp =" yes " >
<name name-style =" western " >
<surname > Konakova </surname >
<given-names > Tatyana </given-names >
</name >
<name name-style =" western " > ... </name >
<email
xlink:type =" simple " > [email protected] </email >
<xref ref-type =" aff " rid =" A1 " > 1 </xref >
</contrib >
<contrib contrib-type =" author " corresp =" yes " > ... </contrib >
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corresp =" no " >
<name name-style =" western " >
<surname > Kolesnikova </surname >
<given-names > Alla </given-names >
</name >
<name name-style =" western " > ... </name >
<xref ref-type =" aff " rid =" A1 " > 1 </xref >
</contrib >
<contrib contrib-type =" author " corresp =" no " > ... </contrib >
<contrib contrib-type =" author "
corresp =" no " >
<name name-style =" western " >
<surname > Taskaeva </surname >
<given-names > Anastasia Anatolevna </given-names >
</name >
<name name-style =" western " > ... </name >
<uri content-type =" orcid " > https://orcid.org/0000-0002-4519-8458 </uri >
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</contrib >
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<addr-line content-type =" verbatim " >
Institute of Biology of Komi Scientific Centre of theInstitute of Biology of Komi Scientific Centre of the Ural Branch of the Russian Academy of Sciences, Syktyvkar, Russia
</addr-line >
<addr-line content-type =" verbatim " > ... </addr-line >
<institution >
Institute of Biology of Komi Scientific Centre of theInstitute of Biology of Komi Scientific Centre of the Ural Branch of the Russian Academy of Sciences
</institution >
<institution > ... </institution >
<addr-line content-type =" city " > Syktyvkar </addr-line >
<country > Russia </country >
</aff >
<aff id =" A1 " > ... </aff >
<author-notes >
<fn fn-type =" corresp " >
<p >
Corresponding author: Tatyana Konakova (
<email
xlink:type =" simple " > [email protected] </email >
).
</p >
<p > ... </p >
</fn >
<fn fn-type =" corresp " > ... </fn >
<fn fn-type =" edited-by " >
<p > Academic editor: Dmitry Schigel </p >
</fn >
<fn fn-type =" edited-by " > ... </fn >
</author-notes >
<author-notes > ... </author-notes >
<pub-date pub-type =" collection " >
<year > 2020 </year >
</pub-date >
<pub-date pub-type =" collection " > ... </pub-date >
<pub-date pub-type =" epub " >
<day > 30 </day >
<month > 11 </month >
<year > 2020 </year >
</pub-date >
<pub-date pub-type =" epub " > ... </pub-date >
<volume > 8 </volume >
<elocation-id > e58836 </elocation-id >
<uri content-type =" arpha "
xlink:href =" http://openbiodiv.net/B5ED5E1F-9C3A-5EAB-85A7-8B9D8C6A6FC1 " > B5ED5E1F-9C3A-5EAB-85A7-8B9D8C6A6FC1 </uri >
<uri content-type =" zenodo_dep_id "
xlink:href =" https://zenodo.org/record/4310608 " > 4310608 </uri >
<history >
<date date-type =" received " >
<day > 21 </day >
<month > 09 </month >
<year > 2020 </year >
</date >
<date date-type =" received " > ... </date >
<date date-type =" accepted " >
<day > 25 </day >
<month > 11 </month >
<year > 2020 </year >
</date >
<date date-type =" accepted " > ... </date >
</history >
<history > ... </history >
<permissions >
<copyright-statement >
Tatyana Konakova, Alla Kolesnikova, Anastasia Anatolevna Taskaeva
</copyright-statement >
<copyright-statement > ... </copyright-statement >
<license license-type =" creative-commons-attribution "
xlink:href =" http://creativecommons.org/licenses/by/4.0/ "
xlink:type =" simple " >
<license-p >
This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
</license-p >
<license-p > ... </license-p >
</license >
<license license-type =" creative-commons-attribution " xlink:href =" http://creativecommons.org/licenses/by/4.0/ " xlink:type =" simple " > ... </license >
</permissions >
<permissions > ... </permissions >
<abstract >
<label > Abstract </label >
<sec sec-type =" background " >
<title > Background </title >
<p >
The European North-East of Russia is the territory which includes the Nenets Autonomous District, represented by the East European tundra (from Kanin Peninsula to Vaigach Island), Komi Republic with its taiga ecosystems and the Urals (Northern, SubPolar and Polar). Over 20 years of systematic studies of soil fauna in the studied region has resulted in a huge amount of data being accumulated that can be analysed from different positions. Considering that the representation of Russian soil biota data, especially from European North-East of Russia in the GBIF database is not large, our data are of great interest to the scientific world community. The accumulation of such data will solve questions on national and global scales using large arrays.
</p >
<p > ... </p >
<p >
This study produced a dataset containing information on occurrences on soil invertebrates (
<tp:taxon-name >
<tp:taxon-name-part taxon-name-part-type =" family " > Lumbricidae </tp:taxon-name-part >
</tp:taxon-name >
<tp:taxon-name > ... </tp:taxon-name >
,
<tp:taxon-name >
<tp:taxon-name-part taxon-name-part-type =" class " > Chilopoda </tp:taxon-name-part >
</tp:taxon-name >
<tp:taxon-name > ... </tp:taxon-name >
, Diplopda,
<tp:taxon-name >
<tp:taxon-name-part taxon-name-part-type =" order " > Collembola </tp:taxon-name-part >
</tp:taxon-name >
<tp:taxon-name > ... </tp:taxon-name >
,
<tp:taxon-name >
<tp:taxon-name-part taxon-name-part-type =" family " > Elateridae </tp:taxon-name-part >
</tp:taxon-name >
<tp:taxon-name > ... </tp:taxon-name >
and
<tp:taxon-name >
<tp:taxon-name-part taxon-name-part-type =" family " > Staphylinidae </tp:taxon-name-part >
</tp:taxon-name >
<tp:taxon-name > ... </tp:taxon-name >
) in the European North-East of Russia. The dataset summarises occurrences noted in natural and disturbed forests, tundra and mountain ecosystems.
</p >
<p > ... </p >
</sec >
<sec sec-type =" background " > ... </sec >
<sec sec-type =" new information " >
<title > New information </title >
<p >
Data from 196 geo-referenced localities of European North-East of Russia (tundra, taiga and mountains ecosystems) have been collated. A total of 5412 occurrences are included in the resource. The current project surveys 13 species of earthworms, 20 species of millipedes, 246 species of springtails, 446 species of rove beetles and 60 species of click beetles. The diversity of soil invertebrates in the European North-East of Russia has not been fully explored and further exploration will lead to more taxa.
</p >
<p > ... </p >
</sec >
<sec sec-type =" new information " > ... </sec >
</abstract >
<abstract > ... </abstract >
<kwd-group >
<label > Keywords </label >
<kwd > occurrence </kwd >
<kwd >
<tp:taxon-name >
<tp:taxon-name-part taxon-name-part-type =" family " > Lumbricidae </tp:taxon-name-part >
</tp:taxon-name >
<tp:taxon-name > ... </tp:taxon-name >
</kwd >
<kwd > ... </kwd >
<kwd >
<tp:taxon-name >
<tp:taxon-name-part taxon-name-part-type =" class " > Chilopoda </tp:taxon-name-part >
</tp:taxon-name >
<tp:taxon-name > ... </tp:taxon-name >
</kwd >
<kwd > ... </kwd >
<kwd >
<tp:taxon-name >
<tp:taxon-name-part taxon-name-part-type =" class " > Diplopoda </tp:taxon-name-part >
</tp:taxon-name >
<tp:taxon-name > ... </tp:taxon-name >
</kwd >
<kwd > ... </kwd >
<kwd >
<tp:taxon-name >
<tp:taxon-name-part taxon-name-part-type =" order " > Collembola </tp:taxon-name-part >
</tp:taxon-name >
<tp:taxon-name > ... </tp:taxon-name >
</kwd >
<kwd > ... </kwd >
<kwd >
<tp:taxon-name >
<tp:taxon-name-part taxon-name-part-type =" family " > Staphylinidae </tp:taxon-name-part >
</tp:taxon-name >
<tp:taxon-name > ... </tp:taxon-name >
</kwd >
<kwd > ... </kwd >
<kwd >
<tp:taxon-name >
<tp:taxon-name-part taxon-name-part-type =" family " > Elateridae </tp:taxon-name-part >
</tp:taxon-name >
<tp:taxon-name > ... </tp:taxon-name >
</kwd >
<kwd > ... </kwd >
<kwd > soil </kwd >
<kwd > tundra </kwd >
<kwd > taiga </kwd >
<kwd > mountains </kwd >
<kwd > North-East of Europe </kwd >
</kwd-group >
<kwd-group > ... </kwd-group >
<funding-group >
<award-group >
<funding-source >
<named-content content-type =" project_title " >
ANNULUS CLOSURE EXPANDABLE DEVICE BASED ON SHAPE-MEMORY MATERIALS AND MEDICAL TEXTILES: SCALE-UP TO PRODUCTION, TESTING AND DEMONSTRATION.
</named-content >
<named-content content-type =" project_title " > ... </named-content >
<named-content content-type =" project_identifier " > 684546 </named-content >
<named-content content-type =" project_funder_id " > 501100000780 </named-content >
<named-content content-type =" project_funder_name " > European Commission </named-content >
<named-content content-type =" project_funder_doi " > http://doi.org/10.13039/501100000780 </named-content >
</funding-source >
<funding-source > ... </funding-source >
</award-group >
<award-group > ... </award-group >
</funding-group >
<funding-group > ... </funding-group >
<counts >
<fig-count count =" 12 " />
<table-count count =" 0 " />
<ref-count count =" 29 " />
</counts >
<counts > ... </counts >
</article-meta >
<article-meta > ... </article-meta >
</front >
<front > ... </front >
<body >
<sec sec-type =" Introduction " >
<title > Introduction </title >
<p >
Soils are increasingly recognised as crucial components of ecosystems and biodiversity (
<xref ref-type =" bibr "
rid =" B6081054 " > Wardle et al. 2004 </xref >
,
<xref ref-type =" bibr "
rid =" B6081096 " > Bardgett and Wardle 2010 </xref >
) and they represent unique compartments of terrestrial ecosystems by comprising components of the atmosphere, biosphere, hydrosphere and lithosphere. Soil biodiversity supports many terrestrial ecosystem functions (
<xref ref-type =" bibr " rid =" B6081113 " > Wall et al. 2012 </xref >
) and delivers important ecosystem services, such as food and fibre production, carbon sequestration and degradation of pollutants. However, the data and information regarding diversity that lives in soil remain insufficiently catalogued and coordinated and this limits our ability to fully assess the key role which soil biodiversity plays in supporting terrestrial systems and ecosystem services (
<xref ref-type =" bibr "
rid =" B6081127 " > Ramirez et al. 2015 </xref >
).
</p >
<p > ... </p >
<p >
Databases of specific soil-animal groups, for example, Chilobase,
<tp:taxon-name >
<tp:taxon-name-part taxon-name-part-type =" order " > Collembola </tp:taxon-name-part >
</tp:taxon-name >
<tp:taxon-name > ... </tp:taxon-name >
.org or
<tp:taxon-name >
<tp:taxon-name-part taxon-name-part-type =" family " > Lumbricidae </tp:taxon-name-part >
</tp:taxon-name >
<tp:taxon-name > ... </tp:taxon-name >
and others, offer complete taxonomical lists of the worldwide known species, partly with bibliographic references to the original descriptions, determination keys etc. Unfortunately, none of these databases collects or offers comprehensive background habitat information and distributional data are often not georeferenced or only available at very large and rough spatial scales. Therefore, they do not provide the data necessary for meta-analyses of detailed species’ spatiotemporal distributions or of species’ ecological niche spaces. However, synthesis of global soil invertebrate data would allow many fundamental questions to be addressed relating to ecology, evolution, ecotoxicology and conservation. For example, basic macroecological patterns, such as effects of elevational and latitudinal gradients on diversity, could be examined with such a dataset. The other special interest is in determining the historical forces driving species biogeography. For many species, the chance of winning the battle against global extinction depends on their ability to both live in a range of environments and the ability to track them. During last 5-10 years, one of the most important questions relating to global distributional patterns of soil animals is related to diversity patterns and the abiotic and biotic factors driving global distributions of native and non-native species. The occurrence dataset in GIBF is the first step to understanding species distribution. These data are able to shed light on the occurrence and distribution pattern of rarely-detected species within a given area of interest. Previously, we have already published data on the occurrence of ground beetles (
<xref ref-type =" bibr "
rid =" B6081145 " > Konakova and Kolesnikova 2020 </xref >
) and sampling datasets of springtails (
<xref ref-type =" bibr "
rid =" B6081305 " > Taskaeva 2020a </xref >
,
<xref ref-type =" bibr "
rid =" B6081324 " > Taskaeva 2020b </xref >
,
<xref ref-type =" bibr "
rid =" B6081332 " > Taskaeva 2020c </xref >
,
<xref ref-type =" bibr "
rid =" B6081340 " > Taskaeva and Melekhina 2020 </xref >
).
</p >
<p > ... </p >
<p >
In this data paper, we describe this dataset and make it freely available online for future use.
</p >
<p > ... </p >
</sec >
<sec sec-type =" Introduction " > ... </sec >
<sec sec-type =" General description " >
<title > General description </title >
<sec sec-type =" Purpose " >
<title > Purpose </title >
<p >
The main goal was to describe a dataset on soil invertebrates (
<tp:taxon-name >
<tp:taxon-name-part taxon-name-part-type =" order " > Collembola </tp:taxon-name-part >
</tp:taxon-name >
<tp:taxon-name > ... </tp:taxon-name >
,
<tp:taxon-name >
<tp:taxon-name-part taxon-name-part-type =" family " > Lumbricidae </tp:taxon-name-part >
</tp:taxon-name >
<tp:taxon-name > ... </tp:taxon-name >
,
<tp:taxon-name >
<tp:taxon-name-part taxon-name-part-type =" subphylum " > Myriapoda </tp:taxon-name-part >
</tp:taxon-name >
<tp:taxon-name > ... </tp:taxon-name >
,
<tp:taxon-name >
<tp:taxon-name-part taxon-name-part-type =" family " > Staphylinidae </tp:taxon-name-part >
</tp:taxon-name >
<tp:taxon-name > ... </tp:taxon-name >
and
<tp:taxon-name >
<tp:taxon-name-part taxon-name-part-type =" family " > Elateridae </tp:taxon-name-part >
</tp:taxon-name >
<tp:taxon-name > ... </tp:taxon-name >
) occurrences in European North-East of Russia. The objectives of this study are (i) to include literature data of observations beginning from 1905 and the last 20 years in the study area, (ii) to provide a basis for analysing spatio-temporal changes in biodiversity and landscape in the study area.
</p >
<p > ... </p >
</sec >
<sec sec-type =" Purpose " > ... </sec >
</sec >
<sec sec-type =" General description " > ... </sec >
<sec sec-type =" Project description " >
<title > Project description </title >
<sec sec-type =" Title " >
<title > Title </title >
<p >
Soil invertebrates occurrences in European North-East of Russia
</p >
<p > ... </p >
</sec >
<sec sec-type =" Title " > ... </sec >
<sec sec-type =" Personnel " >
<title > Personnel </title >
<p >
Tatyana Konakova, Alla Kolesnikova and Anastasia Taskaeva
</p >
<p > ... </p >
</sec >
<sec sec-type =" Personnel " > ... </sec >
<sec sec-type =" Study area description " >
<title > Study area description </title >
<p >
The European North-East of Russia (ENER) is the territory which includes the Nenets Autonomous District, represented by the East European tundra (from Kanin Peninsula to Vaigach Island), Komi Republic with its taiga ecosystems and the Urals (Northern, Subpolar and Polar). The study area is also composed of a diverse set of land parcels of different historical use in agriculture and local activity. There are some enterprises producing paper, oil, coal etc.
</p >
<p > ... </p >
<p >
The largest part of European North-East of Russia is covered by forests. Spruce forests, which are a zonal type of vegetation, dominate. Following the spruce, pine forests also exist in the study area with birch trees being slightly less in number. Forests formed by fir, larch, Siberian cedar and aspen cover much smaller areas and not all territories of the region.
</p >
<p > ... </p >
<p >
In the Far North of the region, there is a tundra zone. The vegetation cover here is represented by various types of tundra combined with swamps. Moss tundra are common on the coast of the Barents Sea. To the south, spotted shrub-moss and shrub tundra prevail. In river valleys, thickets of high willows have developed.
</p >
<p > ... </p >
<p >
The Ural Ridge is represented by the slopes of the Polar, Subpolar and Northern Urals. In mountain conditions, vertical distribution of vegetation stands out: mountain-forest, podholtz, mountain-tundra and a belt of cold deserts. The National Park “Yugyd-Va” and Pechoro-Ilych Reserve, being the zones of ecological, faunistic and floristic interest (UNESKO) and belonging to the national inventory of natural heritage, are situated at the Urals.
</p >
<p > ... </p >
<p >
The climate of the region is temperate continental with local specificities due to the topography
</p >
<p > ... </p >
<p >
and mixed land-cover. Towards to the north, it is replaced by the Arctic. The northern part lies in the permafrost zone. The average July temperature in the north is +15°C, in the southern part +18°C. The duration of the summer period is 50-60 days in the north and 80-100 days in the south. Winter is the longest period of the year and lasts 5-8 months (
<xref ref-type =" bibr "
rid =" B6081348 " > Kolesnikova et al. 2017 </xref >
).
</p >
<p > ... </p >
</sec >
<sec sec-type =" Study area description " > ... </sec >
<sec sec-type =" Design description " >
<title > Design description </title >
<p >
The study of the soil invertebrates diversity of terrestrial ecosystems in the ENER is aimed to implement a species inventory including records from the 20 last years of research. Soil invertebrates sampling took place mainly during the summer period. Records were mostly observations and preserved specimens, because the studied territory places a high priority on biodiversity conservation and protection. The standard methods of soil zoology were used.
</p >
<p > ... </p >
<p >
The results of this study were documented in the Institute of Biology of Komi Scientific Centre of the Ural Branch of the Russian Academy of Sciences.
</p >
<p > ... </p >
</sec >
<sec sec-type =" Design description " > ... </sec >
<sec sec-type =" Funding " >
<title > Funding </title >
<p >
The Ministry of Education and Science of the Russian Federation. Project No АААА-А17-117112850235-2 "Distribution, systematics and spatial organisation of fauna and animals population in taiga and tundra landscapes and ecosystems at the Northeast European Russia"
</p >
<p > ... </p >
</sec >
<sec sec-type =" Funding " > ... </sec >
</sec >
<sec sec-type =" Project description " > ... </sec >
<sec sec-type =" Sampling methods " >
<title > Sampling methods </title >
<sec sec-type =" Study extent " >
<title > Study extent </title >
<p >
We built our database by compiling occurrences of soil invertebrates species, based on an exhaustive search in published and unpublished authors' sources, as well as from museums of the Institute of Biology Komi SC UB RAS, Syktyvkar State University and the personal collection of K.F. Sedykh.
</p >
<p > ... </p >
</sec >
<sec sec-type =" Study extent " > ... </sec >
<sec sec-type =" Sampling description " >
<title > Sampling description </title >
<p >
Soil and litter dwelling invertebrates were sampled at 196 points evenly distributed over the study area. Three sampling methods were used:
</p >
<p > ... </p >
<p >
<list list-type =" order " >
<list-item >
<p >
Soil extraction (0-10 cm deep, 5-10 cm diameter for mesofauna and 25×25 cm for macrofauna), followed by the Tullgren funnel method over a 7-day period.
</p >
<p > ... </p >
</list-item >
<list-item > ... </list-item >
<list-item >
<p > Manual soil sampling. </p >
</list-item >
<list-item > ... </list-item >
<list-item >
<p >
Pitfall traps or Barber traps were made of plastic pots (10 cm deep, 12 cm diameter), filled with salt water (30% v/v) and formalin (5% v/v) and buried to the rim into the soil.
</p >
<p > ... </p >
</list-item >
<list-item > ... </list-item >
<list-item >
<p > A count with an entomological net.
</p >
</list-item >
<list-item > ... </list-item >
<list-item >
<p > Exhauster method </p >
</list-item >
<list-item > ... </list-item >
<list-item >
<p > A visual search </p >
</list-item >
<list-item > ... </list-item >
</list >
<list list-type =" order " > ... </list >
</p >
<p > ... </p >
<p >
All soil invertebrates were identified to the species level using applicable determination keys (
<xref ref-type =" bibr "
rid =" B6081424 " > Andersson et al. 2005 </xref >
,
<xref ref-type =" bibr "
rid =" B6081472 " > Costa et al. 2010 </xref >
,
<xref ref-type =" bibr "
rid =" B6081360 " > Fjellberg 1998 </xref >
,
<xref ref-type =" bibr "
rid =" B6081370 " > Fjellberg 2007 </xref >
,
<xref ref-type =" bibr "
rid =" B6081432 " > Herman 2001 </xref >
,
<xref ref-type =" bibr "
rid =" B6081378 " > Potapov 2001 </xref >
,
<xref ref-type =" bibr "
rid =" B6081407 " > Kaprus et al. 2016 </xref >
,
<xref ref-type =" bibr "
rid =" B6081416 " > Vsevolodova-Perel 1997 </xref >
).
</p >
<p > ... </p >
<p >
On each slide and/or label, the following fields were filled out: “Collection date”, “Locality” (with geographic coordinates), “Habitat”, “Collector name” and “Determined by” (identification).
</p >
<p > ... </p >
</sec >
<sec sec-type =" Sampling description " > ... </sec >
<sec sec-type =" Quality control " >
<title > Quality control </title >
<p >
The data were collected and identified to species by specialists from the Institute of Biology of Komi Scientific Centre of the Ural Branch of the Russian Academy of Sciences. Some
<tp:taxon-name >
<tp:taxon-name-part taxon-name-part-type =" order " > Collembola </tp:taxon-name-part >
</tp:taxon-name >
<tp:taxon-name > ... </tp:taxon-name >
,
<tp:taxon-name >
<tp:taxon-name-part taxon-name-part-type =" family " > Lumbricidae </tp:taxon-name-part >
</tp:taxon-name >
<tp:taxon-name > ... </tp:taxon-name >
,
<tp:taxon-name >
<tp:taxon-name-part taxon-name-part-type =" subphylum " > Myriapoda </tp:taxon-name-part >
</tp:taxon-name >
<tp:taxon-name > ... </tp:taxon-name >
,
<tp:taxon-name >
<tp:taxon-name-part taxon-name-part-type =" family " > Staphylinidae </tp:taxon-name-part >
</tp:taxon-name >
<tp:taxon-name > ... </tp:taxon-name >
and
<tp:taxon-name >
<tp:taxon-name-part taxon-name-part-type =" family " > Elateridae </tp:taxon-name-part >
</tp:taxon-name >
<tp:taxon-name > ... </tp:taxon-name >
specimens were identified by taxonomic specialists from the Severtsov Institute of Ecology and Evolution of the Russian Academy of Sciences, Moscow State Pedagogical University, Institute for Problems of Ecology and Mineral Wealth Use of Tatarstan Academy of Science, Tembotov Institute of Ecology of Mountain Territories of Russian Academy of Science, Institute of the Industrial Ecology Problems of the North, Zoological Institute of Russian Academy of Sciences and the Zoological Museum of Moscow University.
</p >
<p > ... </p >
</sec >
<sec sec-type =" Quality control " > ... </sec >
<sec sec-type =" Step description " >
<title > Step description </title >
<p >
In each biotope, 20-30 soil samples were collected. Barber traps were made of plastic pots (10 cm deep, 12 cm diameter), filled with salt water (30% v/v) and formalin (5% v/v) and buried to the rim into the soil. Individuals, that could not be identified in the field, were stored in 95% ethanol for later identification using binocular loupes.
<tp:taxon-name >
<tp:taxon-name-part taxon-name-part-type =" order " > Collembola </tp:taxon-name-part >
</tp:taxon-name >
<tp:taxon-name > ... </tp:taxon-name >
were then slide-mounted on cavity slides and identified to the species level using applicable determination keys (
<xref ref-type =" bibr "
rid =" B6081360 " > Fjellberg 1998 </xref >
,
<xref ref-type =" bibr "
rid =" B6081370 " > Fjellberg 2007 </xref >
,
<xref ref-type =" bibr "
rid =" B6081407 " > Kaprus et al. 2016 </xref >
,
<xref ref-type =" bibr "
rid =" B6081378 " > Potapov 2001 </xref >
). On each slide, the following fields were filled out: “Collection date”, “Locality” (with geographic coordinates), “Habitat”, “Collector name” and “Determined by” (identification). Some parts of the springtails were kept in alcohol.
</p >
<p > ... </p >
</sec >
<sec sec-type =" Step description " > ... </sec >
</sec >
<sec sec-type =" Sampling methods " > ... </sec >
<sec sec-type =" Geographic coverage " >
<title > Geographic coverage </title >
<sec sec-type =" Description " >
<title > Description </title >
<p >
The study was carried out in the European part of Russia (Fig.
<xref ref-type =" fig "
rid =" F6081650 " > 1 </xref >
). This dataset comprises data for 50 localities of
<tp:taxon-name >
<tp:taxon-name-part taxon-name-part-type =" order " > Collembola </tp:taxon-name-part >
</tp:taxon-name >
<tp:taxon-name > ... </tp:taxon-name >
, 104 – of
<tp:taxon-name >
<tp:taxon-name-part taxon-name-part-type =" family " > Lumbricidae </tp:taxon-name-part >
</tp:taxon-name >
<tp:taxon-name > ... </tp:taxon-name >
, 79 –
<tp:taxon-name >
<tp:taxon-name-part taxon-name-part-type =" subphylum " > Myriapoda </tp:taxon-name-part >
</tp:taxon-name >
<tp:taxon-name > ... </tp:taxon-name >
, 88 –
<tp:taxon-name >
<tp:taxon-name-part taxon-name-part-type =" family " > Staphylinidae </tp:taxon-name-part >
</tp:taxon-name >
<tp:taxon-name > ... </tp:taxon-name >
and 84 –
<tp:taxon-name >
<tp:taxon-name-part taxon-name-part-type =" family " > Elateridae </tp:taxon-name-part >
</tp:taxon-name >
<tp:taxon-name > ... </tp:taxon-name >
(Figs
<xref ref-type =" fig "
rid =" F6081681 " > 2 </xref >
,
<xref ref-type =" fig "
rid =" F6081686 " > 3 </xref >
,
<xref ref-type =" fig "
rid =" F6081690 " > 4 </xref >
,
<xref ref-type =" fig "
rid =" F6081694 " > 5 </xref >
,
<xref ref-type =" fig "
rid =" F6081698 " > 6 </xref >
). Amongst the reviewed groups, earthworms, millipedes, rove beetles and click beetles are better studied in the taiga zone. However, it is worth noting that the majority of springtail records are from tundra (Fig.
<xref ref-type =" fig "
rid =" F6081702 " > 7 </xref >
).
</p >
<p > ... </p >
</sec >
<sec sec-type =" Description " > ... </sec >
<sec sec-type =" Coordinates " >
<title > Coordinates </title >
<p >
56.4 and 70.37 Latitude; 44.06 and 65.29 Longitude.
</p >
<p > ... </p >
</sec >
<sec sec-type =" Coordinates " > ... </sec >
</sec >
<sec sec-type =" Geographic coverage " > ... </sec >
<sec sec-type =" Taxonomic coverage " >
<title > Taxonomic coverage </title >
<sec sec-type =" Description " >
<title > Description </title >
<p > All invertebrates were identified to species. </p >
<p >
European North-East of Russia localities, included in the dataset, account for over 246 springtail species. In the world, there are more than 8.6 thousand species of springtails, but due to the description of new taxa, this number is constantly increasing (
<xref ref-type =" bibr "
rid =" B6081485 " > Zhang et al. 2018 </xref >
). The number of
<tp:taxon-name >
<tp:taxon-name-part taxon-name-part-type =" order " > Collembola </tp:taxon-name-part >
</tp:taxon-name >
<tp:taxon-name > ... </tp:taxon-name >
species in tundra localities ranges from 10 to 105 (mean = 52.2, s.d. = 28.3), in taiga - from 9 to 80 (mean = 41.5, s.d. = 20.8) and in mountains ecosystems – from 12 to 62 (mean = 42.1, s.d. = 19.5, Fig.
<xref ref-type =" fig "
rid =" F6081706 " > 8 </xref >
). Most of the species in the dataset are recorded from tundra as well as the majority of localities studied here. Altogether, these species account for 2,326 unique geo-referenced occurrence records.
</p >
<p > ... </p >
<p >
European North-East of Russia localities included in the dataset account for over 13 species of earthworms. The world earthworm fauna contains 3.7 thousand species (
<xref ref-type =" bibr "
rid =" B6081495 " > Hendrix et al. 2008 </xref >
), while only 50 species are known for Russia (
<xref ref-type =" bibr "
rid =" B6081416 " > Vsevolodova-Perel 1997 </xref >
). The lowest values of species richness occurred across the boreal/subarctic regions, which was expected, based on aboveground biodiversity patterns (
<xref ref-type =" bibr "
rid =" B6081504 " > Phillips et al. 2019 </xref >
). This low earthworm diversity could be due to these regions typically being outside of the optimal temperature range (12-20˚C) for earthworms (
<xref ref-type =" bibr "
rid =" B6081513 " > Reynolds 1994 </xref >
). The number of earthworms species in tundra localities varies frrom 1 to 5 (mean = 1.8, s.d. = 0.2), in taiga – 1-10 (mean = 3.6, s.d. = 0.3) and the Urals – from 1 to 10 (mean = 4.2, s.d. = 0.6, Fig.
<xref ref-type =" fig "
rid =" F6081710 " > 9 </xref >
). In East European tundra,
<italic >
<tp:taxon-name >
<tp:taxon-name-part taxon-name-part-type =" genus " reg =" Dendrobaena " > D.
</tp:taxon-name-part >
<tp:taxon-name-part taxon-name-part-type =" species "
reg =" octaedra " > octaedra </tp:taxon-name-part >
</tp:taxon-name >
<tp:taxon-name > ... </tp:taxon-name >
</italic >
<italic > ... </italic >
and
<italic >
<tp:taxon-name >
<tp:taxon-name-part taxon-name-part-type =" genus " reg =" Eisenia " > E.
</tp:taxon-name-part >
<tp:taxon-name-part taxon-name-part-type =" species "
reg =" nordenskioldi " > nordenskioldi </tp:taxon-name-part >
<tp:taxon-name-part taxon-name-part-type =" subspecies "
reg =" nordenskioldi " > nordenskioldi </tp:taxon-name-part >
</tp:taxon-name >
<tp:taxon-name > ... </tp:taxon-name >
</italic >
<italic > ... </italic >
are well distributed and have a number of adaptations to their existence in harsh northern conditions (
<xref ref-type =" bibr "
rid =" B6081522 " > Makarova and Kolesnikova 2019 </xref >
).
<italic >
<tp:taxon-name >
<tp:taxon-name-part taxon-name-part-type =" genus " reg =" Lumbricus " > L.
</tp:taxon-name-part >
<tp:taxon-name-part taxon-name-part-type =" species "
reg =" rubellus " > rubellus </tp:taxon-name-part >
</tp:taxon-name >
<tp:taxon-name > ... </tp:taxon-name >
</italic >
<italic > ... </italic >
is met very seldom and two species are found only in anthropogenic soils (
<xref ref-type =" bibr "
rid =" B6081531 " > Kolesnikova et al. 2019 </xref >
). It is noticed that, in the Urals, the average number of species of worms is higher than in the taiga and tundra ecosystems (Fig. 4), since here, in addition to the typical inhabitants of taiga and tundra landscapes, there are endemics
<italic >
<tp:taxon-name >
<tp:taxon-name-part taxon-name-part-type =" genus "
reg =" Perelia " > Perelia </tp:taxon-name-part >
<tp:taxon-name-part taxon-name-part-type =" species "
reg =" diplotetratheca " > diplotetratheca </tp:taxon-name-part >
</tp:taxon-name >
<tp:taxon-name > ... </tp:taxon-name >
</italic >
<italic > ... </italic >
and
<italic >
<tp:taxon-name >
<tp:taxon-name-part taxon-name-part-type =" genus "
reg =" Eisenia " > Eisenia </tp:taxon-name-part >
<tp:taxon-name-part taxon-name-part-type =" species "
reg =" atlavinitea " > atlavinitea </tp:taxon-name-part >
</tp:taxon-name >
<tp:taxon-name > ... </tp:taxon-name >
</italic >
<italic > ... </italic >
. Altogether, these species account for 329 unique geo-referenced occurrence records.
</p >
<p > ... </p >
<p >
More than 3100 species of
<tp:taxon-name >
<tp:taxon-name-part taxon-name-part-type =" class " > Chilopoda </tp:taxon-name-part >
</tp:taxon-name >
<tp:taxon-name > ... </tp:taxon-name >
(
<xref ref-type =" bibr "
rid =" B6081541 " > Edgecombe et al. 2010 </xref >
) and more than 11000 species of
<tp:taxon-name >
<tp:taxon-name-part taxon-name-part-type =" class " > Diplopoda </tp:taxon-name-part >
</tp:taxon-name >
<tp:taxon-name > ... </tp:taxon-name >
(
<xref ref-type =" bibr "
rid =" B6081554 " > Enghoff et al. 2015 </xref >
) are known in the world fauna. We reveal 20 species of millipedes for European North-East of Russia.The largest number of species is noticed in the taiga zone, where its value ranges from 1 to 10 (mean = 4, s.d. = 0.5). In tundra, it varies from 1 to 4 (mean = 1.2, s.d. = 0.1) and, in mountains, only 1-2 (mean = 1.1, s.d. = 0.1) species are encountered (Fig.
<xref ref-type =" fig "
rid =" F6081714 " > 10 </xref >
). This trend is natural as the
<italic >
<tp:taxon-name >
<tp:taxon-name-part taxon-name-part-type =" genus "
reg =" Lithobius " > Lithobius </tp:taxon-name-part >
<tp:taxon-name-part taxon-name-part-type =" species "
reg =" curtipes " > curtipes </tp:taxon-name-part >
</tp:taxon-name >
<tp:taxon-name > ... </tp:taxon-name >
</italic >
<italic > ... </italic >
is the dominant species. Altogether, these species account for 202 unique geo-referenced occurrence records.
</p >
<p > ... </p >
<p >
Staphilinids are one of the most extensive and diverse families amongst beetles with about 1500 genera and more than 60000 species known in the world fauna and at least 4000 species in Russia (
<xref ref-type =" bibr "
rid =" B6081432 " > Herman 2001 </xref >
). European North-East of Russia localities, included in the dataset, account for over 446 species of rove beetles, that is only 11% of the Staphilinids diversity of Russia. The number of species per locality ranges from 1 to 76 (mean = 13.1, s.d. = 3) in tundra, from 1-140 (mean = 23.6, s.d. = 4.3) in taiga and from 2 to 58 (mean = 26.4, s.d. = 5.3) in mountains (Fig.
<xref ref-type =" fig "
rid =" F6081718 " > 11 </xref >
). In tundra landscapes, the cold-resistant
<tp:taxon-name >
<tp:taxon-name-part taxon-name-part-type =" subfamily " > Omaliinae </tp:taxon-name-part >
</tp:taxon-name >
<tp:taxon-name > ... </tp:taxon-name >
and
<tp:taxon-name >
<tp:taxon-name-part taxon-name-part-type =" subfamily " > Aleocharinae </tp:taxon-name-part >
</tp:taxon-name >
<tp:taxon-name > ... </tp:taxon-name >
prevail. The slight excess of the average species richness in the Urals mountains compared to the taiga zone is explained by the high-altitude zone of the mountains, where species of boreal and arctic fauna inhabiting the mountain-forest and mountain-tundra belts, as well as the Ural-Siberian species, such as
<italic >
<tp:taxon-name >
<tp:taxon-name-part taxon-name-part-type =" genus "
reg =" Tachinus " > Tachinus </tp:taxon-name-part >
<tp:taxon-name-part taxon-name-part-type =" species "
reg =" bicuspidatus " > bicuspidatus </tp:taxon-name-part >
</tp:taxon-name >
<tp:taxon-name > ... </tp:taxon-name >
</italic >
<italic > ... </italic >
, are registered. Altogether, these species account for 1829 unique geo-referenced occurrence records.
</p >
<p > ... </p >
<p >
The world fauna of click beetles includes more than 10000 species (
<xref ref-type =" bibr "
rid =" B6081472 " > Costa et al. 2010 </xref >
). Amongst them, only 350 species are known for Russia (
<xref ref-type =" bibr "
rid =" B6081568 " > Prosvirov 2013 </xref >
). Our data include 60 species, i.e. more than 17% of their diversity of Russia.
<tp:taxon-name >
<tp:taxon-name-part taxon-name-part-type =" family " > Elateridae </tp:taxon-name-part >
</tp:taxon-name >
<tp:taxon-name > ... </tp:taxon-name >
are also better studied in the taiga zone, where the species richness ranges from 1 to 39 species (mean = 9.5, s.d. = 1.6). In the tundra ecosystems, the number of species is minimal and varies from 1 to 14 species (mean = 3.1, s.d. = 0.9). The fauna is presented by small representatives of the genera
<tp:taxon-name >
<tp:taxon-name-part taxon-name-part-type =" genus "
reg =" Hypnoidus " > Hypnoidus </tp:taxon-name-part >
</tp:taxon-name >
<tp:taxon-name > ... </tp:taxon-name >
and Oedostethus. Actually, only one species
<italic >
<tp:taxon-name >
<tp:taxon-name-part taxon-name-part-type =" genus "
reg =" Hypnoidus " > Hypnoidus </tp:taxon-name-part >
<tp:taxon-name-part taxon-name-part-type =" species "
reg =" rivularis " > rivularis </tp:taxon-name-part >
</tp:taxon-name >
<tp:taxon-name > ... </tp:taxon-name >
</italic >
<italic > ... </italic >
is constantly found. It is numerous and inhabits a wide variety of types of tundra: shrubs, grains, moss-lichen and willow (
<xref ref-type =" bibr "
rid =" B6081577 " > Medvedev 2005 </xref >
). The average number of species in the Urals is slightly higher than in the taiga, due to inhabitants of mountain ecosystems, such as
<italic >
<tp:taxon-name >
<tp:taxon-name-part taxon-name-part-type =" genus "
reg =" Selatosomus " > Selatosomus </tp:taxon-name-part >
<tp:taxon-name-part taxon-name-part-type =" species "
reg =" gloriosus " > gloriosus </tp:taxon-name-part >
</tp:taxon-name >
<tp:taxon-name > ... </tp:taxon-name >
</italic >
<italic > ... </italic >
(Fig.
<xref ref-type =" fig "
rid =" F6081722 " > 12 </xref >
). Altogether, these species account for 727 unique geo-referenced occurrence records.
</p >
<p > ... </p >
</sec >
<sec sec-type =" Description " > ... </sec >
<sec sec-type =" Taxa included " >
<title > Taxa included </title >
<table-wrap id =" taxonomic_coverage "
position =" anchor " orientation =" portrait " >
<table rules =" all " >
<thead >
<tr >
<th rowspan =" 1 " colspan =" 1 " > Rank </th >
<th rowspan =" 1 " colspan =" 1 " > Scientific Name </th >
<th rowspan =" 1 " colspan =" 1 " />
</tr >
<tr > ... </tr >
</thead >
<thead > ... </thead >
<tbody >
<tr >
<td rowspan =" 1 "
colspan =" 1 " > phylum </td >
<td rowspan =" 1 " colspan =" 1 " >
<tp:taxon-name >
<tp:taxon-name-part taxon-name-part-type =" phylum " > Annelida </tp:taxon-name-part >
</tp:taxon-name >
<tp:taxon-name > ... </tp:taxon-name >
</td >
<td rowspan =" 1 " colspan =" 1 " > ... </td >
<td rowspan =" 1 " colspan =" 1 " />
</tr >
<tr > ... </tr >
<tr >
<td rowspan =" 1 " colspan =" 1 " > class </td >
<td rowspan =" 1 " colspan =" 1 " >
<tp:taxon-name >
<tp:taxon-name-part taxon-name-part-type =" class " > Clitellata </tp:taxon-name-part >
</tp:taxon-name >
<tp:taxon-name > ... </tp:taxon-name >
</td >
<td rowspan =" 1 " colspan =" 1 " > ... </td >
<td rowspan =" 1 " colspan =" 1 " />
</tr >
<tr > ... </tr >
<tr >
<td rowspan =" 1 " colspan =" 1 " > order </td >
<td rowspan =" 1 " colspan =" 1 " >
<tp:taxon-name >
<tp:taxon-name-part taxon-name-part-type =" suborder " > Crassiclitellata </tp:taxon-name-part >
</tp:taxon-name >
<tp:taxon-name > ... </tp:taxon-name >
</td >
<td rowspan =" 1 " colspan =" 1 " > ... </td >
<td rowspan =" 1 " colspan =" 1 " />
</tr >
<tr > ... </tr >
<tr >
<td rowspan =" 1 "
colspan =" 1 " > family </td >
<td rowspan =" 1 " colspan =" 1 " >
<tp:taxon-name >
<tp:taxon-name-part taxon-name-part-type =" family " > Lumbricidae </tp:taxon-name-part >
</tp:taxon-name >
<tp:taxon-name > ... </tp:taxon-name >
</td >
<td rowspan =" 1 " colspan =" 1 " > ... </td >
<td rowspan =" 1 " colspan =" 1 " />
</tr >
<tr > ... </tr >
<tr >
<td rowspan =" 1 "
colspan =" 1 " > phylum </td >
<td rowspan =" 1 " colspan =" 1 " >
<tp:taxon-name >
<tp:taxon-name-part taxon-name-part-type =" phylum " > Arthropoda </tp:taxon-name-part >
</tp:taxon-name >
<tp:taxon-name > ... </tp:taxon-name >
</td >
<td rowspan =" 1 " colspan =" 1 " > ... </td >
<td rowspan =" 1 " colspan =" 1 " />
</tr >
<tr > ... </tr >
<tr >
<td rowspan =" 1 " colspan =" 1 " > class </td >
<td rowspan =" 1 " colspan =" 1 " >
<tp:taxon-name >
<tp:taxon-name-part taxon-name-part-type =" class " > Chilopoda </tp:taxon-name-part >
</tp:taxon-name >
<tp:taxon-name > ... </tp:taxon-name >
</td >
<td rowspan =" 1 " colspan =" 1 " > ... </td >
<td rowspan =" 1 " colspan =" 1 " />
</tr >
<tr > ... </tr >
<tr >
<td rowspan =" 1 " colspan =" 1 " > class </td >
<td rowspan =" 1 " colspan =" 1 " >
<tp:taxon-name >
<tp:taxon-name-part taxon-name-part-type =" class " > Diplopoda </tp:taxon-name-part >
</tp:taxon-name >
<tp:taxon-name > ... </tp:taxon-name >
</td >
<td rowspan =" 1 " colspan =" 1 " > ... </td >
<td rowspan =" 1 " colspan =" 1 " />
</tr >
<tr > ... </tr >
<tr >
<td rowspan =" 1 " colspan =" 1 " > order </td >
<td rowspan =" 1 " colspan =" 1 " >
<tp:taxon-name >
<tp:taxon-name-part taxon-name-part-type =" order " > Collembola </tp:taxon-name-part >
</tp:taxon-name >
<tp:taxon-name > ... </tp:taxon-name >
</td >
<td rowspan =" 1 " colspan =" 1 " > ... </td >
<td rowspan =" 1 " colspan =" 1 " />
</tr >
<tr > ... </tr >
<tr >
<td rowspan =" 1 " colspan =" 1 " > order </td >
<td rowspan =" 1 " colspan =" 1 " >
<tp:taxon-name >
<tp:taxon-name-part taxon-name-part-type =" order " > Coleoptera </tp:taxon-name-part >
</tp:taxon-name >
<tp:taxon-name > ... </tp:taxon-name >
</td >
<td rowspan =" 1 " colspan =" 1 " > ... </td >
<td rowspan =" 1 " colspan =" 1 " />
</tr >
<tr > ... </tr >
<tr >
<td rowspan =" 1 "
colspan =" 1 " > family </td >
<td rowspan =" 1 " colspan =" 1 " >
<tp:taxon-name >
<tp:taxon-name-part taxon-name-part-type =" family " > Staphylinidae </tp:taxon-name-part >
</tp:taxon-name >
<tp:taxon-name > ... </tp:taxon-name >
</td >
<td rowspan =" 1 " colspan =" 1 " > ... </td >
<td rowspan =" 1 " colspan =" 1 " />
</tr >
<tr > ... </tr >
<tr >
<td rowspan =" 1 "
colspan =" 1 " > family </td >
<td rowspan =" 1 " colspan =" 1 " >
<tp:taxon-name >
<tp:taxon-name-part taxon-name-part-type =" family " > Elateridae </tp:taxon-name-part >
</tp:taxon-name >
<tp:taxon-name > ... </tp:taxon-name >
</td >
<td rowspan =" 1 " colspan =" 1 " > ... </td >
<td rowspan =" 1 " colspan =" 1 " />
</tr >
<tr > ... </tr >
</tbody >
<tbody > ... </tbody >
</table >
<table rules =" all " > ... </table >
</table-wrap >
<table-wrap id =" taxonomic_coverage " position =" anchor " orientation =" portrait " > ... </table-wrap >
</sec >
<sec sec-type =" Taxa included " > ... </sec >
</sec >
<sec sec-type =" Taxonomic coverage " > ... </sec >
<sec sec-type =" Temporal coverage " >
<title > Temporal coverage </title >
<sec sec-type =" Notes " >
<title > Notes </title >
<p >
Data sources provided the dates when the species was detected for the first time in a given region of the 5412 records included in the dataset. The earliest first record dates back to 1905 and the most recent event occurred in 2019.
</p >
<p > ... </p >
</sec >
<sec sec-type =" Notes " > ... </sec >
</sec >
<sec sec-type =" Temporal coverage " > ... </sec >
<sec sec-type =" Collection data " >
<title > Collection data </title >
<sec sec-type =" Collection name " >
<title > Collection name </title >
<p >
Soil invertebrates occurrences in European North-East of Russia
</p >
<p > ... </p >
</sec >
<sec sec-type =" Collection name " > ... </sec >
<sec sec-type =" Specimen preservation method " >
<title > Specimen preservation method </title >
<p > alcohol, formalin, dried </p >
</sec >
<sec sec-type =" Specimen preservation method " > ... </sec >
</sec >
<sec sec-type =" Collection data " > ... </sec >
<sec sec-type =" Usage licence " >
<title > Usage licence </title >
<sec sec-type =" Usage licence " >
<title > Usage licence </title >
<p > Other </p >
</sec >
<sec sec-type =" Usage licence " > ... </sec >
<sec sec-type =" IP rights notes " >
<title > IP rights notes </title >
<p >
This work is licensed under a Creative Commons Attribution Non Commercial (CC-BY-NC) 4.0 Licence.
</p >
<p > ... </p >
</sec >
<sec sec-type =" IP rights notes " > ... </sec >
</sec >
<sec sec-type =" Usage licence " > ... </sec >
<sec sec-type =" Data resources " >
<title > Data resources </title >
<sec sec-type =" Data package title " >
<title > Data package title </title >
<p >
Soil invertebrates occurrences in European North-East of Russia
</p >
<p > ... </p >
</sec >
<sec sec-type =" Data package title " > ... </sec >
<sec sec-type =" Resource link " >
<title > Resource link </title >
<p >
<ext-link ext-link-type =" uri "
xlink:href =" http://ib.komisc.ru:8088/ipt/resource?r=inv " > http://ib.komisc.ru:8088/ipt/resource?r=inv </ext-link >
</p >
<p > ... </p >
</sec >
<sec sec-type =" Resource link " > ... </sec >
<sec sec-type =" Alternative identifiers " >
<title > Alternative identifiers </title >
<p >
<ext-link ext-link-type =" uri "
xlink:href =" https://www.gbif.org/dataset/a3f7d0d8-d9e1-42ae-b1f7-d1fc445b931d " >
https://www.gbif.org/dataset/a3f7d0d8-d9e1-42ae-b1f7-d1fc445b931d
</ext-link >
<ext-link ext-link-type =" uri " xlink:href =" https://www.gbif.org/dataset/a3f7d0d8-d9e1-42ae-b1f7-d1fc445b931d " > ... </ext-link >
;
<ext-link ext-link-type =" uri "
xlink:href =" https://doi.org/10.15468/5a8ydf " > https://doi.org/10.15468/5a8ydf </ext-link >
</p >
<p > ... </p >
</sec >
<sec sec-type =" Alternative identifiers " > ... </sec >
<sec sec-type =" Number of data sets " >
<title > Number of data sets </title >
<p > 1 </p >
</sec >
<sec sec-type =" Number of data sets " > ... </sec >
<sec sec-type =" Data set 1 " >
<title > Data set 1. </title >
<sec sec-type =" Data set name " >
<title > Data set name </title >
<p >
Soil invertebrates occurrences in European North-East of Russia
</p >
<p > ... </p >
</sec >
<sec sec-type =" Data set name " > ... </sec >
<sec sec-type =" Data format " >
<title > Data format </title >
<p > Darwin Core </p >
</sec >
<sec sec-type =" Data format " > ... </sec >
<sec sec-type =" Download URL " >
<title > Download URL </title >
<p >
<ext-link ext-link-type =" uri "
xlink:href =" http://ib.komisc.ru:8088/ipt/resource?r=inv " > http://ib.komisc.ru:8088/ipt/resource?r=inv </ext-link >
</p >
<p > ... </p >
</sec >
<sec sec-type =" Download URL " > ... </sec >
<sec sec-type =" Description " >
<title > Description </title >
<p >
The current project surveys 13 species of earthworms, 20 species of millipedes, 246 species of springtails, 446 species of rove beetles and 60 species of click beetles. A total of 5412 occurrences are included in the resource (
<xref ref-type =" bibr "
rid =" B6092883 " > Konakova et al. 2020 </xref >
). The earliest first record dates back to 1905 and the most recent event occurred in 2019.
</p >
<p > ... </p >
<table-wrap id =" DS1 "
orientation =" portrait "
position =" anchor " >
<label > Data set 1. </label >
<table rules =" all " >
<thead >
<tr >
<th rowspan =" 1 " colspan =" 1 " > Column label </th >
<th rowspan =" 1 " colspan =" 1 " > Column description </th >
</tr >
<tr > ... </tr >
</thead >
<thead > ... </thead >
<tbody >
<tr >
<td rowspan =" 1 "
colspan =" 1 " > occurrenceID </td >
<td rowspan =" 1 " colspan =" 1 " >
An identifier for the Occurrence (as opposed to a particular digital record of theoccurrence).
</td >
<td rowspan =" 1 " colspan =" 1 " > ... </td >
</tr >
<tr > ... </tr >
<tr >
<td rowspan =" 1 "
colspan =" 1 " > recordedBy </td >
<td rowspan =" 1 " colspan =" 1 " >
A person, group or organisation responsible for recording the original Occurrence.
</td >
<td rowspan =" 1 " colspan =" 1 " > ... </td >
</tr >
<tr > ... </tr >
<tr >
<td rowspan =" 1 "
colspan =" 1 " > verbatimLocality </td >
<td rowspan =" 1 " colspan =" 1 " > Original description of the place of the find.
</td >
</tr >
<tr > ... </tr >
<tr >
<td rowspan =" 1 " colspan =" 1 " > year </td >
<td rowspan =" 1 " colspan =" 1 " >
The four-digit year in which the Event occurred, according to the Common Era Calendar.
</td >
<td rowspan =" 1 " colspan =" 1 " > ... </td >
</tr >
<tr > ... </tr >
<tr >
<td rowspan =" 1 "
colspan =" 1 " > decimalLongitude </td >
<td rowspan =" 1 " colspan =" 1 " >
The geographic longitude (in decimal degrees, using the spatial reference system given in geodeticDatum) of the geographic centre of a Location.
</td >
<td rowspan =" 1 " colspan =" 1 " > ... </td >
</tr >
<tr > ... </tr >
<tr >
<td rowspan =" 1 "
colspan =" 1 " > decimalLatitude </td >
<td rowspan =" 1 " colspan =" 1 " >
The geographic latitude (in decimal degrees, using the spatial reference system given in geodeticDatum) of the geographic centre of a Location.
</td >
<td rowspan =" 1 " colspan =" 1 " > ... </td >
</tr >
<tr > ... </tr >
<tr >
<td rowspan =" 1 "
colspan =" 1 " > stateProvince </td >
<td rowspan =" 1 " colspan =" 1 " >
Administrative-territorial unit of the country (oblast, okrug or republic)
</td >
<td rowspan =" 1 " colspan =" 1 " > ... </td >
</tr >
<tr > ... </tr >
<tr >
<td rowspan =" 1 "
colspan =" 1 " > county </td >
<td rowspan =" 1 " colspan =" 1 " >
The name of the country or major administrative unit in which the Location occurs.
</td >
<td rowspan =" 1 " colspan =" 1 " > ... </td >
</tr >
<tr > ... </tr >
<tr >
<td rowspan =" 1 "
colspan =" 1 " > associatedReferences </td >
<td rowspan =" 1 " colspan =" 1 " >
A list (concatenated and separated) of identifiers (publication, bibliographic reference, global unique identifier, URI) of literature associated with the Occurrence.
</td >
<td rowspan =" 1 " colspan =" 1 " > ... </td >
</tr >
<tr > ... </tr >
<tr >
<td rowspan =" 1 "
colspan =" 1 " > basisOfRecord </td >
<td rowspan =" 1 " colspan =" 1 " >
Recommended best practice is to use the standard label of one of the Darwin Core classes.
</td >
<td rowspan =" 1 " colspan =" 1 " > ... </td >
</tr >
<tr > ... </tr >
<tr >
<td rowspan =" 1 "
colspan =" 1 " > georeferencedBy </td >
<td rowspan =" 1 " colspan =" 1 " >
A list (concatenated and separated) of names of people, groups or organisations who determined the georeference (spatial representation) for the Location.
</td >
<td rowspan =" 1 " colspan =" 1 " > ... </td >
</tr >
<tr > ... </tr >
<tr >
<td rowspan =" 1 "
colspan =" 1 " > geodeticDatum </td >
<td rowspan =" 1 " colspan =" 1 " >
The ellipsoid, geodetic datum or spatial reference system (SRS) upon which the geographic coordinates given in decimalLatitude and decimalLongitude are based.
</td >
<td rowspan =" 1 " colspan =" 1 " > ... </td >
</tr >
<tr > ... </tr >
<tr >
<td rowspan =" 1 "
colspan =" 1 " > kingdom </td >
<td rowspan =" 1 " colspan =" 1 " >
The full scientific name of the kingdom in which the taxon is classified.
</td >
<td rowspan =" 1 " colspan =" 1 " > ... </td >
</tr >
<tr > ... </tr >
<tr >
<td rowspan =" 1 "
colspan =" 1 " > phylum </td >
<td rowspan =" 1 " colspan =" 1 " >
The full scientific name of the phylum in which the taxon is classified.
</td >
<td rowspan =" 1 " colspan =" 1 " > ... </td >
</tr >
<tr > ... </tr >
<tr >
<td rowspan =" 1 " colspan =" 1 " > class </td >
<td rowspan =" 1 " colspan =" 1 " >
The full scientific name of the class in which the taxon is classified.
</td >
<td rowspan =" 1 " colspan =" 1 " > ... </td >
</tr >
<tr > ... </tr >
<tr >
<td rowspan =" 1 " colspan =" 1 " > order </td >
<td rowspan =" 1 " colspan =" 1 " >
The full scientific name of the oder in which the taxon is classified.
</td >
<td rowspan =" 1 " colspan =" 1 " > ... </td >
</tr >
<tr > ... </tr >
<tr >
<td rowspan =" 1 "
colspan =" 1 " > family </td >
<td rowspan =" 1 " colspan =" 1 " >
The full scientific name of the family in which the taxon is classified.
</td >
<td rowspan =" 1 " colspan =" 1 " > ... </td >
</tr >
<tr > ... </tr >
<tr >
<td rowspan =" 1 " colspan =" 1 " > genus </td >
<td rowspan =" 1 " colspan =" 1 " >
The full scientific name of the genus in which the taxon is classified.
</td >
<td rowspan =" 1 " colspan =" 1 " > ... </td >
</tr >
<tr > ... </tr >
<tr >
<td rowspan =" 1 "
colspan =" 1 " > scientificNameAuthorship </td >
<td rowspan =" 1 " colspan =" 1 " >
The authorship information for the scientificName formatted according to the conventions of the applicable nomenclaturalCode.
</td >
<td rowspan =" 1 " colspan =" 1 " > ... </td >
</tr >
<tr > ... </tr >
<tr >
<td rowspan =" 1 "
colspan =" 1 " > scientificName </td >
<td rowspan =" 1 " colspan =" 1 " >
The full scientific name, with authorship and date information, if known. When forming part of an Identification, this should be the name in the lowest level taxonomic rank that can be determined. This term should not contain identification qualifications, which should instead be supplied in the IdentificationQualifier term.
</td >
<td rowspan =" 1 " colspan =" 1 " > ... </td >
</tr >
<tr > ... </tr >
</tbody >
<tbody > ... </tbody >
</table >
<table rules =" all " > ... </table >
</table-wrap >
<table-wrap id =" DS1 " orientation =" portrait " position =" anchor " > ... </table-wrap >
</sec >
<sec sec-type =" Description " > ... </sec >
</sec >
<sec sec-type =" Data set 1 " > ... </sec >
</sec >
<sec sec-type =" Data resources " > ... </sec >
</body >
<body > ... </body >
<back >
<ack >
<title > Acknowledgements </title >
<p >
We are grateful to Alexey Medevedev whose data on the click beetles are used and also to employees of Institute of Biology for their help in field material collecting.
</p >
<p > ... </p >
</ack >
<ack > ... </ack >
<sec sec-type =" Author contributions " >
<title > Author contributions </title >
<p >
Tatyana Konakova prepared the dataset, wrote the metadata description and manuscript
</p >
<p > ... </p >
<p >
Alla Kolesnikova identified earthworms, millipedes, rove beetles species and wrote the manuscript
</p >
<p > ... </p >
<p >
Anastasia Taskaeva identified springtail species and wrote the manuscript.
</p >
<p > ... </p >
</sec >
<sec sec-type =" Author contributions " > ... </sec >
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<surname > Beutel </surname >
<given-names > R </given-names >
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<source >
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<tp:taxon-name > ... </tp:taxon-name >
:
<tp:taxon-name >
<tp:taxon-name-part taxon-name-part-type =" class " > Insecta </tp:taxon-name-part >
</tp:taxon-name >
<tp:taxon-name > ... </tp:taxon-name >
.
<tp:taxon-name >
<tp:taxon-name-part taxon-name-part-type =" order " > Coleoptera </tp:taxon-name-part >
</tp:taxon-name >
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<tp:taxon-name >
<tp:taxon-name-part taxon-name-part-type =" superfamily " > Elateroidea </tp:taxon-name-part >
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<tp:taxon-name > ... </tp:taxon-name >
,
<tp:taxon-name >
<tp:taxon-name-part taxon-name-part-type =" infraorder " > Bostrichiformia </tp:taxon-name-part >
</tp:taxon-name >
<tp:taxon-name > ... </tp:taxon-name >
,
<tp:taxon-name >
<tp:taxon-name-part taxon-name-part-type =" infraorder " > Cucujiformia </tp:taxon-name-part >
</tp:taxon-name >
<tp:taxon-name > ... </tp:taxon-name >
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<source > ... </source >
<volume > Vol. 2 </volume >
<publisher-name > Walter de Gruyter GmbH & Co </publisher-name >
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<surname > Edgecombe </surname >
<given-names > D G </given-names >
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<name name-style =" western " > ... </name >
<name name-style =" western " >
<surname > Zapparoli </surname >
<given-names > M </given-names >
</name >
<name name-style =" western " > ... </name >
<name name-style =" western " >
<surname > Bonato </surname >
<given-names > L </given-names >
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<given-names > A </given-names >
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<tp:taxon-name-part taxon-name-part-type =" subphylum " > Myriapoda </tp:taxon-name-part >
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<given-names > H </given-names >
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<name name-style =" western " > ... </name >
<name name-style =" western " >
<surname > Golovatch </surname >
<given-names > S I </given-names >
</name >
<name name-style =" western " > ... </name >
<name name-style =" western " >
<surname > Short </surname >
<given-names > M </given-names >
</name >
<name name-style =" western " > ... </name >
<name name-style =" western " >
<surname > Stoev </surname >
<given-names > P </given-names >
</name >
<name name-style =" western " > ... </name >
<name name-style =" western " >
<surname > Wesener </surname >
<given-names > T </given-names >
</name >
<name name-style =" western " > ... </name >
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<chapter-title > Diplopoda — taxonomic overview </chapter-title >
<person-group person-group-type =" editor " >
<name name-style =" western " >
<surname > Minelli </surname >
<given-names > A </given-names >
</name >
<name name-style =" western " > ... </name >
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<person-group person-group-type =" editor " > ... </person-group >
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<tp:taxon-name >
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Collembola of Kolguev, Malozemelskaya tundra and Delta Pechora. Version 1.2. Sampling event
</article-title >
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Institute of Biology of Komi Scientific Centre of the Ural Branch of the Russian Academy of Sciences via GBIF.org
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<year > 2020 </year >
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Collembola of Padimeiskie lakes territory on the Bolshezemelskaya tundra (European North-East Russia). Version 1.1. Sampling event dataset
</article-title >
<article-title > ... </article-title >
<publisher-name >
Institute of Biology of Komi Scientific Centre of the Ural Branch of the Russian Academy of Sciences via GBIF.org
</publisher-name >
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<year > 2020 </year >
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Collembola of the Chernaya river basin. Version 1.2. Sampling event dataset
</article-title >
<article-title > ... </article-title >
<publisher-name >
Institute of Biology of Komi Scientific Centre of the Ural Branch of the Russian Academy of Sciences via GBIF.org
</publisher-name >
<publisher-name > ... </publisher-name >
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</name >
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<name name-style =" western " >
<surname > Melekhina </surname >
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</name >
<name name-style =" western " > ... </name >
</person-group >
<person-group person-group-type =" author " > ... </person-group >
<year > 2020 </year >
<article-title >
Collembola of oil polluted soils of Usinsk district (Komi Republic). Sampling event
</article-title >
<article-title > ... </article-title >
<publisher-name >
Institute of Biology of Komi Scientific Centre of the Ural Branch of the Russian Academy of Sciences via GBIF.org
</publisher-name >
<publisher-name > ... </publisher-name >
<pub-id pub-id-type =" doi " > 10.15468/dceqct </pub-id >
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<name name-style =" western " >
<surname > Vsevolodova-Perel </surname >
<given-names > T S </given-names >
</name >
<name name-style =" western " > ... </name >
</person-group >
<person-group person-group-type =" author " > ... </person-group >
<year > 1997 </year >
<source > The earthworms of the fauna of Russia. </source >
<publisher-name > Nauka </publisher-name >
<publisher-loc > Moscow </publisher-loc >
<size units =" page " > 102 </size >
<comment content-type =" language " > Russian </comment >
<isbn > 5-02-5215-9 </isbn >
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</ref >
<ref id =" B6081416 " > ... </ref >
<ref id =" B6081113 " >
<element-citation publication-type =" book " >
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<name name-style =" western " >
<surname > Wall </surname >
<given-names > Diana </given-names >
</name >
<name name-style =" western " > ... </name >
<name name-style =" western " >
<surname > Bardgett </surname >
<given-names > Richard </given-names >
</name >
<name name-style =" western " > ... </name >
<name name-style =" western " >
<surname > Behan-Pelletier </surname >
<given-names > Valerie </given-names >
</name >
<name name-style =" western " > ... </name >
<name name-style =" western " >
<surname > Herrick </surname >
<given-names > Jeffrey </given-names >
</name >
<name name-style =" western " > ... </name >
<name name-style =" western " >
<surname > Jones </surname >
<given-names > Hefin </given-names >
</name >
<name name-style =" western " > ... </name >
<name name-style =" western " >
<surname > Ritz </surname >
<given-names > Karl </given-names >
</name >
<name name-style =" western " > ... </name >
<name name-style =" western " >
<surname > Six </surname >
<given-names > Johan </given-names >
</name >
<name name-style =" western " > ... </name >
<name name-style =" western " >
<surname > Strong </surname >
<given-names > Donald </given-names >
</name >
<name name-style =" western " > ... </name >
<name name-style =" western " >
<surname > Putten </surname >
<given-names > Wim H. van der </given-names >
</name >
<name name-style =" western " > ... </name >
</person-group >
<person-group person-group-type =" author " > ... </person-group >
<year > 2012 </year >
<source > Soil ecology and ecosystem services </source >
<publisher-name > Oxford University Press </publisher-name >
<publisher-loc > Oxford </publisher-loc >
<size units =" page " > 464 </size >
<isbn > 9780199575923 </isbn >
<pub-id pub-id-type =" doi " > 10.1093/acprof:oso/9780199575923.001.0001 </pub-id >
</element-citation >
<element-citation publication-type =" book " > ... </element-citation >
</ref >
<ref id =" B6081113 " > ... </ref >
<ref id =" B6081054 " >
<element-citation publication-type =" article " >
<person-group person-group-type =" author " >
<name name-style =" western " >
<surname > Wardle </surname >
<given-names > David </given-names >
</name >
<name name-style =" western " > ... </name >
<name name-style =" western " >
<surname > Bardgett </surname >
<given-names > Richard D </given-names >
</name >
<name name-style =" western " > ... </name >
<name name-style =" western " >
<surname > Klironomos </surname >
<given-names > John N </given-names >
</name >
<name name-style =" western " > ... </name >
<name name-style =" western " >
<surname > Setälä </surname >
<given-names > Heikki </given-names >
</name >
<name name-style =" western " > ... </name >
<name name-style =" western " >
<surname > Putten </surname >
<given-names > Wim H Van Der </given-names >
</name >
<name name-style =" western " > ... </name >
<name name-style =" western " >
<surname > Wall </surname >
<given-names > Diana H </given-names >
</name >
<name name-style =" western " > ... </name >
</person-group >
<person-group person-group-type =" author " > ... </person-group >
<year > 2004 </year >
<article-title >
Ecological linkages between aboveground and belowground biota
</article-title >
<article-title > ... </article-title >
<source > Science </source >
<volume > 304 </volume >
<fpage > 1629 </fpage >
<lpage > 1633 </lpage >
<pub-id pub-id-type =" doi " > 10.1126/science.1094875 </pub-id >
</element-citation >
<element-citation publication-type =" article " > ... </element-citation >
</ref >
<ref id =" B6081054 " > ... </ref >
<ref id =" B6081485 " >
<element-citation publication-type =" article " >
<person-group person-group-type =" author " >
<name name-style =" western " >
<surname > Zhang </surname >
<given-names > B </given-names >
</name >
<name name-style =" western " > ... </name >
<name name-style =" western " >
<surname > Chen </surname >
<given-names > C </given-names >
</name >
<name name-style =" western " > ... </name >
<name name-style =" western " >
<surname > Matteos </surname >
<given-names > E </given-names >
</name >
<name name-style =" western " > ... </name >
<name name-style =" western " >
<surname > Scheu </surname >
<given-names > S </given-names >
</name >
<name name-style =" western " > ... </name >
<name name-style =" western " >
<surname > Schaefer </surname >
<given-names > I </given-names >
</name >
<name name-style =" western " > ... </name >
</person-group >
<person-group person-group-type =" author " > ... </person-group >
<year > 2018 </year >
<article-title >
Cryptic species in
<italic >
<tp:taxon-name >
<tp:taxon-name-part taxon-name-part-type =" genus "
reg =" Lepidocyrtus " > Lepidocyrtus </tp:taxon-name-part >
<tp:taxon-name-part taxon-name-part-type =" species "
reg =" lanuginosus " > lanuginosus </tp:taxon-name-part >
</tp:taxon-name >
<tp:taxon-name > ... </tp:taxon-name >
</italic >
<italic > ... </italic >
(
<tp:taxon-name >
<tp:taxon-name-part taxon-name-part-type =" order " > Collembola </tp:taxon-name-part >
</tp:taxon-name >
<tp:taxon-name > ... </tp:taxon-name >
:
<tp:taxon-name >
<tp:taxon-name-part taxon-name-part-type =" family " > Entomobryidae </tp:taxon-name-part >
</tp:taxon-name >
<tp:taxon-name > ... </tp:taxon-name >
) are sorted by habitat type
</article-title >
<article-title > ... </article-title >
<source > Pedobiologia </source >
<volume > 68 </volume >
<fpage > 12 </fpage >
<lpage > 19 </lpage >
<pub-id pub-id-type =" doi " > 10.1016/j.pedobi.2018.03.001 </pub-id >
</element-citation >
<element-citation publication-type =" article " > ... </element-citation >
</ref >
<ref id =" B6081485 " > ... </ref >
</ref-list >
<ref-list > ... </ref-list >
</back >
<back > ... </back >
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<label > Figure 1. </label >
<caption >
<p >
Sampling localities for soil invertebrates in the European North-East of Russia included in the dataset (
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xlink:href =" https://www.gbif.org/dataset/a3f7d0d8-d9e1-42ae-b1f7-d1fc445b931d " >
https://www.gbif.org/dataset/a3f7d0d8-d9e1-42ae-b1f7-d1fc445b931d
</ext-link >
<ext-link ext-link-type =" uri " xlink:href =" https://www.gbif.org/dataset/a3f7d0d8-d9e1-42ae-b1f7-d1fc445b931d " > ... </ext-link >
).
</p >
<p > ... </p >
</caption >
<caption > ... </caption >
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<label > Figure 2. </label >
<caption >
<p >
Sampling sites of
<tp:taxon-name >
<tp:taxon-name-part taxon-name-part-type =" order " > Collembola </tp:taxon-name-part >
</tp:taxon-name >
<tp:taxon-name > ... </tp:taxon-name >
in North-East Europe are included in the dataset.
</p >
<p > ... </p >
</caption >
<caption > ... </caption >
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id =" oo_447191.jpg " orientation =" portrait "
xlink:type =" simple " >
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</graphic >
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</fig >
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orientation =" portrait " >
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<label > Figure 3. </label >
<caption >
<p >
Sampling sites of
<tp:taxon-name >
<tp:taxon-name-part taxon-name-part-type =" family " > Lumbricidae </tp:taxon-name-part >
</tp:taxon-name >
<tp:taxon-name > ... </tp:taxon-name >
in North-East Europe are included in the dataset.
</p >
<p > ... </p >
</caption >
<caption > ... </caption >
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id =" oo_447193.jpg " orientation =" portrait "
xlink:type =" simple " >
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</graphic >
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</fig >
<fig id =" F6081686 " position =" float " orientation =" portrait " > ... </fig >
<fig id =" F6081690 " position =" float "
orientation =" portrait " >
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<label > Figure 4. </label >
<caption >
<p >
Sampling sites of
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<tp:taxon-name-part taxon-name-part-type =" subphylum " > Myriapoda </tp:taxon-name-part >
</tp:taxon-name >
<tp:taxon-name > ... </tp:taxon-name >
in North-East Europe are included in the dataset.
</p >
<p > ... </p >
</caption >
<caption > ... </caption >
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id =" oo_447194.jpg " orientation =" portrait "
xlink:type =" simple " >
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</graphic >
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</fig >
<fig id =" F6081690 " position =" float " orientation =" portrait " > ... </fig >
<fig id =" F6081694 " position =" float "
orientation =" portrait " >
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<label > Figure 5. </label >
<caption >
<p >
Sampling sites of
<tp:taxon-name >
<tp:taxon-name-part taxon-name-part-type =" family " > Staphylinidae </tp:taxon-name-part >
</tp:taxon-name >
<tp:taxon-name > ... </tp:taxon-name >
in North-East Europe are included in the dataset.
</p >
<p > ... </p >
</caption >
<caption > ... </caption >
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id =" oo_447202.jpg " orientation =" portrait "
xlink:type =" simple " >
<uri content-type =" original_file " > https://binary.pensoft.net/fig/447202 </uri >
</graphic >
<graphic xlink:href =" bdj-08-e58836-g005.jpg " position =" float " id =" oo_447202.jpg " orientation =" portrait " xlink:type =" simple " > ... </graphic >
</fig >
<fig id =" F6081694 " position =" float " orientation =" portrait " > ... </fig >
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orientation =" portrait " >
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<label > Figure 6. </label >
<caption >
<p >
Sampling sites of
<tp:taxon-name >
<tp:taxon-name-part taxon-name-part-type =" family " > Elateridae </tp:taxon-name-part >
</tp:taxon-name >
<tp:taxon-name > ... </tp:taxon-name >
in North-East Europe are included in the dataset.
</p >
<p > ... </p >
</caption >
<caption > ... </caption >
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id =" oo_447203.jpg " orientation =" portrait "
xlink:type =" simple " >
<uri content-type =" original_file " > https://binary.pensoft.net/fig/447203 </uri >
</graphic >
<graphic xlink:href =" bdj-08-e58836-g006.jpg " position =" float " id =" oo_447203.jpg " orientation =" portrait " xlink:type =" simple " > ... </graphic >
</fig >
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orientation =" portrait " >
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<label > Figure 7. </label >
<caption >
<p >
Number of records included in the datasets for each typology of habitat.
</p >
<p > ... </p >
</caption >
<caption > ... </caption >
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</graphic >
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<label > Figure 8. </label >
<caption >
<p >
Springtail species richness in localities of the European North-East of Russia dataset.
</p >
<p > ... </p >
</caption >
<caption > ... </caption >
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<label > Figure 9. </label >
<caption >
<p >
Earthworms species richness in localities of the European North-East of Russia dataset
</p >
<p > ... </p >
</caption >
<caption > ... </caption >
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Millipedes species richness in localities of the European North-East of Russia dataset.
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Rove beetles species richness in localities of the European North-East of Russia dataset.
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Click beetles species richness in localities of the European North-East of Russia dataset.
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India - royalties for major minerals in Haryana 2015 | Statista
The statistic shows the value of royalties for major minerals across Haryana in India for the financial years 2014 and 2015.
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Value of royalties for major minerals in Haryana, India 2014- 2015
Published byStatista Research Department,May 17, 2016
The statistic shows the value of royalties for major minerals across Haryana in India for the financial years 2014 and 2015. In the financial year 2014, the royalties for major minerals in the state amounted to around 0.8 million Indian rupees.
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Value of royalties for major minerals across Haryana in India for FY 2014 and FY 2015 (in million Indian rupees*
CharacteristicRoyalties in million Indian rupees
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India
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FY 2014 to FY 2015
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India's financial year begins in April and ends in March.
*Major minerals excludes coal, lignite and sand for stowing.
One Indian rupee is equal to 0.015 U.S. dollars and 0.014 euros (as of February 2017).
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Malay traditional houses on the stilts to facilitate ventilation and... | Download Scientific Diagram
Download scientific diagram | Malay traditional houses on the stilts to facilitate ventilation and also panels regulate the ventilation and penetration from outdoor to in door. Source: Photo taken by authors, January 2012 Negeri Sembilan, Malaysia from publication: Values in Traditional Architecture: Malay House | The characteristic of traditional architecture generates a congenial place through a sympathetic design to its cultural environment and local people. The historical precedents demonstrate how the characteristic of traditional architecture accumulates and embodied its... | Tradition, Architecture and Cultural Characteristics | ResearchGate, the professional network for scientists.
<here is a image 17822241105999c9-9700600bcc11c00b>
Malay traditional houses on the stilts to facilitate ventilation and also panels regulate the ventilation and penetration from outdoor to in door. Source: Photo taken by authors, January 2012 Negeri Sembilan, Malaysia
Source publication
Values in Traditional Architecture: Malay House
Conference Paper
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Elham Hosseini
<here is a image e776d6706f6232fd-6fd5419031b49cef> Gurupiah Mursib
<here is a image 1ac270e61f8e7f3a-3821071ca781c8de> Raja Nafida
<here is a image 0edb714d46422c80-7669b693c0324ba2> Bahram Shahedi
The characteristic of traditional architecture generates a congenial place through a sympathetic design to its cultural environment and local people. The historical precedents demonstrate how the characteristic of traditional architecture accumulates and embodied its significance of traditional values in the contemporary architecture. In the recent...
Context in source publication
Context 1
... from cultural experience, which are acceptable to the community [6]. The practical design in contemporary architecture would be proceeding through the exploration of traditional architecture with reference to underlying principles such as values, beliefs, ideologies and etc. [6]. Analysis of traditional architectural building contributes to the constitution of new development schemes in the contemporary architectural language as the set of design tools to increase the freedom of design [9]. The knowledge of traditional values is an asset to practitioners, architects, academicians, and societies. The preservation of originality through the constitution of contemporary regional architecture is a crucial to continuity of Malay traditional houses [10]. This paper focuses on the application of traditional design values in domestic architecture such as residential, home, and family, which is the most social structuralism of society concerning home, family, tradition, ritual, and custom of Malays. It seeks to explore the Malay traditional house, identifying the significant design values to be applicable in innovation of the contemporary Malaysian architecture. Given the essential of cultural stability, contemporary Malay architecture needs to recapture the meaningful design values of traditional Malay architecture such as the spirit of traditional time to generate concepts, preserving its originality to meet users’ demands . Hence, this paper intends to link the knowledge and design values of Malay traditional architecture to the contemporary Malaysian architecture as the manes of a protecting device in the traditional regionalism characters. The questions which posed by this study are; why the Malay traditional architecture is an applicable innovator to the regional Malaysian contemporary architecture and how does it reinterpret to enhance the contemporary Malaysian architectures? The assessment of study achieved through qualitative evidence. The majority of data collected through textual documents and direct field observation where the participant experiencing the phenomenon. The central position of collective notion and shape relies on the concept of traditional architecture, which holding the central position, describing the metaphorical, symbolic and abstract way of approach to originality of architecture. The harmonious life of people’s beliefs, cultural practices, and their lifestyle in Malay traditional houses are in associated with essential part of the Malay culture [1]. The creation of physical and spatial characteristics of traditional buildings is influenced by the needs and customs of purity in the Malays [10]. Furthermore, there is a belief in moral and religious implications in the philosophy of the traditional Malay architecture [11]. Adaptation of the Malay traditional house with the culture, lifestyle, social, and economic needs of Malays, creates a good housing quality, fitting to its built environment [1]. The significant consistency of traditional Malay architecture is demonstrated by the repetitive of elements. The indication of elements depicts the operation of ordering principle in the form of buildings. Additionally, several interrelated systems of these ordering principles constitute a device in traditional Malay houses [11]. The physical characteristics of the form of traditional Malay houses observed and explore through common features of these buildings. These primary visual characteristics are created due to rules or system of orders [10]. Floor, wall, and roof are three basic main elements in manifestation of traditional Malay houses, which have been the most primary considerable elements through the majority of the researches on the traditional Malay architecture [12]. The elevated houses above the ground and various changing of level in different regions are one of the common features and prominent visual character of Malay traditional house [10]. The various types and styles of Malay traditional houses are classified based on the form of roofs and in some cases these variations were defined by the number of columns [1]. The different geometries of the roof shape in the traditional Malay houses are significant in relation to the tropical climate. The variations in typology of Malay traditional houses are as a reaction to the tropical climate of the regions. In addition, they gave an account on constructing the floor of the Malay traditional houses on the stilts to overcome the dampness of underneath ground, flood, and also for facilitating ventilation. Besides, the construction of the high sloped roofs as a convenience device for users against hot and humid weather through penetrable space under the roof overhang as well as protecting from seasonal rain falls [13]. In addition to facilitating ventilation, the carving ornaments of panels regulate the ventilation and penetration of the sun ray through fenestrations of the external vertical plane rather than its visual interest [1],Fig. 2. The cultural and traditional way of life in Malaysia has influence on the physical, Spatial, and functional elements of the houses. These three essential categories of elements subsequently are being constituted by the structural and visual characteristics, spatial organization, and daily activities of users, which have direct influence to the definition of space planning due to meet all functional requirements [3]. Culture is as an essential factor of operation and molding the form of Malay traditional house. The form of Malay traditional house generally constructed by the juxtaposition of solid as wood columns and void consist of various openings such as widows. These opening linings of the wall panels have emerged from the way of life and culture of users [1]. The commonalities of Physical characteristics in Malay traditional houses are acting as existing indicators of the architectural values and phenomena. These values reveal through common patterns, which applicable to the determination of form in Malay traditional house. Additionally, constitutions of spaces in Malay traditional house associated in a firm relation with the human activities, constraints, and space occupation such as utensils and furnishing [10]. The spatial organization of Malay traditional house provided convenience for occupants by consideration towards cultural aspects, daily needs, and activities of ordinary people [14]. The penetrable internal spaces of Malay traditional house express the influence of culture in the planning of layout. These cultural beliefs are in connection with creating a firm relation in family, elderly respectfulness, and definition of women’s position in the house [14]. These multipurpose spaces are in different level and volume with minimum dividing partitions. This hierarchical order is based on the value of spaces [15]. The spatial characteristic of Malay traditional house involved with the occupation of three- dimensional characters of mass, surface, and volume as physical, structural, and invisible attributes [10]. The Malay traditional house is as a flexible guideline and solution, which are applicable in current housing design. In addition, the physical attributes of Malay traditional architecture leads to determination of the underlying principle, which embedded in regulations of its built construction. The integration of these principles has influence in the form of Malay traditional house. Despite regional variations of forms in Malay traditional house, they have three common basic space layouts, Kitchen (Dapur), Private living space (Rumah Ibu) and male reception area (Serambi) [10], Fig. 3. All these three basic spaces have the property of additivity, subtractive, and translocation based on their grid structure. The systems of gridding in most of the Malay traditional houses are irregular based on asymmetrical layouts [10]. The variation and flexibility of the Malay traditional house is in a prefabricated system of construction, which is suited to the needs of users [1]. Traditional houses are the most fundamental architectural phenomenon, performing as humanistic, folklore, and cultural instrumentation in which adopted for the daily needs of society’s demand [14]. Traditional houses are homogeneous and contextual to their built environment. Moreover, traditional houses are the simple and clear constructional heritage, which resulted from sympathy and cooperation of users, construction, and other artifacts through generations [16], Fig.4. In a survey of examining the traditional houses Langhein [9] concluded, that the design aesthetic quality of traditional architecture was based on inherent needs of people for creating an endurable place, adapted to its environmental conditions. The forms of traditional houses influence by cultural aspects and environmental factors. Design process of traditional houses fulfils the most characteristics requirements of society such as preservation toward adjustment of an identical form of dwelling [10]. This identical form as a variable has been capable of modification due to specific demands of families and conditions of built environment (site, climate ...) [2]. Hence, cultural and traditional society’s characters must be transmitted to future generations as the mean of preserving cultural roots [3]. The significance of theoretical evidence in different manner by scholars supports the concepts of traditional architecture and their related features. Theoretically, the numerous concepts and theories have been researched to characterize the relationship between architecture and society [17]. The principle of regionalism theory has been offered to signify the importance of precedent (past) to contemporary (present) in characteristics and cultural context of architectural background [18]. The viewpoint of regionalism as theoretical approach toward issues is considering the actual conditions of life as a mean of manifesting the culture in the regional ...
Many theories have shaped the concept of morality and its development by anchoring it in the realm of the social systems and values of each culture. This review discusses the current formulation of moral theories that attempt to explain cultural factors affecting moral judgment and reasoning. It aims to survey key criticisms that emerged in the pas...
Citations
... Traditional buildings are homogeneous and contextual to their built environment. They are embedded in people's vernacular roots, identity, order, principles, and sustainability
(Hosseini et al. 2012)
... The design of traditional architecture is modernized and altered into more complex and turned into exclusive forms such as the changes in the techniques of making them and its uses (Kamaruddin, 2015).
Hosseini et al. (2012)
stated that the creation and changes of physical and spatial characteristics of traditional Malay house is influenced by the needs and customs of purity among Malays. As example, the traditional Malay houses in Kampung Morten, Malacca are affected by deterioration even has gazetted as heritage village where it is considered as a conservation zone and protected area. ...
... Furthermore, there are many researchers have researched the sustainability value attached on vernacular architecture. Those researchers had proved that vernacular architecture meets the requirements to be categorized as a sustainable building [4] [10] [11]
[15]
. Meanwhile, related to the concept of sustainability in the mosques, some researches had been done by Adi and Puspitasari, and Imriyanti [4] [7]. ...
... To ensure its continuity, the contemporary mosques can adapt some values of Masjid Tuha, Indrapuri especially the sustainable and cultural values; the physical and unphysical. It can be done by replication, critical or interpretive approach
[15]
. The replication approach is limited to constructing and imitate the same form of the vernacular building; the analytical method is adjusting the vernacular architecture to the Integrated management for waste water treatment n/a current need, and interpretive approach is involving the concept of development on the vernacular building to meet the qualification of modern lifestyle [15]. ...
| https://www.researchgate.net/figure/Malay-traditional-houses-on-the-stilts-to-facilitate-ventilation-and-also-panels-regulate_fig2_263580464 |
HR0663 99TH GENERAL ASSEMBLY
HR0663 LRB099 13252 GRL 37159 r 1 HOUSE RESOLUTION 2 WHEREAS, The members of the Illinois House of 3 Representatives wish to congratulate the owners of the Chicago 4 Defender on the occasion of the newspaper's 110th anniversary 5 in 2015; and 6 WHEREAS, The Chicago Defender is a Chicago-based weekly 7 newspaper that was founded in 1905 by Robert S. Abbott for 8 primarily African American readers; the Chicago Defender has 9 attracted the writing talents of many famous writers, including 10 Langston Hughes, Gwendolyn Brooks, and Willard Motley; and 11 WHEREAS, Robert Sengstacke Abbott, editor and founder of 12 the Chicago Defender, played a major role in influencing the 13 Great Migration of African Americans from the rural South to 14 the urban North by means of strong, moralistic rhetoric in his 15 newspaper's editorials and political cartoons, the promotion 16 of Chicago as a destination, and the advertisement of 17 successful African American individuals as inspiration for 18 blacks in the South; the Defender consistently published 19 articles describing lynchings in the south with vivid 20 descriptions and unrestrained blame of the mobs of whites 21 typically involved, forcing readers to accept that these crimes 22 were "systematic and unremitting"; the art in the Defender, 23 particularly its political cartoons, explicitly addressed race
HR0663 - 2 - LRB099 13252 GRL 37159 r 1 issues and advocated northern migration of African Americans; 2 the Defender was also used to initiate and advertise a "Great 3 Northern Drive" day, set for May 15, 1917; and 4 WHEREAS, In 1923, Robert Sengstacke Abbott and editor 5 Lucius Harper created the Bud Billiken Club and later organized 6 parades to promote healthy activity among black children in 7 Chicago; in 1929, the organization began the Bud Billiken 8 Parade and Picnic, which is still held annually in Chicago; in 9 the 1950s, under Sengstacke's direction, the Bud Billiken 10 Parade expanded and emerged as the largest single event in 11 Chicago; today, the event attracts more than one million 12 attendees and more than 25 million television viewers, making 13 it one of the largest parades in the country; and 14 WHEREAS, Robert Sengstacke Abbott's nephew, John H. 15 Sengstacke, took over the Defender in 1940; in 1948, he 16 encouraged President Harry S. Truman to integrate the armed 17 services, which President Truman did soon after; he also served 18 as a member of Truman's appointed committee to assure that the 19 military implemented this plan; and 20 WHEREAS, John Sengstacke brought together for the first 21 time major black newspaper publishers and created the National 22 Negro Publishers Association, later renamed the National 23 Newspaper Publishers Association; today, the Association
HR0663 - 3 - LRB099 13252 GRL 37159 r 1 consists of over 200 member black newspapers; and 2 WHEREAS, Under John Sengstacke's leadership, the Defender 3 became a daily newspaper on February 6, 1956 and changed its 4 name to the Chicago Daily Defender, becoming the nation's 5 second black daily newspaper; it published as a daily until 6 2003; and 7 WHEREAS, In January of 2003, control of the Chicago 8 Defender and her sister publications was transferred to Real 9 Times, Inc., which was organized and led by Thom Picou and 10 Robert (Bobby) Sengstacke, John H. Sengstacke's son; today, the 11 paper continues to serve as a world-class source of local, 12 State, and national news; therefore, be it 13 RESOLVED, BY THE HOUSE OF REPRESENTATIVES OF THE 14 NINETY-NINTH GENERAL ASSEMBLY OF THE STATE OF ILLINOIS, that we 15 congratulate the owners of the Chicago Defender on the occasion 16 of the newspaper's 110th anniversary and wish them continued 17 success and happiness in the future; and be it further 18 RESOLVED, That a suitable copy of this resolution be 19 presented to the Chicago Defender as a symbol of our esteem and 20 respect.
| https://www.ilga.gov/ftp/legislation/99/HR/09900HR0663.htm |
Supreme Court Declines to Clarify the Abstract-Idea Exception to Patentability in Interactive Wearables and Tropp - Lexology
The Supreme Court in Interactive Wearables LLC v. Polar Electro Oy and Tropp, David A. V. Travel Sentry, Inc., et al. Declined to hear a pair of…
Supreme Court Declines to Clarify the Abstract-Idea Exception to Patentability in Interactive Wearables and Tropp
The Supreme Court in Interactive Wearables LLC v. Polar Electro Oyand Tropp, David A. v. Travel Sentry, Inc., et al.declined to hear a pair of cases that could have clarified the abstract-idea exception to patent eligibility. No. 21-1281, 2023 WL 3440746, at *1 (U.S. May 15, 2023); No. 22-22, 2023 WL 3440747 (U.S. May 15, 2023). No opinion was issued, but the Court noted that Justice Kavanaugh would have heard the cases. This marks almost nine years since the Supreme Court last addressed the abstract-idea exception and articulated its current two‑step framework to 35 U.S.C. § 101 in Alice Corp Pty. Ltd.v. CLS Bank Int’l, 573 U.S. 208 (2014).
In both Interactiveand Tropp, the district court found the asserted claims directed to ineligible abstract ideas. The Eastern District of New York dismissed Interactive’s claims related to a “wearable content player” providing information related to media content during a broadcast. 501 F. Supp. 3d 162, 167 (E.D.N.Y. 2020). The claims recited a wearable content player including a receiver, processor, memory, and display, which was controlled by another remote control device to “provide to the user . . . information associated with the content.” Id.The district court found the claims were directed to the abstract idea of “providing information in conjunction with media content.” Id.at 174. The claims also lacked inventive concept, according to the district court, because they merely “invoke[d] conventional and generic components arranged in a conventional manner.” Id.at 179. On appeal, the Federal Circuit summarily affirmed the district court’s dismissal. Interactive Wearables, LLC v. Polar Electro Oy, No. 2021-1491, 2021 WL 4783803, at *1 (Fed. Cir. Oct. 14, 2021) (citing Fed. Cir. R. 36).
In Tropp, the Eastern District of New York granted summary judgment on claims relating to a “dual‑access lock” for airline luggage, which permitted controlled access by airport personnel using a master key. 527 F. Supp. 3d 256, 260 (E.D.N.Y. 2021). The district court found the underlying concept of a dual‑access key “as old as the forgotten high school locker key,” id., and held the claims directed to “the application of dual-access locks to airport luggage inspection,” id.at 265. Critically, the representative claim recited “making available” a dual-access lock applied to a piece of airline luggage, “marketing the special lock to the consumers,” and an “identification structure” signaling an agreement to subject the luggage to screening. Id.at 261. The claim further recited “the luggage screening entity acting . . . to use the master key previously provided to the luggage screening entity to, if necessary, open the individual piece of luggage.” Id.According to the district court, this was “a long-standing fundamental economic practice and method of organizing human activity.” Id.at 265. The district court found a lack of inventive concept because the claimed dual-lock lock was “a well-understood and conventional device” only incorporated into the existing practice of baggage inspection at airports. Id.at 269. On appeal, the Federal Circuit issued a per curiam opinion affirming the district court. Travel Sentry, Inc. v. Tropp, No. 2021-1908, 2022 WL 443202, at *2 (Fed. Cir. Feb. 14, 2022).
Plaintiffs in both proceedings filed petitions for a writ of certiorari to the Supreme Court, and in both cases the Solicitor General was invited to file a brief expressing the views of the United States. As amicus curiae, the Solicitor urged the Supreme Court to grant both petitions to “clarify the proper reach and application of the abstract‑idea exception to patent eligibility under Section 101.” Brief amicus curiae of United States, Nos. 21-1281, 22-22 at 10 (U.S. Apr. 5, 2023) (“Solicitor’s Brief”). The Solicitor noted that, since the Supreme Court’s last decision in Alice, “the Federal Circuit has [been] repeatedly divided in recent years over the content of the abstract-idea exception and the proper application of the two-step methodology under Section 101.” Id.at 11. The Solicitor argued that taking up the cases would allow the Court to “illustrate the types of claimed inventions that fall both within and without the scope of the abstract-idea exception.” Id.
On the merits, the Solicitor argued that Troppwas correctly decided but Interactivewas not. The Solicitor first distinguished the cases by subject matter: The claims in Tropprecited “a ‘process’ for coordinating one aspect of airport luggage inspection,” id.at 12 (quoting Bilski v. Kappos, 561 U.S. 593, 606-07 (2010)), while the claims in Interactiverecited “a ‘machine’—a ‘tangible system’—in the form of a wearable content player and wireless remote-control device,” id.(quoting Alice, 573 U.S. at 224). According to the Solicitor, Interactive’s claims fall within patent law’s “traditional coverage of technological and industrial arts,” including “electronic hardware components that together compose a mechanical device.” Id.at 14. The district court’s articulation of the invention as an abstract idea was nothing more than a “function of the described machine.” Id.at 15 (“The district court’s characterization is akin to saying that a patent for a television is directed to the ‘abstract idea’ of displaying images and sounds.”). For Tropp’s claims, the Solicitor urged the Supreme Court to affirm the district court’s holding that the claims were directed to methods of organizing human activity and not a physical device, such as a lock. Id.at 15. Tropp’s claims recited a process that could also “be conceptualized as a method for ‘marketing’ a lock to consumers on the promise that the TSA is less likely to break it.” Id.at 16.
In arguing for these outcomes, the Solicitor asked the Supreme Court to provide “much-needed clarification” around the abstract idea eligibility test. Id.at 11. The Solicitor urged the Supreme Court to focus 35 U.S.C. § 101 on the “traditional bailiwick of the scientific, technological, and industrial arts,” and carve out technological innovations from the abstract ideas that capture “fundamental building blocks of technological innovations and innovations in non-technological fields.” Id.at 12. For example, the Solicitor distinguished “[s]trategies for achieving non-technological aims, such as improved techniques for ordering economic relationships,” which the Solicitor argued are abstract ideas, from improvements in computer technology, which the Solicitor argued are not. Id.at 13. The Solicitor also identified bright-line examples of non-abstract concepts: “[a]n automobile is not an abstract idea. A remote control is not an abstract idea. A camera is not an abstract idea. Generally speaking, technologies and industrial processes are not abstract ideas.” Id.at 14.
In addition, the Solicitor urged the Supreme Court to decouple the eligibility inquiry from other statutory requirements, such as novelty, obviousness, and written description. Id.at 16-18. The district court’s analysis in Troppwas flawed, according to the Solicitor, for conflating these issues. Id.“[A]pplying modified versions of other doctrines in the guise of a Section 101 analysis unmoors those doctrines from the statutory text and diminishes their analytical rigor.” Id.18. Section 101 and the abstract-idea exception, according to the Solicitor, should be applied to “screen out the sorts of nontechnological innovations that do not warrant patent protection” regardless of novelty, nonobviousness, and adequacy of the written description. Id.
The Solicitor’s brief focused on the eligibility of hardware-based innovations, asserting that these are eligible “technological” advances. The Solicitor offered little guidance on how to handle the “borderline cases” it acknowledged exist between hardware and ineligible, abstract ideas. See id.at 14. This leaves unanswered difficult questions around how to deal with and distinguish eligible, non-abstract advances in software and financial technologies from those that are abstract economic practices applied to a computer. The Solicitor indeed agreed that “a person who invents improved computer technology may receive a patent if other statutory conditions are satisfied, even if the main utility of that technological improvement lies in the conduct of business.” Id.(citations and internal quotations omitted).
Notwithstanding, the Supreme Court declined to revisit its Alicedecision and identify additional guideposts for innovations in these borderline cases that have plagued federal courts since its Alicedecision. As the Solicitor’s brief indicated, Federal courts, practitioners, and even the USPTO have struggled to uniformly apply Alice’s two-step framework. With the rise of artificial intelligence and every advancing technologies in software-based financial technologies, the reach of the abstract-idea exception will continue to be a live issue in patent prosecution and litigation. Further clarification will undoubtedly be needed absent intervention by Congress.
Finnegan, Henderson, Farabow, Garrett & Dunner, LLP - Christopher C. Johns and Alexander M. Boyer
Filed under
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Litigation
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Finnegan, Henderson, Farabow, Garrett & Dunner, LLP
Topics
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Supreme Court of the United States
| https://www.lexology.com/library/detail.aspx?g=ca821a9f-6b72-4f59-ad6d-2da293bc7a76 |
Real-world vs clinical trials | Download Table
Download Table | Real-world vs clinical trials from publication: P3580Which factors influence the choice of a non-vitamin K oral anticoagulant over warfarin for stroke prevention among atrial fibrillation patients? Insights from the prospective SPRINT-AF registry | Stroke Prevention, Warfarin and Anticoagulants | ResearchGate, the professional network for scientists.
Table 1
Real-world vs clinical trials
P3580Which factors influence the choice of a non-vitamin K oral anticoagulant over warfarin for stroke prevention among atrial fibrillation patients? Insights from the prospective SPRINT-AF registry
M. Kajil
[...]
A. Ha
Challenges of Anticoagulant Therapy in Atrial Fibrillation—Focus on Gastrointestinal Bleeding
Article
Full-text available
Apr 2023
Alina Scridon
Alkora-Ioana Balan
The rising prevalence and the complexity of atrial fibrillation (AF) pose major clinical challenges. Stroke prevention is accompanied by non-negligible risks, making anticoagulant treatment an ongoing challenge for the clinician. Current guidelines recommend direct oral anticoagulants (DOACs) over warfarin for stroke prevention in most AF patients,...
Citations
... [1,2] Even considering direct oral anticoagulants (DOACs), VKAs remain interesting in certain contraindications to DOACs and for populations who cannot afford the relatively higher costs of the newer agents.
[3,
4] However, narrow therapeutic range, variability in individual dose response and interactions with other medications may lead to out of range international normalized ratio (INR) values and serious adverse events such as haemorrhagic complications, the first cause of iatrogenic hospital admissions under VKA therapy. [5][6][7] Patient's compliance and knowledge of the indications, potential adverse events and how to use this medication are crucial to maintain an optimal effect and a safe level of VKA anticoagulation. ...
Evaluation of anticoagulant therapy management in a teaching hospital in Tunisia: information and education for vitamin k antagonist newly treated patients need to be improved
Article
May 2021
Int J Pharm Pract
Khouloud Ben Jeddou
Aïmen Abbassi
Fatma Ben M’barka
Yosra Bedoui
Zeineb Ouahchi
Objective
The objective of this study was to assess the level of Vitamin K antagonist (VKA) therapy knowledge among VKA newly treated patients.
Methods
Questionnaire-based interviews were administered in a university hospital to VKA newly treated patients covering both cognitive (i.e. indication, route of administration, treatment monitoring and side effects) and know-how (i.e. safety precautions, what affects anticoagulant therapy and the management of overdose signs) aspects of therapy knowledge.
Key findings
A total of 55 patients were included. The mean overall score of patients’ knowledge was 5.78 (SD = 3.425) out of 20. The mean scores of cognitive and practical knowledge were 3.8 (2.26) and 1.98 (1.78) out of 10, respectively. Factors associated with an insufficient level of VKA therapy knowledge included low level of education, lack of access to therapy information and continuous access to this information.
Conclusions
Knowledge about VKA therapy among newly treated patients is insufficient. Patient’s medication knowledge should be improved to ensure better adherence.
... Age was associated with improved adherence to the CCS-AF guidelines. Similar to previous report of Gupta et al., increase in age was associated with decreased use of NOACs in our cohort
[14]
. Our finding inferred that although Quebec PCPs were comfortable with OAC in older patients, they were potentially at less ease in using NOACs in elderly. ...
Adherence to the Canadian Cardiovascular Society Atrial Fibrillation Guidelines by Family Medicine Groups in Quebec: the I-FACILITER project
Jul 2019
Thao Huynh
Health literacy and knowledge in a cohort of Australian patients taking warfarin
Mar 2018
Angela W Yiu
Beata V Bajorek
Objectives
To 1) characterise older patients taking warfarin, 2) assess these patients’ level of warfarin knowledge, and 3) describe their strengths and limitations in health literacy, and 4) explore relationships between participants’ characteristics, warfarin knowledge and health literacy.
Methods
A warfarin knowledge questionnaire and Health Literacy Questionnaire (HLQ) were administered to older patients (aged >65 years, N=34) taking warfarin in an Australian general practice setting.
Results
Key gaps in participant knowledge pertained to the consequences of an international normalized ratio (INR) being below the target INR range and safety issues such as when to seek medical attention. A limitation for participants with a lower level of health literacy was the ability to appraise health information. Patients who needed assistance in completing the HLQs had significantly lower warfarin knowledge scores (p=0.03). Overseas-born participants and those taking 5 or more long-term medications had lower HLQ scores for specific scales (p<0.05).
Conclusion
In this study warfarin knowledge gaps and a limitation of health literacy amongst a small sample of older patients were identified. The findings suggest that education and resources may need to be tailored to the needs of older patients taking warfarin and their carers to address these knowledge gaps and limitations in health literacy. Patients who may need greater support include those that need assistance in completing the HLQ, are overseas-born, or are taking 5 or more long-term medications.
| https://www.researchgate.net/figure/Real-world-vs-clinical-trials_tbl1_320382598 |
Widely Held Beliefs About Early Cherokee Settlement Patterns Likely Incorrect -- ScienceDaily
By 1763, the world of Cherokee Indians in the Southeastern U.S. was in tatters. The French and Indian War had wracked the sprawling Cherokee settlements that stretched from the headwaters of the Savannah River in South Carolina and Georgia to the Overhills towns in eastern Tennessee. Though 75 years would pass before the Trail of Tears would banish the remnants of the nation west to Oklahoma, the tribe watched hopelessly as much of its history rapidly faded. Researchers have long wondered why the Cherokee settled where they did, building clusters of small towns in fertile river valleys in mostly mountainous areas. Two new studies show for the first time that long-held assumptions about Cherokee settlement patterns may have been incomplete at best.
Widely Held Beliefs About Early Cherokee Settlement Patterns Likely Incorrect
Summary:
By 1763, the world of Cherokee Indians in the Southeastern U.S. was in tatters. The French and Indian War had wracked the sprawling Cherokee settlements that stretched from the headwaters of the Savannah River in South Carolina and Georgia to the Overhills towns in eastern Tennessee. Though 75 years would pass before the Trail of Tears would banish the remnants of the nation west to Oklahoma, the tribe watched hopelessly as much of its history rapidly faded. Researchers have long wondered why the Cherokee settled where they did, building clusters of small towns in fertile river valleys in mostly mountainous areas. Two new studies show for the first time that long-held assumptions about Cherokee settlement patterns may have been incomplete at best.
By 1763, the world of Cherokee Indians in the Southeastern U.S. was in tatters. The French and Indian War had wracked the sprawling Cherokee settlements that stretched from the headwaters of the Savannah River in South Carolina and Georgia to the Overhills towns in eastern Tennessee. Though 75 years would pass before the Trail of Tears would banish the remnants of the nation west to Oklahoma, the tribe watched hopelessly as much of its history rapidly faded.
Researchers have long wondered why the Cherokee settled where they did, building clusters of small towns in fertile river valleys in mostly mountainous areas.
Scientists have also studied why the society collapsed with such relative speed as the eighteenth century unfolded. Now, two new studies show for the first time that long-held assumptions about Cherokee settlement patterns may have been incomplete at best.
“There has been a lot of speculation about these issues, but it’s often been outside the realm of evidence,” said Ted Gragson, an anthropologist in the University of Georgia’s Franklin College of Arts and Sciences. “We were surprised in these studies at the relatively low impact that the Cherokee had on the Southern Appalachian landscape. They really left a very limited footprint on the land they occupied.”
Gragson is co-author of the two new studies with Paul Bolstad, a professor in the department of forest resources at the University of Minnesota. The first research paper was just published in the journal Social Science History, and the second will appear soon in the Journal of Archaeological Sciences.
The new research focuses on the year 1721, which is the first point after the earliest contact between the Cherokee and the British but before major economic and social changes the tribe underwent in the late Colonial and early American periods.
Researchers had believed for more than a century that one reason for the towns’ ultimate demise was a steadily declining abundance of natural resources. In particular, the trade of deerskins from the Cherokee to the British for goods increased dramatically as the eighteenth century progressed. Many who studied the settlement patterns deduced that the distance between towns was because of natural resource limitations.
The new studies, using historical data, mathematical models and statistical inference, imply that an overall lack of natural resources was never the problem, with the possible exception of deer, as the 1800s approached. The new information may help explain subsequent settlement patterns in the South as well.
“[Our] results suggest that the Cherokee population in 1721 did not approach intrinsic landscape limits for obtaining architectural, agricultural, hard mast or fuel wood resources in their environment,” Gragson and Bolstad argue. This stands in sharp contrast to “widely held beliefs” that limits on these necessities affected settlement patterns and their ultimate demise.
Indeed, in his 1775 History of the American Indians, writer James Adair said that Cherokee towns “are still scattered wide of each other because the land will not admit any other settlement.”
Numerous writers have taken that statement as true and repeated it, forming a narrative that has affected histories of Native Americans in the South and even white settlement patterns afterward. In fact, Gragson and Bolstad say, the picture was far more complex, and the supply of natural resources was unlikely to have played a major role.
“We believe that a regional analysis of Cherokee town placement and population makes it possible to build ever-richer syntheses of the forces that shaped the American Indians in the eighteenth century,” Gragson wrote.
The team’s first contribution to the new research is the dataset itself. Using primary and secondary map resources and narrative materials, their new data have enough depth to “sustain several different types of inquiry.” Secondly, they took a novel approach to examining Cherokee settlement patterns by “holding time constant at 1721,” thus avoiding problems inherent in the radical shifts in settlement patterns as war and the encroachment of white settlers began to displace the Cherokee.
The region occupied by the Cherokee in 1721 was huge (nearly 125,000 square miles) and included about 60 towns of varying sizes. And yet the number of Cherokee in this widespread mountain world was probably less than 12,000. While remnants of the original Cherokee inhabitants still live on the Qualla Boundary in North Carolina, most moved to Oklahoma where their descendants now represent the single most populous Indian group in the U.S.
The research of Gragson and Bolstad is part of the Coweeta Long-Term Ecological Research Project, which is directed at understanding natural and human-caused disturbances on ecological processes over large time and geographic scales in Southern Appalachia. The goal of the collaborative effort is to develop an understanding of the social and economic processes tied to land use and land cover change.
“My present research is directed at understanding how the various legacies of human land use at different time periods over the last 300 years influenced subsequent human land use activities and contribute to contemporary patterns,” said Gragson. The Coweeta project and the research on the Cherokee are sponsored by a grant from the National Science Foundation.
Story Source:
Materialsprovided byUniversity of Georgia. Note: Content may be edited for style and length.
| https://www.sciencedaily.com/releases/2007/09/070904175340.htm |
Intel Confirms Fresh Spectre, Meltdown Patch Problems
Intel says firmware updates it developed to help protect users against the Meltdown and Spectre vulnerabilities have been causing not just older CPUs but also its
Endpoint Security,Incident & Breach Response,Managed Detection & Response (MDR)
Intel Confirms Fresh Spectre, Meltdown Patch Problems
Latest CPUs Also Suffer From Frequent Rebooting Problem
Intel says the firmware updates it developed to help protect users againstMeltdown and Spectreflaws are causing stability problems in its newest chips.
On Wednesday, the head of Intel's data center group,Navin Shenoy, said that the firmware updates were causing problems with Ivy Bridge, Sandy Bridge, Skylake and Kaby Lake, which are the codenames of its latest-generation chips .
"While the firmware updates are effective at mitigating exposure to the security issues, customers have reported more frequent reboots on firmware updated systems," Shenoy said in a blog post.
Those security issues are a trio of connected, speculative execution flaws in microprocessors known as Spectre and Meltdown (see Meltdown and Spectre Forecast: Patch Now and Keep Patching).
Intel says it's been working overtime with a number of other business partners -including Dell, HPE, HPI, Lenovo and Microsoft - to address the problems.
"We have reproduced these issues internally and are making progress toward identifying the root cause," Shenoy said. "In parallel, we will be providing beta microcode to vendors for validation by next week."
"We have received reports from a few customers of higher system reboots after applying firmware updates," Shenoy said in a Jan. 11 blog post. "Specifically, these systems are running CPUs for both client and data center."
Patch Development, Deployment Continues
Meanwhile, Intel has not yet finished issuing all of the firmware updates it has promised. "We have now issued firmware updates for 90 percent of Intel CPUs introduced in the past five years," Shenoy says. "But we have more work to do."
In fact, many vendors are continuing to develop and distribute patches for Spectre and Meltdown.
Apple, Cisco, Dell, Fujitsu, Google, IBM, Juniper, Microsoft and Oracle are among the many vendors that must update users' firmware and operating systems with Meltdown and Spectre protections.
On Tuesday, as part of its quarterly patch update,Oraclereleased fixes for 237 flaws across its products, including its first batch of Spectre and Meltdown fixes.
But Oracle and many other vendors have yet to publish a full list of affected products or a timeline for when users can expect to see patches.
Performance Problems
Unfortunately, protecting CPUs from the speculative execution flaws has a performance impact, especially in data centers as well as on clients that don't have the latest and greatest chip architecture or operating system (see Performance Hit: Meltdown and Spectre Patches Slow Systems).
Intel says it's continuing to gauge the impact that its fixes are having. "To date, we have tested server platforms running two-socket Intel Xeon Scalable systems - code-named Skylake, our latest server microarchitecture," Shenoy says.
"Generally speaking, the workloads that incorporate a larger number of user/kernel privilege changes and spend a significant amount of time in privileged mode will be more adversely impacted," he says.
Intel has published the results of these tests and promised to issue more performance data and benchmarks of older systems as quickly as possible.
Patching: Performance Impact
Tested: Server platforms running two-socket Intel Xeon Scalable systems (code-named Skylake), which is Intel's latest server microarchitecture. (Source: Intel )
Intel says that it's trying to also identify workarounds for performance problems. "For example, there are other mitigations options that could yield less impact," Shenoy says, pointing to anIntel white paperfor more information. In addition, Intel is moving to getRetpoline, a security approach discovered by Google that helps address part of the Spectre vulnerability, and which is short for "return trampoline," into place.
Endpoint Security
Incident & Breach Response
Managed Detection & Response (MDR)
Network Detection & Response
Next-Generation Technologies & Secure Development
| https://www.careersinfosecurity.com/intel-confirms-fresh-spectre-meltdown-patch-problems-a-10596 |
| Download Table
Download Table | from publication: The causes and consequences of phase unbalance in single-sided linear induction motors | Unbalance in the phase currents of a single-sided linear induction motor (LIM) under balanced voltage operation is due to asymmetry of the primary windings and to the longitudinal end effect. Two methods of evaluating phase unbalance are presented. The first is analytical and... | Motor, Induction and Circuits | ResearchGate, the professional network for scientists.
Source publication
The causes and consequences of phase unbalance in single-sided linear induction motors
Article
Full-text available
[...]
Unbalance in the phase currents of a single-sided linear induction
motor (LIM) under balanced voltage operation is due to asymmetry of the
primary windings and to the longitudinal end effect. Two methods of
evaluating phase unbalance are presented. The first is analytical and is
based on an equivalent circuit model. The second approach is numerical...
A Modified Dynamic Model of Single-Sided Linear Induction Motors Considering Longitudinal and Transversal Effects
Article
Full-text available
Arash Razzaghi
[...]
Dmitry Lukichev
This paper proposes a modified dynamic equivalent circuit model for a linear induction motor considering both longitudinal end effect and transverse edge effect. The dynamic end effect (speed-dependent end effect) is based on conventional Duncan’s approach. The transverse edge effect is investigated by using three correction factors applied to the...
Citations
... Studies of the longitudinal ends static impact with both linear [8] and non-linear [9] reluctance models have previously been presented in the literature. Reference [10] develops a dynamic model where the longitudinal ends effects are presented as a second magnetic wave within the air gap, whereas
[11,
12] includes the end effects by introducing an end effect correction factor during the dynamic calculations. Reference [12] further gives a review of the impact of the longitudinal end effects and presents results based on numerical calculations are presented for a linear induction motor. ...
... A change of the flux component in the translator, not existing in the rotor in a rotating machine, appears. The time-dependent flux component induces eddy currents in the non-laminated translator with the drawback of both decreasing efficiency and possibly causes thermal issues [10,
11]
. ...
Longitudinal End Effects in a Linear Wave Power Generator
Article
Full-text available
Jan 2020
Boel Ekergård
Mats Leijon
Even though the magnetic circuit of a linear electric machine is very similar to a rotating electric machine, they diverge in one fundamental property. The linear generator is open in both ends, i.e., the magnetic circuit is non-symmetric. This paper investigates and discusses the drawbacks of this non-symmetric design in a linear permanent magnet generator, installed in a wave energy conversion system. A two-dimensional geometry has been utilized for the numerical calculations in a finite element method simulation tool. The results present an increased cogging force and significant core losses in the translator as consequences of the longitudinal ends in the machine.
... The thrust analogous to the RIM torque can be engendered by the reaction between the air-gap flux density and the eddy current in the secondary sheet. The stator engenders a sinusoidal distributed magnetic field air-gap rotating at the uniform speed 2ω/p, with ω representing the network pulsation (cognate to the frequency f by ω = 2πf) and p is the number of poles
(Adamiak et al., 1988)
. ...
Power factor and motor efficiency optimisation of three-phase linear induction motor using NSGA-II algorithm
Article
Full-text available
Jan 2016
Soumya Ranjan
Sudhansu Kumar Mishra
With the increment utilisation of electrical motors in industry and commercial applications, the modelling of machine sizing involves a wide design of parameters. The incrementing size integrates the cost of the material and low power factor. This causes reduced in machine efficiency and it becomes bulky. In order to design a three-phase linear induction motor, NSGA-II algorithm is implemented to amend both efficiency and power factor simultaneously while reducing the power density. Our method handles an analytical model of the machine to calculate the efficiency, power factor and power density while considering various objective constraints. Motor parameters and dimensions can then be optimised by engendering Pareto solutions utilising NSGA-II in a congruous objective function. To validate our optimisation method analysis results along with performance metrics is compared with various traditional techniques.
... Both single and double-sided LIM studies were analyzed for theoretical end effect [4]. Nasar sided LIMs were examined detail in their books [5]-
[7]
. R. M. Pai and Boldea obtained LIM's full equivalent circuits. ...
Simulink Model of Vector Controlled Linear Induction Motor with End Effect for Electromagnetic Launcher System
Article
Full-text available
Jan 2014
ELEKTRON ELEKTROTECH
F. Korkmaz
I. Topaloglu
R. Gurbuz
Today, linear induction motors spread out in the field of transportation and many industrial fields such as railway and electromagnetic launcher systems. Especially, high efficiency control and fast dynamic response are demanded for electromagnetic launcher systems and it's well known that direct torque control scheme provides fast dynamic response for rotary induction motors. This paper describes Simulink model of direct thrust controlled linear induction motor with end effect for electromagnetic launcher system and presents a simple and effective scheme for direct thrust control of a linear induction motor. The Simulink model of single sided linear induction motor with end effect developed to realize the direct thrust control. To show the effectiveness of the improved system, simulation results are presented using commercially available software package Matlab/Simulink.
... Numerous works have been reported in the literature on modeling of internal fault motors and their control strategy [10],
[11]
. The insulation failure often modeled with an additional resistance on the phase winding. ...
Dynamic Modeling and Control for SPMSMs With Internal Turn Short Fault
Article
Jul 2013
IEEE T POWER ELECTR
Ilsu Jeong
Byong Jo Hyon
Kwanghee Nam
A dynamic model for a faulted surface-mount permanent magnet synchronous motor (SPMSM) is derived using a deformed flux model. In reflecting the internal turn short into the dynamics, the variations in inductance and back EMF term were considered. Then, the faulted model was transformed into the two synchronous dq-models: one for the positive sequence and the other for the negative sequence. Also, a torque equation, which shows the relation between the ripple and the negative sequence current, is derived. The negative sequence current should be suppressed to eliminate the torque ripple. The dual current controller is utilized for this purpose: in the dual controller, the positive and negative sequences are controlled separately in their own synchronous frames. Notch filters are utilized in each synchronous frame to extract positive or negative sequence component. Experiments were performed with an SPMSM specially designed to make an internal turn short artificially. The experimental results coincide well with the corresponding simulation results, and exhibit a strength of the dual current controller in suppressing the negative sequence current.
... Nasar and Boldea made very extensive research on linear electric motors. The single-sided linear induction motors were examined detail in their books [5][6]
[7]
. R. M. Pai and Boldea obtained LIM's full equivalent circuits. Also, they obtained steady-state performance characteristics, end effect, transversely with side effects and skin effect of LIM using one-dimensional, two-dimensional and three-dimensional analyzes [8]. ...
Developing design software using Matlab GUI for linear electromagnetic launcher system
Conference Paper
Full-text available
May 2013
Ismail Topaloglu
Fatih Korkmaz
Riza Gurbuz
Osman Gurdal
This paper describes the basic design and corroboration using developed algorithm to get optimum geometric dimensions iteratively, of a single sided linear induction machine for an electromagnetic aircraft launcher. The purpose of the design is to reduce the cost of launching operation and constitute a mobile launcher system. For this aim, the designed prototype motor parameters and geometric dimension equations are presented in study. The software has been developed which can calculate the motor geometric dimensions analytically. The software uses developed algorithm to get optimum geometric dimensions iteratively. The dimension design of linear electromagnetic launchers using equivalent circuit model have been realized via developed software which based on Matlab GUI and iterative optimization algorithm. Based on this methodology, designers will be able to deal with practical design of linear electromagnetic launchers. The applicability of the proposed methodology is demonstrated by designing the linear electromagnetic launchers.
... Hence, the impedance and back emf of the three phase winding are not balanced. As a result, the negative sequence terms are generated in the motor current or the voltage [1]-
[4]
. Note further that the normal fieldoriented control yields torque ripple at the presence of negative sequence terms. ...
Dynamic PMSM Motor Model with Turn Short Fault for Wind Power Generation
Article
Mar 2013
Bon-Gwan Gu
Jun-Hyuk Choi
In-Soung Jung
... Additional harmonics in the induced voltage and torque due to static longitudinal end effects have been shown with classic reluctance modeling [61]. The dynamical longitudinal end effect, on the other hand have become the object of a number of studies, principally concerning linear induction machines [62,
63]
. This effect is also caused by the asymmetry introduced by the longitudinal end, but in contrary to the static longitudinal end effect, it depends on the speed of the actuator and is consequently small at lower speeds. ...
Wave Energy Conversion Linear Synchronous Permanent Magnet Generator
Article
Jan 2006
Oskar Danielsson
Analysis of the Motor Asymmetry Caused by the Static Longitudinal End Effect
Conference Paper
Jul 2021
Weichang Zhou
Zhaolong Sun
Yinhao Mao
Fengrui Cui
Hanning Qian
Phase unbalance compensation in moving-coil type permanent magnet linear synchronous motor
Article
Apr 2004
INT J APPL ELECTROM
Sang-Yong Jung
Ho-Yong Choi
Hyun-Kyo Jung
Song-Yop Hahn
The characteristics of the phase unbalance in a moving-coil type Permanent Magnet Linear Synchronous Motor(PMLSM) for travelling the reciprocating trajectory are presented. The phase unbalance caused at end coils, such as deficiency and asymmetry of each phase EMF, is thoroughly investigated. Moreover, a compensating method that can minimize such phase unbalance by adjusting the mechanical air-gap length is proposed, and its effectiveness is verified in a practical application.
Full-text available
Mar 2013
I. Topaloǧlu
O. Gürdal
In this study, single side linear induction motor has been designed to use in an electromagnetic launcher system that would be alternative of mechanical launcher system for unmanned aerial vehicle. Design specifications are 8 poles, 3 phases, 380 V, 6 m/s rotor velocity, 5.84 kg payload and 409.55N thrust. It is expected that proposed design presents an alternative to conventional launchers. The purpose of the design is to reduce the cost of launching operation and constitute a mobile launcher system. For this aim, the designed prototype motor parameters and geometric dimension equations are presented in study. The software has been developed which can calculate the motor geometric dimensions analytically. The software uses developed algorithm to get optimum geometric dimensions iteratively. The dimension optimization using equivalent circuit model of linear electromagnetic launchers to improve launching performance. Goal function tested at the launcher design parameters on the efficiency, power factor, and weight, which investigated influence on launching performance. Two-dimensional finite-element analysis evaluates the results from the dimension optimization.
| https://www.researchgate.net/figure/tbl1_224070465 |
ON OFF ON OFF ON OFF ON OFF ON OFF 609 0.1857 1241 3.0280
16/243-19:09:06.476 ON ON ON ON ON ON ON OFF ON ON ON OFF ON OFF ON OFF ON OFF ON OFF 610 0.1860 1240 3.0256
16/243-19:09:11.472 ON ON ON ON ON ON ON OFF ON ON ON OFF ON OFF ON OFF ON OFF ON OFF 609 0.1857 1241 3.0280
16/243-19:09:16.476 ON ON ON ON ON ON ON OFF ON ON ON OFF ON OFF ON OFF ON OFF ON OFF 609 0.1857 1240 3.0256
16/243-19:09:21.472 ON ON ON ON ON ON ON OFF ON ON ON OFF ON OFF ON OFF ON OFF ON OFF 610 0.1860 1240 3.0256
16/243-19:09:26.476 ON ON ON ON ON ON ON OFF ON ON ON OFF ON OFF ON OFF ON OFF ON OFF 609 0.1857 1240 3.0256
16/243-19:09:31.476 ON ON ON ON ON ON ON OFF ON ON ON OFF ON OFF ON OFF ON OFF ON OFF 610 0.1860 1240 3.0256
16/243-19:09:36.476 ON ON ON ON ON ON ON OFF ON ON ON OFF ON OFF ON OFF ON OFF ON OFF 609 0.1857 1240 3.0256
16/243-19:09:41.476 ON ON ON OFF ON ON ON OFF ON ON ON ON ON OFF ON OFF ON OFF ON OFF 609 0.1857 1240 3.0256
16/243-19:10:11.476 ON ON ON OFF ON ON ON OFF ON ON ON ON ON OFF ON OFF ON OFF ON OFF 610 0.1860 1240 3.0256
16/243-19:10:31.476 ON ON ON OFF ON ON ON OFF ON ON ON ON ON OFF ON OFF ON OFF ON OFF 610 0.1860 1239 3.0232
16/243-19:10:41.480 ON ON ON OFF ON ON ON OFF ON ON ON ON ON OFF ON OFF ON OFF ON OFF 609 0.1857 1239 3.0232
16/243-19:10:41.480 ON ON ON ON ON ON ON ON ON ON ON OFF ON OFF ON OFF ON OFF ON OFF 609 0.1857 1239 3.0232
16/243-19:10:51.476 ON ON ON ON ON ON ON ON ON ON ON OFF ON OFF ON OFF ON OFF ON OFF 610 0.1860 1239 3.0232
16/243-19:11:51.480 ON ON ON ON ON ON ON ON ON ON ON OFF ON OFF ON OFF ON OFF ON OFF 609 0.1857 1239 3.0232
16/243-19:11:56.484 ON ON ON ON ON ON ON ON ON ON ON OFF ON OFF ON OFF ON OFF ON OFF 610 0.1860 1238 3.0207
16/243-19:12:01.484 ON ON ON ON ON ON ON ON ON ON ON OFF ON OFF ON OFF ON OFF ON OFF 609 0.1857 1238 3.0207
16/243-19:12:16.484 ON ON ON ON ON ON ON ON ON ON ON OFF ON OFF ON OFF ON OFF ON OFF 610 0.1860 1238 3.0207
16/243-19:12:41.484 ON ON ON ON ON ON ON ON ON OFF ON OFF ON OFF ON OFF ON OFF ON OFF 610 0.1860 1238 3.0207
16/243-19:12:56.488 ON ON ON ON ON ON ON ON ON OFF ON OFF ON OFF ON OFF ON OFF ON OFF 609 0.1857 1238 3.0207
16/243-19:13:01.484 ON ON ON ON ON ON ON ON ON OFF ON OFF ON OFF ON OFF ON OFF ON OFF 610 0.1860 1238 3.0207
16/243-19:13:16.488 ON ON ON ON ON ON ON ON ON OFF ON OFF ON OFF ON OFF ON OFF ON OFF 609 0.1857 1238 3.0207
16/243-19:13:21.484 ON ON ON ON ON ON ON ON ON OFF ON OFF ON OFF ON OFF ON OFF ON OFF 610 0.1860 1237 3.0183
16/243-19:13:31.484 ON ON ON ON ON ON ON ON ON OFF ON OFF ON OFF ON OFF ON OFF ON OFF 609 0.1857 1237 3.0183
16/243-19:13:36.488 ON ON ON ON ON ON ON ON ON OFF ON OFF ON OFF ON OFF ON OFF ON OFF 610 0.1860 1237 3.0183
16/243-19:13:41.488 ON ON ON OFF ON ON ON ON ON OFF ON OFF ON OFF ON OFF ON OFF ON OFF 610 0.1860 1237 3.0183
16/243-19:14:06.953 ON ON ON ON ON ON ON ON ON OFF ON OFF ON OFF ON OFF ON OFF ON OFF 610 0.1860 1237 3.0183
16/243-19:14:41.492 ON ON ON OFF ON ON ON ON ON OFF ON OFF ON OFF ON OFF ON OFF ON OFF 610 0.1860 1237 3.0183
16/243-19:14:51.488 ON ON ON OFF ON ON ON ON ON OFF ON OFF ON OFF ON OFF ON OFF ON OFF 610 0.1860 1236 3.0158
16/243-19:15:06.496 ON ON ON OFF ON ON ON ON ON OFF ON OFF ON OFF ON OFF ON OFF ON OFF 610 0.1860 1237 3.0183
16/243-19:15:11.488 ON ON ON OFF ON ON ON ON ON OFF ON OFF ON OFF ON OFF ON OFF ON OFF 610 0.1860 1236 3.0158
16/243-19:15:41.492 ON ON ON ON ON ON ON OFF ON OFF ON OFF ON OFF ON OFF ON OFF ON OFF 610 0.1860 1236 3.0158
16/243-19:16:41.492 ON ON ON ON ON ON ON OFF ON OFF ON OFF ON OFF ON OFF ON OFF ON OFF 610 0.1860 1235 3.0134
16/243-19:17:41.500 ON ON ON ON ON ON ON OFF ON ON ON OFF ON OFF ON OFF ON OFF ON OFF 610 0.1860 1235 3.0134
16/243-19:18:26.500 ON ON ON ON ON ON ON OFF ON ON ON OFF ON OFF ON OFF ON OFF ON OFF 610 0.1860 1234 3.0110
16/243-19:18:41.500 ON ON ON OFF ON ON ON OFF ON ON ON OFF ON OFF ON OFF ON OFF ON OFF 610 0.1860 1234 3.0110
16/243-19:19:41.504 ON ON ON ON ON ON ON OFF ON ON ON OFF ON OFF ON OFF ON OFF ON OFF 610 0.1860 1234 3.0110
16/243-19:20:31.504 ON ON ON ON ON ON ON
| https://lasp.colorado.edu/maven/sdc/public/data/sites/site-20170308T174344/anc/eng/sasm1/sci_anc_sasm116_243_249.drf |
Minerals | Free Full-Text | Granitoids of the Ergelyakh Intrusion-Related Gold–Bismuth Deposit (Kular-Nera Slate Belt, Northeast Russia): Petrology, Physicochemical Parameters of Formation, and Ore Potential
This paper describes features of petrographic and chemical compositions and isotopic dating of the Ergelyakh and Sokh plutons, located within the Kular-Nera slate belt, Verkhoyansk-Kolyma folded region (VKFR), Northeast Russia. Intrusion of the massifs took place approximately 145–150 million years ago. Different isotopic systems on the whole rock samples and mineral separates record at least two stages of later tectono-magmatic activity 130–120 and 110–100 million years ago. Granitoid magmas for the Ergelyakh and Sokh plutons were formed at high temperatures (950–1060 °C) within the amphibolitic lower crust of an island arc setting. The ages of crustal protoliths for granitoids of the Ergelyakh intrusion-related gold–bismuth deposit, calculated on Rb–Sr and Sm–Nd two-stage models, are 1109–1383 and 1199–1322 million years, respectively. Formation of the Ergelyakh and Sokh plutons took place within a significant temperature interval (<450 to 901 °C) and, with regard to the superposition of later events, lasted for a long time. During the cooling process of granitoid melts, at the time of biotite crystallization in both massifs, a significant increase of oxygen fugacity was registered. The ore potential of granitoids of both massifs seems to be similar, but due to some differences in the physicochemical parameters of their formation (redox conditions), it was partially realized only within the Ergelyakh massif with the generation of several minor intrusion-related gold–bismuth deposits. Granitoid melts of the Ergelyakh massif were formed in relatively heterogeneous and oxidizing conditions (∆Ni–NiO = +3.26 to –3.60). Granitoid melts for the Sokh massif (∆Ni–NiO = –2.88 to –9.27) were formed in reducing conditions.
Granitoids of the Ergelyakh Intrusion-Related Gold–Bismuth Deposit (Kular-Nera Slate Belt, Northeast Russia): Petrology, Physicochemical Parameters of Formation, and Ore Potential
by Albert I. Zaitsev , Valery Yu. Fridovsky * and Maxim V. Kudrin
Diamond and Precious Metal Geology Institute, SB RAS, Yakutsk 677000, Russia
Author to whom correspondence should be addressed.
Minerals 2019 , 9 (5), 297; https://doi.org/10.3390/min9050297
Received: 17 January 2019 / Revised: 30 April 2019 / Accepted: 8 May 2019 / Published: 15 May 2019
This paper describes features of petrographic and chemical compositions and isotopic dating of the Ergelyakh and Sokh plutons, located within the Kular-Nera slate belt, Verkhoyansk-Kolyma folded region (VKFR), Northeast Russia. Intrusion of the massifs took place approximately 145–150 million years ago. Different isotopic systems on the whole rock samples and mineral separates record at least two stages of later tectono-magmatic activity 130–120 and 110–100 million years ago. Granitoid magmas for the Ergelyakh and Sokh plutons were formed at high temperatures (950–1060 °C) within the amphibolitic lower crust of an island arc setting. The ages of crustal protoliths for granitoids of the Ergelyakh intrusion-related gold–bismuth deposit, calculated on Rb–Sr and Sm–Nd two-stage models, are 1109–1383 and 1199–1322 million years, respectively. Formation of the Ergelyakh and Sokh plutons took place within a significant temperature interval (<450 to 901 °C) and, with regard to the superposition of later events, lasted for a long time. During the cooling process of granitoid melts, at the time of biotite crystallization in both massifs, a significant increase of oxygen fugacity was registered. The ore potential of granitoids of both massifs seems to be similar, but due to some differences in the physicochemical parameters of their formation (redox conditions), it was partially realized only within the Ergelyakh massif with the generation of several minor intrusion-related gold–bismuth deposits. Granitoid melts of the Ergelyakh massif were formed in relatively heterogeneous and oxidizing conditions (∆Ni–NiO = +3.26 to –3.60). Granitoid melts for the Sokh massif (∆Ni–NiO = –2.88 to –9.27) were formed in reducing conditions.
Keywords:
granitoids
;
isotopic age
;
physicochemical parameters of formation
;
Ergelyakh and Sokh plutons
;
intrusion-related gold–bismuth deposit
1. Introduction
Intrusion-related gold deposits are widespread in Northeast Russia [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 ]. These include both large deposits with gold ore resources and reserves exceeding 50 t (Chepak, Teutedjak, Chistoe), and numerous deposits of smaller size (Dubach, Nenneli, Delyankir, Chuguluk, Levo-Dybinskoe, Kurum, Ergelyakh) [ 1 ]. Gold deposits of this type were first recognized in the Tintina gold belt in Alaska and the Yukon in the 1990s [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ]. The most economically important deposits of the belt include Fort Knox, Pogo, and Dublin Gulch, among others [ 18 ].
Geology, mineralogy, pressure and temperature conditions of ore formation, and the sources of hydrothermal fluids of intrusion-related gold–bismuth deposits of the Verkhoyansk-Kolyma folded region are extensively discussed in [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 19 , 20 ] and references therein. The intrusion-related gold–bismuth mineralization is localized in small stocks of S- and I-type ilmenite series granitoids and/or adjacent hornfels haloes, or in dikes of varying composition (granite–porphyry, porphyrite, lamprophyre, diabase) [ 2 , 6 , 21 ]. Mineralogically, the deposits can be classified into the bismuth–sulfotelluride–quartz (Levo-Dybinskoe, Kular, Ergelyakh, Tuguchak, Basugunya), bismuth–arsenide–sulfoarsenide (Myakit, Chepak, Dubach, Chistoe, Kandidatskoe), and bismuth–siderite–polysulfide (Arkachan) types [ 7 ]. The average gold grade of the deposits varies from 2 to 5 g/t.
This paper first discusses physicochemical parameters of the emplacement of granitoids of the Ergelyakh area related with gold–bismuth deposits, which are very important in evaluating its ore potential. Magmatism of the Ergelyakh gold area (EGA) is poorly studied and its genetic relationship to mineralization is unclear. Here we compare and contrast two plutons from the EGA belt, one (the Ergelyakh massif) mineralized and the other (the Sokh stock) not, to try to understand what aspects of the magmas that formed these two plutons might have controlled mineralization.
2. Methods
Samples were prepared for analysis using standard crushing and grinding procedures [
22
,
23
]. Mineral grains were separated by magnetic and density separation, with final sorting under a binocular microscope to remove altered grains and other accidental minerals, and were ground to 200 mesh. All analyses were performed at the Diamond and Precious Metal Geology Institute (DPMGI), Siberian Branch, Russian Academy of Sciences, Yakutsk. Chemical compositions of the rocks and minerals were determined by classical wet chemistry analysis. Other methods included spectrometry, atomic-emission spectrometry, ionometry with ion-selective electrode, gravimetry, and titrimetry.
O
3
three fractions of CaCO
3
, one fraction of K
2
CO
3
, and 0.02% Bi
2
O
3
. Buffer for carbonates consists of five weight fractions of Al
2
O
3
, four fractions of SiO
2
, one fraction of K
2
CO
3
, and 0.02% Bi
2
O
3
. It is prepared in the same way as for silicates. Standards and samples are diluted with buffer in the optimum weight ratio of 1:2. Buffer for the iron-group elements represented 0.05% internal standard mixed with carbon powder. Carbon powder provides a uniform evaporation of the sample. The weight ratio of the buffer and sample is 1:1. Based on the results of burning the standards, diagrams are constructed which aid in determining the contents of the elements analyzed. To correct variations in the spectrum position we used reference lines (Pd 302.79 nm and 342 nm).
Electron microprobe analysis was performed using a Camebax microanalyzer (Cameca, Courbevoie, France) and a Jeol JSM-6480LV scanning microscope (JEOL, Tokyo, Japan). Chemical compositions and characteristics of minerals and rocks of the studied samples are shown in Table 1 , Table 2 , Table 3 , Table 4 and Table 5 .
Rb–Sr isotope studies were made with a MI-1201-T mass spectrometer (Electron optics, Sumy, Ukraine) in single beam mode using tantalum ribbons. Rb concentrations were calculated by isotope dilution, and those of Sr by double isotope dilution. Sr isotope composition was estimated without adding an indicator. Chemical treatment of samples included decomposition in a mixture of NF + HClO
4
(3:1) in Teflon bombs in autoclave mode at a temperature of 200 °C for 8 h. Elements were separated by the ion-exchange chromatography method with the use of Dowex resin, 50 × 8, 200 mesh. The error in measuring the isotope ratios did not exceed 0.05%. Reproducibility for
87
Rb,
86
Sr, and the
87
Sr/
86
Sr ratio was 0.5, 0.4, and 0.03%, respectively. The blank tests for the laboratory contamination showed 0.007–0.013 g/t Rb and 0.02–0.05 g/t Sr. The accuracy and reproducibility of isotope measurements were controlled by the isotope standard carbonate-70 with an average normalized
87
Sr/
86
Sr value of 0.7089 ± 0.0002. In the analyses we used reagents of very high purity, which were additionally purified when necessary. The composition of feldspars from the EGA granitoids was studied using a combination of methods. We made a full silicate analysis of bulk fractions of K-feldspar and plagioclase and of some specific gravity fractions of plagioclase. For one of the granodiorite samples, mineral composition was determined with the use of a Jeol JSM-6480LV scanning microscope (JEOL, Tokyo, Japan). Results of isotopic dating of granitoids are shown in
Table 6
.
The parameters of the physicochemical conditions of the EGA granitoid fosenations were estimated from both the whole rock and the mineral components using the programs described in [ 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 ].
3. Geology of the Study Areas
3.1. Geology of the Southeastern Part of the Kular-Nera Slate Belt
Granitoids of the Ergelyakh intrusion-related gold–bismuth deposit (EIRGD) are located near the Adycha-Taryn fault (AT) in the Kular-Nera slate belt ( Figure 1 ) [ 6 , 35 , 36 ]. The fault separates the Kular-Nera slate belt from the Verkhoyansk fold-and-thrust belt. It is traced in a northwesterly direction and controls the distribution of orogenic gold (Sana, Drazhnoe, Levoberezhnoe, Pil’, Malo-Tarynskoe, Yakutskoe), intrusion-related Au–Bi (Ergelyakh), gold–antimony (Sarylakh, Maltan, Tan), tin–tungsten (Bekkemskoe, Rep-Yuryue, Baryllyalakhskoe), and silver (Veshnee) deposits ( Figure 1 ). The deposits were formed at different stages of the tectono-magmatic history of the region [ 35 , 36 , 37 , 38 ]. The Late Jurassic–Early Cretaceous time was marked by the collision of the Siberian craton and the Kolyma-Omolon microcontinent accompanied by folding and faulting, intrusion of S- and I-type granitoids, and formation of orogenic Au and intrusion-related Au–Bi and Sn–W deposits. Post-accretionary tectonic events, small granitoid stocks, subvolcanic granite porphyry dikes, and Au–Sb, Ag–Sb, and Ag deposits were related to Late Cretaceous subduction in the Okhotsk-Chukotka arc.
Various magmatic bodies are found in the fault zone, including dolerite, andesite, diorite porphyry, and basalt dikes, and small granitoid plutons, of which the largest are the Ergelyakh, Sokh, Kurdat, Samyr, and Saryllakh massifs (from SE to NW) forming ore clusters [ 40 , 41 , 42 , 43 , 44 , 45 ]. A series of intrusive granitoid bodies of the EIRGD extend northeasterly across the fold structures following the strike of the Ergelyakh transverse fault ( Figure 1 and Figure 2 ) [ 6 ]. The massifs are located in the eastern limb of the Malo-Taryn syncline. The largest is the Ergelyakh massif (50 km 2 ). Other plutons are no larger than 2 km 2 , including the Sokh stock, about 1.7 km 2 in area. Some massifs form a single granodiorite–granite body at depth. The granitoids intrude into the Norian and Carnian sedimentary formations, which are metamorphosed to biotite and biotite–cordierite hornfels in exocontact zones of the plutons. The Carnian rocks include sandstones, siltstones, and clay shales. The Norian deposits are divided into the lower (sandstones and shales) and upper (shales and siltstones) substages. The alteration of the rocks is represented by greisenization.
The Ergelyakh massif has a zonal structure. Granodiorites (42%) make up the periphery of the massif, adamellites (20%) its apical part, and leucocratic granites (38%) the core. Dikes and veins of aplitic granites and aplites are widely developed, and pegmatite bodies occur locally. Relationships between various rock types of the massif are not well understood. Both sharp contacts and gradual transitions are observed.
The Sokh massif is composed of granodiorite porphyries intruded by leucocratic granites with an aplitic margin [ 6 ]. The aplite veins in the granodiorites of the massif transect quartz veinlets and are in turn cut by them. Between the Ergelyakh and Sokh massifs there are widespread dikes and veins of leucocratic and aplitic granites and aplites.
3.2. Petrography of Igneous Rock of the Ergelyakh and Sokh Massifs
Granitoids of the Ergelyakh massif are represented by light gray equigranular rocks with a grain size up to 0.5 cm. They have a hypidiomorphic granular texture with elements of porphyritic texture (
Figure 3
A). The mineral contents of the granodiorites are plagioclase (42–60%), orthoclase (8–19%), quartz (17–35%), and biotite (7.5–16%). Plagioclase is present as phenocrysts of prismatic form with signs of sericitization both in the center and at the periphery of crystals (
Figure 3
B). It is zonal, with 33–45% An in the core and 15–31% An in the rim. K-feldspar occurs as porphyric crystals, rarely of microperthitic texture (albite ingrowths in orthoclase) (
Figure 3
). Very rarely, the grain cores are partly replaced by the secondary alteration products (pelitization), which gives them a light-brownish color. Quartz has an irregular form and occurs interstitially between the grains of salic minerals. Dark-colored minerals are dominated by biotite, which occurs in two generations (
Figure 3
C). The first generation is represented by idiomorphic frequently chloritized porphyric grains, and the second generation occurs as small irregular grains.
Adamellites grade into granodiorites on the peripheral part of the massif. The mineral contents are plagioclase (31–51%), K-feldspar (16–32%), quartz (25–34%), and biotite (4–16%). The texture of the rocks is hypidiomorphic granular ( Figure 3 D). Plagioclase occurs as prismatic crystals with a characteristic polysynthetic twinning. It is zonal with 30–40% An in the core and 10–31% An in the rim ( Figure 3 E). K-feldspar has irregular form and contains microperthitic segregations ( Figure 3 F) rich in albite component (2.1–24%). Biotite is present as tablets and flakes of irregular form.
Granites make up the central part of the massif and also form numerous dike-like bodies in adamellites of the apical zone of the massif and in sedimentary rocks beyond its limits. Their contacts with granodiorites are both gradual and sharp. The quantitative mineralogical compositions of the granites are plagioclase (30–36%), K-feldspar (30–40%), quartz (25–34%), and biotite (3–6%). They have a hypidiomorphic granular texture (
Figure 3
G). Plagioclase is present as prisms of irregular form, often as polysynthetic and simple twins or zonal individuals, and is partly sericitized (
Figure 3
H). The An content is 20–30% in the core and 4–13% in the rim. K-feldspar occurs as irregular and rectangular crystals, is weakly pelitized, and has a perthitic texture (
Figure 3
I). Quartz forms grains of various forms and sizes (up to 2 mm) with mosaic and wavy extinction. Biotite has isomorphous form, a characteristic pleochroism, and straight, sometimes wavy extinction.
Aplitic granites and aplites of the veined facies are widespread in both the granitoids and the enclosing sedimentary rocks. They are made of plagioclase (22–28%), K-feldspar (29–41%), quartz (36–42%), and biotite (0.1–0.7%). They have a granitic, aplitic texture (
Figure 3
J). Plagioclase is unzonal (5–12% An) and partly sericitized (
Figure 3
K). K-feldspar is perthitized and contains inclusions of plagioclase and granular quartz (
Figure 3
G). Quartz in the form of irregular and rounded grains is included in plagioclase and K-feldspar, and also forms small veinlets (
Figure 3
L). Rare inclusions of reddish-brown biotite are found in all of the rock-forming minerals.
The Sokh massif is composed of granodiorite porphyries, adamellites, granites, and aplites. Granodiorite porphyries are represented by phenocrysts of light-gray plagioclase (up to 1 cm in size) set in the fine-grained groundmass (
Figure 4
A). The mineral contents of the rocks are plagioclase (41–44%), K-feldspar (17–23%), quartz (25–26%), and biotite (9–13%). Plagioclase is present in two generations. The early generation is represented by porphyric prismatic crystals. Simple and polysynthetic twins (
Figure 4
B) and zonal individuals are observed. Most of the crystals show evidence of insignificant sericitization both in the core and at the periphery. Plagioclase of the late generation is observed in the groundmass. Cores of the crystals contain 50–55% An and the rims contain 23–45% An. K-feldspar forms xenomorphic phenocrysts in the rock matrix. The amount of albite component in it is 15.4%. Quartz forms grains of various forms and sizes (up to 2 mm). Biotite is reddish-brown in color, occurs in peripheral zones of plagioclase, and is often corroded by quartz. It is normally partly chloritized on cleavage or in the form of spots (
Figure 4
C).
The mineral contents of adamellites are plagioclase (31–50%), K–Na–feldspar (16–30%), quartz (up to 15%), and biotite (up to 5%). The texture of the rocks is hypidiomorphic granular with porphyric elements (
Figure 4
D). Two generations of plagioclase are present. The first generation includes intensely sericitized porphyric prismatic crystals represented by polysynthetic and zonal individuals (
Figure 4
E). The An content is 20–30% in the core and 4–13% in the rim. Plagioclase of the second generation occurs in interstices between porphyric grains of K-feldspar and plagioclase. K-feldspar is also of two generations. The early generation includes irregular porphyric grains, and the later one is represented by small grains set in the groundmass. Biotite is tabular and irregular in form. Along with quartz, it fills interstices between salic minerals of the first generation or includes K-feldspar and plagioclase of the later generation (
Figure 4
F).
The quantitative mineralogical composition of the grains is plagioclase (30–45%), K-feldspar (up to 30%), quartz (up to 20%), and biotite (up to 5%). The texture is hypidiomorphic granular and granitic (
Figure 4
G). Plagioclase of the first generation occurs as prisms of irregular form, and is mainly represented by fractured zonal individuals that are partly sericitized (
Figure 4
H). The second-generation plagioclase is found in the groundmass in the form of simple and polysynthetic twins. An content amounts to 20–30% in the core and 4–13% in the rim. Irregular and rectangular crystals of K-feldspar are weakly pelitized. Quartz forms grains of various forms and sizes with mosaic and/or wavy extinction. Biotite occurs as isomorphous grains of two generations. The first generation includes large individuals present in interstices between porphyric grains of K-feldspar and plagioclase, and the second is represented by late-magmatic biotite in the groundmass (
Figure 4
I).
Aplitic granites are made of plagioclase (22–30%), K-feldspar (29–40%), quartz (up to 25%), and biotite (up to 5%). The texture of the rocks is granitic and aplitic ( Figure 4 J). Plagioclase is unzonal (5–12% An) and partly sericitized ( Figure 4 K). K-feldspar is partly perthitized and contains inclusions of plagioclase and granular quartz ( Figure 4 L). Quartz occurs as irregular or rounded grains. Biotite of irregular form is partly chloritized ( Figure 4 C,D).
3.3. Geology of the Ergelyakh Gold-Bismuth Deposit
The EIRGD occurs above the cupola of the Ergelyakh granitoid massif [
6
]. The granitoids and adjacent biotite hornfels are cut by en echelon lens-like, steeply dipping quartz veins up to 1 m thick and 250 m long. The main ore bodies contain a successive series of mineral associations: muscovite–tourmaline–quartz metasomatic, wolframite–tourmaline–quartz, pyrrhotite–loellingite–danaite–arsenopyrite, and bismuth–sulfotelluride [
6
]. Finely disseminated (0.006–0.1 mm) native gold is present in sulfoarsenides in the amount of 50–150 g/t, and free small-size gold with widely ranging fineness (750–960‰) is associated with bismuth minerals. As-bearing minerals are Co–Ni–loellingite, gersdorffite, Ni–danaite, and arsenopyrite. The late gold-bearing association of bismuth minerals includes tetradymite, A-joseite, B-joseite, and tellurobismuthite. Within the deposit and in near intrusive zones, polymetallic gold–silver mineralization has been reported [
6
].
Early quartz of the Ergelyakh deposit crystallized at 265–305 °C and 0.2 kbar from dilute Na and Mg chloride solutions with salinity of 4.5 wt. % to 8.6 wt. % NaCl equivalent [
46
]. Quartz from productive Au-bearing associations are characterized by inclusions of concentrated Na–Ca chloride solutions with salinity of 32.9–32.7 wt. % NaCl equivalent, which homogenize to liquid at temperatures of 360–255 °C, and by inclusions of Na–Mg chloride solution (3.7–6.9 wt. % NaCl equivalent) with homogenization temperatures from 360 to 190 °C and a pressure of 0.06 kbar [
44
]. The depth of mineralization formation is 1–2 km [
1
].
The intrusion-related gold–bismuth mineralization is known from polychronous compound gold deposits of the Kular-Nera slate belt [ 43 ]. It normally predates the formation of orogenic gold–quartz mineralization [ 9 , 47 ]. As exemplified by the Malo-Tarynskoe deposit, the orogenic Au mineralization is superposed by the intrusion-related gold–bismuth mineralization [ 43 ]. The 40 Ar/ 39 Ar age of sericite from quartz veinlets of the Malo-Tarynskoe deposit is 142.7 ± 1.4 Ma [ 43 ]. At the Malo-Tarynskoe gold–sulfide–quartz deposit, quartz–muscovite–pyrrhotite–Co–Ni– sulfoarsenide and bismuth–sulfotelluride mineral associations are identified [ 43 ]. The orogenic gold–quartz low sulfide ore bodies the Malo-Tarynskoe deposit have a sufficiently uniform mineral composition: quartz 85–95%, carbonate (ankerite) 5–15%, and ore minerals around 1–2%. The identified ore mineral assemblages are: metasomatic pyrite–arsenopyrite–sericite–quartz; veined pyrite–arsenopyrite–quartz; gold–chalcopyrite–sphalerite–galena, and carbonate–sulfosalt. Studies of stable isotopes and the fluid regime of ore formation have shown an association of the intrusion-related gold–bismuth mineralization with shallow-depth chambers of the granitoid massifs, and of orogenic gold deposits with intermediate chambers and metamorphic processes [ 43 , 44 ].
4. Results
4.1. Chemical Composition of Rock-Forming Minerals
The most informative rock-forming minerals of the studied massifs are K-feldspars, plagioclase, and biotite. In our study we paid special attention to them.
The data obtained show that K-feldspar in all granitoid types is characterized by wide variations in orthoclase (54.5–93.2%) and plagioclase (11.7–40.8%) components (
Table 1
and
Table 2
). Plagioclase is high in orthoclase component (2.4–8.4%) irrespective of its basicity and the type of granitoids. The content of anorthite mineral in plagioclase ranges from 42.0% to 7.6%, i.e., from andesine to albite, indicating that formation of plagioclase from the EIRGD granitoids took a long time and occurred under nonequilibrium conditions. Chemically, it contains, on average, 25–33% anorthite and 4.6–6.3% orthoclase components.
Biotites from granitoids of the EIRGD ( Table 3 ) are mainly represented by Fe–biotite (Fe# = 0.57–0.95) except for two samples from granodiorites and one sample from adamellites of the Ergelyakh massif. The oxidation degree of Fe (Fe 3+ /ƩFe) in biotites of the Ergelyakh massif varies from 0.05 to 0.30, and in those of the Sokh pluton from 0.05 to 0.22. Biotite is highly ferruginous (f = 75.7–93.6%) and aluminous (K Al = 0.22–0.27).
The biotite in Sokh massif is moderately ferruginous (f = 57.4–60.7%) and high in alumina (K
Al
= 0.23). Chlorites, developed after mica, are represented by ripidolite. The degree of biotite chloritisation in granodiorites of the Ergelyakh massif is 15.0–4.7%; in adamellites, 11.4 ± 1.1%, and in granites, 9.7 ± 3.6%. For the Sokh massif, the values are 12.3 ± 0.3% in granodiorites, 10.7% in adamellites, and 9.0 ± 8.9% in granites.
4.2. Chemical Composition of Accessory Minerals
The principal accessory minerals of granitoids from the Ergelyakh and Sokh massifs are ilmenite, zircon, and apatite. Grains of orthite, anatase, fluorite, monazite, rutile, garnet, and sulfides (arsenopyrite, loellingite, pyrrhotite, pyrite, bismuth minerals, galena) are rare to solitary [ 6 ].
Garnets from granitoids of both massifs are represented by almandine with varying amounts of spessartine, pyrope, andradite, grossular, and majorite. In the Ergelyakh massif, the quantity of almandine component in garnets (
Table 4
) increases from granodiorites (76.2–80.9%) to granites (82.2–83.3%). The amount of andradite component also grows from 1.3–2.0% in granodiorites to 1.2–3.4% in granites. Most pronounced are changes in pyrope and spessartine components. The content of spessartine in garnets from granodiorites is 4.2–6.2%, and in garnets from granites is up to 9.6–11.2%. Pyrope in garnets sharply decreases from granodiorites (10.12–13.65%) to granites (2.01–3.0%). This is accompanied by decreasing Mg content (Mg#) of garnets from granodiorites (0.14–0.15) to granites (0.03–0.04) and by an increasing degree of iron oxidation (Fe
3+
/ƩFe) from 1.6–1.9 to 3.6–4.2, respectively.
Garnets from the Sokh massif do not exhibit a distinct trend in composition. The amount of almandine in garnets from granitoids (
Table 4
) varies within a narrow range (69.7–78.2%). Garnets from adamellites are somewhat higher in almandine (70.8–78.2%) and those from granodiorites and aplitic granites have lower almandine content: 71.7–72.9% and 69.7–71.8%, respectively. A more pronounced trend is observed for spessartine in garnets, which is high in granodiorite porphyries and aplitic granites (24.6–25.6%) and low in adamellites (1.7–5.5%). Garnets from adamellites are also marked by elevated pyrope mineral content (13.5–22.0%), which is much higher than in granodiorites and aplitic granites (0.4%). This promotes differences in Mg# value, which is higher in garnets from adamellites (0.02–0.23) than from granodiorites and aplitic granites (0.03–0.14). Garnets from adamellites also exhibit a higher degree of iron oxidation (Fe
3+
/ƩFe = 1.2–2.6) as compared to granodiorites and aplitic granites, which is zero. These differences in the composition of garnets are due to different conditions of their formation.
4.3. Petro- and Geochemical Composition of Granitoids of Ergelyakh and Sokh Massifs
Granitoids of both massifs belong to the alkaline series due to their high-K variety (
Table 5
). They contain moderate amounts of alumina (ASI for the Ergelyakh massif is 1.0–1.2 and for the Sokh massif is 1.0–1.1). In terms of petrographic and petrochemical data, the rocks of both massifs correspond to the granodiorite–granite complex. They have similar petrochemical composition (
Table 5
) but differ in the number of alkaline elements. Granodiorite porphyries and adamellites of the Sokh massif characteristically have a higher K
2
O + Na
2
O sum (7.9 ± 0.4% and 7.9 ± 0.2%, respectively) in contrast to the same rocks from the Ergelyakh massif (6.6 ± 0.6% and 7.0 ± 1.0%) (
Figure 5
A). They are rather close in Na
2
O content (3.9 ± 0.1 and 3.8 ± 0.2 in the Sokh and 3.6 ± 0.3 and 3.5 ± 0.6 in the Ergelyakh, respectively) but differ drastically in K
2
O quantity (
Figure 5
B,C). In granodiorite porphyries and adamellites of the Sokh massif, K
2
O content is equal to 4.0 ± 0.02% and 4.1 ± 0.3%, respectively, while in the same rocks of the Ergelyakh pluton it is 2.9 ± 0.3% and 3.4 ± 1.0%. Accordingly, they differ in K
2
O/Na
2
O value, which is higher for granodiorites and adamellites of the Sokh massif (1.05 ± 0.03 and 1.1 ± 0.14, respectively) than for analogous rocks of the Ergelyakh massif (0.81 ± 0.08 and 0.99 ± 0.33). Na content slightly decreases in the granodiorite–adamellite–granite–aplite series of the Ergelyakh (2.7 ± 0.26%, 2.62 ± 0.3%, 2.58 ± 0.1%, 2.48 ± 0.21%) and Sokh (2.88 ± 0.07%, 2.8 ± 0.17%, 2.82 ± 0.37%, 2.51 ± 0.21%) massifs. K content exhibits a more pronounced tendency to increase: 2.42 ± 0.28%, 2.84 ± 1.0%, 3.83 ± 0.3%, 4.12 ± 0.32% for granitoids of the Ergelyakh massif and 3.32 ± 0.03%, 3.42 ± 0.4%, 3.47 ± 0.29%, 4.66 ± 0.61% for rocks of the Sokh massif. The K/Na value, accordingly, increases from granodiorites through granites to aplites. This is particularly evident for the Ergelyakh massif granitoids. In granodiorites this value is 0.9 ± 0.1; in adamellites, 1.1 ± 0.41; in granites, 1.5 ± 0.19; and in aplites, 1.68 ± 0.27. The K/Na ratio in the Sokh massif granodiorites (1.16 ± 0.04), adamellites (1.23 ± 0.22), and granites (1.24 ± 0.11) also follows this tendency, with a sharp increase observed in aplites (1.82 ± 0.32).
A higher content of spessartine mineral and a lower amount of pyrope component may indicate relatively low pressures during the rock emplacement [ 48 ].
Granitoids of the early phases of both massifs differ in Li and Rb contents (
Table 5
). In granodiorites and adamellites of the Ergelyakh massif, the Li content is 52.8 ± 7.2 and 45.01 ± 5.3 ppm, and in analogous rocks of the Sokh massif it is 85 ± 2.9 and 73.5 ± 2.1 ppm, respectively. In granites and aplites of both massifs, the Li content is nearly identical: 46.9 ± 22.5 and 18.5 ± 11.0 ppm in the Ergelyakh massif and 45.3 ± 8.0 and 18.6 ± 5.6 ppm in the Sokh massif, respectively (
Figure 5
D). In general, there is a tendency for decreased Li content from early to late phases of the two massifs. No regularity is observed in Rb distribution in granitoids of different phases of the massifs. Its content is somewhat higher in the Sokh massif rocks. Granodiorites and adamellites of the Ergelyakh massif contain 108.3 ± 18.3 and 101.4 ± 37.1 ppm Rb, respectively, and analogous rocks of the Sokh pluton contain 132 ± 20 and 147.6 ± 18.7 ppm Rb. However, average Rb content in the granites of the Ergelyakh massif (158.2 ± 21) is higher than in those of the Sokh massif (125.3 ± 7.5). In aplites from these massifs, Rb content is rather close (117.9 ± 21 and 125.6 ± 7.5 ppm, respectively). The K/Rb value for granitoids of the Ergelyakh massif increases from granodiorites (227 ± 27) through adamellites (277 ± 84) and granites (244 ± 17) to aplites (362 ± 89). A similar tendency for K/Rb variation is characteristic of the Sokh massif granitoids: granodiorites (254 ± 36) and adamellites (232 ± 2) have low K/Rb ratios, while granites (277 ± 11) and aplites (372 ± 51) exhibit higher values. On the K/Rb–Rb diagram (
Figure 6
), granitoids of the studied massifs do not follow a general trend typical of granitoids differentiated from a single magma chamber, but rather form a series of individual fractionation trends for the rocks of different phases in the massif emplacement. The K/Rb ratio increases from granitoids of the early to late phases, which corresponds to anatectic granites [
49
].
Granitoids of the Ergelyakh massif have a generally close Sr content (granodiorites, 259 ± 53 ppm; adamellites, 238 ± 136 ppm; granites, 244 ± 17 ppm), with a sharply decreased aplite content (74 ± 51 ppm). In the Sokh massif, Sr content in granodiorites is 235 ± 21 ppm, close to that in analogous rocks of the Ergelyakh pluton, but decreases from adamellites (180 ± 21 ppm) through granites (117 ± 50 ppm) to aplites (58 ± 33 ppm). The Rb/Sr ratio varies in different phases of the massifs depending on the distribution of these elements in the rocks. A tendency is observed for an increase in this value from granodiorites to aplites: 0.41 ± 0.1 and 0.57 ± 0.14 in granodiorites, 0.55 ± 0.31 and 0.84 ± 0.24 in adamellites, 2.43 ± 1.38 and 1.28 ± 0.77 in granites, and 2.51 ± 1.85 and 2.87 ± 1.55 in aplites of the Ergelyakh and Sokh massifs, respectively.
Ba from the Sokh massif granitoids follows the same trend as Sr ( Table 5 ). The maximum concentration is found in granodiorites (545 ± 120 ppm), with lower amounts observed in adamellites (395 ± 64 ppm), granites (347 ± 102 ppm), and aplites (300 ± 147 ppm). The Ergelyakh massif granitoids do not show regular changes in Ba content between rocks of different phases. The maximum quantity of the element is recorded in granites (637 ± 349 ppm), with lower values found in granodiorites and adamellites (507 ± 92 and 468 ± 39 ppm, respectively). Aplites contain the lowest amount of Ba (434 ± 432 ppm).
F behavior is nearly similar in the rocks of the two massifs, but the Sokh massif granitoids are markedly richer in F (
Table 5
,
Figure 5
E). The highest F concentrations are found in adamellites (0.15 ± 0.03% in the Ergelyakh and 0.26 ± 0.08% in the Sokh massif). Granodiorites of the Ergelyakh and Sokh massifs contain 0.1 ± 0.07% and 0.17 ± 0.04%; granites, 0.05 ± 0.04% and 0.09 ± 0.07%; and aplites 0.01 ± 0.02% and 0.05 ± 0.02% F, respectively. A similar tendency is observed for biotites of the Ergelyakh massif. Biotites from granodiorites of the Ergelyakh massif contain 0.47 ± 0.13%; from adamellites, 0.75 ± 0.32%; and from granites, 0.8–0.5% F. Biotites of the Sokh massif are somewhat richer in F as compared to the Ergelyakh massif (0.59 ± 0.06% from granodiorites and 0.88 ± 0.11% from granites).
The distribution of the discussed elements in granitoids is controlled by the mineral content of the rocks and the amounts of these elements in the minerals. Particularly, K-feldspar and biotite are the main carriers of Rb in the rocks. K-feldspars and biotites from granodiorites of the Ergelyakh massif contain 199 ± 58 and 544 ± 68 ppm Rb, respectively. In adamellites, these minerals are richer in Rb (258 ± 93 and 568 ± 65 ppm). The highest Rb values are found in K-feldspar and biotite from granites (514 ± 334 and 665 ± 191 ppm). Sr in the EIRGD granitoids is mainly concentrated in feldspars. K-feldspars from the Ergelyakh massif granodiorites contain 257 ± 57 ppm Sr; from adamellites, 150 ppm; and from granites, 134 ± 93 ppm. Plagioclase from granodiorites is high in Sr (417 ± 104 ppm) and that from adamellites contains 177 ± 209 ppm Sr. K/Rb ratios in K-feldspars and plagioclases of the massif show a similar trend. K-feldspars from granodiorites have the highest K/Rb ratio (538 ± 102).
The value is decreased in adamellites (419 ± 105) and is the lowest in granites (247 ± 149). Plagioclases from Ergelyakh massif granodiorites have a K/Rb value of 278 ± 98, and those from adamellites have a value of 227 ± 171. K/Rb ratios of K-feldspars from the Sokh massif decrease from granodiorites (423) through adamellites (390) to aplites (350). Rb/Sr values in K-feldspars of the Ergelyakh massif increase from granodiorites (0.67 ± 0.33) through adamellites (1.28) to granites (4.09 ± 0.11).
Ore elements are unevenly and irregularly distributed in granodiorites of both massifs (
Table 5
). In the Ergelyakh massif, high V and Co concentrations (46.8 ± 15.2 and 42.0 ± 23.5, and 7.8 ± 2.3 and 8.9 ± 2.3 ppm, respectively) are found in granodiorites and adamellites, with lower contents recorded in granites and aplites (10.8 ± 7.4 and 8.1 ± 6.1, and 2.4 ± 1.5 and 2.3 ± 1.4 ppm). Granodiorites and adamellites of the Sokh massif are also characterized by large amounts of V and Co (45.5 ± 0.7 and 21 ± 1.4, and 8.2 ± 0.6 and 5.1 ± 1.1 ppm, respectively), while granites and aplites contain smaller amounts of these elements (10.5 ± 7.8 and 4.0 ± 2.3, and 4.2 ± 1.5 and 2.4 ± 0.4 ppm, respectively). Ni is irregularly distributed in the rocks of the massifs and varies within a narrow range. Maximum concentrations are observed in granodiorites of the Sokh and adamellites of the Ergelyakh massif (19.5 ± 0.7 and 18.3 ± 7.9 ppm, respectively), and minimum values in granites of the Ergelyakh massif (9.9 ± 6.1 ppm) and granites and aplites of the Sokh pluton (11.0 ± 2.1 and 9.2 ± 2.9 ppm, respectively). Granodiorites and aplites of the Ergelyakh pluton have similar Ni content (15.5 ± 6.1 and 14.0 ± 9.8 ppm, respectively). Cu is evenly distributed in the Ergelyakh massif rocks: 11.6 ± 2.5 ppm in granodiorites, 12.0 ± 1.3 ppm in adamellites, 10.4 ± 1.1 ppm in aplites, and 7.2 ± 3.2 ppm in granites. In the Sokh massif, Cu distribution is less even. Maximum concentration of the element is registered in aplites (25.3 ± 37.3 ppm). Granodiorites and granites contain less Cu (13.8 ± 1.1 ppm and 8.0 ± 1.2 ppm, respectively). Minimum Cu content is found in adamellites (2.6 ± 3.7 ppm).
Sn content is low in both massifs, but is somewhat higher in the Ergelyakh granitoids (1.7 ± 0.8 to 3.4 ± 1.3 ppm) than in rocks of the Sokh massif (1.4 ± 0.3 to 2.7 ± 1.4 ppm) (
Table 5
,
Figure 5
F). Zn distribution in the rocks of the massifs is uneven and irregular. The highest Zn content is observed in granodiorites of the Sokh massif (170 ppm) and the lowest in granites of both the Ergelyakh (47.2 ± 44.5 ppm) and Sokh (45.3 ± 29.4 ppm) massifs. In the Ergelyakh massif, the highest Zn values are found in adamellites (128.8 ± 73.3 ppm) (
Figure 5
G). Granodiorites and aplites contain 81.2 ± 49.0 and 78.7 ± 41 ppm Zn, respectively. In the Sokh pluton, close Zn amounts are noted in adamellites (109.5 ± 14.8 ppm) and aplites (114.2 ± 129.6 ppm). Pb content is almost identical in granodiorites (22.6 ± 13.6 ppm) and adamellites (19.8 ± 7.1 ppm) of the Ergelyakh massif and in granodiorites (22.0 ppm), adamellites (23.0 ± 1.4 ppm), and granites (25.0 ± 6.1 ppm) of the Sokh pluton (
Figure 5
H). Granites and aplites have relatively large amounts of this element (30.4 ± 9.5 ppm and 37.3 ± 11.5 ppm, respectively). The highest Pb value (49.4 ± 26.4 ppm) is found in adamellites (128.8 ± 73.3 ppm). Granodiorites and aplites contain 81.2 ± 49.0 and 78.7 ± 41 ppm Zn, respectively. In the Sokh pluton, close Zn amounts are noted in adamellites (109.5 ± 14.8 ppm) and aplites (114.2 ± 129.6 ppm). Pb content is almost identical in granodiorites (22.6 ± 13.6 ppm) and adamellites (19.8 ± 7.1 ppm) of the Ergelyakh massif and in granodiorites (22.0 ppm), adamellites (23.0 ± 1.4 ppm), and granites (25.0 ± 6.1 ppm) of the Sokh pluton. Granites and aplites have relatively large amounts of this element (30.4 ± 9.5 ppm and 37.3 ± 11.5 ppm, respectively). The highest Pb value (49.4 ± 26.4 ppm) is found in aplites of the Sokh massif.
4.4. Isotope Systematics and Ages of the Massifs
The geologic age of magmatism at the EIRGD is not well constrained. The lower age limit is defined by the age of the overlying sedimentary rocks (T3–J1). The oldest manifestations of magmatic activity in the region are mafic dikes (Rb–Sr, 145–162 Ma) of the orogenic Malo-Tarynskoe gold deposit located north of the EIRGD [
41
]. The upper age limit of magmatism at the EIRGD is not established. The first K–Ar and Rb–Sr isotope dates obtained from granitoids of the Ergelyakh and Sokh massifs were discussed previously [
6
]. Based on these data, we compiled a summary of isotope ages of the rocks in these massifs determined by different isotope methods (
Table 6
).
Isotope ages of the EIRGD granitoids, irrespective of the determination method, vary within a wide range (97–196 Ma). This is probably due to the effects of various geological processes, including hybridism and assimilation of the enclosing rocks (sample 204, 196 ± 5 Ma) and the younging of isotope dates as a result of superposed later processes. This is discussed in detail in [ 6 ], where a conclusion is made that formation of the EIRGD granitoids occurred in the time interval 160–145 Ma with the subsequent cooling of the thermal field until 136 Ma. These results are in agreement with Ar–Ar ages of the Ergelyakh pluton (biotite, 142.9 ± 0.4 Ma [ 50 ]) and Rb–Sr ages of the Samyr and Kurdat plutons (bulk sample, 140–145 Ma [ 10 ]) and other intrusives of the Tas-Kystabyt plutonic belt [ 50 , 51 ].
In the interval 125–120 Ma, a new episode of tectono-magmatic activity occurred at the EIRGD as inferred from Rb–Sr dates of biotites from the Ergelyakh massif granitoids and K–Ar ages of K-feldspars from adamellites of the Sokh pluton. One of the late geological events probably took place at 110–100 Ma. These processes, likely of hydrothermal-tectonic nature, caused destruction of the isotopic systems of minerals and rocks. The possibility of a late superposed process is confirmed by young Sr biotite dates (101–106 Ma) and K–Ar plagioclase ages obtained from some EIRGD granitoid samples. The process may be synchronous with the manifestation of hydrothermal metamorphism. For example, sericite–quartz from a quartz vein with wolframite and bismuthine has a K–Ar age of 114 Ma. These events are associated with subduction-accretion processes in the rear part of the Uda-Murgal and Okhotsk-Chukotka magmatic belts of the East Asian active continental margin.
The initial Sr isotope composition (I
0
) for the EIRGD granitoids varies within a wide range (0.7065–0.7093). Sr isotope heterogeneity may be due to primary and secondary reasons. Primary isotope heterogeneity (I
0
= 0.707–0.708) may be related to the heterogeneous composition of the substratum, whose melting occurred without homogenization of magma upon ascent to the emplacement level and caused local isotope microheterogeneity. Secondary isotope heterogeneity in granitoids (I
0
> 0.708) was likely caused by late superposed processes conditioned by a long-term tectono-magmatic evolution of the whole ore-magmatic system of EIRGD. In general, there is a reverse correlation between the Rb–Sr dates of the rocks and minerals and the I
0
value, which is indicative of the evolution of the Sr isotope composition of granitoids under conditions of a thermostatic ore-magmatic system. I
0
values obtained for the EIRGD granitoids (0.707–0.709) suggest their lower crustal protoliths, which agrees well with the Nd isotope composition (εNd(T) = –4.4 and –2.90) of the Ergelyakh massif magmatites [
52
].
5. Discussion
5.1. Petrogenesis
Petrogenetically, the EIRGD granitoids are transitional between the S- and I-types ( Figure 7 ).
To determine the primary sources of the EIRGD granitoids, we recalculated the data on the chemical composition of rocks according to [
54
] and plotted them on a discrimination diagram (
Figure 8
), where the fields of magma-generating substrata are outlined from the results of experimental studies [
54
]. Data points for granodiorites and adamellites of both massifs plot into the field of amphibolites just as those for the Sokh massif granites, whereas the Ergelyakh pluton granites fall mainly into the field of amphibolites and partly greywackes, with some altered varieties falling into the field of metapelites.
The age of protoliths calculated from the Rb–Sr model dates ( Table 7 ) with the use of the method described in [ 55 ] varies within a narrow range (1035–1383 Ma), coinciding with their Sm–Nd model ages (1199–1322 Ma) ( Table 8 ) [ 52 ]. Their formation was likely related to Mesoproterozoic (Riphean) geodynamic events. Figure 9 shows the plot of 87 Rb/ 86 Sr vs 87 Sr/ 86 Sr. For all igneous rocks of the Ergelyakh and Sokh massifs, a positive relationship is observed between the 87 Rb/ 86 Sr and 87 Sr/ 86 Sr parameters.
Some data available on the rare elements from the Ergelyakh massif granitoids plotted on the discrimination geodynamic diagrams suggest that they were formed in an island arc or a continental arc setting ( Figure 10 and Figure 11 ). The new data obtained indicate that the granitoids of the Ergelyakh and Sokh massifs were formed in relation to subduction in the Uyandina-Yasachnaya volcanic arc.
5.2. Physicochemical Conditions of Granitoid Formation
The conditions of formation of the EIRGD granitoids were determined by different methods based on the chemical composition of the rocks and their minerals (biotite, feldspars). Temperatures of the melt generation based on the empirical petrochemical geothermometer [ 24 , 25 ] are similar for granitoids of the Ergelyakh and Sokh plutons: granodiorites, 1010–1065 °C; adamellites, 977–1033 °C; and granites, 958–985 °C ( Table 9 and Table 10 ).
Aplitic melts of the Ergelyakh pluton were formed at a higher temperature (952–980 °C) than aplitic granites of the Sokh massif (970–718 °C). Water content in the parent melt for the Ergelyakh massif granitoids, determined with a model from [
25
], was 2.0–5.0% (3.2 ± 0.9% for granodiorites and 3.1 ± 0.1% for adamellites). The melt for the Sokh massif granitoids contained 3.4–3.7% water. Formation of the melt for granodiorites of the Ergelyakh massif occurred at a pressure of 8.5 ± 3.6 kbar, for adamellites at 10.0 ± 1.6 kbar, and for granitoids of the Sokh massif at 11.2 kbar. Assuming that the density of the overlying rocks is 2.7g/cm
3
, these pressures approximately correspond to melt formation depths of 22.9 ± 8.7 km, 27.0 ± 4.2 km, and 30.2 km, respectively. Magma ascending to the surface and its cooling-initiated crystallization of Ti-bearing phases. The highest crystallization temperatures were obtained from the Ti geothermometer [
26
] for granodiorites and adamellites (827–901 °C) and the lowest ones for granites and aplites (602–793 °C) of both massifs. The temperatures of rocks saturated with apatite (T
Ap
= 630–892 °C) indicate that its crystallization began practically synchronously with Ti minerals but lasted somewhat longer. High temperatures of apatite saturation in some rocks (>900 °C) (
Table 9
) may be due to the presence of restitic apatites. Temperatures of zircon (T
Zr
= 680–786 °C) and monazite (TREE = 660–851 °C) saturation indicate that these minerals were formed under conditions of decreasing magmatic melt temperature.
The rock-forming minerals crystallize within a wide range of temperatures. Biotite crystallizes at temperatures of 574–749 °C from Ti geothermometry [
27
] (
Table 11
). For one granodiorite sample (1181/3a), using a technique from [
58
], we determined a temperature of co-crystallization of three garnet–biotite pairs in the range of 653–674 °C, which is in agreement with the temperature estimated from Ti geothermometer (676 °C). Similar crystallization temperatures are characteristic of quartz (623–653 °C) from granitoids of the Ergelyakh massif (Ti quartz geothermometer [
59
]). Some biotite grains that were modified in the course of subsolidus reactions in oxidizing conditions have lower crystallization temperatures (441–574 °C).
Crystallization temperatures of feldspars determined on the basis of the albite–orthoclase–anorthite thermometer [
28
] and two-feldspar thermometer [
29
] range widely (939–327 °C) (
Table 12
). This is indicative of the long history of their formation under nonequilibrium conditions during the magma evolution. Lower temperatures obtained from K-feldspar geothermometers reflect the effect of superposed processes. Plagioclase is among the first rock-forming minerals to crystallize at high temperatures. It continues crystallizing with decreasing temperature simultaneously with later minerals (biotite, quartz). The basicity of plagioclase reduces, and at the lowest magma temperatures formation of albite begins, likely in relation to post-solidus conditions of the pluton emplacement. It is probable that crystallization of a portion of biotite and more basic plagioclase already began at the ascent of magma to the pluton emplacement level. Final crystallization of more acidic plagioclase, quartz, and K-feldspar from the melt occurred in the magma chamber with formation of plutonic bodies. Subsequent post-solidus and post-magmatic processes caused re-equilibration of the mineral composition and formation of secondary minerals (chlorite, sericite, albite).
Emplacement of granitoids of both plutons occurred at pressures of 1.3–4.4 kbar (Al–biotite barometer) [ 30 ]. Granodiorites, adamellites, and granites of the Ergelyakh massif were formed at 2.1 ± 0.6 (4), 1.31, and 2.7 ± 1.3 (4) kbar, respectively, and those of the Sokh massif at 2.4 ± 0.4 (2), 2.0, and 2.0 ± 0.4 (2) kbar ( Table 11 ).
Partial pressure of oxygen (log fO 2 ) in granitoids of both massifs was estimated on bulk rock samples [ 33 ] for temperatures at the onset of crystallization (Tt2) and on biotite [ 31 ]. Values of log fO 2 were recalculated relative to Ni–NiO buffer (ΔNi–NiO) and are listed in Table 13 . The ΔNi–NiO values range widely in granitoids of the Ergelyakh (–9.8 to +10.2) and Sokh (–9.2 to 1.0) massifs ( Table 13 ). This reflects varying redox conditions of their formation. Different types of granitoids in the massifs are also characterized by varying ΔNi–NiO values. In the Ergelyakh massif, mean value of this parameter is –0.695 ± 2.44 (–3.60 to +3.26) in granodiorites, –4.8 ± 4.0 (–9.8 to –1.0) in adamellites, –1.8 ± 3.2 (–8.2 to +2.6) in granites, and –1.2 ± 6.1 (–8.2 to +10.2) in aplites. In the Sokh massif, the values are –5.8 ± 4.1 (–8.7 to –2.9) in granodiorites, –6.4 ± 3.5 (–3.9 to –8.8) in adamellites, –8.7 ± 0.5 (–8.2 to –9.3) in granites, and –5.2 ± 3.8 (–8.0 to –0.8) in aplites. In general, crystallization of granitoids of both massifs occurred in reducing conditions, more strongly reducing in the Sokh massif. The degree of reduction increased irregularly from the early to late intrusion phases, which was likely related to the initial heterogeneity of their primary protoliths. Cooling of the melts down to the crystallization temperature of micas led to a higher degree of oxidation of a magmatic system and to an increase in ΔNi–NiO values as determined from the biotite composition ( Table 13 ). Biotites from granodiorites of the Ergelyakh massif were formed at ΔNi–NiO equal to –0.01 ± 0.8 (–1.1 to +0.4), those from adamellites at +0.5, and from granites at +1.8 ± 2.7 (–0.7 to +6.3). Biotites from granodiorites of the Sokh massif crystallized at ΔNi–NiO equal to +0.7 ± 0.2 (+0.5 to +0.9), from adamellites at –0.6, and from granites at +0.3 ± 0.9 (–0.4 to + 1.0).
In general, there is a tendency toward varying oxygen fugacity during the evolution of biotites from granitoids of the massifs (r(To–ΔNi) = –0.8), which is indicative of the increasing oxidation degree of the rocks with decreasing emplacement temperature. The lowest-temperature biotites (441 °C) are characterized by the maximum ΔNi–NiO value (+6.3), which suggests that they were formed under conditions of a magnetite–hematite buffer. They are likely to be the products of re-equilibration during late geological processes.
Thus, the P-T data obtained for the granitoids of the studied massifs characterize wide variations of their temperature regime (901 to <450 °C, with consideration of late chloritization and albitization) and pressures of 2.3 ± 1.1 kbar (Ergelyakh massif) and 2.2 ± 0.4 kbar (Sokh massif) during the long emplacement period.
5.3. Mineragenic Potential
According to [ 30 ], the formation of ore occurrences associated with granitoids is controlled by the pressure conditions in the course of their emplacement. Particularly, pressure less than 1 kbar is favorable for the formation of Pb–Zn and Mo mineralization, while pressure of 1–2 kbar is responsible for Cu–Fe and Sn and 2–3 kbar for W occurrences. At pressures exceeding 3 kbar, no mineralization can form. From the Ti–biotite geobarometer data, the EIRGD granitoids were formed within a wide pressure range from 1.67 to 3.4 kbar ( Table 12 ), and thus can be considered promising for certain types of mineralization. Mason [ 60 ] believes, however, that granitoids that initially formed at low fO 2 values can hardly be prospective of any mineralization, even with subsequently increasing oxygen fugacity. The data we obtained on oxygen fugacity in EIRGD rocks ( Table 13 ) show that at the onset of the Ergelyakh granitoid crystallization, their parent magma was inhomogeneous in terms of oxygen fugacity (ΔNi–NiO from +3.3 to –3.6), becoming more oxidized in the period of biotite formation. Granitoids of the Sokh massif initially formed under reducing conditions (ΔNi–NiO = –8.7 to –2.9 for granitoids, –8.8 to –3.9 for adamellites, –9.3 to –8.2 for granites). On the FeO–Fe 2 O 3-log fO 2 diagram ( Figure 12 ), data points for the EIRGD granitoids fall into fields of different mineralization types (Cu–Mo, Mo, W, Sn, and, partly, moderately reduced lithophile element Au association).
Data points for biotites on the IV(F/Cl)–IV(F) diagram are plotted into the field of rocks promising for Sn–W–Be and Cu–porphyry mineralization ( Figure 13 ). While schematic, the discrimination diagrams presented here well illustrate the mineragenic specialties of the EIRGD.
6. Conclusions
In summary, it can be concluded that localization of the EIRGD granitoids in the Adycha-Taryn fault zone, at the boundary of the Verkhoyansk fold-and-thrust and Kular-Nera slate belts, suggests a long, multistage history of tectono-magmatic activity there. Emplacement of the granitoid massifs in the region occurred no later than 145 Ma. Various isotope systems of the rocks and minerals record at least two more stages of tectono-magmatic activity at 130–120 and 110–100 Ma. These events were likely responsible for modification of initial features of magmatic rocks and minerals and re-equilibration of their isotope systems.
Formation of granitoid magmas occurred at high temperatures (1060–950 °C) within the lower amphibolite crust, in an island-arc setting. The ages of protoliths for the EIRGD granitoids calculated from two-stage Rb–Sr and Sm–Nd models are 1109–1383 and 1199–1322 Ma, respectively. Emplacement of the Ergelyakh and Sokh massifs took place within a wide range of temperatures (900–450 °C) over a long period, taking into account late superposed processes. Parent melts for the Ergelyakh granitoids were formed in heterogeneous, more oxidizing conditions (ΔNi–NiO = +3.3 to –3.6) in contrast to granitoid melts of the Sokh massif (ΔNi–NiO = –2.9 to 9.3) that originated under reducing conditions. As the granitoid melts cooled down, a slight increase in oxygen fugacity occurred by the time of biotite crystallization in both massifs. The mineragenic potential of granitoids in both massifs seems to be similar, but owing to differences in physicochemical parameters of their formation (redox conditions), it was only partly developed in the Ergelyakh massif with the formation of small intrusion-related gold–bismuth deposits.
Author Contributions
Idea of the study conceived by A.I.Z. and V.Y.F. Methodology by A.I.Z. Treatment of data and writing the text of the paper by A.I.Z and V.Y.F. Figure drawing by M.V.K.
Funding
The reported study was done as part of the research program of DPMGI, SB RAS (project no. 0381-2019-0004).
Acknowledgments
The authors would like to thank A.I. Ivanov for preparing photomicrographs and participating in petrographic studies of the rocks. In our investigations we used thin sections made by A.G. Bakharev. We are also indebted to the reviewers for their critical comments, constructive suggestions, and valuable recommendations, which greatly improved the manuscript.
Conflicts of Interest
The authors declare no conflicts of interest.
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Figure 1. Location of Ergelyakh intrusion-related gold–bismuth deposit in the southeastern Kular-Nera slate belt. Circled figures: 1, Samyr; 2, Kurdat; 3, Ergelyakh; 4, Sokh; 5, Nelkan; 6, Baryllyalakh; 7, Kuranakh-Sala; 8, Taryn subvolcano. Inset shows (modified after [ 39 ]): Orogenic belts: SA, South Anyuy; PA, Penzha-Anadyr; Ch, Chukotka; KR, Koryak; OK, Olyutora-Kamchatka; VKFR, Verkhoyansk-Kolyma folded region; KNSB, Kular-Nera slate belt; OH, Okhotsk terrain. The red frame shows the position of Figure 2 .
Figure 1. Location of Ergelyakh intrusion-related gold–bismuth deposit in the southeastern Kular-Nera slate belt. Circled figures: 1, Samyr; 2, Kurdat; 3, Ergelyakh; 4, Sokh; 5, Nelkan; 6, Baryllyalakh; 7, Kuranakh-Sala; 8, Taryn subvolcano. Inset shows (modified after [ 39 ]): Orogenic belts: SA, South Anyuy; PA, Penzha-Anadyr; Ch, Chukotka; KR, Koryak; OK, Olyutora-Kamchatka; VKFR, Verkhoyansk-Kolyma folded region; KNSB, Kular-Nera slate belt; OH, Okhotsk terrain. The red frame shows the position of Figure 2 .
Figure 2. Geologic map of the area of the Ergelyakh and Sokh massifs, including the Ergelyakh intrusion-related gold–bismuth deposit.
Figure 2. Geologic map of the area of the Ergelyakh and Sokh massifs, including the Ergelyakh intrusion-related gold–bismuth deposit.
Figure 3.
Photomicrographs of igneous rocks of the Ergelyakh massif, x-nicols: (
A
) hypidiomorphic granular texture of granodiorite with features of porphyric texture provided by phenocrysts of K-feldspars (Kfs) and plagioclase (sample 1184); (
B
) sericitized (Ser) plagioclase (Pl) (sample 1213); (
C
) biotite of different generations: first Bt(I), second Bt(II) (sample 1213); (
D
) general texture of adamellite (sample 1209); (
E
) zonal plagioclase (sample 1209); (
F
) microperthitic texture of K-feldspar (central part) (sample 1209); (
G
) hypidiomorphic granular texture of granite (sample 1183); (
H
) sericitized plagioclase of first-generation Pl(I), simple twins of plagioclase of second-generation Pl(II) (sample 1183); (
I
) perthitic texture of K-feldspar (center of thin section) (sample 1183); (
J
) general texture of aplite (sample 1211/2); (
K
) sericitized plagioclase Pl (sample 1211/2); (
L
) perthitized K-feldspar (upper left corner), sericite in plagioclase cores (upper right corner), quartz (Q) veinlet (dashed black line) (sample 1211/2). Or, orthoclase; Mc, microcline.
Figure 3. Photomicrographs of igneous rocks of the Ergelyakh massif, x-nicols: ( A ) hypidiomorphic granular texture of granodiorite with features of porphyric texture provided by phenocrysts of K-feldspars (Kfs) and plagioclase (sample 1184); ( B ) sericitized (Ser) plagioclase (Pl) (sample 1213); ( C ) biotite of different generations: first Bt(I), second Bt(II) (sample 1213); ( D ) general texture of adamellite (sample 1209); ( E ) zonal plagioclase (sample 1209); ( F ) microperthitic texture of K-feldspar (central part) (sample 1209); ( G ) hypidiomorphic granular texture of granite (sample 1183); ( H ) sericitized plagioclase of first-generation Pl(I), simple twins of plagioclase of second-generation Pl(II) (sample 1183); ( I ) perthitic texture of K-feldspar (center of thin section) (sample 1183); ( J ) general texture of aplite (sample 1211/2); ( K ) sericitized plagioclase Pl (sample 1211/2); ( L ) perthitized K-feldspar (upper left corner), sericite in plagioclase cores (upper right corner), quartz (Q) veinlet (dashed black line) (sample 1211/2). Or, orthoclase; Mc, microcline.
Figure 4.
Photomicrographs of igneous rocks of the Sokh massif, x-nicols: (
A
) general texture of granodiorite (sample 1183); (
B
) simple twins of plagioclase of first-generation Pl(I) and second-generation Pl(II) (sample 1183); (
C
) biotite of two generations: first (Bt(I)), second (Bt(II)) (sample 1183); (
D
) general texture of adamellite (sample 1174); (
E
) sericitized plagioclase (sample 1174); (
F
) biotite with inclusions of plagioclase and K-feldspar (sample 1174); (
G
) hypidiomorphic granular texture of granite (sample 1176/1A); (
H
) zonal sericitized plagioclase (sample 1176/1A); (
I
) biotite of two generations: first (Bt(I)), second (Bt(II)) (sample 1176/1A); (
J
) general texture of aplite, porphyric grains of K-feldspar of xenogenic nature (sample 1177/8); (
K
) rare sericite in plagioclase (sample 1177/8); (
L
) perthites in K-feldspar (sample 1177/8).
Figure 4. Photomicrographs of igneous rocks of the Sokh massif, x-nicols: ( A ) general texture of granodiorite (sample 1183); ( B ) simple twins of plagioclase of first-generation Pl(I) and second-generation Pl(II) (sample 1183); ( C ) biotite of two generations: first (Bt(I)), second (Bt(II)) (sample 1183); ( D ) general texture of adamellite (sample 1174); ( E ) sericitized plagioclase (sample 1174); ( F ) biotite with inclusions of plagioclase and K-feldspar (sample 1174); ( G ) hypidiomorphic granular texture of granite (sample 1176/1A); ( H ) zonal sericitized plagioclase (sample 1176/1A); ( I ) biotite of two generations: first (Bt(I)), second (Bt(II)) (sample 1176/1A); ( J ) general texture of aplite, porphyric grains of K-feldspar of xenogenic nature (sample 1177/8); ( K ) rare sericite in plagioclase (sample 1177/8); ( L ) perthites in K-feldspar (sample 1177/8).
Figure 5. Variation diagrams for granitoids of Ergelyakh and Sokh massifs: ( A ) K 2 O + Na 2 O–SiO 2 ; ( B ) Na 2 O–SiO 2 ; ( C ) K 2 O–SiO 2 ; ( D ) F–SiO 2 ; ( E ) Li–SiO 2 ; ( F ) Sn–SiO 2 ; ( G ) Zn–SiO 2 ; ( H ) Pb–SiO 2 .
Figure 5. Variation diagrams for granitoids of Ergelyakh and Sokh massifs: ( A ) K 2 O + Na 2 O–SiO 2 ; ( B ) Na 2 O–SiO 2 ; ( C ) K 2 O–SiO 2 ; ( D ) F–SiO 2 ; ( E ) Li–SiO 2 ; ( F ) Sn–SiO 2 ; ( G ) Zn–SiO 2 ; ( H ) Pb–SiO 2 .
Figure 6. Rb–K/Rb diagram for granitoids of Ergelyakh and Sokh massifs. 1–4—trend lines for granitoids: 1—granodiorite, 2—adamellites, 3—granites, 4—aplites and aplitic granites.
Figure 6. Rb–K/Rb diagram for granitoids of Ergelyakh and Sokh massifs. 1–4—trend lines for granitoids: 1—granodiorite, 2—adamellites, 3—granites, 4—aplites and aplitic granites.
Figure 7. Petrogenetic types of the EIRGD granitoids [ 53 ].
Figure 7. Petrogenetic types of the EIRGD granitoids [ 53 ].
Figure 8. (Na 2 O + K 2 O)/(FeO + MgO + TiO 2 ) – (Na 2 O + K 2 O + FeOT + MgO + TiO 2 ) diagram for EIRGD granitoids [ 54 ]. MP, metapelites; MGW, metagraywackes; AMF, amphibolites.
Figure 8. (Na 2 O + K 2 O)/(FeO + MgO + TiO 2 ) – (Na 2 O + K 2 O + FeOT + MgO + TiO 2 ) diagram for EIRGD granitoids [ 54 ]. MP, metapelites; MGW, metagraywackes; AMF, amphibolites.
Figure 9. Rb-Sr isocron diagram for granitoids of the Ergelyakh and Sokh massifs.
Figure 9. Rb-Sr isocron diagram for granitoids of the Ergelyakh and Sokh massifs.
Figure 10. Discrimination ( A ) Nb–Y and ( B ) Rb–(Y + Nb) diagrams for Ergelyakh massif granitoids [ 56 ]. WPG, within-plate; VAG, volcanic island area; COLG, collisional; ORG, oceanic ridges.
Figure 10. Discrimination ( A ) Nb–Y and ( B ) Rb–(Y + Nb) diagrams for Ergelyakh massif granitoids [ 56 ]. WPG, within-plate; VAG, volcanic island area; COLG, collisional; ORG, oceanic ridges.
Figure 11. Discrimination Rb/Zr–Nb diagram for Ergelyakh massif granitoids [ 57 ].
Figure 11. Discrimination Rb/Zr–Nb diagram for Ergelyakh massif granitoids [ 57 ].
Figure 12. Schematic diagram of relationship between fractionation degree and oxidation state of magma and dominant metal paragenesis with reference to granitoids of Ergelyakh and Sokh massifs [ 11 ].
Figure 12. Schematic diagram of relationship between fractionation degree and oxidation state of magma and dominant metal paragenesis with reference to granitoids of Ergelyakh and Sokh massifs [ 11 ].
Figure 13. Discrimination diagram of IV(F/Cl)–IV(F) coordinates for biotites from Ergelyakh and Sokh massif granitoids [ 60 ].
Figure 13. Discrimination diagram of IV(F/Cl)–IV(F) coordinates for biotites from Ergelyakh and Sokh massif granitoids [ 60 ].
Table 1. Electron microprobe analysis of K-feldspars in granodiorite from Ergelyakh massif.
Table 1. Electron microprobe analysis of K-feldspars in granodiorite from Ergelyakh massif.
Sample SiO 2 Al 2 O 3 MgO CaO Na 2 O K 2 O ∑ Anorthite Albite Orthoclase 1213b14 64.63 18.09 - - 1.83 15.00 99.55 - 15.64 84.36 1213b15 60.55 26.21 - 6.90 8.32 - 101.99 31.43 68.57 - 1213b22 63.59 21.25 - 1.72 11.63 - 98.19 7.56 92.44 - 1213b23 63.93 18.48 - - 1.60 14.43 98.45 - 14.42 85.56 1213 b27 65.47 24.10 - 3.16 10.81 - 103.54 13.91 86.09 - 1213b28 66.13 23.49 - 2.88 11.37 - 103.87 12.28 87.72 - 1213b41 68.30 20.15 - 2.02 11.52 - 101.90 8.63 81.17 - 1213b42 66.88 18.64 0.28 - 0.72 15.17 101.69 - 6.73 93.27 1213b51 61.03 26.40 - 7.22 7.57 - 102.71 34.52 65.48 - 1213b55 65.85 20.31 - - 4.86 10.83 101.85 - 40.86 59.45
Table 2. Chemical analysis of major and trace elements of feldspars from Ergelyakh and Sokh massifs.
Table 2. Chemical analysis of major and trace elements of feldspars from Ergelyakh and Sokh massifs.
Sample Rock Mineral SiO 2 TiO 2 Al 2 O 3 Fe 2 O 3 MgO CaO Na 2 O K 2 O H 2 O + P 2 O 5 Σ Li Rb Ba Sr Anorthite Albite Orthoclase Ergelyakh Massif 1181/3a Granodiorite Plagioclase 61.57 0.03 24.28 0.15 0.07 5.81 6.19 1.28 0.17 0.03 99.58 3.7 24.7 370 300 31.34 60.46 8.2 K-feldspar 69.7 0.01 17.31 0.05 0.3 1.91 3.21 7.77 0.16 0.01 100.43 6 93.2 1300 320 11.23 34.23 54.54 1022 Plagioclase 61.67 0.06 24.28 0.16 0.02 5.64 6.74 0.7 0.25 0.04 99.56 10.7 39.3 290 500 30.2 65.33 4.47 K-feldspar 64.99 0.02 18.77 0.09 0.34 0.48 2.4 11.95 0.24 - 99.28 2.3 191 980 210 2.5 22.81 74.69 1184 Plagioclase 60.3 0.03 24.98 0.13 0.11 6.2 7.01 0.74 - 0.04 99.54 3.7 - 250 450 31.35 64.19 4.46 K-feldspar 65.26 0.01 18.98 0.12 0.17 - 1.68 13.22 0.2 - 99.64 2.3 191 1400 240 0 16.21 83.79 1181/3b Adamellite Plagioclase 64.94 0.03 21.98 0.21 0.31 5.57 5.67 0.88 0.21 0.03 99.83 9.3 21 220 325 32.98 60.79 6.23 K-feldspar 66.21 - 18.35 0.05 0.36 0.18 2.43 11.41 0.24 - 99.23 2.8 191.9 1000 150 1 24.22 74.78 1211/3 Plagioclase 69.57 0.07 18.14 0.23 0.02 3.07 5.39 0.8 - 0.1 97.39 12.5 63 180 29 22.29 70.82 6.88 K-feldspar 64.05 0.06 17.9 0.36 0.2 0.01 1.18 13.47 - 0.13 97.36 6 323.6 - - 0.05 11.72 88.23 1183 Granite K-feldspar 64.82 0.04 19.1 0.13 0.31 - 2.2 12.85 0.13 0.07 99.65 8.8 750.4 1800 <200 0 20.66 79.34 1021 66.11 - 18.46 0.03 0.27 0.18 2.78 11.77 0.31 0.12 100.03 8.4 276.9 1400 69 0.95 26.17 72.88 1017 Granodiorite K-feldspar (14.8%) 65.36 0.01 18.94 0.09 0.59 0.06 2.39 12.17 0.2 0.12 99.93 2.8 237.6 - - 0.32 22.91 76.77 Oligoclase (33%) 64.51 0.01 21.56 - 0.02 3.1 9.54 0.66 0.39 0.06 99.85 - 18.3 - - 14.66 81.63 3.72 Oligoclase (24.8%) 62.13 0.1 23.45 0.21 0.31 4.84 8.02 0.56 - 0.1 99.72 - - - - 24.18 72.49 3.33 Oligoclase (9.98%) 61.75 - 24.08 0.29 0.2 5.24 7.54 0.49 - 0.09 99.68 - - - - 26.92 70.09 3 Andesine (13.7%) 58.87 0.04 25.74 - 0.08 6.79 6.85 0.55 0.54 0.04 99.5 - 27.4 - - 34.22 62.48 3.3 Andesine (3.8%) 57.45 0.14 26.66 0.14 0.61 7.26 6.25 0.73 0.2 0.13 99.57 - - - - 37.35 58..18 4.47 1184 Granodiorite K-feldspar 65.26 0.01 18.98 0.12 0.17 0 1.68 13.22 0.2 - 99.64 2.3 227.6 - - 0 16.19 83.81 Oligoclase 64.41 0.02 21.64 - 0.02 3.79 8.77 0.76 0.25 0.03 99.69 - 18.3 - - 18.43 77.17 4.4 64.4 0.07 21.92 0.26 0.04 4.27 7.76 0.6 - 0.08 99.4 - 18.3 - - 22.44 73.8 3.75 Andesine 63.61 0.03 22.51 0.62 0.31 6.92 5.02 0.65 0.05 0.16 99.88 7.9 18.3 - - 41.24 54.14 4.61 1181/3b Adamellite K-feldspar 66.21 - 18.35 0.05 0.36 0.18 2.43 11.41 0.24 - 99.23 2.8 191.9 - - 0.99 24.21 74.8 Andesine 62.69 0.06 23.02 0.3 0.16 6.83 6.38 0.38 - 0.09 99.91 - - - - 36.28 61.32 2.4 56.44 0.1 26.76 0.54 0.45 8.19 5.87 0.56 0.64 0.12 99.67 - - - - 42.05 54.53 3.42 Sokh Massif 1177/5 Granodiorite Plagioclase 66.12 0.06 21 0.19 0.01 0.01 0.1 3.93 6.54 1.22 99.18 0.23 0.09 - 22.83 68.74 8.44 K-feldspar 65.09 0.03 18.94 0.1 0.01 0 0.35 0.15 1.57 13.06 99.3 0.2 0.17 - - 0.8 15.3 83.9 1174 Adamellite Plagioclase 64.84 0.03 22.16 0.13 0.01 0.01 0.01 4.63 7.01 0.71 99.54 0.12 0.05 - - 25.5 69.85 4.66 K-feldspar 65.14 0.01 19.06 0.08 0.01 0 0.56 0.12 2.15 11.94 99.07 0.12 0.14 - - 0.66 21.34 78 1177/9 Aplitic granite Plagioclase 77.9 0.06 14.32 0.42 0 0 0.09 1.78 4.56 0.53 99.66 0 0.13 - - 16.69 77.39 5.92 1175/1 K-feldspar 66.02 0.01 18.75 0.07 0 0 0.24 0 2.44 11.6 99.13 0.23 0 - - 0 24.22 78.78
Table 3. Chemical analysis of biotite from Ergelyakh and Sokh massifs.
Table 3. Chemical analysis of biotite from Ergelyakh and Sokh massifs.
Ergelyakh Massif Sokh Massif Rock Granodiorite Adamellite Granite Granodiorite Adamellite Granite–Porphyry Granite Mineral Fe–Biotite Mg–Biotite Fe–Biotite Fe–Biotite Sample 1017 1022 1181/3a 1184 1181/3b 1211/3 1021 1183 278 288-g 1177/11 1177/5 1174 1177/9 1177 SiO 2 33.54 35.36 34.95 35.4 35.59 34.9 34.05 34.47 34.52 35.53 35.22 34.7 34.69 32.53 34.41 TiO 2 3.18 3.74 4.12 4.25 4.13 3.61 1.3 2.03 4 3.7 4.19 4.63 3.74 2.08 4.03 Al 2 O 3 18.22 16 14.41 14.02 14.14 15.02 21.07 18.86 15.71 14.31 16.44 16.82 15.01 15.42 14.83 Fe 2 O 3 4.87 4.22 3.76 3.62 0.63 1.01 9.08 4.94 0.91 3.16 3.1 0.59 0.63 2.29 1.61 FeO 20.19 20.1 20 20.87 21.77 23.61 19.73 24.22 22.63 20.46 20.16 20.86 22.73 27.92 22.76 MnO 0.18 0.31 0.3 0.28 0.3 0.28 0.29 0.36 0 0.28 0.26 0.24 0.28 0.68 0.3 MgO 8.18 8.82 9.41 9.44 9.75 9.13 1.05 1.52 8.63 7.91 8.35 8.84 8.19 5.39 7.23 CaO 0.4 0.28 0.16 0.06 0.2 0.48 0.11 0.4 0.3 0.55 - - - - 1.36 Na 2 O 0.33 0.22 0.18 0.22 0.17 0.2 0.26 0.18 0.23 0.38 0.24 0.22 0.23 0.13 0.21 K 2 O 7.69 8.37 9.13 8.73 8.52 8.48 8.2 8.92 8.41 8.76 9.09 8.68 8.6 8.17 8.42 H 2 O 1.77 2.5 3.1 2.84 3.31 2.59 3.22 3.73 3.58 3.29 2.63 3.15 4.07 3.65 3.57 P 2 O 5 0.12 0.14 0.02 0.06 0.06 0.08 0.08 0.06 0.52 0.18 0.06 0.06 0.06 0.06 0.16 F 0.65 0.37 0.4 0.45 0.52 0.97 0.28 0.63 1.15 1.22 0.54 0.63 1.4 0.8 0.95 Cl 0.3 0.2 0.2 0.22 0.25 0.35 0.23 0.2 - - 0.1 0.15 0.15 0.35 0.2 O=F,Cl 0.29 0.2 0.21 0.24 0.28 0.49 0.17 0.31 - - - - - - - Li 2 O 0.797 0.06 0.07 0.14 0.09 0.13 0.198 0.12 0.1 0.1 0.65 0.14 0.1401 0.1603 0.1503 Rb 2 O 0.068 0.06 0.06 0.05 0.067 0.057 0.091 0.09 0.05 0.06 0.07 0.085 0.0661 0.1202 0.0591 ∑ 99.56 100.6 100.1 100.4 99.38 100.5 99.17 100.4 100.7 99.89 101.1 99.8 99.99 99.75 100.25 Si 2.45 2.58 2.61 2.63 2.74 2.66 2.46 2.59 2.66 2.69 2.57 2.64 2.71 2.58 2.66 Al 4+ 1.55 1.38 1.27 1.23 1.26 1.34 1.54 1.41 1.34 1.28 1.41 1.36 1.29 1.42 1.34 Al 6+ 0.3 - - - 0.02 0.01 0.25 0.27 0.08 - 0 0.15 0.09 0.02 0.01 Ti 0.18 0.21 0.23 0.24 0.24 0.21 0.07 0.11 0.23 0.21 0.23 0.26 0.22 0.12 0.23 Fe 3+ 0.54 0.43 0.29 0.25 0.07 0.12 0.99 0.56 0.11 0.36 0.32 0.07 0.07 0.27 0.19 Fe 2+ 1.24 1.23 1.25 1.29 1.4 1.51 1.19 1.52 1.46 1.3 1.23 1.33 1.49 1.85 1.47 Mn 0.01 0.02 0.02 0.02 0.02 0.02 0.02 0.02 - 0.02 0.02 0.02 0.02 0.05 0.02 Mg 0.89 0.96 1.05 1.04 112 1.04 0.11 0.17 0.99 0.89 0.91 1 0.95 0.64 0.03 Li - - - - - - - - - - 0.19 0.04 0.04 0.05 0.05 Ca 0.03 0.02 0.01 - 0.02 0.04 0.01 0.03 0.02 0.04 0 0 0 0 0.11 Na 0.05 0.03 0.03 0.03 0.03 0.03 0.04 0.03 0.03 0.06 0.03 0.03 0.03 0.02 0.03 K 0.72 0.78 0.87 0.83 0.84 0.82 0.75 0.86 0.83 0.85 0.84 0.84 0.86 0.83 0.83 OH 1.84 1.89 1.89 1.87 1.84 1.72 1.91 1.82 1.72 1.71 1.86 1.83 1.63 1.75 1.74 F 0.15 0.09 0.09 0.11 0.13 0.23 0.06 0.15 0.28 0.29 0.12 0.15 0.35 0.2 0.23 Cl 0.01 0.02 0.03 0.03 0.03 0.05 0.03 0.03 - - 0.01 0.02 0.02 0.05 0.03 Mg# 0.33 0.36 0.39 0.38 0.43 0.39 0.05 0.08 0.39 0.35 0.37 0.42 0.38 0.23 0.33 Fe 2 /SFe 0.7 0.73 0.75 0.76 0.95 0.93 0.55 0.73 0.93 0.78 0.78 0.95 0.95 0.87 0.89 Al/(Al + Si) 0.64 0.53 0.49 0.47 0.47 0.51 0.73 0.64 0.54 0.47 0.55 0.57 0.51 0.56 0.51
Table 4. Chemical analysis of garnets from Ergelyakh and Sokh massifs.
Table 4. Chemical analysis of garnets from Ergelyakh and Sokh massifs.
Ergelyakh Massif Sokh Massif Rock Granodiorite Granite Granodiorite Adamellite Aplitic Granite Sample 1181/3a 1181/34 1021 1177/11 1177/5 1177/7 1 2 3 1 2 1 2 3 1 2 3 4 5 1 2 3 1 2 3 4 SiO 2 32.7 37.7 37.8 37.7 37.8 36.7 36.6 36.8 38.2 37.8 37.7 38.3 36.7 36.4 36.2 36.7 37.3 37.4 37.0 37.4 TiO 2 0.13 0.16 0.02 0.16 - - 0.01 0.03 0 0.14 0.16 0.01 0.14 0 0.05 0.02 0 0.09 0.02 0 Al 2 O 3 20.1 20.0 20.2 20.0 20.2 20.3 20.1 20.2 20.9 20.6 20.4 21.0 20.6 20.0 19.9 20.4 20.3 20.1 20.5 20.2 Fe 2 O 3 - 1.47 1.61 - - - - - 0 1 0 0 1.06 0 0 0 0 0 0 0 FeO 35.8 33.5 35.4 34.8 36.8 38.6 38.9 38.3 33.2 35.6 35.7 32.7 35.6 31.2 31.4 31.4 31.1 31. 27 30.6 31.4 MnO 2.3 2.8 1.9 2.8 1.9 4.7 4.9 4.2 2.3 0.7 2.4 2.2 0.7 10.6 10.5 10.6 10.9 10.8 11.1 10.7 MgO 3.5 3.5 3.5 3.5 3.5 0.6 0.5 0.8 5.7 4.2 3.5 5.7 4.2 0.5 0.5 0.5 1.0 1.1 0.9 1.1 CaO 1.1 1.5 0.7 1.5 0.7 0.8 0.5 1.2 0.8 1.2 1.3 0.8 1.3 0.3 0.4 0.3 0.4 0.4 0.4 0.4 Cr 2 O 3 - 0.21 - - - - 0.02 - - - - 0.06 - - 0.01 0.01 - 0.02 - - Σ 101.8 100.7 100.8 100.5 100.8 101.7 101.5 101.4 101.1 101.2 101.2 100.7 100.2 98.9 98.9 99.8 101.0 101.2 100.5 101.2 Fe 2+ 2.34 2.29 2.43 2.29 2.43 2.52 2.54 2.51 2.12 2.36 2.32 2.12 2.35 2.17 2.19 2.16 2.12 2.12 2.09 2.13 Mn 0.15 0.19 0.13 0.19 0.13 0.32 0.33 0.29 0.15 0.05 0.16 0.15 0.05 0.75 0.74 0.74 0.75 0.74 0.77 0.74 Mg 0.41 0.40 0.39 0.39 0.39 0.07 0.06 0.10 0.67 0.49 0.42 0.66 0.50 0.05 0.04 0.06 0.10 0.10 0.11 0.10 Ca 0.10 0.13 0.06 0.13 0.06 0.07 0.04 0.10 0.07 0.10 0.11 0.07 0.11 0.03 0.03 0.02 0.04 0.04 0.04 0.04 Σ dodecahedron 2.99 3.00 3.00 3.00 3.00 2.98 2.98 3.00 3.00 3.00 3.00 3.00 3.00 3.00 3.00 2.99 3.00 3.00 3.00 3.00 Si - 0.019 0.027 0.024 0.027 - - - 0.002 - 0.004 0.011 - 0.036 0.019 0.027 0.032 0.036 0.023 0.035 Ti 0.008 0.096 0.001 0.010 - - 0.001 0.002 - 0.008 0.010 0.001 0.008 - 0.003 0.001 - 0.006 0.001 0 Al 1.96 1.89 1.90 1.89 1.90 1.92 1.91 1.92 1.94 1.92 1.92 1.95 1.89 1.96 1.96 1.99 1.94 1.93 1.98 1.93 Cr - 0.0133 - - - - 0.0013 - - - - 0.0037 - - 0.0007 0.0007 0 0.0013 - 0 Fe 2+ - 0.0096 0.0012 0.0097 - - - - - 0.004 0.0096 0.0006 0.039 - 0.0012 - - - - 0 Fe 3+ 0.036 0.038 0.041 0.038 0.042 0.102 0.108 0.091 0.062 0.063 0.056 0.025 0.064 - - - - - - 0.002 Mg - 0.019 0.027 0.024 0.027 - - - 0.002 - 0.004 0.011 - 0.004 0.019 - 0.242 - 0.0008 0.035 Σ octahedron 2.01 2.09 2 2 2 2.01 2.01 2.00 2 2 2 2 2 2 2 2.0143 2 2 2 2 Si 2.99 3 3 3 3 2.98 2.98 2.99 3 3.00 3 3 2.94 3 3 3 3 3 3 3 Al 0.04 - - - - 0.02 0.02 0.02 - 0.00 - - 0.06 - - - - - - - Σ tetrahedron 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 Fe 3+ /∑Fe 1.6 1.7 1.9 1.6 1.7 4.0 4.2 3.6 2.8 2.6 2.3 1.2 2.6 0 0 0 0 0 0 0.08 Mg# - - - - - - - - 0.24 0.17 0.15 0.02 0.17 0.03 0.03 0.03 0.14 0.04 0.05 0.06 Spess 5.1 6.2 4.2 6.2 4.2 10.7 11.2 9.6 5.1 1.7 5.5 4.9 1.7 24.9 24.7 24.7 24.9 24.6 25.6 24.6 Pyr 13.7 11.3 10.2 10.7 10.1 2.3 2.1 3.0 22.0 16.4 13.5 21.0 16.5 1.4 0 1.9 0.9 0.8 3.5 0 Alm 77.8 76.2 80.8 76.3 80.9 83.0 82.2 83.3 69.7 78.2 77.0 70.8 76.2 71.7 72.9 72.2 70.5 71.8 69.7 71.0 Gros 1.5 0.9 - 1.5 - - - - - 0 - 0.7 - - 0.3 0.6 0.9 0.1 0.0 0.8 Andr 1.3 1.9 1.9 1.9 2.0 2.4 1.2 3.4 2.2 2.8 2.6 1.1 3.2 - 0 0 - 0 - - Skageti - - - - 0.1 - - 0.3 0.8 0.3 - - 0.01 - - - - - - - Maigorit - 1.9 2.7 2.4 2.7 - - - - - 0.4 1.1 - 0.4 1.4 - 2.4 2.5 - 3.2 Shorlomit 0.4 - - - - - 0.0 0.1 - 0.2 - - 0.4 - - - - - - - Morimotoit - 1.0 0.1 1.0 - - - - - 0.4 1.0 0.1 - - 0.3 - - 0.6 0.1 - Uvarovite - 0.7 - - - - 0.1 - - - - 0.2 - - 0.0 0.0 0.0 0.1 - -
Table 5. Chemical analysis of Ergelyakh and Sokh massif granitoids.
Table 5. Chemical analysis of Ergelyakh and Sokh massif granitoids.
Sample Rock SiO 2 TiO 2 Al 2 O 3 Fe 2 O 3 FeO MnO MgO CaO Na 2 O K 2 O H 2 O + P 2 O 5 S Cl F ∑ Li Rb Sr Ba V Co Ni Cu Zn Sn Pb Y Nb Zr Hf Ta Ergelyakh Massif 1181/3a Granodiorite 66 0.8 16.1 - 4.8 0.06 1.53 3.6 3.04 2.9 0.61 0.2 0.09 - 0.21 100.2 52 104 260 500 49 9 19 13 149 2.1 21 23 12 139 4 1.2 1017 67 0.8 15.8 1.2 3.1 0.01 1.38 2.4 4.12 3.2 0.85 0.2 0.02 0.1 0.03 100.2 59 127 360 400 33 7 12 8.7 27 2.8 33 23 13 160 - - 1022 67 0.6 15.1 - 4 0.01 2.05 3.1 3.7 2.8 1.15 0.2 0.02 0.1 0.02 99.76 50 97 213 493 - 4 6 13 40 7.2 44 - - 180 - - 1184 67 0.6 15.7 0.11 4 0.06 1.22 3.1 3.64 3.2 0.8 0.2 0.02 - 0.15 100.2 47 117 240 450 32 8 15 - 96 2.3 15 30 13 190 5 - 1016 68 0.6 15.4 0.31 3.9 0.06 1.16 3 3.88 3 0.67 0.2 - - 0.08 100.1 60 91 220 670 51 10 17 - - 2.6 - - - 140 - - 1015 67 0.7 15.2 0.71 4.2 0.07 1.22 2.8 3.74 3.1 - 0.2 - - 0.09 99.18 60 137 - - - - - - - 2.7 16 - - - - - 1212 62 0.8 16.8 0.87 4 0.09 2.3 4.2 3.33 2.3 1.41 0.2 0.07 - 0.13 98.49 41 85 260 530 69 10 24 - 94 2.6 7 - - - - - 1178/4 Adamellite 69 0.4 15 - 3.1 0.03 0.92 2.3 4.01 3.6 0.67 0.1 0.01 - 0.16 99.23 42 87 190 510 30 7 13 - 170 1.4 25 - - - 3 1.3 1210 69 0.5 14.8 0.34 3.5 0.05 1.21 2.4 3.44 3.8 1.03 0.2 - - 0.11 100.5 53 122 200 490 34 8 14 - 150 2.8 19 - - 200 - - 1181/3b 71 0.5 14.2 0.26 2.2 0.03 0.74 2.4 2.91 3.8 1.07 0.1 0.07 - 0.17 99.74 40 84 160 440 27 5 16 11 175 1.8 25 32 9 91 - - 1019 69 0.8 15.6 - 3.1 0.02 1.47 4.1 3.7 1.4 - 0.2 - - 0.15 99.51 45 69 480 430 77 16 30 13 20 0.9 10 - - - - - 1211/3 Granite 73 0.2 14.2 0.12 2.4 0.03 0.57 1.5 3.45 4.5 0.19 0.1 - - 0.16 100.5 54 139 120 510 21 5 13 - 35 1.9 32 - - - - - 1021 74 0.1 12.9 2.25 1.6 0.01 0.35 0.4 3.45 4.1 0.76 0.1 - - 0.01 99.72 59 138 30 670 - - - - - - - - - - - - 1182 74 0.1 13 - 2.1 0.02 0.09 0.5 3.78 4.3 0.97 0.1 - - 0.08 98.95 53 139 37 710 5 2 12 7 100 2.8 22 31 10 57 2 0.9 1213/1 74 0.1 13.4 - 1.8 0.03 0.1 0.5 3.73 4.6 0.51 0.1 - - 0.04 98.87 62 152 49 640 3 2 6 4 37 3.1 22 3 - - - - 1211/2 76 0 12.6 - 1.5 0.01 0.1 0.4 3.53 4.8 0.69 0.1 0.02 - 0.05 99.38 24 139 16 89 3 5 2 12 11 2.8 38 17 6 39 2 1.9 1016/3 76 0.1 12.8 0.31 0.6 0.01 - 0.6 3.85 4.8 0.64 - - - 0.02 100 14 101 140 1300 9 2 19 - - - 21 - - - - - 1211 77 0.1 12.6 - 1.1 0.01 0.06 0.4 3.47 5.1 0.34 0.1 0.01 - 0.02 99.92 8.4 80 19 130 5 3 8 - 120 2.3 51 - - - - - 1020/1 73 0.2 14 0.39 1.7 0.03 0.25 0.6 3.22 5.1 - 0.2 - - 0.08 99.04 65 174 130 650 19 2 21 10 - 5.1 28 - - - - - 1020/4 73 0.2 14 0.53 1.6 0.04 0.21 0.5 3.09 5 - 0.2 - - 0.09 98.89 70 183 120 840 15 2 13 6 14 5.4 32 - - - - - 1020/3 75 0.2 13.5 0.65 1.4 0.04 0.11 0.5 3.36 4.8 - 0.1 - - 0.04 99.54 60 183 120 830 18 2 12 4.3 13 3.5 28 - - - - - 1017/1 Aplite 75 - 12.2 0.13 0.5 0 1.79 0.4 3.29 5.2 0.28 - 0.02 - - 98.83 13 122 - 528 5 5 11 38 4.8 34 - - - - 1211/2 76 - 12.6 - 1.5 0.01 0.1 0.4 3.53 4.8 0.69 0.1 0.02 - 0.05 98.67 24 139 - 89 3 2 9 9.3 78 2.8 38 - - - - - 1018 76 0.2 12.7 0.3 1.6 0.01 0.11 0.7 3.43 4.5 - 0.1 - - 0.01 99.33 41 137 83 590 19 4 34 10 - 1.1 36 - - - - - 1016/3 76 0.1 12.8 0.31 0.6 0.01 - 0.6 3.85 4.8 - - - - 0.01 99.38 14 101 140 1300 9 2 19 10 - 0.3 21 - - - - - 1211 77 0.1 12.6 - 1.1 - 0.06 0.4 3.47 5.1 0.34 0.1 0.01 - 0.02 99.56 8.4 80 19 130 3 2 8 13 120 2.3 51 - - - - - 1016/1 77 - 12 0.15 0.7 - - 0.3 3.65 4.8 - - - - - 98.99 16 128 27 93 7 2 13 10 - 0.8 53 - - - - - 1016/2 78 0.1 12.8 0.74 - - - 0.4 2.94 5.7 - - - - 0.01 100.3 13 119 100 330 9 2 10 10 - 0.3 28 - - - - - Sokh Massif 1177/11 Granodiorite 66 0.6 15.6 - 4 0.03 1.35 2.4 3.94 4 0.82 0.2 0.14 - - 99.32 83 118 250 460 46 9 20 13 170 2.4 22 7 - - - - 1177/5 68 0.5 15.3 0.13 3.3 0.05 1.42 2.3 3.81 4 0.68 0.2 0.19 0.1 - 99.61 87 146 220 630 45 8 19 15 170 2 22 9 - - - - 1174 Adamellite 69 0.4 14.8 0.07 2.8 0.04 0.64 2.2 3.94 3.8 0.27 0.2 0.27 - - 98.35 75 134 200 350 22 43 12 5.2 120 2.1 22 9 - - - 1177/1 71 0.4 13.4 - 3.3 0.05 0.7 1.5 3.61 4.5 0.53 0.1 0.24 - - 98.96 72 136 160 440 20 6 14 0 99 2.1 24 7 - - - - 1177 Granite 73 0.3 13.9 0.51 2.1 0.04 0.45 1.7 3.42 4.2 0.64 0.1 0.17 - - 100.3 53 121 160 420 18 5 13 9.2 79 2 22 10 - - - - 1176 74 0.2 13.6 - 2 0.03 0.43 1.2 3.62 3.9 0.51 0.1 0.06 - - 99.2 37 121 130 390 11 5 11 8.1 25 1.7 21 14 - - - - 1177/9 74 0.1 13.3 - 2 0.03 0.1 0.7 4.37 4.6 0.21 0.2 0.05 - - 99.52 46 134 62 230 3 3 9 6.8 32 4.3 32 4 - - - - 1177/2 Aplitic granite 75 0.1 12.6 - 1.6 0.02 0.37 0.7 3.32 5.2 0.32 0.1 0.07 0.1 - 99.53 25 117 96 550 8 3 14 92 270 1.1 96 7 - - - - 1177/6 75 0.1 13 0.12 0.7 0.02 0.3 0.3 2.96 6.6 0.19 0.1 0.07 - - 99.54 14 124 89 300 3 2 7 5.7 32 1.4 37 11 - - - - 1177/8 75 - 13.3 0.2 0.7 0.02 0.01 0.4 3.68 5.7 0.18 0.1 0.05 - - 99.75 17 121 28 170 3 3 7 10 29 1.1 44 10 - - - - 1175/1 77 - 12.5 - 1.4 0.01 0.13 0.3 3.39 4.7 0.58 - 0.02 - - 99.97 24 130 29 240 3 2 10 8.9 0 1.3 33 9 - - - - 1177/3 75 0.1 12.8 - 1.1 - 0.11 0.3 3.58 6 0.36 0.1 0.03 - - 99.42 13 136 46 240 5 2 8 9.7 240 1.9 37 13 - - - -
Table 6. Results of isotopic dating of granitoids of Ergelyakh intrusion-related gold–bismuth deposit.
Table 6. Results of isotopic dating of granitoids of Ergelyakh intrusion-related gold–bismuth deposit.
Sample Rock K–Ar Age Rb–Sr Age Rock Biotite K-Feldspar Isochron (I 0 ) Biotite (I 0 ) Ergelyakh Massif 204 Granodiorite–porphyry from endocontact zone 196 ± 5 - - - - 1017 Granodiorite - 146 ± 4 - - - 1181/3a Granodiorite - - - 153 ± 67 (0.7071) 105 ± 0.4 (0.7080) 1022 Granodiorite - - - 157 ± 74 (0.7076) 120 ± 0.7 (0.7093) 1184 Granodiorite - - - 159 (0.7073) 132 ± 9 (0.7082) 1178/5 Granodiorite - 143 * - - - 184 Granodiorite–porphyry 138 - - - - 1183/3b Adamellite - - - 171 ± 28 (0.7065) 122 ± 0.4 (0.7073) 1021 Granite 110 ± 3 131 ± 1 111 ± 1 131 ± 9 (0.7083) 134 ± 2 (0.7079) 1183 Granite - - - 101 ± 28 (0.7088) 98 (0.7113) 140 Granite 148 146 - - - 196 Fine-grained biotite granite 144 ± 4 142 ± 1 - - 148 (0.7082) 66 Plagiogranite 157 - - - - 200 Fine-grained aplitic granite 140 ± 1 - - - - 89 Sericitized rock, exocontact of Au rare metal vein 125 ± 1 - - - - 202 Sericite–quartz vein with wolframite and bismuthine 114 ± 5 - - - - Sokh Massif 1177/5 Granodiorite - - - 140 ± 7 (0.7079) 107 ± 0.4 (0.7091) 1174 Adamellite 120 ± 4 158 ± 3 122 ± 2 137 ± 1 (0.7079) 142 ± 0.3 (0.7077) 1174 Plagioclase - - 97 ± 4 - - 1177/9 Granite 136 ± 4 147 ± 3 131 ± 1 138 ± 17 (0.7078) 143 ± 0.4 (0.7070)
Notes: Dates were obtained at DPMGI SB RAS (Yakutsk). Isochron data obtained from mineral isochron (rock + plagioclase + K-feldspar+biotite); I 0 , initial Sr composition. * Ar–Ar data [ 51 ].
Table 7. Model Rb–Sr age and parameters of protoliths for EIRGD granitoids.
Table 7. Model Rb–Sr age and parameters of protoliths for EIRGD granitoids.
Sample Rock 87 Rb/ 86 Sr 87 Sr/ 86 Sr I 0 f Rb/Sr ε Sr T DM -2st Ergelyakh Massif 1181/3a Granodiorite 1.422 0.710 0.707 16.19 39.56 1117 1022 Granodiorite 4.776 0.718 0.708 56.75 46.63 1109 1184 Granodiorite 4.493 0.718 0.707 53.33 42.40 1207 1181/3b Adamellite 1.309 0.710 0.707 14.82 41.95 1136 1021 Granite 10.731 0.728 0.708 128.76 56.13 1383 196 Granite 0.38 0.709 0.708 3.59 55.00 1354 1183 Granite 9.532 0.725 0.709 114.27 30.61 1035 Sokh Massif 1177/5 Granodiorite 3.08 0.714 0.708 36.24 50.60 1284 1174 Adamellite 1.99 0.712 0.708 23.03 47.80 1270 1177/9 Granite 10.373 0.728 0.708 124.43 49.15 1185
Notes: f Rb/Sr and ε Sr are deviations of the 87 Rb/ 86 Sr ratio and Sr isotope ratio relative to primitive mantle reservoir in the protolith of granitoids; T DM -2st is the two-stage model age of the protolith formation.
Table 8. Model Sm–Nd age and parameters of protoliths for EIRGD granitoids.
Table 8. Model Sm–Nd age and parameters of protoliths for EIRGD granitoids.
Sample Rock Sm Nd 147 Sm/ 144 Nd 143 Nd/ 144 Nd f Sm/Nd ε Nd T DM T DM -2St 1184 Granodiorite 5.83 29.47 0.1196 0.5123 −0.39 −4.38 1317 1322 1183 Granite 4.34 16.33 0.1607 0.5125 −0.18 −2.90 2001 1199
Notes: f Sm-Nd and ε Nd are deviations of the 147 Sm/ 144 Nd ratio and Nd isotope ratio relative to the primitive mantle reservoir in the protolith of granitoids; T DM and T DM -2st are the one- and two-stage model ages of the protolith.
Table 9. Formation and crystallization temperatures of EIRGD granitoids.
Table 9. Formation and crystallization temperatures of EIRGD granitoids.
Sample Rock Quartz Biotite K-feldspar–An T p (1) T Ti T Zr T REE T Ap ASI T T P, kbar T Ergelyakh Massif Granodiorite 1181/3a 1036 882 771 770 837 1.11 - 676 1.82 838 1017 1018 901 749 - 876 1.08 - 638 3.08 - 1022 1035 857 786 - 895 1.03 - 661 1.95 695 1184 1023 866 - - 765 1.04 653 682 1.67 694–727 1016 1021 868 764 - 813 1.02 - - - - 1212 1065 881 - Daika 809 1.08 - - - - 1015 1024 870 - - 697 1.05 - - - - Adamellite 1178/4 1008 839 - - 775 1.02 - - - - 1210 1013 855 - - 747 1.04 - - - - 1181/3B 1003 852 741 743 830 1.08 623 679 1.31 743–692 1019 1033 890 - 761 1.04 - - - - Granite 1211/3 985 792 - - 677 1.06 - 663 1.77 483 1021 979 721 722 763 763 1.18 - 441 4.40 - 1183 973 724 712 745 814 1.12 634 574 3.71 - 1213/1 976 707 - - 825 1.10 - - - - 1211/2 965 657 682 660 892 1.08 643 - - - 1211 958 688 - - 868 1.05 - - - - 1020/1 971 776 - - 869 1.19 - - - - 1020/4 972 772 - - 840 1.22 - - - - 1020/3 966 761 - - 838 1.16 - - - - Aplite 1017/1 980 602 701 - 789 1.04 - - - - 1018 968 759 - - 874 1.08 - - - - 1016/3 959 701 - - 842 1.02 - - - - 1211 958 688 - - 868 1.05 - - - - 1016/1 958 660 - - 831 1.02 - - - - 1016/2 952 679 - - 838 1.08 - - - - Sokh Massif Granodiorite 1177/11 1020 862 - - 754 1.04 - 715 2.15 - 1177/5 1015 853 - - 774 1.04 - 749 2.70 520 Adamellite 1174 1006 842 - 741 846 1.01 - 709 2.01 602 1177/1 999 827 - - 929 0.99 - - - - Granite 1177 987 538 - - 630 1.06 - 713 1.76 - 1176 982 793 - 768 830 1.11 - - - - 1177/9 969 722 - - 991 0.99 - 600 2.33 - Aplitic granite 1177/2 970 737 - - 738 1.02 - - - - 1177/6 960 688 - - 888 1.0 - - - - 1177/8 957 640 - - 737 1.04 - - - - 1175/1 718 658 - - 786 1.12 - - - - 1177/3 757 686 - - 886 0.99 - - - -
Table 10. Plagioclase–liquidus equilibrium parameters of formation of EIRGD granitoids.
Table 10. Plagioclase–liquidus equilibrium parameters of formation of EIRGD granitoids.
Sample Rock An (%) H 2 O (%) P (kbar) T (°C) Ergelyakh Massif 1181/3a Granodiorite 31 3.25 ± 0.05 10.6 1049 ± 12 1022 Granodiorite 30 3.1 ± 0.60 7.4 1010 ± 13 1184 Granodiorite 31 3.25 ± 0.15 9.1 1026 ± 14 1184 Granodiorite 41 2.35 ± 0.15 6.1 1034 ± 9 1184 Granodiorite 22 4.45 ± 0.05 12.9 1014 ± 22 1017 Granodiorite 34 2.30 ± 0.60 4.4 1015 ± 17 1017 Granodiorite 27 3.10 ± 0.60 7.1 1010 ± 23 1017 Granodiorite 24 3.45 ± 0.55 8.5 1008 ± 25 1017 Granodiorite 23 1.95 ± 0.55 3.6 1019 ± 12 1017 Granodiorite 15 4.95 ± 0.55 15.0 1004 ± 30 1211/3 Adamellite 22 2.85 ± 0.45 11.5 982 ± 27 1181/3b Adamellite 42 2.45 ± 0.45 8.1 982 ± 16 1181/3b Adamellite 36 3.00 ± 0.40 9.4 977 ± 17 1181/3b Adamellite 33 3.10 ± 0.30 11.0 980 ± 16 Sokh Massif 1177/5 Granodiorite 23 3.65 ± 0.05 11.2 1012 1174 Adamellite 26 3.4 ± 0.0 11.2 1013
Table 11. Parameters of biotite formation from EIRGD granitoids.
Table 11. Parameters of biotite formation from EIRGD granitoids.
Sample IV (F) IV (Cl) IV (F/Cl) T °C (Ti) P (kbar) Buffer T °C Log fO 2 ΔNi–NiO Mg# Ergelyakh Massif Granodiorite 1181/3a 2.03 –3.82 5.85 676 1.8 Ni-Ni 764 –14.95 0.29 0.39 1017 1.72 –3.28 5.01 638 3.1 Ni-Ni 743 –15.10 –1.13 0.33 1022 2.04 –3.77 5.81 661 2.0 Ni-Ni 754 –15.02 0.44 0.36 1184 1.98 –3.85 5.83 682 1.7 Ni-Ni 762 –14.96 0.34 0.38 Adamellite 1181/3b 1.94 −4.301 5.96 679 1.3 FMQ 848 –12.97 0.51 0.43 Granite 1211/3 1.60 –4.12 5.72 663 1.8 FMQ 829 –14.48 0.66 0.39 1021 1.75 –3.26 5.01 441 4.4 Ge-Mg 448 –19.17 6.29 0.05 1183 1.40 –3.26 4..68 574 3.7 Ni-Ni 654 –18.74 0.36 0.08 278 1.50 - - 681 2.2 FMQ 828 –14.48 –0.69 0.39 288-g 1.46 - - 669 1.3 Ni-Ni 749 –13.32 2.33 0.35 Sokh Massif Granodiorite 1177/11 1.86 –3.47 5.34 715 2.2 Ni-NiO 756 –14.55 0.86 0.39 1177/5 1.79 –3.72 5.51 749 2.7 F MQ 842 –13.00 0.53 0.42 Adamellite 1174 1.38 –3.74 5.12 709 2.0 F MQ 825 –14.51 –0.63 0.38 Granite 1177/9 1.48 –3.86 5.33 600 2.3 Ni-NiO 704 –15.74 0.97 0.24 1177 1.54 –3.77 5.31 713 1.8 F MQ 806 –14.64 –0.36 0.35
Notes: Temperatures are calculated for 2 kbar pressure. IV (F), IV (Cl), and IV (F/Cl), geochemical parameters of F–OH, Cl–OH, and F–Cl exchange reactions in biotite after [ 31 ]; T °C (Ti), crystallization temperature of biotite according to [ 27 ]; P, kbar, crystallization pressure according to [ 30 ]; buffer parameters T °C, Log fO 2 , ΔNi–NiO, Mg# calculated by model after [ 32 ] using MICA + program [ 31 ]. Buffer: FMQ, fayalite–magnetite–quartz; Ni–NiO, nickel–nickel; Ge–Mg, hematite–magnetite. T °C, crystallization temperature; Log fO 2 , oxygen fugacity in biotite; ΔNi–NiO, oxygen fugacity relative to Ni–NiO buffer (ΔNi–NiO = LogfO 2 (sample)–LogfO 2 (Ni–NiO)) at given temperatures.
Table 12. Formation temperatures of feldspars from EIRGD granitoids.
Table 12. Formation temperatures of feldspars from EIRGD granitoids.
Sample Rock An (%) SolvCalc Stormer Alb Ort An Alb Ergelyakh Massif 1181/3a Granodiorite 31 923 870 923 838 1022 Granodiorite 30 695 695 695 644 1184 Granodiorite 31 534 534 534 568 1184 Granodiorite 18 480 480 480 518 1184 Granodiorite 22 489 489 489 530 1184 Granodiorite 41 586 586 586 620 1017 Granodiorite 15 542 497 542 565 1017 Granodiorite 24 644 644 644 618 1017 Granodiorite 27 604 604 604 606 1017 Granodiorite 34 670 670 670 663 1017 Granodiorite 37 727 727 727 694 1213 B15 Granodiorite 31 543 543 543 542 1213 B22 Granodiorite 8 442 442 442 458 1213 B27 Granodiorite 14 463 463 463 474 1213 B28 Granodiorite 13 463 463 463 470 1213 B41 Granodiorite 9 327 327 327 383 1213 B51 Granodiorite 34 939 939 939 867 1181/3B Adamellite 33 706 720 706 692 1181/3B Adamellite 36 739 739 739 688 1181/3B Adamellite 42 761 761 761 743 1211/3 Adamellite 22 416 416 416 483 Sokh Massif 1177/5 Granodiorite 23 552 670 552 520 1174 Adamellite 26 569 574 574 602
Notes: Temperatures are calculated for 2 kbar pressure.
Table 13. fO 2 values for Ergelyakh and Sokh massif granitoids.
Table 13. fO 2 values for Ergelyakh and Sokh massif granitoids.
Sample Rock Rock Biotite Log fO 2 (T Ti ) ΔNi–NiO Log fO 2 (T Bi ) ΔNi–NiO Ergelyakh Massif 1181/3a Granodiorite –16.098 (882) –3.35 –14.950 (764) 0.292 1017 –11.292 (901) 1.18 –16.74 (743) –1.134 1022 –16.826 (857) –3.60 –15.02 (754) 0.443 1184 –16.317 (866) 3.26 –14.96 (796) 0.344 1016 –14.517 (870) –1.54 - - 1212 –12.138 (881) –0.634 - - 1015 –13.161 (870) –0.18 - - 1178/4 Adamellite –17.159 (839) –3.82 - - 1210 –14.492 (855) –1.22 - - 1181/3b –14.321 (852) –0.99 –12.97 (848) 0.509 1177/1 –22.565 (828) –9.75 - - 1019 –20.783 (890) –8.18 - - 1211/3 Granite –17.38 (792) –2.79 –14.48 (829) –0.66 1021 –13.833 (721) 2.58 –19.17 (448) 6.285 1183 –19.599 (724) –3.41 –18.74 (654) 0.355 1211/2 –21.207 (657) –3.20 - - 1211 –19.780 (688) –2.65 - - 1213/1 –24.870 (707) –8.241 - - 1020/1 –15.121 (776) –0.175 - - 1020/4 –14.491 (772) 0.546 - - 1020/3 –14.495 (761). 0.798 - - 278 - - –14.48 (828) –0.687 288-g - - –13.32 (749) 2.333 1017/1 Aplite –20.701 (602) –1.003 - - 1211/2 –26.214 (657) –8.21 - - 1018 –16.160 (759) –0.82 - - 1016/3 –16.360 (701) 0.426 - - 1211 –24.788 (688) –7.65 - - 1016/1 –19.266 (660) –1.349 - - 1016/2 –7.174 (679) 10.207 - - Sokh Massif 1177/11 Granodiorite –21.864 (862) –8.729 –14.55 (756) 0.86 1177/5 –16.167 (853) –2.885 –13.00 (842) 0.53 1174 Adamellite –17.450 (842) –3.918 –14.51 (825) –0.63 1177/1 –22.666 (827) –8.828 - - 1177 Granite –22.882 (538) –9.270 –14.64 (806) –0.36 1176 –22.807 (792) –8.22 - - 1177/9 –24.890 (722) –8.65 –15.74 (704) 0.97 1177/2 Aplite –23.895 (737) –8.026 - - 1177/6 –18.468 (688) –1.334 - - 1177/8 –19.268 (640) –0.763 - - 1175/1 –25.961 (658) –7.986 - - 1177/3 –25.068 (686) –7.879 - -
Note: ΔNi–NiO fO 2 value relative to Ni–NiO buffer calculated for 2 kbar. Temperature in parentheses.
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Zaitsev, A.I.; Fridovsky, V.Y.; Kudrin, M.V. Granitoids of the Ergelyakh Intrusion-Related Gold–Bismuth Deposit (Kular-Nera Slate Belt, Northeast Russia): Petrology, Physicochemical Parameters of Formation, and Ore Potential. Minerals 2019, 9, 297.
https://doi.org/10.3390/min9050297
AMA Style
Zaitsev AI, Fridovsky VY, Kudrin MV. Granitoids of the Ergelyakh Intrusion-Related Gold–Bismuth Deposit (Kular-Nera Slate Belt, Northeast Russia): Petrology, Physicochemical Parameters of Formation, and Ore Potential. Minerals. 2019; 9(5):297.
https://doi.org/10.3390/min9050297
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Zaitsev, Albert I., Valery Yu. Fridovsky, and Maxim V. Kudrin. 2019. "Granitoids of the Ergelyakh Intrusion-Related Gold–Bismuth Deposit (Kular-Nera Slate Belt, Northeast Russia): Petrology, Physicochemical Parameters of Formation, and Ore Potential" Minerals9, no. 5: 297.
https://doi.org/10.3390/min9050297
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Zaitsev, A.I.; Fridovsky, V.Y.; Kudrin, M.V. Granitoids of the Ergelyakh Intrusion-Related Gold–Bismuth Deposit (Kular-Nera Slate Belt, Northeast Russia): Petrology, Physicochemical Parameters of Formation, and Ore Potential. Minerals 2019, 9, 297.
https://doi.org/10.3390/min9050297
AMA Style
Zaitsev AI, Fridovsky VY, Kudrin MV. Granitoids of the Ergelyakh Intrusion-Related Gold–Bismuth Deposit (Kular-Nera Slate Belt, Northeast Russia): Petrology, Physicochemical Parameters of Formation, and Ore Potential. Minerals. 2019; 9(5):297.
https://doi.org/10.3390/min9050297
Chicago/Turabian Style
Zaitsev, Albert I., Valery Yu. Fridovsky, and Maxim V. Kudrin. 2019. "Granitoids of the Ergelyakh Intrusion-Related Gold–Bismuth Deposit (Kular-Nera Slate Belt, Northeast Russia): Petrology, Physicochemical Parameters of Formation, and Ore Potential" Minerals9, no. 5: 297.
https://doi.org/10.3390/min9050297
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About DAVID CREIGHTON SULLIVAN
David Sullivanis a pediatrician established inWashington, District Of Columbiaand his medical specialization isPediatrics. The NPI number of this provider is1124295985and was assigned on May 2008. The practitioner's primary taxonomy code is208000000Xwith license number MD044794 (DC). The provider is registered as an individual and his NPI record was last updated 6 years ago.
NPI 1124295985
Provider Name DAVID CREIGHTON SULLIVAN
Location Address 111 MICHIGAN AVE NW WASHINGTON, DC 20010
Location Phone (202) 476-5000
Mailing Address PO BOX 37215 BALTIMORE, MD 21297
Gender Male
NPI Entity Type Individual
Is Sole Proprietor? Yes
Enumeration Date 05-12-2008
Last Update Date 02-13-2017
A pediatrician like David Sullivan is a physician who has completed a pediatric residency and is board-certified or board-eligible in a pediatric specialty. Pediatric care providers are trained to care for newborns, infants, children and adolescents. A pediatrician could perform physical exams, manage vaccinations, monitor development milestones, diagnose illnesses, infections, injuries or other health problems, etc.David Sullivan isenrolled in PECOSand is eligible to order or refer health care services for Medicare patients. The provider is eligible to order or refer: Part B Clinical Laboratory and Imaging, Durable Medical Equipment (DME), a Home Health Agency (HHA) and Power Mobility Devices..
Primary Taxonomy
The primary taxonomy code defines the provider type, classification, and specialization. There could be only one primary taxonomy code per NPI record. For individual NPIs the license data is associated to the taxonomy code.
Taxonomy Code 208000000X
Classification Pediatrics
Type Allopathic & Osteopathic Physicians
License No. MD044794
License State DC
Taxonomy Description
A pediatrician is concerned with the physical, emotional and social health of children from birth to young adulthood. Care encompasses a broad spectrum of health services ranging from preventive healthcare to the diagnosis and treatment of acute and chronic diseases. A pediatrician deals with biological, social and environmental influences on the developing child, and with the impact of disease and dysfunction on development.
Business Address
111 MICHIGAN AVE NW
WASHINGTON, DC
ZIP 20010
Phone: (202) 476-5000
Mailing Address
PO BOX 37215
BALTIMORE, MD
ZIP 21297
Phone: (202) 476-5000
Location Map
PECOS Enrollment and Medicare Participation Status
What is PECOS?
PECOS is the Medicare Provider, Enrollment, Chain and Ownership System. PECOS is Medicare's enrollment and revalidation system and it is the primary source of information about verified Medicare professionals. A NPI number is necessary to register in PECOS. Providers must enroll in PECOS to avoid denied claims.
Registered in PECOS? Yes
Eligible order / refer Part B Clinical Laboratory and Imaging Yes
Eligible order / refer Durable Medical Equipment Yes
Eligible order / refer Home Health Agency (HHA) Yes
Eligible order / refer Power Mobility Devices Yes
Physician Office Visit Costs
The provider accepts as payment the Medicare approved amount. Medicare beneficiaries should not be billed for more than the Medicare deductible and coinsurance amounts. Medicare pricing is usually a reference point for private insurance covered patients. The prices below reflect the costs for new and established patients in the 20010 ZIP code area.
<table><tr><th colspan=3> New Patients Office Visits Costs *</th></tr><tbody><tr><td colspan=3> Most Utilized Procedure Code for new patients office visits: 99203</td></tr><tr><td> Minimum New Patient Pricing</td><td> Maximum New Patient Pricing</td><td> Typical New Patient Pricing</td></tr><tr><td> $68.56</td><td> $204.56</td><td> $104.59</td></tr><tr><td> Minimum New Patient Copayment</td><td> Maximum New Patient Copayment</td><td> Typical New Patient Copayment</td></tr><tr><td> $17.14</td><td> $51.14</td><td> $26.14</td></tr></tbody></table>
<table><tr><th colspan=3> Established Patients Office Visits Costs *</th></tr><tbody><tr><td colspan=3> Most Utilized Procedure Code for established patients office visits: 99214</td></tr><tr><td> Minimum Established Patient Pricing</td><td> Maximum Established Patient Pricing</td><td> Typical Established Patient Pricing</td></tr><tr><td> $21.87</td><td> $167.24</td><td> $120.2</td></tr><tr><td> Minimum Established Patient Copayment</td><td> Maximum Established Patient Copayment</td><td> Typical Established Patient Copayment</td></tr><tr><td> $5.46</td><td> $41.81</td><td> $30.05</td></tr></tbody></table>
* The physician office visit costs information is obtained by Medicare's statistical analysis of similar providers in the same geographical area. The pricing information above IS NOT the amount charged by this provider.
NPI Validation Check Digit Calculation
The following table explains the step by step NPI number validation process using the ISO standard Luhn algorithm.
Start with the original NPI number, the last digit is the check digit and is not used in the calculation.
1 1 2 4 2 9 5 9 8 5
Step 1: Double the value of the alternate digits, beginning with the rightmost digit.
2 1 4 4 4 9 10 9 16
Step 2: Add all the doubled and unaffected individual digits from step 1 plus the constant number 24.
2 + 1 + 4 + 4 + 4 + 9 + 1 + 0 + 9 + 1 + 6 + 24= 65
Step 3: Subtract the total obtained in step 2 from the next higher number ending in zero, the result is the check digit.
70 - 65 = 5 5
The NPI number 1124295985 is valid because the calculatedcheck digit 5using the Luhn validation algorithm matches the last digit of the original NPI number.
1417957879
DR. KELLY D. STONE M.D., PH.D.
Individual
Pediatrics (Pediatric Allergy/Immunology)
111 MICHIGAN AVE NW 111 MICHIGAN AVENUE, NW
WASHINGTON, DC 20010
(202) 884-4013
1457351819 DR. TERRY R KIND M.D., MPH
Individual Pediatrics 111 MICHIGAN AVE NW
WASHINGTON, DC 20010
(202) 884-4013
1184604050 DR. RUTH ELLEN HOLLO MD
Individual Pediatrics 111 MICHIGAN AVE NW
WASHINGTON, DC 20010
(202) 476-6878
1518935451
DR. GEETANJALI SRIVASTAVA MD
Individual
Pediatrics (Pediatric Emergency Medicine)
111 MICHIGAN AVE NW CHILDREN'S NATIONAL MEDICAL CENTER
WASHINGTON, DC 20010
(202) 884-4177
1194785311
DR. LAWRENCE J. D'ANGELO MD
Individual
Internal Medicine
111 MICHIGAN AVE NW CHILDREN'S NATIONAL MEDICAL CENTER
WASHINGTON, DC 20010
(202) 476-3068
1831156942
DR. ANASTASSIOS CONSTANTIN KOUMBOURLIS MD, MPH
Individual
Pediatrics (Pediatric Pulmonology)
111 MICHIGAN AVE NW CHILDREN'S NATIONAL MEDICAL CENTER, SUITE 1030
WASHINGTON, DC 20010
(202) 476-2642
1457319006
DR. ANITHA SARA JOHN MD PHD
Individual
Internal Medicine (Cardiovascular Disease)
111 MICHIGAN AVE NW
WASHINGTON, DC 20010
(301) 572-1320
1831149426 CLARIVET TORRES MD
Individual Pediatrics (Pediatric Gastroenterology) 111 MICHIGAN AVE NW
WASHINGTON, DC 20010
(202) 884-3058
1396797023 BRIAN R JACOBS M.D.
Individual Pediatrics (Pediatric Critical Care Medicine) 111 MICHIGAN AVE NW CMIO
WASHINGTON, DC 20010
(202) 884-3969
1538104120 ANIL DARBARI M.D.
Individual Pediatrics 111 MICHIGAN AVE NW GASTROENTEROLOGY, WW2.5
WASHINGTON, DC 20010
(202) 476-3032
1073541173 MS. CHRISTINE LYNN DANIELSON CPNP
Individual Nurse Practitioner (Pediatrics) 111 MICHIGAN AVE NW UROLOGY
WASHINGTON, DC 20010
(202) 476-5042
1043240674
PETER R. HOLBROOK MD
Individual
Pediatrics (Pediatric Critical Care Medicine)
111 MICHIGAN AVE NW
WASHINGTON, DC 20010
(202) 884-3256
1912938929 DIANE L MORRISON NP
Individual Nurse Practitioner 111 MICHIGAN AVE NW
WASHINGTON, DC 20010
(202) 476-5000
1013949726 PAUL EDWARD MANICONE MD
Individual Pediatrics 111 MICHIGAN AVE NW WEST WING, FLOOR 1.5 SUITE 600
WASHINGTON, DC 20010
(202) 884-5000
1992723845
DR. PAVAN PRADHUMA ZAVERI MD
Individual
Pediatrics (Pediatric Emergency Medicine)
111 MICHIGAN AVE NW
WASHINGTON, DC 20010
(202) 884-4177
1982611059
DR. JUDY SHIH-HWA LIU MD. PHD.
Individual
Psychiatry & Neurology (Neurology)
111 MICHIGAN AVE NW
WASHINGTON, DC 20010
(202) 476-2383
1902817422 DOUGLAS MARC SILVERSTEIN MD
Individual Pediatrics (Pediatric Nephrology) 111 MICHIGAN AVE NW
WASHINGTON, DC 20010
(202) 884-5058
Frequently Asked Questions
What is David Sullivan NPI number?
The NPI number assigned to this healthcare provider is 1124295985, registered as an "individual" on May 12, 2008
Where is David Sullivan located?
The provider is located at 111 Michigan Ave Nw Washington, Dc 20010 and the phone number is (202) 476-5000
Which is David Sullivan specialty?
The provider's speciality is Pediatrics
Is David Sullivan registered in PECOS?
Yes, as of June 08, 2023 the provider is registered in PECOS and is eligible to order health care services or supplies for Medicare patients. If you are a Medicare beneficiary the provider is eligible to order or refer: Part B Clinical Laboratory and Imaging, Durable Medical Equipment (DME), a Home Health Agency (HHA) and Power Mobility Devices.
How much is a visit to David Sullivan ?
Medicare beneficiaries should expect a typical cost of $104.59 with an average copayment of $26.14 for new patient appointments. Established patients should expect a typical charge of $120.2 and an average copayment of 30.05. Please review your insurance plan or contact the provider directly to determine your specific costs.
How do I update my NPI information?
The NPI record of David Sullivan was last updated on May 12, 2008. To officially update your NPI information contact the National Plan and Provider Enumeration System (NPPES) at 1-800-465-3203 (NPI Toll-Free) or by email [email protected].
NPI Profile data is regularly updated with the latest NPI registry information, if you would like to update or remove your NPI Profile in this website pleasecontact us.
| https://npiprofile.com/npi/1124295985 |
Question for experienced cattle people | BackYard Chickens - Learn How to Raise Chickens
I have a Dexter cow that is due now and last Wednesday just before I left on a mini vacation, I noticed her udder was huge looked like a jersey ready to...
Question for experienced cattle people
I have a Dexter cow that is due now and last Wednesday just before I left on a mini vacation, I noticed her udder was huge looked like a jersey ready to milk. I asked DH to keep an eye on her I thought she'd deliver within a few days. When I came home Sunday, her udder was only half the size and the vulva looked a little gaping. I was sure she had delivered so I looked all over for a baby in hiding and couldn't find anything. She stays with the herd, moving back and forth between the barn and the 40 acres they have. I'm a little befuddled. Do they normally have the udder go back down in size? I'm thinking either she had it and lost it to a predator or ???? This is her first calf and it's hard to tell looking at her if there's still a baby in there.
Does she have any discharge or possibly even part of a placenta hanging out? Is she "off" at all?
That does sound odd...
Quote:
No discharge, isn't off her feed. She's approached me a few times which she normally doesn't do, she's usually a little stand offish. I had the guy I bought her from come look at her and he was a little stumped too. He said her udder looked like she'd been nursing a calf or possibly drying up or maybe still pregnant. Wasn't much help! I'll post if I find anything.
I don't really know anything about cows, but I thought that they'd leave their newborn calf laying hidden somewhere and the cow would return to the calf periodically to feed the calf.
Any chance the calf is hidden somewhere in the pasture?
Please ignore this post if it's completely ignorant....I just thought I'd ask...
Good luck!
Some cows are really good at hiding those babies and will take up to a week before allowing them to join the herd. Occasionally a cow will allow another calf to nurse. Rarely but at times share-nursing will happen. If she is eating well and appears comfortable I think you are okay. Although you can always have a vet come out and palpate to be on the safe side.
If she had lost her calf, her udder would be even larger and engorged with milk plus she'd more than likely be hollering for it. Also if she's delivered her vulva won't be as swollen looking as it does before they calve. She's probably just got it hidden well. We've about walked right over a new calf hidden and hunkered down in the grass or bushes before.
Is hiding the calf a dairy thing? We have beef cows and all our calves are up walking around with the mothers after they're born. Of course, they aren't on hundreds of acres of pasture - more like 6 acres. The cows and calves would stay basically in the area they were born in for the first few days and then the mothers pushed the calves up to the "main" pasure area (if they weren't already born there).
Can you take a picture of her udder and teats and vagina? If she's being nursed, her teats will look either wet/shiny/shrivled or dry/cracked/shrivled depending on how recently she was nursed. And looking at her vagina will help in seeing how swollen or unswollen she is too.
All our beef cows do it when they calve out in the pasture......not when they're in the lot here at home tho.
Katy, I was wondering when you'd join in here!
I just got home from work and checked on her. It looks to me like her udder is even smaller. The pastures are cross fenced with 2 strand hot wire. The lowest strand is 24 inches so I'd think a little Dexter could get underneath it without a problem. The grass is not high enough for one to hide in but just outside the fence it is. I've driven around it several times now and can't find a thing. I would think that if she had a baby hidden somewhere that she wouldn't stray very far from it??? She moves up to the barn with the herd which is a fair distance to leave behind a newborn. But then I don't know cows. I raise donkeys and this is my first experience with a bred heifer. I'm just totally confused. It seems to me like shes's drying up. I've not heard her call for baby nor have I heard a baby bawling. I've been watching her frequently and haven't seen any different kind of behavior. Vulva looks normal, no discharge or swelling. Is it possible for coyotes to drag one off?
<here is a image b1e175597dc56652-b25c477d2bf7edd6>
Some cows can really hide a calf. The calf will hunker down and not move. Mom will not acknowledge her calf or call to it until she's ready.
Check out this photo of one of our hidden calves. Not a sound out of her. Mom totally ignored her until I got too close.
<here is a image 0d80ad057b0d0b60-5db24cb55552c385>
| https://www.backyardchickens.com/threads/question-for-experienced-cattle-people.478463/ |
Pressure and temperature effects on planktonic stages of benthic invertebrates with regard to their potential for invasion of the deep sea
Download Citation | Pressure and temperature effects on planktonic stages of benthic invertebrates with regard to their potential for invasion of the deep sea | p>This thesis investigates the embryonic and larval responses to changes in hydrostatic pressure and temperature in four species of shallow-water... | Find, read and cite all the research you need on ResearchGate
Thesis
Pressure and temperature effects on planktonic stages of benthic invertebrates with regard to their potential for invasion of the deep sea
Abstract
p>This thesis investigates the embryonic and larval responses to changes in hydrostatic pressure and temperature in four species of shallow-water invertebrates.
Chapters 2 and 3 describe the results obtained for echinoid species. Results from Psammechinus miliaris are similar to previous work on echinoids. Despite the negative effects of hydrostatic pressures and low temperatures on embryonic development, larvae of Psammechinus miliaris were able to tolerate hydrostatic pressure and temperatures conditions that prevail far beyond the depth limit of the adult. Differences in temperature/pressure effects on dispersal stages between a northern and a southern population of Echinus esculentus were also investigated. The results suggest that the northern population is better adapted to low temperature.
Chapter 4 and 5 focus on Patellidae (Gastropoda) species. Increasing hydrostatic pressure and low temperature had strong negative effects on trochophores of Patella vulgata and Patella ulyssiponensis. These results do not conform to previous results in this field and show that many more taxonomic groups need to be investigated before we know how widespread, among shallow-water invertebrates, is the physiological potential for larval migration into deep sea. The implications of larval temperature tolerances for latitudinal distributions are also discussed.</p
Discover the world's research
25+ million members
... Another layer of complexity resides in the fact that the measurable effects of pressure may vary both across taxa and across life stages of a given species (e.g. Tyler & Dixon 2000
, Aquino-Souza 2006
, Villalobos et al. 2006, Yoshiki et al. 2006, Munro et al. 2015, Brown et al. 2017. Beyond the choice of model animals (or life stages), procuring them may present additional challenges. ...
... Pressure tolerance is often viewed as one of the predictors of vertical migration in marine species (Young et al. 1997, Tyler & Young 1998
, Aquino-Souza 2006
, Villalobos et al. 2006, Smith & Thatje 2012, Sumida et al. 2015. Based on this assumption, we evaluate whether empirical data of pressure tolerance (as per cent survival and survival duration; see Appendix) provide support for shallow-deep or deep-shallow transitions, or whether bi-directional colonization may offer a more parsimonious explanation. ...
... Echinodermata. Species of shallow-water echinoderms (sea stars and sea urchins) collected from the Northeast Atlantic and Antarctica had high survival (mostly >80%) when compressed for 24-48 hours to pressures characteristic of depths greater than their natural occurrence (Tyler & Young 1998
, Aquino-Souza 2006
, Villalobos et al. 2006. Other experiments tested the larvae of sea cucumbers Apostichopus japonicus from the western Pacific for as little as 7 minutes and found that survival reduced as pressure increased (Ding et al. 2007). ...
Vertical Faunal Exchange in the Ocean and the Deep Source-Sink Hypotheses: A Review from the Perspective of Pressure Tolerance Studies
Chapter
Full-text available
Justine Ammendolia
Alastair Brown
... These studies also suggest that hydrostatic pressure tolerance is influenced by species' thermal adaptive history. Experimental evidence assessing tolerance to hydrostatic pressure indicates that organismal tolerance to the effects of high hydrostatic pressure can vary through ontogeny (George, 1984;Young et al., 1997;Tyler & Young, 1998;
Aquino-Souza, 2006;
Benitez Villalobos et al., 2006;Yoshiki et al., 2006Yoshiki et al., , 2008Yoshiki et al., , 2011Aquino-Souza et al., 2008;Smith & Thatje, 2012;Mestre et al., 2013). ...
... Seasonal acclimatisation to low temperature appears to increase tolerance to hydrostatic pressure (Naroska, 1968) implying that the requirements for thermal and hyperbaric acclimatisation may be congruent. Similar variation in hydrostatic pressure tolerance has been reported for latitudinally distinct populations of a single species, although genetic variation may contribute to this pattern
(Aquino-Souza, 2006)
. Surprisingly, however, limited research has so far indicated that critical pressure tolerance is unaffected by hydrostatic pressure acclimation (Mickel & Childress, 1982a;. ...
Explaining bathymetric diversity patterns in marine benthic invertebrates and demersal fishes: physiological contributions to adaptation of life at depth
Article
Sven Thatje
Bathymetric biodiversity patterns of marine benthic invertebrates and demersal fishes have been identified in the extant fauna of the deep continental margins. Depth zonation is widespread and evident through a transition between shelf and slope fauna from the shelf break to 1000 m, and a transition between slope and abyssal fauna from 2000 to 3000 m; these transitions are characterised by high species turnover. A unimodal pattern of diversity with depth peaks between 1000 and 3000 m, despite the relatively low area represented by these depths. Zonation is thought to result from the colonisation of the deep sea by shallow-water organisms following multiple mass extinction events throughout the Phanerozoic. The effects of low temperature and high pressure act across hierarchical levels of biological organisation and appear sufficient to limit the distributions of such shallow-water species. Hydrostatic pressures of bathyal depths have consistently been identified experimentally as the maximum tolerated by shallow-water and upper bathyal benthic invertebrates at in situ temperatures, and adaptation appears required for passage to deeper water in both benthic invertebrates and demersal fishes. Together, this suggests that a hyperbaric and thermal physiological bottleneck at bathyal depths contributes to bathymetric zonation. The peak of the unimodal diversity–depth pattern typically occurs at these depths even though the area represented by these depths is relatively low. Although it is recognised that, over long evolutionary time scales, shallow-water diversity patterns are driven by speciation, little consideration has been given to the potential implications for species distribution patterns with depth. Molecular and morphological evidence indicates that cool bathyal waters are the primary site of adaptive radiation in the deep sea, and we hypothesise that bathymetric variation in speciation rates could drive the unimodal diversity–depth pattern over time. Thermal effects on metabolic-rate-dependent mutation and on generation times have been proposed to drive differences in speciation rates, which result in modern latitudinal biodiversity patterns over time. Clearly, this thermal mechanism alone cannot explain bathymetric patterns since temperature generally decreases with depth. We hypothesise that demonstrated physiological effects of high hydrostatic pressure and low temperature at bathyal depths, acting on shallow-water taxa invading the deep sea, may invoke a stress–evolution mechanism by increasing mutagenic activity in germ cells, by inactivating canalisation during embryonic or larval development, by releasing hidden variation or mutagenic activity, or by activating or releasing transposable elements in larvae or adults. In this scenario, increased variation at a physiological bottleneck at bathyal depths results in elevated speciation rate. Adaptation that increases tolerance to high hydrostatic pressure and low temperature allows colonisation of abyssal depths and reduces the stress–evolution response, consequently returning speciation of deeper taxa to the background rate. Over time this mechanism could contribute to the unimodal diversity–depth pattern.
... These studies also suggest that hydrostatic pressure tolerance is influenced by species' thermal adaptive history. Experimental evidence assessing tolerance to hydrostatic pressure indicates that organismal tolerance to the effects of high hydrostatic pressure can vary through ontogeny (George, 1984;Young et al., 1997;Tyler & Young, 1998;
Aquino-Souza, 2006;
Benitez Villalobos et al., 2006;Yoshiki et al., 2006Yoshiki et al., , 2008Yoshiki et al., , 2011Aquino-Souza et al., 2008;Smith & Thatje, 2012;Mestre et al., 2013). ...
... Seasonal acclimatisation to low temperature appears to increase tolerance to hydrostatic pressure (Naroska, 1968) implying that the requirements for thermal and hyperbaric acclimatisation may be congruent. Similar variation in hydrostatic pressure tolerance has been reported for latitudinally distinct populations of a single species, although genetic variation may contribute to this pattern
(Aquino-Souza, 2006)
. Surprisingly, however, limited research has so far indicated that critical pressure tolerance is unaffected by hydrostatic pressure acclimation (Mickel & Childress, 1982a;. ...
Explaining bathymetric diversity patterns in marine benthic invertebrates and demersal fishes: Physiological contributions to adaptation of life at depth
BIOL REV
Alastair Brown
Sven Thatje
Bathymetric biodiversity patterns of marine benthic invertebrates and demersal fishes have been identified in the extant fauna of the deep continental margins. Depth zonation is widespread and evident through a transition between shelf and slope fauna from the shelf break to 1000 m, and a transition between slope and abyssal fauna from 2000 to 3000 m; these transitions are characterised by high species turnover. A unimodal pattern of diversity with depth peaks between 1000 and 3000 m, despite the relatively low area represented by these depths. Zonation is thought to result from the colonisation of the deep sea by shallow-water organisms following multiple mass extinction events throughout the Phanerozoic. The effects of low temperature and high pressure act across hierarchical levels of biological organisation and appear sufficient to limit the distributions of such shallow-water species. Hydrostatic pressures of bathyal depths have consistently been identified experimentally as the maximum tolerated by shallow-water and upper bathyal benthic invertebrates at in situ temperatures, and adaptation appears required for passage to deeper water in both benthic invertebrates and demersal fishes. Together, this suggests that a hyperbaric and thermal physiological bottleneck at bathyal depths contributes to bathymetric zonation. The peak of the unimodal diversity-depth pattern typically occurs at these depths even though the area represented by these depths is relatively low. Although it is recognised that, over long evolutionary time scales, shallow-water diversity patterns are driven by speciation, little consideration has been given to the potential implications for species distribution patterns with depth. Molecular and morphological evidence indicates that cool bathyal waters are the primary site of adaptive radiation in the deep sea, and we hypothesise that bathymetric variation in speciation rates could drive the unimodal diversity-depth pattern over time. Thermal effects on metabolic-rate-dependent mutation and on generation times have been proposed to drive differences in speciation rates, which result in modern latitudinal biodiversity patterns over time. Clearly, this thermal mechanism alone cannot explain bathymetric patterns since temperature generally decreases with depth. We hypothesise that demonstrated physiological effects of high hydrostatic pressure and low temperature at bathyal depths, acting on shallow-water taxa invading the deep sea, may invoke a stress-evolution mechanism by increasing mutagenic activity in germ cells, by inactivating canalisation during embryonic or larval development, by releasing hidden variation or mutagenic activity, or by activating or releasing transposable elements in larvae or adults. In this scenario, increased variation at a physiological bottleneck at bathyal depths results in elevated speciation rate. Adaptation that increases tolerance to high hydrostatic pressure and low temperature allows colonisation of abyssal depths and reduces the stress-evolution response, consequently returning speciation of deeper taxa to the background rate. Over time this mechanism could contribute to the unimodal diversity-depth pattern.
Two main stages in the evolution of the deep-sea fauna of elasipodid holothurians
Zonation of Deep Biota on Continental Margins
| https://www.researchgate.net/publication/361919029_Pressure_and_temperature_effects_on_planktonic_stages_of_benthic_invertebrates_with_regard_to_their_potential_for_invasion_of_the_deep_sea |
Does God Love the Devil? | Reasonable Faith
Dr. William Craig answers weekly Questions and Answers on Christian Doctrine and apologetics. Read question Does God Love the Devil? here.
#524 Does God Love the Devil?
Q
Greetings Dr Craig,
I am a Muslim, from the westernmost parts of Africa. I have been following your work for years, watching practically all your debates, reading some of your articles and much of the weekly Q&A section.
Even though I am not a Christian, you have helped me greatly in my own pursuit of truth, to identify much more with the issues that Christians face today, and in learning to appreciate the Christian tradition in philosophical and theological thought.
What I would like to have some clarification about is the following (I will use quotes for things you affirmed):
You have argued in some of your work that since God is the greatest conceivable being, since He is morally perfect and since loving is morally better than not loving, then He must be "all-loving"; also, as the greatest conceivably loving being His love must be "unconditional, impartial and universal" even for those who are “damned and who have rejected Him forever”.
- Is it not true then that His love for all includes the Devil? For if it were not the case then there would be at least one eternally damned being whom God does not love or loves less, i.e., He is not all-loving or the greatest conceivably loving being.- Is it not true that His impartial love is for Jesus as much as it is for the Devil?- Is it not true that His love for the Devil prior to his falling is the same as it is after, since it is unconditional, not conditioned by the choices of the Devil?
Thank you immensely.
Best regards,
Adami
Mauritania
Dr. craig’s response
A
It’s wonderful to think that you’ve been reading and reflecting on my work all these years, Adami! I should very much like to visit your region of the world someday.
Your question derives from my plausibility argument for the doctrine of the Trinity. Since God is essentially loving and love involves giving oneself to another person, and since created persons exist only contingently, God must be a plurality of persons, in contradiction to unitarian conceptions of God as a single person.
I’m not sure if the intent of your questions is to force me into an awkward position. But I feel no awkwardness whatever in affirming that God most certainly does love Satan. Indeed, what I should find awkward would be affirming that He does not! God is a perfectly loving being, whose love is not based on a person’s performance. Satan is a person, indeed, on the traditional conception an angelic person of unparalleled beauty and perfection among creatures. How could God not love him? The fact that that person is now fallen and unspeakably evil does not imply that God ceases to love him, any more than He ceased to love us when we fell and became enemies of God (Romans 5.10).
Notice that my claim is that God loves everyone universally, impartially, and unconditionally. It is no part of my claim that God loves everyone equally. Even if God loves all human persons equally, Christ on the Christian conception is not a human person, but a divine person, the second person of the Trinity, and therefore plausibly the special object of the Father’s love.
So in short answer to your questions:
- Is it not true that God’s love for all includes the Devil?It is true.- Is it not true that His impartial love is for Jesus as much as it is for the Devil?I see no reason to think so.- Is it not true that His love for the Devil prior to his falling is the same as it is after?It is true.
- William Lane Craig
| https://www.reasonablefaith.org/question-answer/P150/does-god-love-the-devil |
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From:
Laurie Kamrowski-Lamb
Date:
Wed, Feb 20 2019 11:28AM
Subject:
Making older PDFs accessible
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Hi all!
I'm new to the forum, and I work for a small community college and have
been tasked with updating all previous PDFs created by the school for
accessibility. I am working with the table editor in Adobe Acrobat DC Pro
Continuous Release, on a Windows 10 machine. I am using
NVDA to check everything.
The majority of the project is that:
1) I can only work with Metadata
2) I cannot alter or change anything because these particular PDFs are the
official meeting minutes of the board of directors
The biggest problem that I am encountering are multi-level deep complex
tables (I have an example image if anyone wants to look but wasn't sure
about attaching it directly to the list serv) that are financial in nature.
In addition to other things such as power point and 'Statements of
revenues and expenses', etc..
So here are my questions:
1) How reliable is the accessibility check in Adobe Acrobat? I have been
having multiple crashes a day when I work with the larger tables.
2) Is there a way to manually encode the tables metadata? I am having
multiple issues where, for an unknown reason, the tables are either
skipping lines or occupying two or three rows, with no rhyme or reason. Is
there a different program to be able to encode these tables or is there a
way to manually encode these?
Any and all input or advice is more than welcome and appreciated,
Laurie
From:
glen walker
Date:
Wed, Feb 20 2019 11:59AM
Subject:
Re: Making older PDFs accessible
← Previous message
| Next message →
Sounds like you might be having trouble with colspan or rowspan if it's
skipping rows. Adobe is in the middle of a 6-part webinar series talking
about PDF remediation. Last week they talked about tables so it might be
worth watching:
https://youtu.be/kcM_jyHGd6Y?t=339
(the url skips the first 5-ish minutes but you can move the seek bar to the
beginning if you want)
Glen
From:
Philip Kiff
Date:
Wed, Feb 20 2019 12:40PM
Subject:
Re: Making older PDFs accessible
← Previous message
| Next message →
Hi Laurie,
Welcome to the WebAIM mailing list!
As Glen suggest, if a table is causing your table editor to crash, the
problem is usually related to incorrect row or column "span" settings on
one or more cells. PDF files that have been generated by (especially old
versions of) Microsoft Office sometimes have all kinds of extra cells or
rows or columns with incorrect span settings.
You can sometimes get a table back into an editable state by changing
all the span attributes (both row span and column span) on all TH's to
TD's for all cells in a table to 1. But this can be tricky to do in
Acrobat unless you can actually open the table in the table editor.
You can manually edit a span by editing the properties of the TH or TD
tag, but I don't have a good online explanation of how to do that:
- Right-click on a tag to pull up the Properties dialog (shortcut P), then
- Select Edit Tag (shortcut Alt-E), then
- Find the right Tag Element to change (!)
Also, Glen, I didn't know about these webinars, thanks for highlighting
them!
Phil.
Philip Kiff
D4K Communications
On 2019-02-20 1:59 PM, glen walker wrote:
> Sounds like you might be having trouble with colspan or rowspan if it's
> skipping rows. Adobe is in the middle of a 6-part webinar series talking
> about PDF remediation. Last week they talked about tables so it might be
> worth watching:
>
> https://youtu.be/kcM_jyHGd6Y?t=339
> (the url skips the first 5-ish minutes but you can move the seek bar to the
> beginning if you want)
>
> Glen
> > > >
From:
Philip Kiff
Date:
Wed, Feb 20 2019 1:04PM
Subject:
Re: Making older PDFs accessible
← Previous message
| Next message →
On 2019-02-20 1:28 PM, Laurie Kamrowski-Lamb wrote:
> 1) How reliable is the accessibility check in Adobe Acrobat? I have been
> having multiple crashes a day when I work with the larger tables.
The built-in Accessibility checker is a rough tool for doing a quick
check on the accessibility of a PDF. There are many things that cannot
be checked by any automated accessibility checker. And there are some
accessibility features that the automated Acrobat checker does not
evaluate.
I used to get crashes in Acrobat Pro DC more often than I do now. I find
the current release in the "Continuous Release" program to be very stable.
The most important thing for Acrobat's checker and table editor to work
is that the calculated number of cells in each row match what it
expects. If you have a TD spanning two rows, then the number of TD's in
that row must be one less than in a row which does not contain a span.
Same with columns. I have found that if you tag a complex table
perfectly, then the table editor can always open it without crashing,
and the Accessibility checker will always pass it without errors.
Note that the Acrobat table editor is not capable of managing tables
that span multiple pages. I think it should open them without crashing,
but you probably will not be able to edit anything beyond the first page
without corrupting the table.
Phil.
Philip Kiff
D4K Communications
From:
Donna Anspach
Date:
Thu, Feb 21 2019 8:32AM
Subject:
Re: Making older PDFs accessible
← Previous message
| Next message →
Hi Laurie,
Adobe just did an accessibility webinar on tables. You can access it here:
https://adobe.ly/2TJUMcb
Look for Advanced PDF Accessibility Complex Tables. There are other
sessions that may be helpful to you as well.
Hope this helps.
Donna
On Wed, Feb 20, 2019 at 11:28 AM Laurie Kamrowski-Lamb < = EMAIL ADDRESS REMOVED = >
wrote:
> Hi all!
>
> I'm new to the forum, and I work for a small community college and have
> been tasked with updating all previous PDFs created by the school for
> accessibility. I am working with the table editor in Adobe Acrobat DC Pro
> Continuous Release, on a Windows 10 machine. I am using
> NVDA to check everything.
>
> The majority of the project is that:
>
> 1) I can only work with Metadata
> 2) I cannot alter or change anything because these particular PDFs are the
> official meeting minutes of the board of directors
>
> The biggest problem that I am encountering are multi-level deep complex
> tables (I have an example image if anyone wants to look but wasn't sure
> about attaching it directly to the list serv) that are financial in nature.
> In addition to other things such as power point and 'Statements of
> revenues and expenses', etc..
>
> So here are my questions:
>
> 1) How reliable is the accessibility check in Adobe Acrobat? I have been
> having multiple crashes a day when I work with the larger tables.
>
> 2) Is there a way to manually encode the tables metadata? I am having
> multiple issues where, for an unknown reason, the tables are either
> skipping lines or occupying two or three rows, with no rhyme or reason. Is
> there a different program to be able to encode these tables or is there a
> way to manually encode these?
>
> Any and all input or advice is more than welcome and appreciated,
>
> Laurie
> > > > >
--
Donna Anspach
ATFL, LLC
(970) 227-5308
From:
Elizabeth Thomas
Date:
Thu, Feb 21 2019 12:49PM
Subject:
Re: WebAIM-Forum Digest, Vol 167, Issue 17- making older PDFs accessible
← Previous message
| No next message
Just wanted to comment that even though Adobe's webinar on remediating complex tables is great, don't be discouraged if remediating your table is not as easy as the webinar makes it seem. He made it look much easier than it normally is (especially in regards to the multi- page tables).
Sent from my iPhone
> On Feb 21, 2019, at 2:00 PM, = EMAIL ADDRESS REMOVED = wrote:
>
> Send WebAIM-Forum mailing list submissions to
> = EMAIL ADDRESS REMOVED =
>
> To subscribe or unsubscribe via the World Wide Web, visit
>
http://list.webaim.org/mailman/listinfo/webaim-forum
> or, via email, send a message with subject or body 'help' to
> = EMAIL ADDRESS REMOVED =
>
> You can reach the person managing the list at
> = EMAIL ADDRESS REMOVED =
>
> When replying, please edit your Subject line so it is more specific
> than "Re: Contents of WebAIM-Forum digest..."
> Today's Topics:
>
> 1. Re: Making older PDFs accessible (Philip Kiff)
> 2. Re: Making older PDFs accessible (Philip Kiff)
> 3. Android larg text on Chrome web view (Ajay Sharma)
> 4. Re: Android larg text on Chrome web view (Jonathan Avila)
> 5. Re: Making older PDFs accessible (Donna Anspach)
> 6. NVDA - aria-live=polite not announced (Tomlins Diane)
> <mime-attachment>
> <mime-attachment>
> <mime-attachment>
> <mime-attachment>
> <mime-attachment>
> <mime-attachment>
> > > > | https://webaim.org/discussion/mail_thread?thread=9135&id=39468 |
MTT assay of cell viability for pHLIP-modified MNPs. | Download Scientific Diagram
Download scientific diagram | MTT assay of cell viability for pHLIP-modified MNPs. from publication: Immobilization of a pH-low insertion peptide onto SiO2/aminosilane-coated magnetite nanoparticles | The covalent immobilization of a pH-low insertion peptide to aminosilane-coated magnetic nanoparticles with two core diameters (10 and 20 nm) was carried out. The materials obtained were characterized by TEM, XRD, vibrating sample magnetometry, DLS, IR spectroscopy, TGA and... | Magnetite Nanoparticles, Immobilization and Peptides | ResearchGate, the professional network for scientists.
MTT assay of cell viability for pHLIP-modified MNPs.
Source publication
Immobilization of a pH-low insertion peptide onto SiO2/aminosilane-coated magnetite nanoparticles
Alexandra Gennadevna Pershina
[...]
Alexander G. Majouga
The covalent immobilization of a pH-low insertion peptide to aminosilane-coated magnetic nanoparticles with two core diameters (10 and 20 nm) was carried out. The materials obtained were characterized by TEM, XRD, vibrating sample magnetometry, DLS, IR spectroscopy, TGA and elemental analyses. The materials did not have significant cytotoxicity, an...
Citations
... It is known that various surfactants used to stabilize MNPs significantly affect the morphology and properties of the coating formed on particles during silanization [66]. Before applying the SiO 2 coating, MNPs are commonly stabilized with organic compounds of various nature such as citric acid [19,67,68], oleic acid [69], poly(vinylpyrroli done) [19,70], poly(oxyethylene)nonylphenyl ether [71,72], lactose-f-chitosan [73], cetyltrimethylammonium bromide [74,
75]
, and others. Phosphonic acid derivatives can also be used to obtain stable colloidal solutions of MNPs [76,77]. ...
Effect of the Silica–Magnetite Nanocomposite Coating Functionalization on the Doxorubicin Sorption/Desorption
Full-text available
Alexander V. Vakhrushev
Marina S. Valova
Marina A. Korolyova
Valery N. Charushin
A series of new composite materials based on Fe3O4 magnetic nanoparticles coated with SiO2 (or aminated SiO2) were synthesized. It has been shown that the use of N-(phosphonomethyl)iminodiacetic acid (PMIDA) to stabilize nanoparticles before silanization ensures the increased content of a SiO2 phase in the Fe3O4@SiO2 nanocomposites (NCs) in comparison with materials obtained under similar conditions, but without PMIDA. It has been demonstrated for the first time that the presence of PMIDA on the surface of NCs increases the level of Dox loading due to specific binding, while surface modification with 3-aminopropylsilane, on the contrary, significantly reduces the sorption capacity of materials. These regularities were in accordance with the results of quantum chemical calculations. It has been shown that the energies of Dox binding to the functional groups of NCs are in good agreement with the experimental data on the Dox sorption on these NCs. The mechanisms of Dox binding to the surface of NCs were proposed: simultaneous coordination of Dox on the PMIDA molecule and silanol groups at the NC surface leads to a synergistic effect in Dox binding. The synthesized NCs exhibited pH-dependent Dox release, as well as dose-dependent cytotoxicity in in vitro experiments. The cytotoxic effects of the studied materials correspond to their calculated IC50 values. NCs with a SiO2 shell obtained using PMIDA exhibited the highest effect. At the same time, the presence of PMIDA in NCs makes it possible to increase the Dox loading, as well as to reduce its desorption rate, which may be useful in the design of drug delivery vehicles with a prolonged action. We believe that the data obtained can be further used to develop stimuli-responsive materials for targeted cancer chemotherapy.
... For this, we used a bifunctional PEG derivative with an active ester group capable of reacting with NH 2 groups on the MNP-SiO 2 -APS surface and a maleimide group capable of interacting with the mercapto group on the N-terminus of pHLIP. 21,22,
55
Sequential conjugation of PEG and pHLIP with APS-modified MNPs was performed according to Scheme 1b. ...
... The MNP-PEG-pHLIP nanoparticles obtained in this work have a higher peptide loading level (16 μmol/g) compared to some of previously obtained nanoconjugates (3.5 μmol/g) 22 and (4.6 μmol/g).
55
Interaction of MNPs with Cells In Vitro. Both types of tested MNPs (PEGylated and pHLIP-modified MNPs) were internalized by 4T1 and MDA-MB231 cells. ...
Smart Design of a pH-Responsive System Based on pHLIP-Modified Magnetite Nanoparticles for Tumor MRI
ACS APPL MATER INTER
Alexander M Demin
Alexandra G Pershina
Artem S Minin
Olga Ya Brikunova
Victor P Krasnov
... The synthesized MNP10 in chloroform were hydrophilized according to the protocol described by Demin et al.
[20]
: 5 mL of 50 mg/mL MNP solution in chloroform was sonicated intensively with 15 mL of 0.2 M CTAB solution in water until the grey emulsion was formed. Then the chloroform was evaporated via continuous sonication in an ultrasonic bath. ...
Non-magnetic shell coating of magnetic nanoparticles as key factor of toxicity for cancer cells in a low frequency alternating magnetic field
COLLOID SURFACE B
A.R. Iliasov
T.R. Nizamov
V.A. Naumenko
A.S. Garanina
M.A. Abakumov
This work is devoted to studying the effects of non-magnetic shell coating on nanoparticles in a low frequency alternating magnetic field (LF AMF) on tumor cells in vitro. Two types of iron oxide nanoparticles with the same magnetic core with and without silica shells were synthesized. Nanoparticles with silica shells significantly decreased the viability of PC3 cancer cells in a low frequency alternating magnetic field according to the cytotoxicity test, unlike uncoated nanoparticles. We showed that cell death results from the intracellular membrane integrity failure, and the calcium ions concentration increase with the subsequent necrosis. Transmission electron microscopy images showed that the uncoated silica nanoparticles are primarily found in an aggregated form in cells. We believe that uncoated nanoparticles lose their colloidal stability in an acidic endosomal environment after internalization into the cell due to surface etching and the formation of aggregates. As a result, they encounter high endosomal macromolecular viscosity and become unable to rotate efficiently. We assume that effective rotation of nanoparticles causes cell death. In turn, silica shell coating increases nanoparticles stability, preventing aggregation in endosomes. Thus, we propose that the colloidal stability of magnetic nanoparticles inside cells is one of the key factors for effective magneto-mechanical actuation.
... Currently, the development of approaches to produce MNPs with porous silica-shell is a hot topic due to their large specific surface area and specific porous channels, which can increase the binding capacity of biomolecules. To create thick mesoporous coating on MNPs long chain hydrophobic molecules, for example, cetyltrimethylammonium bromide (CTAB)
[37]
[38][39][40] or n-octadecyltrimethoxysilane [21] can be used. So, the great efficiency of DNA separation on magnetic nanoparticles with mesoporous compared with dense silica shell obtained without CTAB was demonstrated in Ref. [22]. ...
... Conjugation of MNP-APS or MNP@SiO 2 -APS with pHLIP was carried out by analogy with the described procedure
[37,
50,52]. A solution of EMCS (5 mg, 0.016 mmol) in MeCN (3 mL) was added to a suspension of 50 mg of MNP-APS or MNP@SiO 2 -APS in MeCN (25 mL). ...
... Based on the data of EDX and CHN-elemental analysis (wt.% of carbon), we calculated the content of the main organic components on the MNP surface (Table 1) by analogy with [43,50,52]. The resulting MNP@SiO 2 -pHLIP is turned out to contain a much larger amount of peptide (up to 22 μmol pHLIP per g of MNPs) than the materials we previously obtained based on MNPs synthesized by the co-precipitation method (3.5 μmol g − 1 ) [52] and by the method of thermal decomposition of iron (III) compounds (4.6 μmol g − 1 )
[37]
. It should be noted that in some other works [48,[61][62][63][64] describing the preparation of pHLIP nanoconjugates, the peptide content was not evaluated. ...
Silica coating of Fe3O4 magnetic nanoparticles with PMIDA assistance to increase the surface area and enhance peptide immobilization efficiency
CERAM INT
Aleksei I. Maksimovskikh
Alexander V. Mekhaev
Dmitry K. Kuznetsov
Victor P. Krasnov
The high efficiency of using N-(phosphonomethyl)iminodiacetic acid (PMIDA) as a surfactant for formation of a silica coating on Fe3O4 magnetic nanoparticles (MNPs) with a large surface area has been demonstrated. The coating of PMIDA-stabilized MNPs with silica and their further APS-functionalization significantly increased the specific area (up to 203 m² g⁻¹) and the number of amino groups (up to 1.12 mmol/g) grafted on their surface compared to nanomaterials synthesized without preliminary SiO2-coating. The comparative study of the peptide modification efficiency, using as an example pH-low insertion peptide (pHLIP), of MNPs coated with 3-aminopropylsilane (APS) or SiO2/APS was carried out. It has been shown that silica coating of PMIDA-stabilized MNPs leads to a significant increase in the degree of immobilization of the peptide (up to 22 μmol per g of MNPs). Comprehensive characterization of the obtained materials at each stage of the synthesis was carried out using scanning electron microscopy (SEM), energy dispersive X-ray fluorescence spectroscopy (EDX), BET analysis, ATR Fourier transformed infrared spectroscopy (FTIR), termogravimetric analysis (TGA), CHN-elemental analysis, dynamic light scattering (DLS), and vibrating sample magnetometry (VSM). The proposed approach to applying SiO2-coating of MNPs can be useful for design of new materials for biomedical and chemical purposes.
View
... In this work, the number of immobilized organic molecules on the surface of MNPs was calculated using the results of CHN elemental analysis and TGA. 31,
[40]
[41][42] The amount of APS residues on the nanoparticle surface was determined according to the results of CHN elem ental analysis based on the percentage of C in the sample 31,34,41 using formula (1) and according to the results of IR spectroscopy by means of the procedure developed earlier 42 using formula (2) ( Table 1): ...
Derivatives of RGD peptides are promising vector molecules for targeting biomolecules and nanoparticles into tumor tissues and are used for the design of diagnostic agents. The immobilization of the glutaryl-containing derivative of Gly-l-Arg(Pbf)-Gly-l-Asp(OMe)2 (GRGD) tetrapeptide on Fe3O4 magnetic nanoparticles (MNPs) was studied. The results of thermogravimetric and elemental analysis, as well as IR spectroscopy, were used to estimate the amount of organic components at each stage of modification of MNPs.
... The successful immobilization of PEG and pHLIP on the MNP-APS surface was verified by FTIR spectroscopy (Figures 1, E and S3). The immobilization of the organic components on NPs was quantified by TGA as described in Demin et al and Pershina et al. 9 ,21,
22
The resulting MNP-PEG-pHLIP contained 1.1-1.2 wt.% of physically adsorbed H 2 O, 0.73 mmol/g APS, and up to 19 μmol/g PEG-pHLIP (Figure 1, D, Tables S4 and S5). ...
5]
(Scheme 1). (3-Aminopropyl) trimethoxysilane (APTMS, 97%; Alfa Aesar, England), 6-maleimidohexanoic acid N-hydroxysuccinimide ester (EMCS; Fluka, USA), pHlow insertion peptide (NH 2 -ACEQNPIYWARYADWLFTTPLLLLDLALLVDADEGT-COOH) (pHLIP; Bachem, USA) were applied. ...
| https://www.researchgate.net/figure/MTT-assay-of-cell-viability-for-pHLIP-modified-MNPs_fig4_337449734 |
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18/299-15:02:38.209 CLOSED OPEN OPEN CLOSED OPEN OPEN OPEN O | https://lasp.colorado.edu/maven/sdc/public/data/sites/site-20200925T163914/anc/eng/usm1/sci_anc_usm118_299_300.drf |
(PDF) Extreme Infrared Stars Discovered in Magellanic Cloud Globular Clusters
PDF | We report preliminary results of our systematic survey for infrared stars in the globular clusters of the Magellanic Clouds. In the course of an... | Find, read and cite all the research you need on ResearchGate
Extreme Infrared Stars Discovered in Magellanic Cloud Globular Clusters
January 1997
Astrophysics and Space Science255(1):407-413
DOI: 10.1023/A:1001581017746
Authors:
<here is a image f2f62089ad6ff61c-d19572ff1996375a>
T. Tanabé
T. Tanabé
<here is a image f2f62089ad6ff61c-d19572ff1996375a>
S. Nishida
S. Nishida
<here is a image f2f62089ad6ff61c-d19572ff1996375a>
Y. Nakada
Y. Nakada
<here is a image f2f62089ad6ff61c-d19572ff1996375a>
T. Onaka
T. Onaka
Abstract
We report preliminary results of our systematic survey for infrared stars in the globular clusters of the Magellanic Clouds.
In the course of an ISOCAM survey for AGB stars in the intermediate-age clusters, we have discovered extremely red AGB stars
in NGC 419 and NGC 1978. From their colours and luminosities, they are thought to be experiencing intense mass-loss and to
be in the final or superwind phase of the AGB evolution. However, they seem to be of somewhat lower luminosity than the corresponding
visible AGB stars when only the mid-infrared data are taken into account. This suggests that hitherto unobserved infrared
excesses may exist at longer wavelengths.
... The 5 s exposure time is chosen so that we can simultaneously detect bright AGB stars as well as red giants well below the tip of the first red giant branch (RGB). Therefore we can measure Cepheid variables and all of the AGB variables except extremely red ones (such as those found in NGC 419 and NGC 1978 by
Tanabé et al. (1998)
and Kamath et al. (2010) and those found in the LMC by Gruendl et al. (2008) and reach several magnitudes below the RGB tip. Extremely red sources and/or faint sources will be detected, and their variability studied, from the data obtained in VMC (Cioni et al. 2011) and in the SAGE-Var program (e.g. ...
A near-infrared variable star survey in the Magellanic Clouds: The Small Magellanic Cloud data
Article
Dec 2018
MON NOT R ASTRON SOC
Yoshifusa Ita
Noriyuki Matsunaga
Toshihiko Tanabe
Hidehiko Nakaya
A very long-term near-infrared variable star survey towards the Large and Small Magellanic Clouds (LMC and SMC) was carried out using the 1.4 m InfraRed Survey Facility at the South African Astronomical Observatory. This project was initiated in 2000 December in the LMC, and in 2001 July in the SMC. Since then an area of 3 deg² along the bar in the LMC and an area of 1 deg² in the central part of the SMC have been repeatedly observed. This survey is ongoing, but results obtained with data taken until 2017 December are reported in this paper. Over more than 15 yr we have observed the two survey areas more than one hundred times. This is the first survey that provides near-infrared time-series data with such a long time baseline and on such a large scale. This paper describes the observations in the SMC and publishes a point source photometric catalogue, a variable source catalogue, and time-series data. © 2018 The Author(s). Published by Oxford University Press on behalf of the Royal Astronomical Society.
Observing third dredge up in NGC 1846
Article
Apr 2008
<here is a image 6d1bc217f372186b-b51d32c2b8e11586> Thomas Lebzelter
K. H. Hinkle
M. T. Lederer
P. Wood
In this contribution we present the first measurements of the C/O ratio for a sample of AGB stars in the LMC globular cluster NGC 1846. From a variability study we set strong constraints on the mass of the cluster stars, which is an important quantity for comparison with evolutionary models. Variations of the surface abundance both with luminosity and pulsation properties were found and the various relevant factors are discussed. We find a good agreement with our synthetic models if we assume [O/Fe] = +/-0.2 dex. The F abundance seems to increase with the C/O ratio. As variability plays a key role on the AGB we give some preliminary results from our study of abundance determination in the dynamical case at the end of this paper.
Evolution and Nucleosynthesis of Asymptotic Giant Branch Stars in Three Magellanic Cloud Clusters
Article
Full-text available
Jan 2012
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Devika Kamath
<here is a image a0b14b4b35d47bb3-01cd0b92feb0d7cd> Amanda I. Karakas
and P. R. Wood
We present stellar evolutionary sequences for asymptotic giant branch (AGB) stars in the Magellanic Cloud clusters NGC 1978, NGC 1846, and NGC 419. The new stellar models for the three clusters match the observed effective temperatures on the giant branches, the oxygen-rich to carbon-rich transition luminosities, and the AGB-tip luminosities. A major finding is that a large amount of convective overshoot (up to 3 pressure scale heights) is required at the base of the convective envelope during third dredge-up in order to get the correct oxygen-rich to carbon-rich transition luminosity. The stellar evolution sequences are used as input for detailed nucleosynthesis calculations. For NGC 1978 and NGC 1846 we compare our model results to the observationally derived abundances of carbon and oxygen. We find that additional mixing processes (extra mixing) are required to explain the observed abundance patterns. For NGC 1846 we conclude that non-convective extra mixing processes are required on both the red giant branch and the AGB, in agreement with previous studies. For NGC 1978 it is possible to explain the C/O and 12C/13C abundances of both the O-rich and the C-rich AGB stars by assuming that the material in the intershell region contains high abundances of both C and O. This may occur during a thermal pulse when convective overshoot at the inner edge of the flash-driven convective pocket dredges C and O from the core to the intershell. For NGC 419 we provide our predicted model abundance values although there are currently no published observed abundance studies for the AGB stars in this cluster.
ISOCAM Observations of Globular Clusters in the Magellanic Clouds: The Data
Full-text available
Dec 2004
T. Tanabe
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Arunas Kucinskas
Yoshikazu Nakada
<here is a image 17fb13751291d958-99a767d932245353> Marc Sauvage
Seventeen globular clusters in the Large and Small Magellanic Clouds were observed in the mid-infrared wavelength region with the ISOCAM instrument on board the Infrared Space Observatory (ISO). Observations were made using the broadband filters LW1, LW2, and LW10, corresponding to the effective wavelengths of 4.5, 6.7, and 12 m, respectively. We present the photometry of point sources in each cluster, as well as their precise positions and finding charts.
Nir Monitoring of Star Clusters in the Magellanic Clouds
Chapter
Jan 2003
Toshihiko Tanabe
Yoshifusa Ita
Noriyuki Matsunaga
I. S. Glass
From the near-infrared monitoring observations of intermediate-age clusters, we found that most AGB stars near the tip luminosity
are variables in the infrared. It is also suggested that their amplitude may increase with their luminosities
KeywordsAGB–variables–stellar evolution–Magellanic Clouds
The pulsation of AGB stars in the Magellanic Cloud clusters NGC 1978 and 419
Article
Full-text available
Jun 2010
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Devika Kamath
P. R. Wood
I. Soszynski
<here is a image 6d1bc217f372186b-b51d32c2b8e11586> Thomas Lebzelter
The intermediate-age Magellanic Cloud clusters NGC 1978 and 419 are each found to contain substantial numbers of pulsating
asymptotic giant branch (AGB) stars, both oxygen rich and carbon rich. Each cluster also contains two pulsating AGB stars
which are infrared sources with a large mass-loss rate. Pulsation masses have been derived for the AGB variables, from the
lowest luminosity O-rich variables to the most evolved infrared sources. It is found that the stars in NGC 1978 have a mass
of 1.55 M⊙ early on the AGB while the NGC 419 stars have a mass of 1.87 M⊙ early on the AGB. These masses are in good agreement with those expected from the cluster ages determined by main-sequence
turn-off fitting. Non-linear pulsation models fitted to the highly evolved AGB stars show that a substantial amount of mass-loss
has occurred during the AGB evolution of these stars. An examination of the observed mass-loss on the AGB, and the AGB tip
luminosities, shows that in both clusters the mass-loss rates computed from the formula of Vassiliadis & Wood reproduce the
observations reasonably well. The mass-loss rates computed from the formula of Blöcker terminate the AGB in both clusters
at a luminosity which is much too low.
Pulsation at the tip of the first giant branch?
Article
Oct 2002
MON NOT R ASTRON SOC
Yoshifusa Ita
Toshihiko Tanabe
Noriyuki Matsunaga
Yoshikazu Nakada
The first results of our ongoing near-infrared (NIR) survey of the variable red giants in the Large Magellanic Cloud, using the Infrared Survey Facility (IRSF) and the SIRIUS infrared camera, are presented. Many very red stars were detected and found that most of them are variables. In the observed colour-magnitude diagram ($J-K, K$) and the stellar $K$ magnitude distribution, the tip of the first giant branch (TRGB), where helium burning in the core starts, is clearly seen. Apart from the genuine AGB variables, we found many variable stars at luminosities around the TRGB. From this result, we infer that a substantial fraction of them are RGB variables. Comment: 5 pages, 3 figures; accepted for publication in MNRAS Letters
AGB stars of the intermediate-age LMC cluster NGC 1846
Article
Full-text available
May 2008
<here is a image 6d1bc217f372186b-b51d32c2b8e11586> Thomas Lebzelter
M. T. Lederer
<here is a image 1577ba1e68e1c995-aebdad2a3770c5a9> Sergio Cristallo
B. Aringer
Aims: We investigate the change in the surface abundance of $^{12}$C during the evolution along the AGB, aiming to constrain third dredge-up models. Methods: High-resolution, near-infrared spectra of a sample of AGB stars in the LMC cluster NGC 1846 were obtained. A cluster sample ensures a high level of homogeneity with respect to age, metallicity, and distance. The C/O ratio and the ratio of $^{12}$C/$^{13}$C were measured and compared with our evolutionary models. Results: For the first time, we show the evolution of the C/O and $^{12}$C/$^{13}$C ratios along a cluster AGB. Our findings allow us to check the reliability of the evolutionary models and, in particular, the efficiency of the third dredge up. The increase in both C/O and $^{12}$C/$^{13}$C in the observed O-rich stars is reproduced by the models well. However, the low carbon isotopic ratios of the two C-stars in our sample indicate the late occurrence of moderate extra mixing. The extra mixing affects the most luminous AGB stars and is capable of increasing the abundance of $^{13}$C, while leaving unchanged the C/O ratio, which has been fixed by the cumulative action of several third dredge-up episodes. We find indications that the F abundance also increases along the AGB, supporting an in situ production of this element. Comment: 11 pages, accepted for publication in A&A
The AGB stars of the intermediate-age LMC cluster NGC 1846 Variability and age determination
Article
Full-text available
Nov 2007
<here is a image 6d1bc217f372186b-b51d32c2b8e11586> Thomas Lebzelter
P. R. Wood
Aims: To investigate variability and to model the pulsational behaviour of AGB variables in the intermediate-age LMC cluster NGC 1846. Methods: Our own photometric monitoring has been combined with data from the MACHO archive to detect 22 variables among the cluster's AGB stars and to derive pulsation periods. According to the global parameters of the cluster we construct pulsation models taking into account the effect of the C/O ratio on the atmospheric structure. In particular, we have used opacities appropriate for both O-rich stars and carbon stars in the pulsation calculations. Results: The observed P-L-diagram of NGC 1846 can be fitted using a mass of the AGB stars of about 1.8 M$_{\sun}$. We show that the period of pulsation is increased when an AGB star turns into a carbon star. Using the mass on the AGB defined by the pulsational behaviour of our sample we derive a cluster age of $1.4\times10^{9}$ years. This is the first time the age of a cluster has been derived from the variability of its AGB stars. The carbon stars are shown to be a mixture of fundamental and first overtone radial pulsators.
The asymptotic giant branch of Magellanic Cloud clusters
Article
<here is a image c0d406f4804096e4-93653e7354fae0ff> Jay A. Frogel
<here is a image 021920033f1bcbb3-527fb0503e73df75> Jeremy Mould
V. M. Blanco
The present search for carbon and M-type asymptotic giant branch (AGB)
stars in the 39 clusters of the Magellanic Clouds has yielded
identifications and near-IR photometry for about 400 such stars. The
Searle et al. (1980) cluster-age-related classification scheme is a
basic element of the present analysis of these data. In a C-M diagram,
the cluster M stars shift steadily redward as one proceeds from clusters
of SWB type I to VI, due to the increasing age of the clusters along the
sequence. Luminous carbon stars are present only in SWB IV-VI clusters,
and are easily distinguished from M stars by their color and luminosity.
PANIC (PtSi Astronomical Near-Infrared Camera) in South Africa and its astronomical applications
Article
Toshihiko Tanabe
Shinji Nishida
Yoshikazu Nakada
David B. Carter
A large-format PtSi array (effectively 1040 by 520 pixels) has been incorporated into an astronomical infrared camera (named PANIC: PtSi astronomical near-infrared camera) intended for wide-field survey work using the 0.75-m telescope at Sutherland and the 0.4-m one at Capetown. Here we briefly describe our camera and its astronomical applications.
Aerospace/Defense Sensing and Controls
Article
Toshihiko Tanabe
Shinji Nishida
Yoshikazu Nakada
David B. Carter
A large-format PtSi array (effectively 1040 by 520 pixels) has been incorporated into an astronomical infrared camera (named PANIC: PtSi astronomical near-infrared camera) intended for wide-field survey work using the 0.75-m telescope at Sutherland and the 0.4-m one at Capetown. Here we briefly describe our camera and its astronomical applications.© (1996) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.
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Major Depression and Subthreshold Depression among Older Adults Receiving Home Care | Request PDF
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Major Depression and Subthreshold Depression among Older Adults Receiving Home Care
The American journal of geriatric psychiatry: official journal of the American Association for Geriatric Psychiatry 26(9)
DOI: 10.1016/j.jagp.2018.05.001
Authors:
University of Michigan
Joseph A. Himle
Joseph A. Himle
Helen Kales
University of California, Davis
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Abstract
Objective:
This study aims to estimate the prevalence and correlates of major and subthreshold depression and the extent of treatment utilization in older adults receiving home care.
Methods:
The study sample included 811 community-dwelling adults aged 60 and over who received paid home care during the 2008-2014 waves of the Health and Retirement Study. Depression was assessed using short forms of the Composite International Diagnostic Interview and the Center for Epidemiologic Studies Depression Scale. Logistic regression was used to examine correlates of depression type and treatment utilization.
Results:
One in two older home care recipients suffered from probable depression; 13.4% of the sample suffered from major depression and an additional 38.7% met study criteria for subthreshold depression. The majority (72.7%) of participants with major depression and almost half (44.5%) of participants with subthreshold depression reported taking medication for anxiety or depression. One-third (33.2%) of older home care recipients with major depression and 14.2% of those with subthreshold depression reported receiving formal psychiatric or psychological treatment. Males as compared with females and persons with pain problems as compared with no pain complaints had a higher risk of subthreshold and major depression. The receipt of medication or psychiatric treatment declined with age. African Americans were less likely to receive medication for anxiety or depression compared with non-Hispanic whites.
Conclusion:
Depression affects a substantial proportion of older adults receiving home care and may be inappropriately treated. Future research is needed to develop optimal strategies for integrating depression assessment and treatment into home care.
... Considering the rapidly aging population and the increasing prevalence of chronic diseases among older adults, the Korea Ministry of Health and Welfare implemented customized community care to advance the quality of life for older adults. However, this policy presented challenges because older adults who received community care were at higher risk of depression than the general elderly population [5,
6]
. Depression among the elderly population appears to be significantly associated with chronic disease, disability, dementia, and/or other comorbidities, since the inability of older adults to meet their basic daily needs creates an additional strain that increases their risk of depression [3]. ...
... Adding to the challenges of coping with serious health conditions, other stressors among community care recipients such as role loss, disengagement from social activities, and social isolation may further contribute to depression [5,7]. Recent research on the mental health of older adults has focused not only on their vulnerability to depression, but also on providing appropriate treatment options and intervention strategies
[6]
. However, it has not yet been confirmed what features of community care utilization increase the risk of depression, and what role leisure life satisfaction plays in helping older adults cope with the stressful aspects of their community care settings. ...
... Our findings confirmed that older community care recipients had a higher risk of depression than non-recipients, which mirrored the research findings of United States longitudinal studies
[6,
15]. In the United States more than a third of older community care recipients displayed subthreshold depression and 13.4% had major depressive disorder [6]. ...
"Leisure Life Satisfaction:" Will It Have a Beneficial Impact on Depression Among Older Adults in Community Care Settings in Korea?
Cheong-Seok Kim
Objectives:
While the risk of depression is expected to substantially increase among older adults receiving community care, leisure life satisfaction can be regarded as a key component in enhancing the mental health of those receiving community care. However, it is not yet known whether community care utilization increases the risk of depression, or what role is played by leisure life satisfaction in these settings. This study investigated the relationship between community care utilization and depression, as well as the main effect and the moderating role of leisure life satisfaction on the link between community care utilization and depression among older adults.
Methods:
This study, using the 2019 Korean Welfare Panel Survey, conducted multiple regression analysis on data from 4494 elderly people aged 65 years or older.
Results:
After controlling for potential covariates, older community care recipients were more likely to report symptoms of depression than those who did not receive community care. Meanwhile, leisure life satisfaction was negatively associated with depression in older adults. The test for interaction between community care utilization and leisure life satisfaction revealed that leisure life satisfaction significantly attenuated the link between depression and community care utilization.
Conclusions:
The findings of this study imply that leisure life satisfaction could play a meaningful role in improving the mental health of older adults receiving community care. Welfare policies affecting older adults should consider leisure life satisfaction as an important resource for reducing depression in community care settings.
... A quarter of seniors over the age of 65 receive some form of homecare service, with rates on the rise as the population continues to age (Pepin et al., 2017). Typically, these recipients are older, have multiple comorbidities, and experience greater social isolation compared to older adults in the general population (Pepin et al., 2017;
Xiang, Leggett, Himle, & Kales, 2018)
. Cognitive impairment (CI) is prevalent in up to 51% of homecare recipients and is an important predictor of homebound status (Musich, Wang, Hawkins, & Yeh, 2015;Xiang et al., 2018). ...
... Typically, these recipients are older, have multiple comorbidities, and experience greater social isolation compared to older adults in the general population (Pepin et al., 2017;Xiang, Leggett, Himle, & Kales, 2018). Cognitive impairment (CI) is prevalent in up to 51% of homecare recipients and is an important predictor of homebound status (Musich, Wang, Hawkins, & Yeh, 2015;
Xiang et al., 2018)
. Depression is also highly prevalent in this population, with nine to 30% of all homecare recipients (Li & Conwell 2009;Sirey et al., 2008;Wang, Kearney, Jia, & Shang, 2016;Xiang et al., 2018) and 24 to 30% of homecare recipients with CI having clinically significant depression (Boyle et al., 2011;Brown et al., 2004). ...
... Cognitive impairment (CI) is prevalent in up to 51% of homecare recipients and is an important predictor of homebound status (Musich, Wang, Hawkins, & Yeh, 2015;Xiang et al., 2018). Depression is also highly prevalent in this population, with nine to 30% of all homecare recipients (Li & Conwell 2009;Sirey et al., 2008;Wang, Kearney, Jia, & Shang, 2016;
Xiang et al., 2018)
and 24 to 30% of homecare recipients with CI having clinically significant depression (Boyle et al., 2011;Brown et al., 2004). Subthreshold depression is also common, where 19 to 60% of all individuals in homecare have clinically significant depressive symptoms (Giebel et al., 2016;Helvik et al., 2019). ...
Screening for depression in older adults with cognitive impairment in the homecare setting: a systematic review
Iulia Niculescu
Twinkle Arora
Andrea Iaboni
Objective
Previous systematic reviews have examined depression screening in older adults with cognitive impairment (CI) in outpatient and inpatient clinics, nursing homes, and residential care. Despite an increasing number of older adults with CI receiving care in their homes, less is known about best depression screening practices in homecare. The objective of this review is to identify evidence-based practices for depression screening for individuals with CI receiving homecare by assessing tool performance and establishing the current evidence for screening practices in this setting.
Methods
This review is registered under PROSPERO (ID: CRD42018110243). A systematic search was conducted using MEDLINE, EMBASE, Health and Psychosocial Abstracts, PsycINFO and CINAHL. The following criteria were used: assessment of depression at home in older adults (>55 years) with CI, where performance outcomes of the depression screening tool were reported.
Results
Of 5,453 studies, only three met eligibility criteria. These studies evaluated the Patient Health Questionnaire (n = 236), the Geriatric Depression Scale (n = 79) and the Mental Health Index (n = 1,444) in older adults at home with and without CI. Psychometric evaluation demonstrated moderate performance in the subsamples of people with CI.
Conclusion
At present, there is insufficient evidence to support best practices in screening for depression in people with CI in homecare.
... Subthreshold depression (StD) has been characterized as the presence of clinically significant depressive symptoms that do not satisfy the criteria for major depressive disorder (MDD). [1] Previous studies have shown that StD has a prevalence rate of 4.0% to 38.7%,
[2]
[3][4] which is higher than that for MDD. [5,6] Despite being a precursor to MDD, [7] StD has been associated with poor quality of life, [1,7,8] poor health, [9] impaired daily activities, [2,10] considerable economic burden, [11] and mortality. ...
... [1] Previous studies have shown that StD has a prevalence rate of 4.0% to 38.7%, [2][3][4] which is higher than that for MDD. [5,6] Despite being a precursor to MDD, [7] StD has been associated with poor quality of life, [1,7,8] poor health, [9] impaired daily activities,
[2,
10] considerable economic burden, [11] and mortality. [12] Of particular importance, StD has been considered an significant risk factor for developing MDD given that many individuals with StD develop sustained depressive symptoms and are expected to progress to MDD. [5,13,14] Moreover, MDD is likely to recur once established and often tends to be resistant to treatment. ...
... StD has been considered an important risk factor for the development of MDD. [5,13,14] Moreover, despite being a precursor to MDD, [7] StD has been associated with poor quality of life, [1,7,8] poor health, [9] impaired daily activities,
[2,
10] economic costs, [11] mortality, [12] etc. Therefore, interventions aimed at addressing StD are important to prevent the onset of MDD. ...
Study protocol for a pilot randomized controlled trial on a smartphone application-based intervention for subthreshold depression: Study protocol clinical trial (SPIRIT Compliant)
Yudai Kato
Kaito Kageyama
Takanori Mesaki
Kazuki Hirao
Introduction:
Interventions aimed at addressing subthreshold depression (StD) are important to prevent the onset of major depressive disorder. Our video playback application (SPSRS) is designed to reduce depressive symptoms by presenting positive words in videos, shedding new light on the treatment of StD. However, no randomized controlled trial (RCT) has utilized this video playback application for the treatment of individuals with StD. Therefore, a pilot RCT was designed to determine the feasibility of a full-scale trial. We herein present a study protocol for investigating the utility of a video playback application intervention for individuals with StD.
Methods:
This 5-week, single-blind, 2-arm, parallel-group, pilot RCT will determine the effectiveness of the video playback application by comparing individuals who had and had not been exposed to the same. A total of 32 individuals with StD will be randomly assigned to the experimental or control group at a 1:1 ratio. The experimental group will receive a 10-minute intervention containing the video playback application per day, whereas the control group will receive no intervention. The primary outcome will include changes in the Center for Epidemiologic Studies Depression Scale score after the 5-week intervention, while secondary outcomes will include changes in the Kessler Screening Scale for psychological distress and the generalized anxiety disorder 7-item scale score after the 5-week intervention. Statistical analysis using linear mixed models with the restricted maximum likelihood estimation method will then be performed.
Discussion:
This pilot RCT will have been the first to explore the utility of SPSRS application interventions that display positive words in videos for individuals with StD. The results of this pilot trial are expected to help in the design and implementation of a full-scale RCT that investigates the effects of SPSRS applications among individuals with StD.
Trial registration:
ClinicalTrials.gov Identifier: NCT04136041.
... A recent systematic review and meta-analysis reported an average prevalence of depression of almost 32% among older adults (Zenebe et al., 2021). Home-living vulnerable older adultsincluding older homebound, functionally, and cognitively impaired individualshave higher rates of depression than their counterparts who live at home independently (Bruce et al., 2002;
Xiang et al., 2018;
Choi et al., 2013). However, the diagnostics and treatment of depression in late life remain deficient, and research on needs-oriented healthcare provision for home-living, vulnerable older adults with depression is lacking . ...
... Thus, a better understanding of the motivational resources of this vulnerable group of older adults is urgently needed to improve tailored and need-based psychotherapy. In this group of patients, cognitive deficits, chronic physical conditions, and sensory limitations often go hand in hand with functional impairment
(Xiang et al., 2018)
. Additionally, depression has enormous consequences for older individuals, including an increased risk of morbidity and suicide as well as decreased physical, cognitive, and social functioning, all of which are associated with higher rates of service utilization, premature institutionalization, and mortality (Alexopoulos, 2019;Fiske et al., 2009). ...
Motivation and Psychotherapy in Older Adults with Care Needs and Depression
Article
Dec 2022
Sonia Lech
Claudia Vathke
Eva-Marie Kessler
Paul Gellert
The utilization of psychotherapy for home-living, vulnerable older adults with depression is limited. Understanding patients' motivation is essential to tailoring psychotherapy to their needs and improving therapeutical efficacy. Based on cross-sectional data obtained from a pragmatic, randomized controlled trial (PSY-CARE study), this study investigated general intake concerns (ICs) and patients' treatment goals (PTG) of home-living older adults with depression. Data on ICs (N = 251 older adults interested in participation) were analyzed using qualitative content analysis. Data on PTGs (N = 86 participants receiving psychotherapy) were analyzed quantitatively. Main ICs included reducing depressive symptoms and coping with new (health) situations. PTGs focused on coping with health problems and age-related losses. The results provide clinicians with valuable insights into motivational factors in this vulnerable and hard-to-reach population.
... A recent systematic review and meta-analysis reported an average prevalence of depression of almost 32% among older adults (Zenebe et al., 2021). Home-living vulnerable older adultsincluding older homebound, functionally, and cognitively impaired individualshave higher rates of depression than their counterparts who live at home independently (Bruce et al., 2002;
Xiang et al., 2018;
Choi et al., 2013). However, the diagnostics and treatment of depression in late life remain deficient, and research on needs-oriented healthcare provision for home-living, vulnerable older adults with depression is lacking . ...
... Thus, a better understanding of the motivational resources of this vulnerable group of older adults is urgently needed to improve tailored and need-based psychotherapy. In this group of patients, cognitive deficits, chronic physical conditions, and sensory limitations often go hand in hand with functional impairment
(Xiang et al., 2018)
. Additionally, depression has enormous consequences for older individuals, including an increased risk of morbidity and suicide as well as decreased physical, cognitive, and social functioning, all of which are associated with higher rates of service utilization, premature institutionalization, and mortality (Alexopoulos, 2019;Fiske et al., 2009). ...
Motivation and Psychotherapy in Older Adults with Care Needs and Depression
Article
Full-text available
Claudia Vathke
Eva-Marie Kessler
Paul Gellert
Utilization of psychotherapy for home-living vulnerable older adults with
depression is limited. Understanding patients’ motivation is important to tailor
psychotherapy to their needs and improve therapeutical efficacy. Based on
cross-sectional data obtained from a pragmatic, randomized controlled trial
(PSY-CARE study), this study investigated general intake concerns (ICs) and
patients’ treatment goals (PTG) of home-living older adults with
depression. Data on ICs (N = 251 older adults interested in participation) were
analyzed using qualitative content analysis. Data on PTGs (N = 86 participants
receiving psychotherapy) were analyzed quantitatively. Main ICs included
reducing depressive symptoms and coping with new (health) situations. PTGs
focused on coping with health problems and age-related losses. Results provide
valuable insights for clinicians on motivational factors in this vulnerable
and hard-to-reach population
... A most recent systematic review and meta-analysis reported an average prevalence of depression of almost 32% among older adults (Zenebe et al., 2021). Home-living vulnerable older adults -including older homebound, functionally and cognitively impaired individuals -have higher rates of depression than their counterparts who live at home independently (Bruce et al., 2002;
Xiang et al., 2018;
Choi et al., 2013). However, diagnostics and treatment of depression in late life remain deficient and research on needs-oriented healthcare provision for home-living vulnerable older adults with depression is lacking (Tegeler et al., 2020). ...
... Thus, a better understanding of motivational resources of this vulnerable group of older adults is urgently needed to improve tailored and need-based psychotherapy. In this group of patients, cognitive deficits, chronic physical conditions and limitations in sensory often go along with functional impairment
(Xiang et al., 2018)
. Additionally, depression has enormous consequences for older individuals including an increased risk of morbidity and suicide as well as decreased physical, cognitive and social functioning, all of which are in turn associated with higher rates of service utilization, premature institutionalization and mortality (Alexopoulos, 2019;Fiske et al., 2009). ...
Motivation and psychotherapy in older adults with care needs and depression
Preprint
Julie Lorraine O'Sullivan
Paul Gellert
Eva-Marie Kessler
... Consequently, depression is the leading contributor to disability globally (World Health Organization, 2017), and a significant factor affecting chronic disease management (Chapman, Perry, & Strine, 2005). Non-Hispanic black and Hispanic older adults have higher prevalence of subthreshold and major depression compared to non-Hispanic white older adults
(Xiang, Leggett, Himle, & Kales, 2018)
. Furthermore, racial and ethnic minorities have poor access to mental health care, leading to undiagnosed depression and inadequate treatment (Kim, 2014) that can exacerbate chronic disease and its management. ...
... Our findings of increased AL are with subthreshold depressive, but not depression-likely, symptoms may have occurred for several reasons. Persons with subthreshold depression may be less likely to be prescribed medication and/or given appropriate mental health support (Tuithof et al., 2018), compared to persons with major depression
(Xiang et al., 2018)
. At baseline, our participants with depression-likely symptoms were more likely to report taking depression medication. ...
Depressive symptoms and allostatic load have a bidirectional association among Puerto Rican older adults
Article
Amanda C McClain
Rui Sherry Xiao
Katherine L Tucker
Background
Depression is strongly associated with chronic disease; yet, the direction of this relationship is poorly understood. Allostatic load (AL) provides a framework for elucidating depression-disease pathways. We aimed to investigate bidirectional, longitudinal associations of baseline depressive symptoms or AL with 5-year AL or depressive symptoms, respectively.
Methods
Data were from baseline, 2-year, and 5-year visits of 620 adults (45–75 years) enrolled in the Boston Puerto Rican Health Study. The Center for Epidemiology Studies Depression (CES-D) scale (0–60) captured depressive symptoms, which were categorized at baseline as low (<8), subthreshold (8–15), or depression-likely (⩾16) symptoms. AL was calculated from 11 parameters of biological functioning, representing five physiological systems. Baseline AL scores were categorized by the number of dysregulated parameters: low (0–2), moderate (3–5), or high (⩾6) AL. Multivariable, multilevel random intercept and slope linear regression models were used to examine associations between 3-category baseline CES-D score and 5-year continuous AL score, and between baseline 3-category AL and 5-year continuous CES-D score.
Results
Baseline subthreshold depressive symptoms [(mean (95% CI)): 4.8 (4.5–5.2)], but not depression-likely symptoms [4.5 (4.2–4.9)], was significantly associated with higher 5-year AL scores, compared to low depressive symptoms [4.3 (3.9–4.7)]. Baseline high AL [19.4 (17.6–21.2)], but not low AL [18.5 (16.5–20.6)], was significantly associated with higher 5-year CES-D score, compared to baseline moderate AL [16.9 (15.3–18.5)].
Conclusions
Depressive symptoms and AL had a bi-directional relationship over time, indicating a nuanced pathway linking depression with chronic diseases among a minority population.
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Show abstract
... Depression is a common phenomenon among vulnerable older adults. Compared with the general older population, community-based studies have consistently documented at least two or three times higher rates of depression among older adults with chronic physical conditions, cognitive deficits and/ or sensory limitations, i.e. conditions that often along with functional impairment and dependence on informal and formal support systems for medical care, transport and other essential needs (e.g., [1][2][3][4]
[5]
). Conversely, depression has devastating consequences for older individuals including an increased risk of morbidity and suicide, decreased physical, cognitive and social functioning, all of which are in turn associated with higher rates of service utilization, premature institutionalization and mortality [6,7]. ...
... Participants will be included in the study if they [1] are 60 years and older (women/ men) [2]; are living at home (Berlin, Germany) [3]; have a long-term care grade, as assessed by the German compulsory state nursing care insurance (1 = little impairment to 5 = hardship case; see [29]) [4]; show clinically relevant depressive symptoms (major depression; adjustment disorder with depressive symptoms; dysthymia); and
[5]
are willing to participate in one of the two treatments. Exclusion criteria will be moderate to severe dementia as well as delirium, acute psychosis or other cognitive disorders, mania or hypomania or terminal stage of a disease. ...
Outpatient psychotherapy for home-living vulnerable older adults with depression: study protocol of the PSY-CARE trial
Article
Full-text available
Christina Tegeler-Nonnen
Eva-Marie Kessler
Background:
There is a need to improve psychotherapeutic approaches to treatment for vulnerable older adults with depression in terms of both clinical practice and health care supply. Against this background, PSY-CARE is testing the feasibility and effectiveness of outpatient psychotherapy for home-living older adults in need of care with depression in Berlin, Germany, and neighboring suburban areas.
Methods:
In a two-arm single-center pragmatic randomized controlled trial (RCT), manual-guided outpatient psychotherapy will be compared to brief psychosocial counseling. The study population will be compromised of older adults with clinically significant depressive symptoms who have a long-term care grade, as assessed by the German compulsory state nursing care insurance. In the intervention group, individual cognitive-behavioral psychotherapy tailored to the specific needs of this population will be offered by residential psychotherapists as part of the regular healthcare service. In the active control group, participants will receive individual psychosocial telephone counselling and a self-help guide. The planned sample size is N = 130 (n = 65 participants per group). The reduction of depressive symptoms (primary outcome) as well as the maintaining of activities of daily living, quality of life, and functioning will be assessed with questionnaires provided at baseline, after the end of the intervention and after three months. Feasibility and process evaluation will be conducted qualitatively based on documentation and interviews with psychotherapists, gatekeepers and the participants.
Discussion:
PSY-CARE investigates the potentials and limitations of providing outpatient psychotherapeutic treatment meeting the demands of vulnerable home-living older adults with depression under the real conditions of the health care system. The study will provide practical implications to improve access to and quality of outpatient psychotherapy for this poorly supplied population.
Trial registration:
The trial is registered at ISRCTN55646265 ; February 15, 2019.
... The odds of untreated depression increased 2.471 times (95% CI: 1.187-5.146) for middle aged participants (55)(56)(57)(58)(59)(60)
(61)
(62)(63)(64), compared with participants with no depression. Similarly, respondents with no high school diploma were 0.542 times (95% CI: 0.591-0.904) ...
... Untreated depression was associated with belonging to the oldest age cohort (75 years and older) and lower educational attainment (less than a high school diploma). This study is consistent with previous findings indicating that AAs experience lower rates of depression and mental health treatment, as well as decreased access to and quality of depression care [57][58][59][60]
[61]
. ...
Depression Treatment Status of Economically Disadvantaged African American Older Adults
BSRCCS
Sharon Cobb
Background:
It is known that depression remains largely untreated in underserved communities. Hence, it is desirable to gain more knowledge on the prevalence and correlates of untreated depression among African-American (AA) older adults in economically disadvantaged areas. This knowledge may have the public health benefit of improving detection of AA older adults with depression who are at high risk of not receiving treatment, thereby reducing this health disparity.
Objective:
To study health and social correlates of untreated depression among AA older adults in economically disadvantaged areas.
Methods:
Between 2015 and 2018, this cross-sectional survey was conducted in South Los Angeles. Overall, 740 AA older adults who were 55+ years old entered this study. Independent variables were age, gender, living arrangement, insurance type, educational attainment, financial strain, chronic medical conditions, and pain intensity. Untreated depression was the dependent variable. Logistic and polynomial regression models were used to analyze these data.
Results:
According to the polynomial regression model, factors such as number of chronic medical conditions and pain intensity were higher in individuals with depression, regardless of treatment status. As our binary logistic regression showed, age, education, and number of providers were predictive of receiving treatment for depression.
Conclusion:
Age, educational attainment, number of providers (as a proxy of access to and use of care) may be useful to detect AA older adults with depression who are at high risk of not receiving treatment. Future research may focus on decomposition of the role of individual-level characteristics and health system-level characteristics that operate as barriers and facilitators to AA older adults receiving treatment for depression.
... The results of the sensitivity analyses showed that the age difference was not driven by the large number of young people in the sample. The lower GPS total symptom and subdomain scores for PTSD, depressive, and anxiety symptoms and self-harm in older adults are consistent with the well-documented data on older adults having a higher prevalence of subthreshold mental disorders (e.g., PTSD, depression) compared to younger adults (Van Zelst et al., 2006;
Xiang et al., 2018)
. A possible explanation might be that the clinical presentation in older adults with mental disorders may differ from that of other age groups (Gulpers, 2019;Pless Kaiser et al., 2019). ...
The mental health impact of the COVID-19 pandemic and exposure to other potentially traumatic events up to old age
Demi Havermans
Chris Hoeboer
We investigated whether the impact of potentially traumatic events (PTEs) on trauma-related symptoms changes across the transitional adult lifespan (i.e., 16-100 years old) and if this association differs for self-reported COVID-19-related PTEs compared to other PTEs. A web-based cross-sectional study was conducted among 7,034 participants from 88 countries between late April and October 2020. Participants completed the Global Psychotrauma Screen (GPS), a self-report questionnaire assessing trauma-related symptoms. Data were analyzed using linear and logistic regression analyses and general linear models. We found that older age was associated with lower GPS total symptom scores, B = -0.02, p < .001; this association remained significant but was substantially weaker for self-reported COVID-19-related PTEs compared to other PTEs, B = 0.02, p = .009. The results suggest an association between older age and lower ratings of trauma-related symptoms on the GPS, indicating a blunted symptom presentation. This age-related trend was smaller for self-reported COVID-19-related PTEs compared to other PTEs, reflecting the relatively higher impact of the COVID-19 pandemic on older adults.
... Around 10% of older U.S. adults have experienced one or more forms of elder abuse (Kaplan & Pillemer, 2015). Older people receiving care in their own home are also two to three times more likely to have clinically-relevant depressive symptoms than their peers living independently (Choi et al., 2013;Zenebe et al., 2021), and one in two older home EXPERIENCES TREATING OLDER PEOPLE IN NEED OF CARE 5 care recipients is at risk of a depressive episode
(Xiang, Leggett, et al., 2018)
. Depression has devastating consequences for older adults, including increased risk of suicide and decreased physical, cognitive, and social functioning, all of which are in turn associated with higher service utilization, premature institutionalization and mortality (Alexopoulos, 2018;Gallo et al., 2013;Sivertsen et al., 2015). ...
Psychotherapists’ Experiences Providing At-Home Psychotherapy for Home-living Older Adults with Long-Term Care Needs and Depression
This study used qualitative methods to explore psychotherapists’ experiences conducting athome psychotherapy with older adults (60+ years) with long-term care needs and depression.
We conducted semi-structured interviews with 16 female psychotherapists (26-70 years old)
who delivered at-home cognitive behavioral therapy to home-living older adults with longterm care needs and depression. We additionally conducted 10 patient case studies. Using an
adaption of the methodology of grounded theory, we iteratively developed a hierarchical
model. Results showed that psychotherapists experienced three dilemmas: (1) pushing for
change versus acknowledging limitations, (2) providing help versus maintaining boundaries,
and (3) being a guest in the patient’s home versus the host of a psychotherapy session. The
absence of a shared understanding of therapy and confrontation with patients’ existential
suffering intensified the experience of the dilemmas. The dilemmas generated professional
self-doubt and negative emotions, which in turn triggered a reflexive process and ultimately
participants’ professional development. Participants found a way to integrate drives initially
perceived as mutually exclusive, and further developed their professional self-image and
therapeutic techniques. We interpret the dilemmas as reflecting difficulty reconciling the
“curing” and “caring” treatment paradigms. Practice and support managing the three
dilemmas along with reflection on the curing paradigm, views on old age, and fear of
existential suffering should be part of qualifications for psychotherapists working with older adults in need of care. Cooperating with other care providers may relieve the pressure on psychotherapists to provide forms of support that could lead to overburden and impede
therapeutic progress.
... Low-income and homebound older adults are especially at high risk for experiencing depression. In one US representative sample, estimates for rates of depression in homebound older adults were approximately 40%
[9]
. Further complicating this burden of depression is a recent steep increase in the number of homebound older adults, likely in part driven by COVID-19 [10]. ...
Layperson-Facilitated Internet-Delivered Cognitive Behavioral Therapy for Homebound Older Adults with Depression: Protocol for a Randomized Controlled Trial (Preprint)
Article
Dec 2022
Background:
Depression in older adults has serious biological, psychological, and social consequences. Homebound older adults experience a high burden of depression and significant barriers to accessing mental health treatments. Few interventions to address their specific needs have been developed. Existing treatment modalities can be challenging to scale up, are not tailored to unique population concerns, and require significant staffing support. Technology-assisted, layperson-facilitated psychotherapy has the potential to overcome these challenges.
Objective:
The aim of this study is to assess the efficacy of a layperson-facilitated internet-delivered cognitive behavioral therapy program tailored for homebound older adults. The novel intervention, Empower@Home, was developed based on user-centered design principles and partnerships between researchers, social service agencies, care recipients, and other stakeholders serving low-income homebound older adults.
Methods:
This 2-arm, 20-week pilot randomized controlled trial (RCT) with a waitlist control crossover design aims to enroll 70 community-dwelling older adults with elevated depressive symptoms. The treatment group will receive the 10-week intervention immediately, whereas the waitlist control group will cross over and receive the intervention after 10 weeks. This pilot is part of a multiphase project involving a single-group feasibility study (completed in December 2022). This project consists of a pilot RCT (described in this protocol) and an implementation feasibility study running in parallel with the pilot RCT. The primary clinical outcome of the pilot is the change in depressive symptoms after the intervention and at the 20-week postrandomization follow-up. Additional outcomes include acceptability, adherence, and changes in anxiety, social isolation, and quality of life.
Results:
Institutional review board approval was obtained for the proposed trial in April 2022. Recruitment for the pilot RCT began in January 2023 and is anticipated to end in September 2023. On completion of the pilot trial, we will examine the preliminary efficacy of the intervention on depression symptoms and other secondary clinical outcomes in an intention-to-treat analysis.
Conclusions:
Although web-based cognitive behavioral therapy programs are available, most programs have low adherence and very few are tailored for older adults. Our intervention addresses this gap. Older adults, particularly those with mobility difficulties and multiple chronic health conditions, could benefit from internet-based psychotherapy. This approach can serve a pressing need in society while being cost-effective, scalable, and convenient. This pilot RCT builds on a completed single-group feasibility study by determining the preliminary effects of the intervention compared with a control condition. The findings will provide a foundation for a future fully-powered randomized controlled efficacy trial. If our intervention is found to be effective, implications extend to other digital mental health interventions and populations with physical disabilities and access restrictions who face persistent disparities in mental health.
Trial registration:
ClinicalTrials.gov NCT05593276; https://clinicaltrials.gov/ct2/show/NCT05593276.
International registered report identifier (irrid):
PRR1-10.2196/44210.
... Although depression tends to be less prevalent among older than younger adults, homebound older adults are an exception. With multiple chronic medical conditions, disability, and hospitalizations restricting their social engagement and activities, older adults who are homebound experience depression at two-to-three times higher rates than their peers who are not homebound [5][6][7]
[8]
. Women, racial/ethnic minorities, and more socioeconomically disadvantaged are overrepresented among homebound older adults. [2,6] Financial stressors are a significant depression risk factor among low-income homebound older adults [9,10]. ...
Cost-effectiveness of Tele-delivered behavioral activation by Lay counselors for homebound older adults with depression
Background
Low-income homebound older adults have limited access to psychosocial treatments because of their homebound state and geriatric mental health workforce shortages. Little is known about cost effectiveness of lay-counselor-delivered, videoconferenced, short-term behavioral activation on this study population. The objective of this study was to assess the cost-effectiveness of lay-counselor-delivered, videoconferenced, short-term behavioral activation (Tele-BA) compared to clinician-delivered, videoconferenced problem-solving therapy (Tele-PST) and telephone support calls (attention control; AC) for low-income homebound older adults.
Methods
We performed a cost-effectiveness analysis based on data from a recently completed, 3-group (Tele-BA, Tele-PST, and AC) randomized controlled trial with 277 participants aged 50+. We measured total costs of (1) intervention and (2) outpatient care, ED visits, and inpatient care using the Cornell Services Index. The effectiveness outcome was quality-adjusted life-years (QALY). We used EuroQol’s EQ-5D-5L to assess each participant’s health-related quality of life (HRQoL) at baseline and at 12, 24, and 36 weeks. The end-point measure of cost-effectiveness was the incremental cost-effectiveness ratio (ICER) of (1) Tele-BA versus AC, (2) Tele-PST versus AC, and (3) Tele-BA versus Tele-PST.
Results
Relative to AC, both Tele-BA and Tele-PST are cost-saving treatment options. The ICERs for both Tele-BA and Tele-PST were well below $50,000, the lower-bound threshold for cost-effectiveness. Relative to AC, both Tele-PST, Tele-BA are cost-saving treatment options (i.e. lower costs and more QALYs).
Conclusion
Costs of tele- and lay-counselor-delivered depression treatment are modest and cost effective relative to providing telephone support. Though our results show that Tele-BA may not be cost effective relative to Tele-PST, a clinician-delivered psychotherapy, when a low bound ICER threshold of $50,000 would be used, lay counselors can fill the professional geriatric mental health workforce shortage gap and Tele-BA by lay counselors can improve homebound older adults’ access to evidence-and skills-based, cost effective depression care.
Trial registration
ClinicalTrials.gov identifier: NCT02600754 (11/09/2015).
... The results of a study conducted on patients admitted to a Chinese hospital, including 143 participants, among which 26 people infected with Covid-19, 86 people with pneumonia, and 30 healthy individuals, show that the depression assessment index is significantly high in patients with . Depression is one of the most common mental health problems and psychiatric illnesses that lead to lack of pleasure, motivation, and intolerance of failure, avoidance of friends and family, loss of libido, increased or decreased appetite, decreased energy, premature fatigue, and sleep disorder
(18)
. ...
The Clinical Trial of COVID-19 Patients: The Effectiveness of Emotion-Focused Therapy on Post-Traumatic Stress and Depression
At the end of 2019, the world faced a phenomenon that plunged all human beings into extreme fear and anxiety. A new type of coronavirus began to spread among people around the world, and this was the beginning of one of the greatest pandemics and its problems in the world.The present study aimed to study the effect of Emotion-Focused Therapy (EFT) on reducing post-traumatic stress and depression among Covid-19 patients. The statistical population was all English language students at the University of Tehran who had recovered from Covid-19. A total of three students (with a mean age of 22±2 years old) were selected from those who had recovered from Covid-19 using convenience sampling.The data were analyzed using visual inspection, Reliable Change Index (RCI), and percentage change formula. The results of the study indicated that the mean improvement of post-traumatic stress variable for the three patients in the post-treatment and follow-up was 42.39% and 41.54%, respectively. Additionally, this value for the depression variable was 60.78 and 60.22% in the post-treatment and the follow-up. Based on the results of the study, EFT was effective on post-traumatic stress and depression in students infected with Covid-19. Therefore, it is recommended to use this treatment to reduce post-traumatic stress and depression in patients with Covid-19.
... Homebound older adults receive services and support from home care workers (HCWs) to help them maintain community living [1]. Up to half of these older adults experience clinically significant depressive symptoms, and 14% of them meet the diagnostic criteria for current major depression
[2]
. Untreated and undertreated depression, even when the symptoms are mild, can lead to various adverse health events and decrease life expectancy [3,4]. ...
Internet-based psychotherapy intervention for depression among older adults receiving home care: A qualitative study of participants’ experiences (Preprint)
Joseph A. Himle
Background
Depression is common among homebound older adults. Internet-based cognitive behavioral therapy (iCBT) is a promising but understudied approach for treating depression among older adults with disabilities.
Objective
This study aims to understand the experiences of homebound older adults who participated in a pilot feasibility trial of an iCBT for depression.
Methods
The participants included 21 homebound older adults who participated in a generic iCBT program that was not specifically designed for older adults and 8 home care workers who assisted in the iCBT program. Informants completed semistructured individual interviews, which were transcribed verbatim and analyzed using methods informed by grounded theory. A hierarchical code structure of themes and subthemes was developed after an iterative process of constant comparisons and questionings of the initial codes. The data analysis was conducted by using dedoose, a web app for mixed methods research.
Results
Three themes and various subthemes emerged related to participants’ experience of the iCBT intervention, as follows: intervention impact, which involved subthemes related to participants’ perceived impact of the intervention; challenges and difficulties, which involved subthemes on the challenges and difficulties that participants experienced in the intervention; and facilitators, which involved subthemes on the factors that facilitated intervention use and engagement.
Conclusions
iCBT is a promising intervention for homebound older adults experiencing depression. Home care workers reported improved relationships with their clients and that the program did not add a burden to their duties. Future programs should involve accessible technical features and age-adapted content to improve user experience, uptake, and adherence.
Trial Registration
ClinicalTrials.gov NCT04267289; https://clinicaltrials.gov/ct2/show/NCT04267289
... While differences exist, some characteristics of HBPC veterans are generalizable to nonveterans that receive home care. Older adults who utilize home care across the United States have high rates of depression and anxiety
(Xiang et al., 2018)
. Older adults electing to remain in place in general face similar issues and goals that those receiving HBPC do, including staying socially connected, engaging in activities, maintaining health and quality of life, and preserving independence and autonomy (Chum et al., 2020). ...
Adapting a whole health model to home-based primary care: Bridging person-driven priorities with veteran and family-centered geriatric care
Full-text available
Cynthia M. Knight
Nicole Downing
Michelle E Mlinac
Through the integration of Whole Health for Life into the Department of Veterans Affairs (VA) health care system, the VA aims to transform health care delivery from a disease management approach to one that embraces person-centered care. The home-based primary care (HBPC) program is a care model that, within the VA, provides holistic primary care services to homebound veterans with multiple chronic medical conditions, mental health issues, and functional declines. These veterans may have limited access to VA programs delivered in a traditional outpatient format. This article describes adaptations to the whole health model of care that could improve its accessibility and applicability to HBPC veterans, caregivers, and the interdisciplinary teams that serve this population. These modifications are informed by whole-person geriatric and gerontological and family-systems theories and address population-based differences in the focus and approach to care. The focus on care is expanded to (a) reflect the importance of attending to caregiver needs and well-being and (b) shift from a preventative model to one that prioritizes resilience and maintenance. The approach to care emphasizes alternative modes of delivery, adaptations to interventions, and integration of geriatric-specific medical considerations into the self-care domains and more directly centers the collaboration between family, the VA, and community partners. This adapted model also addresses the unique needs of health care teams providing in-home services to medically complex veterans and offers suggestions for enhancing self-care and preventing burnout. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
... 8 The prevalence of StD is 4.0%-53.2%, [9][10][11]
[12]
which is an important risk factor for the development of MDD. 13 Therefore, several effective intervention strategies for StD have been proposed. 13,14 In particular, substantial evidence states that psychotherapy can reduce depressive symptoms in people with StD and prevent future developments of MDD. ...
Effects of Smartphone-Delivered Positive-Word Stimulation on Depressed Mood in People with Subthreshold Depression: Protocol for a Pilot Randomized Controlled Trial
Article
Full-text available
Aug 2021
Hitomi Ejiri
Hiroyuki Uchida
Kenji Tsuchiya
Kazuki Hirao
Background:
Major depressive disorder (MDD) is an important public health problem. Thus, preventive interventions against subthreshold depression (StD), which is one of the key risk factors for the development of MDD, are important. The study developed a smartphone application (SPSRS) that improves depressive symptoms in people with StD by automatically presenting positive word stimuli during videos. The SPSRS application has the potential to improve depressive symptoms in people with StDs. However, whether it can immediately improve depressed moods in people with StD is unclear. The study presents a protocol for investigating the immediate effects of the SPSRS application intervention on depressed mood in people with StD.
Methods:
The study is designed as an open-label, parallel-group, and pilot randomized controlled trial (RCT). Thirty-two people who meet the criteria for StD (Beck Depression Inventory-II score of 10 points or more and fails to meet the diagnostic criteria for MDD) will be recruited and studied. It compares the immediate effects of the SPSRS application intervention (with positive word stimulus in a 10-minute video; n = 16) and YouTube application intervention (without positive word stimulus in 10-minute video; n = 16). The primary outcome is the change in the score for the Profile of Mood States 2nd Edition-Adult Short after 10 minutes of intervention. The secondary outcome is the change in the State-Trait Anxiety Inventory State after 10 min of intervention.
Discussion:
The pilot RCT is the first to evaluate the immediate effects of the SPSRS application intervention on depressed mood in people with StD. The results are expected to provide a preliminary outcome of the immediate effect of the SPSRS application on the depressed mood of people with StD and aid in planning a full-scale trial.
Trial registration:
ClinicalTrials.gov; Identifier: NCT03864484.
... Given their high medical burden, limited social engagement due to mobility impairment, and financial distress among many of them, it is not surprising that depression is 2-3 times higher among homebound than nonhomebound older adults (Choi, Teeters, Perez, Farar, & Thompson, 2010;
Xiang, Leggett, Himle, & Kales, 2018)
. Pharmacotherapy, the most common treatment for geriatric depression, is effective to a low-to-medium degree (Kok, Nolen, & Heeren, 2012;Mallery et al., 2019) but less effective in socioeconomically disadvantaged older adults living with multiple health-related and other life stressors (Cohen, Gilman, Houck, Szanto, & Reynolds, 2009). ...
Reasons for refusing referrals and challenges to effectual engagement in tele-treatment for depression among low-income homebound older adults
Namkee Choi
Kelly Vences
Julieta Caamano
Objectives: To describe reasons for refusal to be referred to or enroll in a depression treatment study and post-enrollment challenges to treatment engagement and technology-related problems among low-income homebound individuals aged 50+ years with depression.
Methods: Data came from a 3-arm randomized clinical trial that evaluated real-world effectiveness of lay counselor-delivered behavioral activation (BA) versus clinician-delivered problem-solving therapy (PST). Interventionists were embedded in a large home-delivered meals program and treatment sessions were videoconferenced; hence Tele-BA and Tele-PST. We described refusal reasons of those who refused initial case manager referrals (n = 279), telephone screening (n = 64), enrollment (n = 47), or post-enrollment baseline assessments (n = 18). We used inductive thematic analysis to explore challenges to effectual treatment engagement and tele-delivery-related problems among Tele-PST or Tele-BA participants (n = 183) from the interventionists’ tele-session process recordings.
Results: More than a third of potentially eligible older adults refused their case managers’ referral, and a quarter of those who accepted referral refused further screening or enrollment. Three quarters of those who refused reported no interest or need or declined to talk about depression. Others refused given their busy schedule with medical appointments and caregiving. Nearly 80% of Tele-BA or Tele-PST participants had some challenges to effectual engagement in treatment sessions due to environmental and health-related conditions and other life stressors including financial distress. Though many tele-sessions had connectivity and other technology-related problems, these did not affect depression outcomes.
Conclusion: Mental health service providers for low-income older adults need to be aware of these challenges when adopting best practice strategies for them.
... Older adults who are homebound due to mobility impairments are at particularly higher risk of depression than their nonhome-bound peers. 10,[18][19]
[20]
Because mobility impairment restricts engagement in social activities, homebound older adults may become depressed and the depression, in turn, may contribute to further disability in a downward spiral. 21,22,23 For low-income homebound older adults, financial strain is also an added depression risk factor. ...
The reciprocal relationship between depression and disability in low‐income homebound older adults following tele‐depression treatment
Article
C. Nathan Marti
Mark Kunik
Namkee Choi
Objectives
Research has shown ample evidence for reciprocity between depression and disability. We examined whether decreases in disability among low‐income, homebound older adults who received brief depression treatments were mediated by improvement in depressive symptoms and vice versa and whether the mediation effects varied by treatment modality.
Methods
In a 3‐arm randomized clinical trial, 277 low‐income homebound individuals aged 50+ participated in behavioral activation tele‐delivered by bachelor's‐level lay counselors (Tele‐BA), problem‐solving therapy tele‐delivered by licensed clinicians (Tele‐PST), or telephone support calls (attention control). Depressive symptoms were assessed with the 24‐item Hamilton Rating Scale for Depression and disability with the 12‐item World Health Organization Disability Schedule 2.0. Along with mediation models, mediation was assessed controlling for autoregressive and contemporaneous effects.
Results
Mediation models showed evidence of postintervention disability and depression mediating each other in separate mediation models. In the cross‐lagged model, in which autoregressive and contemporaneous effects were included, only the depression‐to‐disability path exhibited mediation. There was no evidence of difference between Tele‐BA and Tele‐PST. Although the temporal precedence of treatment conditions on the outcomes is apparent, we could not establish a temporal precedence between disability and depression as these two measures exhibited parallel improvement.
Conclusions
Brief depression treatments for low‐income homebound older adults were effective in reducing both depression and disability among these disabled older adults. The importance of this study lies in the comparable effects of Tele‐BA and Tele‐PST. Lay‐counselor model is a promising alternative to clinician‐delivered psychotherapy for growing numbers of homebound older adults.
... Of Medicare beneficiaries aged 65 years or older, 8.3% were chronically homebound between 2011 and 2017, and 26.2% were at rapid risk of becoming homebound over the 7-year period. 1 Older adults who are homebound (three-quarters of whom are women and one-third of whom are not White) tend to be socioeconomically disadvantaged. 2 In addition, their rates of depression are 2-to 3-fold higher than their nonhomebound peers. [3][4]
[5]
While pharmacotherapy is the primary treatment for geriatric depression, its effectiveness is especially low for these older adults, as it does not address their multiple life stressors that are depression risk factors. 6 Pharmacotherapy has also been found inadequate for treating older adults with persistent depressive disorder with cerebrovascular or neurodegenerative comorbidities. ...
Effect of Telehealth Treatment by Lay Counselors vs by Clinicians on Depressive Symptoms Among Older Adults Who Are Homebound A Randomized Clinical Trial + Visual Abstract + Invited Commentary + Supplemental content
Article
Full-text available
Nancy Wilson
Namkee Choi
C. Nathan Marti
Mark Kunik
Importance
Older adults who are homebound and have low income have limited access to psychosocial treatments because of their homebound state and geriatric mental health workforce shortages.
Objective
To evaluate clinical effectiveness of a brief, aging service–integrated, videoconferenced behavioral activation (tele-BA) treatment delivered by lay counselors compared with videoconferenced problem-solving therapy (tele-PST) delivered by licensed clinicians and attention control (AC; telephone support calls).
Design, Setting, and Participants
This 3-group randomized clinical trial using a randomization prior to consent approach included individuals aged 50 years or older who were homebound and had 24-item Hamilton Depression Rating Scale (HAMD) scores of 15 or greater between February 15, 2016, and April 15, 2019. Tele-BA and tele-PST participants received 5 weekly treatment sessions. Assessments were performed at baseline and 12, 24, and 36 weeks after baseline. Intention-to-treat statistical analyses were performed from January 1, 2020, to February 15, 2020.
Interventions
Tele-BA participants were taught 5 steps for reinforcing healthy behaviors to improve mood, physical functioning, and social engagement. Tele-PST participants were taught a 7-step approach for problem solving coping skills.
Main Outcomes and Measures
The primary outcome was the 24-item HAMD scores. Response (ie, ≥50% reduction in HAMD) and remission (ie, HAMD <10) rates and effect sizes for clinically meaningful differences were examined. Secondary outcomes were disability, social engagement and activity frequency, and satisfaction with participation in social roles.
Results
A total of 277 participants were enrolled, including 193 (69.7%) women, 83 (30.0%) who were Black, 81 (29.2%) who were Hispanic, and 255 (92.1%) with income of $35 000 or less. The mean (SD) age was 67.5 (8.9) years. Among these, 90 participants were randomized to tele-BA, 93 participants were randomized to tele-PST, and 94 participants were randomized to the AC. Compared with participants in the AC group, participants in the tele-BA and tele-PST groups had significantly higher response and remission rates and medium to large effect sizes (tele-BA: raw growth modeling analysis d = 0.62 [95% CI, 0.35 to 0.89]; P < .001; tele-PST: raw growth modeling analysis d = 1.00 [95% CI, 0.73 to 1.26]; P < .001) for HAMD scores. While tele-PST was significantly more effective than tele-BA for reducing HAMD scores (t258 = −2.79; P = .006), there was no difference between tele-BA and tele-PST on secondary outcomes.
Conclusions and Relevance
In this randomized clinical trial, participants who received tele-BA by lay counselors achieved statistically and clinically meaningful changes in depressive symptoms. Given shortages of licensed mental health clinicians, tele- and lay counselor–delivered services may help improve access to evidence-based depression treatment for large numbers of underserved older adults.
Trial Registration
ClinicalTrials.gov Identifier: NCT02600754.
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Show abstract
... A study of 736 home-delivered meals recipients aged 50þ found that 17.5% had clinically significant depressive symptoms (Patient Health Questionnaire-9 [PHQ-9] 10; Kroenke, Spitzer, & Williams, 2001), and 8.8% had probable major depressive disorder (PHQ-9 21) (Choi, Teeters, Perez, Farar, & Thompson, 2010). Another study found that of a nationally representative sample of those aged 60þ receiving home care services, 38.7% had subthreshold depression and 13.4% had major depression, and a significant proportion of those with depression also had anxiety symptoms
(Xiang, Leggett, Himle, & Kales, 2018)
. ...
Acceptability and effects of tele-delivered behavioral activation for depression in low-income homebound older adults: in their own words
Julieta Caamano
Kelly Vences
Namkee Choi
Mark Kunik
Objectives
To examine experiences and perspectives of low-income homebound older adults (N = 90) who participated in tele-delivered behavioral activation (Tele-BA) treatment for depression by bachelor’s-level lay counselors.
Methods
We used the 11-item Treatment Evaluation Inventory (TEI) to measure participants’ acceptability of Tele-BA. We used inductive thematic analysis to explore participants’ Tele-BA session goals and activities and unsolicited and solicited comments about their Tele-BA experience.
Results
Participant’s TEI score averaged 70 out of maximum possible 77. The most frequently chosen Tele-BA goals were to improve self-care management of physical and mental health, engage in self-enrichment/self-enjoyment, improve living environment and daily routine, and to increase social connectedness. The themes that emerged from participants’ comments about Tele-BA were: (1) benefits of psychoeducation; (2) importance of and gratitude for working with a counselor; (3) benefits of activity planning; (4) understanding of behavior and mood connection; (5) positive effects of increased activity on health and self-enjoyment; (6) sense of being productive and useful from accomplishing goals; (7) hope for the future; and (8) pride in tele-treatment.
Conclusion
Participants’ comments show that Tele-BA aimed at reinforcing healthy behaviors that improve both physical functioning and mood is well aligned with these older adults’ perception of what treatment should be. The findings also provide support for lay counselors’ clinical capacity. Given geriatric mental health workforce shortages, lay counselors may be able to effectively supplement existing professional mental health service systems.
... 1 According to data from the Chinese National Bureau of Statistics, the number of people aged 65 years or older in 2018 accounted for 11.9% of the population; 2 by 2053, 34.9% of the population will be over 65. 3 As age increases, people are likely to face greater physical and mental health problems such as diabetes, hearing loss, Parkinson's disease, and depression. [4][5][6]
[7]
Many older adults have multiple comorbidities 8 and they may experience ageism in attempting to confront their complex health challenges. ...
Teaching and Learning in Medicine Chinese Medical Students' Attitudes toward Older Adults and Willingness To Consider a Career in Geriatric Medicine: A Cross-Sectional Survey Chinese Medical Students' Attitudes toward Older Adults and Willingness To Consider a Career in Geriatric Medicine: A Cross-Sectional Survey
Article
Jul 2020
Huimin Zhao
Bei Wu
Jing Shi
Jing Mao
Phenomenon: Ageism is a significant social issue, especially in China. Ageism adversely affects willingness to consider a career in geriatric medicine. However, few studies have examined this topic among Chinese medical students. This study aimed to investigate attitudes toward older people among medical students in China, examine the factors related to these attitudes, and determine the relationships between attitudes and willingness to consider geriatric medicine as a career after graduation. Approach: Responses from 1,022 Chinese medical students were included in the analyses. Students provided demographic information and completed the Fraboni Scale of Ageism (FSA). The data were analyzed using the Statistical Package for Social Sciences, version 24.0 (IBM SPSS Corp). Findings: The mean score of the FSA was 64.42 ± 6.58. Multiple regression analysis showed that the significant predictors of ageism were being male, longer years of training in medical school, and no caregiving experiences with older adults during clinical practice (R 2 ¼ .038, F ¼ 13.520, p < .001). Students who had higher FSA scores were more unwilling to consider a career in geriatric medicine after graduation (t ¼ 4.281, p < .001, Cohen's d ¼ .268). Insights: Chinese medical students have fewer positive attitudes toward older adults than what has been reported in other countries. Future studies should examine the determinants of ageism among medical students in various cultures to guide the development, implementation, and assessment of interventions designed to nurture a more positive attitude toward older adults and increase willingness to consider a career in geriatric medicine.
... Only 4% of all collected CSPs represented specific categories of depression, dementia, suicide, and abuse. These numbers were surprising considering what patient need in the community may actually be given the reported prevalence of mental illness in the Canadian home care population (Sinha & Bleakney, 2014), which is also consistent with other reported rates of depression in older adult home health populations of between 13% and 23% (Pickett, Raue, & Bruce, 2012;Xiang, Danilovich, et al., 2018;
Xiang, Leggett, Himle, & Kales, 2018)
. This disconnect between underutilization of social work and patient need may be explained by some of the availability of community supports such as elder abuse teams, mental health associations, and inpatient hospital supports for mental illness. ...
Utilization of social workers in home care: An analysis of service use
Angela Hovey
Cole Edick
Keith Brownlee
Social workers are well positioned to address mental health complications impacting home care populations, yet social work has one of the lowest utilization rates of offered home care supports in Ontario. This study analyzed care plan data of frontline in-home social work services. Results identified adjustment to illness as the most common category and that seniors required significantly fewer visits and days on service than non-seniors. Most patients were able to accomplish their social work-based goals. Results highlight a need for further research and for capitalizing on the untapped potential value of social work home care services for patients.
For possible copy (50 free) see: https://www.tandfonline.com/eprint/IDGBCGJTHN2TXRJWSM3G/full?target=10.1080/01621424.2020.1749920
... Along with high medical burden, homebound older adults suffer from depression at rates two to three times higher than their ambulatory peers (Choi, Teeters, Perez, Farar, & Thompson, 2010;Johnson, Sharkey, & Dean, 2011;
Xiang, Leggett, Himle, & Kales, 2018)
. Depression exacerbates the clinical manifestations of comorbid medical conditions, such as diabetes and hypertension, and is a risk factor for poor outcomes in these conditions, owing partly to the negative influence of depression on self-care management (American Psychiatric Association, 2010). ...
Religious coping and acceptability and outcome of short-term psychotherapeutic treatments for depression among low-income homebound older adults
Dec 2019
John E. Sullivan
C. Nathan Marti
Mark Kunik
Namkee Choi
Objectives: To examine (1) correlates of religious coping, and (2) associations of religious coping at baseline with evaluation of treatment acceptability and depressive symptom severity outcomes of short-term psychotherapeutic depression treatments among 277 low-income homebound older adults (70% female; 41% non-Hispanic White, 30% African American, and 29% Hispanic) who participated in a treatment effectiveness trial.
Method: Religious coping was measured with a 2-item subscale of the Brief COPE. Treatment acceptability was measured with the 11-item Treatment Evaluation Inventory (TEI). Depressive symptoms were measured with the 24-item Hamilton Rating Scale for Depression (HAMD). We used linear regression modeling to examine correlates of religious coping at baseline and to examine associations of religious coping with treatment acceptability and depression outcome at 12 weeks.
Results: Being female and being African American predicted higher religious coping. Additionally, active coping, emotional support coping, and clergy consultation on depression were significantly associated with higher religious coping. Religious coping was not significantly associated with TEI and HAMD scores at 12 weeks.
Conclusion: The findings show that once these older adults participate in depression treatment, they find it highly acceptable and benefit from treatment, regardless of their religious coping, and that psychotherapeutic treatment is a highly acceptable and effective addition to those with religious-oriented coping.
... Depression is the most common disease among the teenagers these days. Depression is the sudden loss of interest in person's usual activities
[1]
. It is a mood disorder and there is a feeling of sadness. ...
Depression: The Growing Mental Disease and its Treatment by SSRI
Deepa Yadav
... Of Medicare beneficiaries aged 65 years or older, 8.3% were chronically homebound between 2011 and 2017, and 26.2% were at rapid risk of becoming homebound over the 7-year period. 1 Older adults who are homebound (three-quarters of whom are women and one-third of whom are not White) tend to be socioeconomically disadvantaged. 2 In addition, their rates of depression are 2-to 3-fold higher than their nonhomebound peers. [3][4]
[5]
While pharmacotherapy is the primary treatment for geriatric depression, its effectiveness is especially low for these older adults, as it does not address their multiple life stressors that are depression risk factors. 6 Pharmacotherapy has also been found inadequate for treating older adults with persistent depressive disorder with cerebrovascular or neurodegenerative comorbidities. ...
TELE-BEHAVIORAL ACTIVATION FOR SOCIAL ISOLATION IN OLDER HOME-DELIVERED MEALS RECIPIENTS: PRELIMINARY RESULTS FROM AN ONGOING RANDOMIZED CONTROLLED TRIAL
AM J GERIAT PSYCHIAT
Renee Pepin
Peter R. Dimilia
Namkee Choi
Martha L Bruce
Introduction
Homebound older adults are often unable to participate in social interactions and activities that require leaving the home, resulting in a high prevalence of isolation among this population. Isolation is associated morbidity, disability, and mortality. Technology has been explored as a potential avenue for meaningful social interaction for homebound seniors. We present preliminary results of an ongoing randomized controlled trial evaluating the acceptability, feasibility and comparative effectiveness of delivering two interventions by video-conferencing technology to promote social connectedness among homebound older adults receiving home-delivered meals: 1. Behavioral activation (tele-BA) vs. 2. Friendly visitors (tele-FV). To our knowledge, this is the first randomized controlled trial to leverage local Meals on Wheels (MoWs) agencies to engage homebound, socially isolated older adults in a telehealth intervention for social isolation.
Methods
Older adults in New Hampshire and central Texas were recruited for our study by local MoWs agencies during the routine annual evaluation of their home-delivered meals clients. After a brief eligibility screening by their MoWs case workers and indicated interest, MoWs clients were referred to our study team and contacted by telephone for a full eligibility assessment. Eligible participants endorsed social isolation (6 or greater on the 3-item UCLA Loneliness Scale), but did not report symptoms of moderate to severe depression (PHQ-9 < 10) or suicidal ideation. Those with hearing, vision, or memory impairment and active psychiatric illness were excluded. Participants were randomly assigned to either participate in the tele-BA intervention or the tele-FV comparison condition for hour-long, weekly videoconference sessions for five weeks. Both interventions were delivered by a trained lay provider. The tele-BA intervention included a version of behavioral activation modified for social isolation and tele-delivery; the comparison condition (tele-FV) consisted of unstructured friendly visits. Participants were assessed at baseline, post-intervention, and 12 weeks post-intervention with the PROMIS 8-Item Social Isolation measure and 9-item Patient Health Questionnaire. Participants were also asked questions related to their experience with tele-BA or tele-FV at the post-intervention assessment.
Results
In the first year of our study, 50 socially isolated older adults (age M±SD73.5±9.2 years; range 51 to 90 years) participated in either the tele-BA intervention (n=28) or tele-FV comparison condition (n=22). Participants were predominantly non-Hispanic white (70%), female (65%), of lower SES (56% less than $20,000 annual income) and living alone (68%). When asked, all participants indicated they would recommend this tele-program to family and friends (Net Promotor Scale 0-10: M±SD 9.7±0.9; range 6-10). Most participants (92%) found these tele-sessions moderately to very acceptable for their social isolation and 95% indicated somewhat positive to very positive general reaction to the program. Preliminary data at 12-week follow-up showed reduction on the 8-item Social Isolation measure and the PHQ-9, with a trend towards greater improvement in participants who participated in the tele-BA group.
Conclusions
Overall, participants found tele-Behavioral Activation and tele-Friendly Visits to be positive experiences and acceptable for their social isolation, and would recommend the program to their friends and family. Preliminary data showed improvement in isolation and depressive symptoms for both groups, which is sustained through 12 weeks of post-intervention follow-up. Our preliminary results suggest the feasibility, acceptability and potential effectiveness of using tele-technology to deliver interventions for homebound older adults who report social isolation. We also found potential evidence of the effectiveness of modified tele-behavioral activation program, compared to friendly visitors, in reducing social isolation and subclinical depressive symptoms in this population. Finally, we demonstrated the feasibility of working in collaboration with community-based Meals on Wheels agencies to identify socially isolated clients and refer them to this program.
This research was funded by
AARP-Foundation
The heterogeneity of the homebound: A latent class analysis of a national sample of homebound older adults
Mar 2023
J AM GERIATR SOC
Harriet Mather
Hannah Kleijwegt
Evan Bollens-Lund
Katherine Ornstein
Background:
Homebound status is a final common pathway for people with a variety of diseases and conditions. There are 7 million homebound older adults in the United States. Despite concerns regarding their high healthcare costs and utilization and limited access to care, the unique subsets within the homebound population are understudied. Better understanding of distinct homebound groups may enable more targeted and tailored approaches to care delivery. Therefore, in a nationally representative sample of homebound older adults we used latent class analysis (LCA) to examine distinct homebound subgroups based on clinical and sociodemographic characteristics.
Materials and methods:
Using data from the National Health and Aging Trends Study (NHATS) 2011-2019, we identified 901 newly homebound persons (defined as never/rarely leaving home or leaving home only with assistance and/or difficulty). Sociodemographic, caregiving context, health and function, and geographic covariates were derived from NHATS via self-report. LCA was used to identify the existence of distinct subgroups within the homebound population. Indices of model fit were compared for models testing 1-5 latent classes. Association between latent class membership and 1 year mortality was examined using a logistic regression.
Results:
We identified four classes of homebound individuals differentiated by their health, function, sociodemographic characteristics, and caregiving context: (i) Resource constrained (n = 264); (ii) Multimorbid/high symptom burden (n = 216); (iii) Dementia/functionally impaired (n = 307); (iv) Older/assisted living (n = 114). One year mortality was highest among the older/assisted living subgroup (32.4%) and lowest among the resource constrained (8.2%).
Conclusions:
This study identifies subgroups of homebound older adults characterized by distinct sociodemographic and clinical characteristics. These findings will support policymakers, payers, and providers in targeting and tailoring care to the needs of this growing population.
Subthreshold depression - concept, operationalisation and epidemiological data. A scoping review
Full-text available
Jun 2022
INT J PSYCHIAT CLIN
hans-peter Volz
Johanna Stirnweiß
Siegfried Kasper
Erich Seifritz
Purpose: In diagnostic systems (e.g., DSM-5, ICD-10), depression is defined categorically. However, the concept of subthreshold depression (SD) has gained increasing interest in recent years. The purpose of the present paper was to review, based on a scoping review, the relevant papers in this field published between October 2011 and September 2020.
Materials and methods: Of the 1,160 papers identified, 64 records could be included in further analysis. The scoping review was conducted using both electronic and manual methods.
Results: The main result of the analysis is that the operationalisation criteria used are highly heterogeneous, which also leads to very heterogenous epidemiological data.
Conclusions: Clear conclusions are not possible scrutinising the reported results. Most definitions seem to be arbitrary, with considerable overlap (e.g., between SD and minor depression). The review also revealed that the impact of SD on quality of life and related parameters appear to be in the range of the respective impact of major depression (MD) and therapeutic approaches might be helpful for SD and also for the prevention of conversion from SD to MD. Keeping the presented difficulties in mind, a proposal for the definition of SD is made in the present paper in order to facilitate the discussion leading to more homogeneous criteria.
Rehabilitation of The Depressed Elderly Psychiatric clinic with a Healing Garden Approach (Case Study: Ayatollah Modarres Psychiatric Hospital)
Thesis
Sep 2021
Sahar Ilkhan
Amirhosein Shabani
Fatemeh Rajabi
منظر شفابخش یک فرآیند و یک مکان است. این باغ نقطه تقاطع پزشکی و طراحی محسوب می شود که هدف از ایجاد آن در مراکز درمانی و نگهداری، کمک به بیماران برای دستیابی و یا حفظ بالاترین حد کاربری فیزیکی، روانی و بهبودی عمومی در آن ها است. این مساله در مورد بیماران اهمیت بیشتری می یابد، زیرا بیماری و بستری شدن یكی از پراسترس ترین موقعیت های زندگی انسان است. سعی نگارنده در این پایان نامه بر آن بوده است با توجه به اصول کلی باغ های شفابخش، راهكارهایی برای طراحی فضاهای شفابخش در کلینیک روانپزشکی سالمندان ارائه دهد و به ارتباط بین فضای داخلی و محوطه خارجی کلینیک و تأثیر آنها بر روی بیماران سالمند اشاره داشته باشد و با شناخت دقیق رفتارها، تجربیات و نیازهای بیماران سبب افزایش کارایی منظر شفابخش و در نتیجه بهبود وضعیت روحی سالمندان گردد. در این پژوهش فرآیند تأثیر پذیری انسان از محیط و مفاهیم شفابخشی و تأثیر آن بر سالمندان افسرده در مراکز درمانی مورد بررسی قرار گرفته و در ادامه تکنیک Grounded Theory یا نظریه زمینه ای به عنوان روش انجام پژوهش اتخاذ شده و اصول و گام های انجام تحقیق توسط مصاحبه نیمه ساختار یافته و مشاهدات بر روی 15 نفر انجام شد. همچنین نتایج گردآوری اطلاعات و تحلیل های پژوهشگر با کمک نرم افزار MAXQDA به انجام رسیده و در نتیجه عوامل ذیل به عنوان شاخص های یک باغ شفابخش در جهت سلامت روان سالمندان افسرده منتج شده است: آرامش و امنیت، تحریک حواس 5گانه، حواس پرتی مثبت، کاهش استرس محیط بر روی بیماران، انتخاب آزادانه فضا توسط بیمار و ارتباط بیمار با طبیعت و در نهایت بنیان طراحی توسط این داده ها درفصل پایانی فراهم آمد. در ادامه کلینیک روانپزشکی سالمندان با استناد به داده ها تحلیل و فرصت های موجود شناسایی و در نهایت چهارچوب طراحی در سه محور: بهسازی فضاهای موجود در سطح یک و دو به همراه پیشنهاد برای طرح توسعه در سایت بیمارستان آیت الله مدرس ارائه گردید.
Subthreshold lifetime depression and anxiety are associated with increased lifetime suicide attempts: A Korean nationwide study
Article
Jan 2022
J AFFECT DISORDERS
Ji Hyun An
Hong Jin Jeon
SeongJin Cho
Jin Pyo Hong
Background
: Subthreshold depression and anxiety are highly prevalent and known to be associated with functional limitations and future onset of major depression or anxiety disorders. However, studies regarding suicidality at subthreshold levels of depression and anxiety are limited.
Methods
: A total of 17,639 Koreans aged from 18 to 64 responded to the Korean version of the WHO-composite international diagnostic interview (K-CIDI) version 2.1 between 2006 and 2016. Prevalence of subthreshold depression and anxiety, and information on lifetime suicide attempt (SA) were assessed. Multivariable logistic regression was performed to calculate the risk of SA by the level of depression or anxiety.
Results
: The risk of lifetime SA increased incrementally according to the level of depression and anxiety. In the subthreshold depression group, individuals with subthreshold anxiety increased the odds about threefold (OR = 3.15, 95% CI 3.12–3.18) and the threshold anxiety disorder group increased the odds about fivefold (OR = 5.33, 95% CI 5.27–5.38) for SA, compared to the group without any level of anxiety. In threshold depressive disorder, the subthreshold anxiety group showed about 1.8-fold higher odds (OR = 1.76, 95% CI 1.75–1.77) and the threshold anxiety disorder group showed threefold higher odds (OR = 2.93, 95% CI 2.92–2.95) for SA compared to the group without any level of anxiety.
Conclusions
: Subthreshold levels of depression and anxiety were prevalent among Koreans and were associated with an increased prevalence of lifetime SA. A detailed assessment of depression and anxiety symptoms according to their level should be performed on a diagnostic continuum to prevent suicide.
How Does Care Management Interface with Behavioral Health?
Generations
Namkee Choi
Care management in individuals with depression can result in highly positive outcomes, especially for socioeconomically disadvantaged older adults. Outcomes of intensive care management for homeless older adults with mental and substance use issues also are positive when accompanied by housing. But care management programs tested to date appear to have limited positive effects on people with dementia and their caregivers, as they cannot be standardized. More studies are needed to nd care management models and practices that would be work with this population.
Unmet Behavioral Health and Social Needs of Home Healthcare Patients and Their Caregivers
Mar 2021
Home Health Care Manag Pract
Angela M. Gerolamo
Monika Pogorzelska-Maziarz
Alexzandra T. Gentsch
Kristin L. Rising
Lack of recognition and treatment of mental health disorders in the home healthcare (HHC) population has been recognized as a national public health problem. However, there is a gap in understanding the behavioral health needs of HHC patients and caregivers from the perspectives of HHC patients, caregivers, and HHC personnel. These perspectives are critical for informing an acceptable and scalable integrated care model. We conducted semi-structured interviews with HHC patients, caregivers, and HHC personnel to assess the unmet behavioral health needs of HHC patients and their caregivers. Participants were recruited from a Medicare-certified HHC agency that is part of a large health system on the east coast. We completed a total of 31 interviews between January and May 2020. Findings suggest that HHC patients have significant unmet behavioral health and social needs and their caregivers are emotionally and physically drained. Reasons that patients may not be receiving adequate behavioral health services include denial, cost, culture, lack of awareness of available resources, lack of transportation, and homebound status. While most patients discussed the emotional toll of their illness, few were connected to services. HHC personnel offered suggestions on how to meet the behavioral health needs of patients, with the primary focus on providing in-home options. Gaps in meeting the needs of the HHC population necessitate integrated care models that can effectively address the behavioral health and social needs of HHC patients and their families. Future research should develop and test patient and caregiver-directed integrated care models in the HHC setting.
Effects of video viewing smartphone application intervention involving positive word stimulation in people with subthreshold depression: A pilot randomized controlled trial
J AFFECT DISORDERS
Kaito Kageyama
Yudai Kato
Takanori Mesaki
Kazuki Hirao
Background
: A smartphone application (i.e., SPSRS) was developed to help people with subthreshold depression (StD) improve depressive symptoms by presenting positive word stimuli in videos. However, to date, no randomized controlled trials (RCTs) were conducted to investigate SPSRS application interventions for depressive symptoms in people with StD. Therefore, a pilot RCT was conducted to assess the preliminary efficacy of the SPSRS application intervention for people with StD.
Methods
In a pilot RCT, 32 participants (female = 34.4%, mean age = 20.06, SD = 1.24) with StD were randomized to SPSRS application intervention for approximately 10 min/a day for 5 weeks (experimental group; n = 16) or no intervention (wait list control group; n = 16). The primary outcome is the change from baseline in the Center for Epidemiologic Studies Depression Scale (CES-D) score after the 5-week intervention. The secondary outcomes are the change from baseline in the Kessler Screening Scale for Psychological Distress (K-6) score and the Generalized Anxiety Disorder 7-item scale (GAD-7) after the 5-week intervention.
Results
No participants dropped out of the study. The experimental group displayed medium, small, and small improvements in CES-D, K-6, and GAD-7 scores (adjusted Hedge's g = −0.64, −0.29, and −0.40), respectively, compared with control.
Limitations
The observed effects must be considered preliminary due to the small sample size.
Conclusions
The results suggest the potential of intervention using the SPSRS application to reduce depressive symptoms in people with StD. Future studies should replicate these findings in a full-scale RCT.
Internet-Based Cognitive Behavioral Therapy for Depression: A Feasibility Study for Home Care Older Adults
RES SOCIAL WORK PRAC
Yihang Sun
Shawna N. Smith
Joseph A. Himle
Xiaoling Xiang
Purpose
The present study examined the feasibility of internet-based cognitive behavioral therapy (iCBT) for home care older adults.
Method
A feasibility open trial was conducted with 26 recipients of nonmedical home care with depressive symptoms. When possible, home care workers (HCWs) of older adults ( n = 13) were recruited to provide external support for iCBT usage.
Results
The mean therapy sessions completed was 4.7 out of 8, and 86% would recommend the program to others with depressed mood. Participants’ depressive symptoms and anxiety symptoms decreased, whereas their quality of life ratings improved.
Discussion
iCBT is a feasible and acceptable treatment modality for home care older adults with depressive symptoms and is potentially effective. Future studies are warranted to refine the existing treatment platform to achieve a better fit between the demands of the program and the needs and capabilities of homebound older adults and to examine treatment effectiveness as a function of HCW support.
Perceptions and practice behaviors regarding late-life depression among private duty home care workers: a mixed-methods study
Ashley Zuverink
Background: This study aimed to examine personal care aides (PCAs)’ knowledge, beliefs, and attitudes towards late-life depression and their experience caring for older adults with depression.
Method: This study used a mixed-methods convergent parallel design involving an online survey (n = 87) and semi-structured interviews (n = 22). Survey respondents were recruited using convenience sampling and interviewees using purposive sampling from private duty home care agencies in Michigan. Qualitative data analyzed using a technique involving data reduction and open coding. Survey data were analyzed using descriptive statistics.
Results: Most PCAs underestimated suicide rate among older adults, overrated self-help ability of the depressed person, underrated difficulty diagnosing depression, and attributed depression to personality flaws. PCAs favored psychotherapy and informal support and generally regarded medication as unhelpful, particularly in mild/moderate depression. Despite these discordances, PCAs’ self-reported practice behaviors included strategies (i.e., communication, behavioral, cognitive, emotional regulation, relational, and external) that were largely consistent with the scientific view, particularly relating to behavioral activation. A prominent theme from PCAs’ narratives was individualized care, reflected in their assessment of depressive symptoms, attitude towards depression treatment, and strategies caring for clients.
Conclusions: Several areas of PCAs’ perceptions regarding late-life depression were discordant with the current scientific view, although their practice behaviors were largely consistent with the principles of evidence-based practice for depression. Specialized mental health training, a standard depression care protocol, and higher training standards are essential to mobilize the large number of PCAs to improve the mental health outcomes of hard-to-reach older adults.
Effectiveness of Frankl’s Logotherapy on Health (Decreasing Addiction Potential and Increasing Psychological Well-being) of Students with Depression
Paridokht Esalati
Ali Arab
Background and Objective: Depression is one of the most common psychological problems that can increase addiction potential and decrease psychological well-being. There are different methods to improve the psychological status of people and logotherapy is one of them. As a result, present research aims to determine effectiveness of Frankl’s logotherapy on addiction potential and psychological well-being of girl students with depression.
Methods: This was a semi-experimental study with a pre-test and post-test design. The research population included girl students with depression in Farhangian University of Birjand Pardis in the 2017-18 academic years. 30 people were selected via available sampling method and were randomly assigned to two equal groups. The experimental group was trained for 8 sessions of 90 minutes (twice a week) using Frankl’s logotherapy method. The instruments included the questionnaires of depression, addiction potential, and psychological well-being. The data were analyzed using t-test and MANCOVA methods.
Results: The findings showed that there was a significant difference between the two groups in terms of addiction potential and psychological well-being. In the other words, the Frankl’s logotherapy significantly led to decreased addiction potential (F=57/10, P
Pride and Prejudice in the Treatment of Depression and Anxiety in Acutely Ill Older Adults
AM J GERIAT PSYCHIAT
Eric J. Lenze
Michael S. Avidan
Late-Life Depressive and Anxiety Symptoms Following Rehabilitation Services in Medicare Beneficiaries
Objective:
The aim of this study was to determine whether patients who received rehabilitation services had an increased risk of having late-life depressive or anxiety symptoms within the year following termination of services.
Methods:
The National Health and Aging Trends Study (NHATS) is a population-based, longitudinal cohort survey of a nationally representative sample of Medicare beneficiaries aged 65years and older. This study involved 5,979 participants from the 2016 NHATS survey. The Patient Health Questionnaire-2 and Generalized Anxiety Disorder 2-item assessed for clinically significant depressive and anxiety symptoms.
Results:
The prevalence of depressive and anxiety symptoms was higher in older adults who had received rehabilitation services in the year prior and varied by site: no rehabilitation (depressive and anxiety symptoms): 10.4% and 8.8%; nursing home or inpatient rehabilitation: 38.8% and 23.8%; outpatient rehabilitation: 8.6% and 5.5%; in-home rehabilitation: 35.3% and 20.5%; multiple rehabilitation sites: 20.3% and 14.4%; and any rehabilitation site: 18.4% and 11.8%. In multiple logistic regression analyses, nursing home and inpatient and in-home rehabilitation services, respectively, were associated with an increased risk of having subsequent depressive symptoms (odds ratio: 3.51; 95% confidence interval [CI]: 1.85-6.63; OR: 2.15; 95% CI: 1.08-4.30) but not anxiety symptoms.
Conclusion:
Older adults who receive rehabilitation services are at risk of having depressive and anxiety symptoms after these services have terminated. As mental illness is associated with considerable morbidity and may affect rehabilitation outcomes, additional efforts to identify and treat depression and anxiety in these older adults may be warranted.
Correlates of Depressive Symptoms among Homebound and Semi-Homebound Older Adults
This study aimed to provide a national profile of homebound and semi-homebound older adults with depressive symptoms and to compare risk factors of depressive symptoms by homebound status. A sample of 1,885 homebound and semi-homebound older adults were selected from Round 1 of the National Health and Aging Trends Study. The prevalence of depressive symptoms was 43.9% in homebound older adults and 28.1% in semi-homebound older adults, representing over 830,000 and 1.4 million individuals in the population, respectively. Nearly two-thirds of homebound and over half of semi-homebound older adults with clinically significant depressive symptoms also had significant anxiety symptoms. Results from logistic regression showed that younger age, certain medical morbidities, severity of functional limitations, and pain were common risk factors for depressive symptoms among homebound and semi-homebound older adults. Some differences in the risk factor profile emerged between the homebound and the semi-homebound populations. Alleviating the burden of depression in the semi-homebound population may focus on early prevention that considers the diversity of this population. Home-based, integrated programs of health and mental health services that simultaneously address the medical, psychiatric, and neurologic comorbidities and disabilities of homebound older adults are needed to meet the complex needs of this population.
Jan 2016
2230-2231
J Wong
A Motulsky
T Eguale
Wong J, Motulsky A, Eguale T, et al: Treatment indications for antidepressants prescribed in primary care in Quebec, Canada, 20062015. JAMA 2016; 315:2230-2231. doi:10.1001/jama.2016.3445
| https://www.researchgate.net/publication/325026697_Major_Depression_and_Subthreshold_Depression_among_Older_Adults_Receiving_Home_Care |
Marie Skłodowska Curie | Changeset | Radiopaedia.org
Marie Skłodowska Curie
Marie S Curie(1867-1934) was a Polish-born, French scientist known for her work in discoveringradioactivity. Her work shaped medicine, warfare and scientific research for countless generations, earning herNobel prizes in both physics and chemistry 1,3.
Early life
Maria Salomea Skłodowska was born 7
th
November
November
1867
in
Warsaw, Poland into a once noble Polish family under heavy
Czarist
Tsarist
Russia oppression
1
. Marie’s upbringing would focus heavily on the gift of education and the power of passing it onto others, a mantra to which Marie abided wholeheartedly
1,3
. She excelled in both private and public education, considered gifted among her peers. Upon graduation, Marie and her sisters embarked on what is now known as a ‘gap year’ travelling to outskirts of the country visiting relatives and indulging in festivities.
Marie eventually sought further education at the ‘Flying University’, an illegal university based in Warsaw dedicated to the education of female scientists under Russian oppression 2.
Education
Marie agreed to provide financial support to her sister, Bronisława, while she studied medicine in Paris. The agreement was that the favour would be repaid in turn. While working as a governess in Warsaw, Maria would work in secret with her cousin Jozef Boguski, studying chemistry and performing 'wet chemistry' experiments, the birth of her passion 2.
In 1891, at the age of 23, Marie enrolled to study at the Sorbonne, graduating in 1893 with a “Licence des Sciences”, furthermore receiving a licence in mathematics in 1894. In that same year, she would eventually meet her future husband, a scientist named Pierre Curie 1-3.
Research into radioactivity
Pierre and Marie examined magnetism in their laboratories for years, though it was the 1895 discovery of x-rays byWilhelm Roentgenthat would change the direction of their research 1-3.
An experiment in which uranium rays, like x-rays, were observed to ‘electrify’ the air sparked Marie's interest so much that she decided this to be the basis of her doctrine. Marie measured radioactivity using piezoelectric electrometers developed by her husband, Pierre. In 1898, a paper was presented to the Academy of Sciences titled ‘"Rays emitted by uranium and thorium compounds", in which it was proposed that each element had unique ‘radioactivity’ and one could conclude the composition of a material based on its ‘radioactivity’.
Polonium and Radium
Curie then proposed one could isolate a new element in the radioactive substance known as ‘pitchblende’ (now known as uraninite).
For years Marie and her husband worked on isolating, purifying and describing polonium and radium thanks to a sizeable donation of 10 tonnes of pitchblende by the Austrian Government.
The Curies' shed was known to have beamed with luminescence from the radioactive materials, a fact today that would concern any occupational health and safety pundit. Consequently, the entire family would develop signs of ill health.
Marie succeeded in extracting radium and polonium, concluding her thesis in 1903 successfully obtaining a ‘Docteur des Sciences Physiques’.
Radiology cars
Marie went on to design ‘radiology cars’ to assist soldiers in the front line during the First World War. The cars were equipped with x-ray units and darkrooms, bringing these facilities to tents throughout the front lines 1. During this time Marie oversaw the training of 400 physicians as radiologists and over 1000 technologists to operate the machinery.
Death
Curie passed away on the 4
th
July
July
1934 in Passy, Haute-Savoie, from what is now believed to be
aplastic anaemia
from long-term exposure to radiation.
Awards
Nobel Prize in Physics, 1903
Nobel Prize in Chemistry, 1911
Legacy
fundamental research into radioactivity
discovery of polonium and radium
curium, the chemical element with atomic number 96
the
curie
is
the
a
former unit
for
of
radioactive decay
her daughter Irene 1897-1956 was to win a chemistry Nobel Prize in 1935 with her husband Frederic Joliot Curie for work on artificial radioactivity
the Marie Curie museum in Warsaw housed in her birthplace is the only museum in the world devoted to her life and remarkable career
- <p><strong>Marie S Curie</strong> (1867-1934) was a Polish-born, French scientist known for her work in discovering radioactivity. Her work shaped medicine, warfare and scientific research for countless generations, earning her <a title="Nobel Prizes for radiology" href="/articles/nobel-prizes-for-radiology">Nobel prizes in both physics and chemistry</a> <sup>1,3</sup>.</p><h4>Early life</h4><p>Maria Salomea Skłodowska was born 7<sup>th</sup> November 1867 Warsaw, Poland into a once noble Polish family under heavy Czarist Russia oppression <sup>1</sup>. Marie’s upbringing would focus heavily on the gift of education and the power of passing it onto others, a mantra to which Marie abided wholeheartedly <sup>1,3</sup>. She excelled in both private and public education, considered gifted among her peers. Upon graduation, Marie and her sisters embarked on what is now known as a ‘gap year’ travelling to outskirts of the country visiting relatives and indulging in festivities.</p><p>Marie eventually sought further education at the ‘Flying University’, an illegal university based in Warsaw dedicated to the education of female scientists under Russian oppression <sup>2</sup>.</p><h4>Education</h4><p>Marie agreed to provide financial support to her sister, Bronisława, while she studied medicine in Paris. The agreement was that the favour would be repaid in turn. While working as a governess in Warsaw, Maria would work in secret with her cousin Jozef Boguski, studying chemistry and performing 'wet chemistry' experiments, the birth of her passion <sup>2</sup>.</p><p>In 1891, at the age of 23, Marie enrolled to study at the Sorbonne, graduating in 1893 with a “Licence des Sciences”, furthermore receiving a licence in mathematics in 1894. In that same year, she would eventually meet her future husband, a scientist named Pierre Curie <sup>1-3</sup>.</p><h4>Research into radioactivity</h4><p>Pierre and Marie examined magnetism in their laboratories for years, though it was the 1895 discovery of x-rays by <a href="/articles/wilhelm-roentgen-1">Wilhelm Roentgen</a> that would change the direction of their research <sup>1-3</sup>.</p><p>An experiment in which uranium rays, like x-rays, were observed to ‘electrify’ the air sparked Marie's interest so much that she decided this to be the basis of her doctrine. Marie measured radioactivity using piezoelectric electrometers developed by her husband, Pierre. In 1898, a paper was presented to the Academy of Sciences titled ‘"Rays emitted by uranium and thorium compounds", in which it was proposed that each element had unique ‘radioactivity’ and one could conclude the composition of a material based on its ‘radioactivity’.</p><h4>Polonium and Radium</h4><p>Curie then proposed one could isolate a new element in the radioactive substance known as ‘pitchblende’ (now known as uraninite).</p><p>For years Marie and her husband worked on isolating, purifying and describing polonium and radium thanks to a sizeable donation of 10 tonnes of pitchblende by the Austrian Government.</p><p>The Curies' shed was known to have beamed with luminescence from the radioactive materials, a fact today that would concern any occupational health and safety pundit. Consequently, the entire family would develop signs of ill health.</p><p>Marie succeeded in extracting radium and polonium, concluding her thesis in 1903 successfully obtaining a ‘Docteur des Sciences Physiques’.</p><h4>Radiology cars</h4><p>Marie went on to design ‘radiology cars’ to assist soldiers in the front line during the First World War. The cars were equipped with x-ray units and darkrooms, bringing these facilities to tents throughout the front lines <sup>1</sup>. During this time Marie oversaw the training of 400 physicians as radiologists and over 1000 technologists to operate the machinery.</p><h4>Death</h4><p>Curie passed away on the 4<sup>th</sup> July 1934 in Passy, Haute-Savoie, from what is now believed to be aplastic anaemia from long-term exposure to radiation.</p><h4>Awards</h4><ul>
- <li>her daughter <a title="Irene Joliot Curie" href="/articles/irene-joliot-curie">Irene</a> 1897-1956 was to win a chemistry Nobel Prize in 1935 with her husband <a title="Frederic Joliot Curie" href="/articles/frederic-joliot-curie">Frederic Joliot Curie</a> for work on artificial radioactivity</li>
+ <li>her daughter <a href="/articles/irene-joliot-curie">Irene</a> 1897-1956 was to win a chemistry Nobel Prize in 1935 with her husband <a href="/articles/frederic-joliot-curie">Frederic Joliot Curie</a> for work on artificial radioactivity</li>
Cases and figures
Figure 1: Marie Curie Figure 1: Marie Curie
:
| https://radiopaedia.org/articles/marie-sklodowska-curie-1/changesets/240838/edits?from_revision_history=true&iframe=true&lang=gb |
Clinical implications of tenascin‑C and OX40 ligand in patients with acute coronary syndrome
Clinical implications of tenascin‑C and OX40 ligand in patients with acute coronary syndrome
Authors:
Feng Ren
Published online on: November 4, 2013 https://doi.org/10.3892/br.2013.195
Pages: 132-136
Metrics:
Abstract
Acute coronary syndrome (ACS) typically occurs when coronary artery disease results in the obstruction of the coronary arteries. Tenascin‑C (TNC) and OX40 ligand (OX40L) were shown to be involved in the pathogenesis of atherosclerosis. In this study, 50 healthy controls and 170 patients, including 50 patients with stable angina (SA), 70 with unstable angina and 50 with acute myocardial infarction, were evaluated to assess serum TNC and plasma OX40L levels. The serum TNC levels were measured by a quantitative automated particle‑enhanced immunonephelometric assay. ELISA was used to determine the expression levels of OX40L. All the coronary stenoses with a ≥30% diameter reduction were assessed by angiographic coronary stenosis morphology. The patients with ACS exhibited a significant increase in TNC expression levels (39.39±19.80 ng/ml) compared to the levels in the control and SA groups (28.65±12.32 ng̸ml, P<0.01 and 31.22±18.92 ng/ml, P<0.05, respectively). The levels of OX40L were also found to be higher in patients with ACS (38.59±15.76 ng̸ml) compared to those in the control and SA groups (19.42±11.19 ng̸ml, P<0.001 and 21.52±10.30 ng/ml, P<0.001, respectively). The TNC and OX40L levels were positively correlated with each other (r1=0.68; P<0.001) and with fibrinogen levels (r3=0.76 and r4=0.45, respectively; P<0.001). A positive correlation was also observed between the expression of TNC and OX40L and complex coronary stenosis (r5=0.69 and r6=0.55, respectively; P<0.001). We concluded that TNC and OX40L may act synergistically in coronary plaque formation and may be also be involved in the pathogenesis of coronary lesions. Patients with ACS exhibited increased TNC and OX40L expression levels, which may have created a prothrombotic milieu, aggravating the development of atherosclerosis and the instability of atherosclerotic plaques. Therefore, the expression of TNC and OX40L may be a valuable marker for predicting the severity of ACS.
Introduction
Acute coronary syndrome (ACS) typically occurs when
coronary artery disease (CAD) results in the obstruction of
coronary arteries. This may lead to myocardial infarction (MI),
heart failure (HF), arrhythmias, cardiac arrest and death (
1
,
2
). The
current clinical practice includes rapid patient evaluation and
risk stratification based on clinical and electrocardiographic
characteristics, as well as the assessment of biochemical markers
(
3
). Cardiovascular diseases, such
as MI, hypertension, hypertrophy or HF, are accompanied by changes
in the composition of the cardiac extracellular matrix (ECM). These
dynamic alterations may determine the mechanical properties of the
damaged heart and directly modulate the inflammatory and reparative
response (
Tenascin-C (TNC) is a multifunctional hexameric
glycoprotein that is a major component of the ECM. It is
synthesized by interstitial fibroblasts and its levels are
increased in inflammatory diseases. Upon tissue damage, TNC has a
multitude of functions that mediate inflammatory and fibrotic
processes, in order to enable effective tissue repair. Over the
last decade, accumulating evidence indicated a vital role for TNC
in cardiac and arterial injury, tumor angiogenesis and metastasis,
as well as in the modulation of stem cell behavior (
5
). Previous
in vitro
studies
demonstrated that a range of factors implicated in cardiovascular
disease appear to be able to stimulate TNC synthesis by fibroblasts
(
6
,
7
).
OX40, also referred to as CD134 or TNFRSF4, is a
member of the tumor necrosis factor (TNF) co-stimulatory receptor
family and is expressed on activated T cells. OX40 is specifically
upregulated by the human T-lymphotropic virus type I (HTLV-1) viral
transactivator, Tax. The ligand of OX40 (OX40L), which belongs to
the TNF superfamily, was first identified as glycoprotein 34 on
HTLV-1-transformed cells and was found to bind OX40. OX40-OX40L
interactions may affect the activity and differentiation of several
types of immune cells (
8
). It was
recently demonstrated that genetic variants in the OX40L locus are
associated with MI and the severity of CAD in humans. OX40-OX40L
pairs were shown to be involved in ACS (
9
).
Willett
et al
(
10
) demonstrated that the enforced
trimerization of feline CD134L (OX40L) via the introduction of a
subdomain of the TNC oligomerization domain, was able to restore
full ligand-binding activity. The resulting fusion protein was
proven to be as effective as the anti-CD134 monoclonal antibody in
detecting CD134 expression and displayed a strain-specific blocking
of viral entry. Therefore, we surmised that the interaction of TNC
and OX40L is important in atherosclerosis. In the present study, we
investigated the expression of serum TNC and OX40L and assessed the
correlation between their expression and the number of complex
lesions in the patients. In addition, the statistical correlation
between TNC and OX40L or fibrinogen was evaluated.
Patients and methods
Subjects
The patients and healthy controls were involved in
the present study over a period of 18 months. Patients undergoing
clinically indicated diagnostic coronary angiography in the
coronary care unit of The Fourth People’s Hospital of Wuxi, were
consecutively registered. The patients were classified into the ACS
and the stable angina (SA) groups. The ACS group consisted of
patients with unstable angina (UA) and acute myocardial infarction
(AMI). The patients with UA experienced ischemic chest pain at rest
within the preceding 48 h, without enzymatic evidence of myocardial
necrosis; the AMI patients were defined as those with an occurrence
of MI within the preceding 4 weeks. The diagnosis of MI was based
on typical chest pain and ST segment elevation in at least two
contiguous electrocardiographic leads. The patients with SA (n=50)
underwent coronary angiography due to signs and symptoms of
clinical SA. For comparison, 50 gender- and age-matched donors
served as the control group. Patients with concurrent infection,
tumor, liver or kidney diseases were excluded (
Table I
). All the patients provided written
informed consent prior to their inclusion in the study. This study
was approved by the ethics committee of the Affiliated Hospital of
Jiangnan University.
Table I Statistical comparison of demographic
and clinical characteristics of patients with CAD vs. those of
healthy controls.
Table I
Statistical comparison of demographic
and clinical characteristics of patients with CAD vs. those of
healthy controls.
Groups Control (n=50) SA (n=50) UA (n=70) AMI (n=50) P-value Characteristics Age (years) 53±11.2 61±9.3 58±8.4 65±10.2 <0.01 Gender Male 26 29 42 31 Female 24 21 28 19 NS Total cholesterol
(mmol/l) 4.86±0.71 4.91±0.86 5.11±0.63 5.22±1.12 <0.01 HDL (cholesterol
mmol/l) 2.05±0.72 1.34±0.52 1.14±0.65 0.92±0.46 <0.01 Triglycerides
(mmol/l) 1.62±0.36 1.52±0.42 1.76±0.87 1.82±0.92 NS Apolipoprotein B
(g/l) 0.80±0.31 0.92±0.11 0.69±0.35 0.79±0.26 NS Lipoprotein (a)
(g/l) 0.58±0.10 0.33±0.18 0.41±0.22 0.51±0.27 <0.01 Direct bilirubin
(μmol/l) 2.85±1.01 2.60±0.57 2.85±0.86 2.59±0.75 NS Indirect bilirubin
(μmol/l) 13.24±2.73 11.75±3.09 12.59±2.47 13.79±1.23 NS Medication (%) Calcium
antagonist 0 9 11 13 <0.001 Nitroglycerin 3 12 20 21 <0.001 ACEI 8 10 17 15 <0.001 β-blockers 15 72 78 85 <0.001 HMG-CoA reductase
inhibitors 2 61 64 77 <0.001 Aspirin 1 85 91 98 <0.001
[i]Data are
expressed as means ± standard deviation unless otherwise specified.
CAD, coronary artery disease; SA, stable angina; UA, unstable
angina; AMI, acute myocardial infarction; NS, no statistically
significant differences between groups (P>0.05); HDL,
high-density lipoprotein; ACEI, angiotensin-converting-enzyme
inhibitor; HMG-CoA, 3-hydroxy-3-methylglutaryl-coenzyme.
Blood sampling protocol
Peripheral venous blood samples were drawn into
blood collection tubes using a suction catheter (BD Vacutainer,
Franklin Lakes, NJ, USA). The blood to be used for the assessment
of serum TNC levels was collected in tubes containing coagulant and
sent to the clinical laboratory. The blood to be used for the
assessment of plasma OX40L levels was collected in tubes containing
Na
2
-EDTA at a final concentration of 0.1% and
immediately centrifuged at 1,000 × g for 10 min at 4°C. The
supernatant was stored at −80°C until analysis. The samples were
thawed only once.
The serum TNC levels were measured by a quantitative
automated particle-enhanced immunonephelometric assay (Boehringer
Mannheim, Mannheim, Germany). The plasma levels of OX40L were
determined using a rat anti-human-OX40L ELISA kit (Assay Designs,
Inc., Ann Arbor, MI, USA) according to the manufacturer’s
instructions. Additional laboratory measurements were performed
using standard methods. Fibrinogen was measured using the clotting
method (
11
).
Coronary angiography
Coronary angiography was performed using a femoral
approach with 6-Fr diagnostic catheters (Cordis Corp., FL, USA).
Images were recorded in multiple projections for the right and left
coronary arteries. All the coronary stenoses with a ≥30% diameter
reduction were assessed by two experienced cardiologists who were
blinded to the levels of TNC and OX40L, as well as to the identity
and clinical characteristics of the patients. Complex lesions were
defined by the following characteristics: i) irregular morphology,
or scalloped borders, or both; ii) overhanging or abrupt edges
perpendicular to the vessel wall; iii) ulceration; and/or iv) the
presence of filling defects consistent with intracoronary thrombus.
The Gensini’s scoring system (
12
)
was used to quantitatively assess the degree of stenosis for each
coronary vascular lesion.
Statistical analysis
All the numerical data are expressed as means ±
standard deviation. Statistical evaluation was performed with
GraphPad software (Prism 5.0) and SPSS software, version 11.7
(SPSS, Inc., Chicago, IL, USA). The correlation was evaluated using
a regression analysis. The Spearman’s two-way test was used to
assess the correlation between two quantitative variables with
non-normal distribution. The Pearson’s two-way test was used to
assess the correlation between two quantitative variables with
normal distributions. P<0.05 was considered to indicate a
statistically significant difference.
Results
Subject characteristics
The demographic and clinical characteristics of the
study participants are presented in
Table I
. The study included 170 patients
with angiographically documented CAD. A total of 120 patients
constituted the ACS group (70 patients with UA, without evidence of
myocardial necrosis, and 50 with recent MI) and 50 patients
constituted the SA group. The healthy control group comprised 50
subjects. The patients with CAD were significantly older compared
to the controls (P<0.01). The levels of total cholesterol,
high-density lipoprotein (HDL), cholesterol and lipoprotein (a)
were significantly different between the CAD and the control groups
(P<0.001). The use of medications (calcium antagonists,
nitroglycerine, angiotensin-converting enzyme inhibitors,
β-blockers, 3-hydroxy-3-methylglutaryl-coenzyme A reductase
inhibitors or aspirin) was significantly higher in the ACS and SA
groups compared to that in the control group (P<0.001 for all
the medications).
Serum TNC and plasma OX40L levels
As shown in
Table
II
, the TNC levels in the serum samples obtained from patients
with ACS were significantly higher (39.39±19.80 ng/ml) compared to
those obtained from patients in the control and SA groups
(28.65±12.32 ng/ml, P<0.01 and 31.22±18.92 ng/ml, P<0.05,
respectively). The OX40L levels were also significantly higher in
the plasma samples obtained from patients with ACS (38.59±15.76
ng/ml) compared to those obtained from patients in the the control
and SA groups (19.42±11.19 ng/ml and 21.52±10.30 ng/ml,
respectively; P<0.001 for both differences).
Table II Statistical comparison between
patients with ACS or SA and healthy controls regarding serum TNC,
OX40L and fibrinogen concentrations.
Table II
Statistical comparison between
patients with ACS or SA and healthy controls regarding serum TNC,
OX40L and fibrinogen concentrations.
Groups Variables Control (n=50) SA (n=50) ACS (UA and AMI)
(n=120) P-value TNC (ng/ml) 28.65±12.32 31.22±18.92 39.39±19.80 <0.05 OX40L (ng/ml) 19.42±11.19 21.52±10.30 38.59±15.76 <0.001 Fibrinogen (g/l) 16.32±7.87 19.00±11.17 28.24±16.14 <0.001
[i]Data are
expressed as means ± standard deviation unless otherwise specified.
ACS, acute coronary syndrome; SA, stable angina; TNC, tenascin-C;
OX40L, OX40 ligand; UA, unstable angina; AMI, acute myocardial
infarction.
Correlation between TNC and OX40L
expression
The seum levels of TNC in patients with ACS
exhibited a positive correlation with the plasma levels of OX40L
(r
1
=0.68; P<0.001;
Fig.
1A
). However, in the SA group, such a correlation was not
observed (r
2
=0.19; P<0.001;
Fig. 1B
).
Figure 1Correlation between the levels of
serum TNC and plasma OX40L in patients with (A) acute coronary
syndrome (n=120) and (B) stable angina (n=50). TNC, tenascin-C;
OX40L, OX40 ligand.
Correlation of TNC and OX40L with
fibrinogen and coronary artery stenosis
In patients with ACS, the levels of TNC and OX40L
were significantly correlated with the levels of fibrinogen
(r
3
=0.76 and r
4
=0.45, respectively,
P<0.001) (
Fig. 2A and B
). There
was a significant correlation between the number of complex lesions
and the TNC (r
5
=0.69; P<0.001;
Fig. 2C
) and OX40L levels
(r
6
=0.55; P<0.001;
Fig.
2D
).
Figure 2Correlation between the levels of (A)
TNC and fibrinogen; (B) OX40L and fibrinogen; (C) TNC and coronary
artery stenosis; and (D) OX40L and coronary artery stenosis. TNC,
tenascin-C; OX40L, OX40 ligand.
Discussion
To the best of our knowledge, this study was the
first to assess the correlation between serum TNC and plasma OX40L
levels and angiographically demonstrated complex stenosis in
patients with ACS. The results of this study demonstrated that the
TNC and OX40L levels were increased as clinical severity increased
from SA to ACS. We also observed that there was a positive
correlation between TNC and OX40L expression and the number of
complex lesions in patients with ACS.
Atherosclerosis is a multifactorial disease, in
which inflammatory processes play an important role. Inflammation
underlies lesion evolution at all stages, from plaque establishment
to rupture and thrombosis (
13
–
15
).
ACSs (UA, AMI and ischemic sudden death) may result from the
disruption of atherosclerotic plaques, leading to coronary
thrombosis. The potential cellular mechanisms involved in plaque
disruption are also complex (
16
).
We hypothesized that the levels of TNC and OX40L in patients with
ACS reflect the activity of endothelial cells in coronary plaques,
which may result in higher levels of adhesion molecules,
proinflammatory cytokines and monocyte chemotactic proteins in the
circulation during plaque rupture. Circulating plasma OX40L may
pass through the damaged atherosclerotic endothelium and come into
direct contact with the cells inside the lesion, increasing the
inflammation of the coronary plaque.
TNC is involved in the physiological as well as the
pathological remodelling of blood vessels. TNC is expressed in the
heart in the early embryo, where it contributes to the development
of the myocardium, valves and coronary vessels (
6
). In cardiovascular pathology, TNC is
involved in post-MI remodelling, neointimal hyperplasia and
restenosis following percutaneous transluminal coronary angioplasty
and bypass grafting, as well as pulmonary vascular disease and
hypertension (
17
). Under normal
conditions, only low levels of TNC are found in adult tissue.
However, higher levels of TNC expression were previously reported
in areas of wound healing, cancer development and cardiovascular
disease, where the level of expression appears to be a reliable
biomarker of disease progression and poor patient prognosis
(
18
). Emerging evidence (
6
) has highlighted a number of novel roles
for TNC in cardiovascular disease.
Although a previous study indicated that the
OX40/OX40L pathway is crucial in atherosclerosis (
19
), the precise function of the OX40L
system in ACS has not been fully elucidated. The present study
demonstrated that the OX40L expression levels were increased in
patients with ACS. The regression analysis indicated that the serum
levels of TNC, which degrades the connective tissue matrix protein,
ultimately resulting in plaque rupture and the development of ACS,
were significantly associated with the levels of OX40L. These
findings suggested that TNC and OX40L expression in patients with
ACS may affect the development of atherosclerosis and the
instability of atherosclerotic plaques. However, further studies
are required to verify these findings.
Compared to patients with SA, those with UA and AMI
exhibited a higher number of complex coronary lesions (
20
). In our study population, complex
coronary stenosis morphology was found in ~68% of the patients with
UA, 60% of the patients with MI and ~24% of the patients with
chronic SA. A positive correlation between TNC and OX40L expression
and the number of complex lesions was observed in patients with
ACS. However, in SA patients, such a correlation was not observed.
Therefore, our findings suggest that the increased expression of
serum TNC and plasma OX40L in patients with ACS may be a marker of
immune activation and may also be involved in the underlying
pathogenic processes. The interruption of the OX40-OX40L
interaction was shown to ameliorate several autoimmune-like
diseases (
21
,
22
), indicating that the downregulation of
the OX40-OX40L interaction and TNC and OX40L expression may
represent a novel therapeutic approach for patients with ACS.
However, the results of this study should be interpreted with
caution, due to the relatively limited patient sample. In addition,
coronary angiography has certain limitations compared to angioscopy
and intravascular ultrasound and further investigation is required
to clarify its role in ACS.
In conclusion, our results suggest that the
concentrations of serum TNC and plasma OX40L may be of value as
clinical markers of the severity of CAD and the downregulation of
TNC and OX40L expression may represent a novel therapeutic approach
for patients with ACS. However, the precise mechanisms underlying
the involvement of TNC and OX40L in ACS have not been fully
elucidated. Further investigation is required to determine whether
TNC and OX40L may be used as biomarkers in the clinical setting to
guide intervention strategies in patients with CAD, or serve as
markers under emergency conditions to diagnose ACS more
efficiently.
Acknowledgements
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| https://www.spandidos-publications.com/10.3892/br.2013.195 |
Materials | Free Full-Text | Microstructural Characteristics and Subsequent Soften Mechanical Response in Transverse Direction of Wrought AZ31 with Elevated Compression Temperature
In order to investigate the effect of temperature on the microstructure evolution and mechanical response in the transverse direction of a wrought AZ31 (AZ31-TD) alloy under a high strain rate, the dynamic compression was conducted using Split Hopkinson Pressure Bar (SHPB) apparatus and a resistance-heated furnace under 1000 s−1 at 20–250 °C. By combining optical and EBSD observations, the microstructure’s evolution was specifically analyzed. With the help of theoretically calculated Schmid Factors (SF) and Critical Resolved Shear Stress (CRSS), the activation and development deformation mechanisms are systematically discussed in the current study. The results demonstrated that the stress–strain curves are converted from a sigmoidal curve to a concave-down curve, which is caused by the preferentially and main deformation mechanism {101¯2} tension twinning gradually converting to simultaneously exist with the deformation mechanism of a non-basal slip at an elevated temperature, then completing with each other. Finally, the dynamic recrystallization (DRX) and non-basal slip are largely activated and enhanced by temperature elevated to weaken the {101¯2} tension twinning.
Microstructural Characteristics and Subsequent Soften Mechanical Response in Transverse Direction of Wrought AZ31 with Elevated Compression Temperature
by Mengmeng Yang 1,2 , Feng Zhang 1 , Wei Yu 1,* , Yikui Bai 1 and Zheng Liu 3
Materials 2021 , 14 (14), 4055; https://doi.org/10.3390/ma14144055
Received: 11 June 2021 / Revised: 8 July 2021 / Accepted: 9 July 2021 / Published: 20 July 2021
(This article belongs to the Special Issue Study on the Development and Applications of Magnesium Alloys )
Abstract
In order to investigate the effect of temperature on the microstructure evolution and mechanical response in the transverse direction of a wrought AZ31 (AZ31-TD) alloy under a high strain rate, the dynamic compression was conducted using Split Hopkinson Pressure Bar (SHPB) apparatus and a resistance-heated furnace under 1000 s
−1
at 20–250 °C. By combining optical and EBSD observations, the microstructure’s evolution was specifically analyzed. With the help of theoretically calculated Schmid Factors (SF) and Critical Resolved Shear Stress (CRSS), the activation and development deformation mechanisms are systematically discussed in the current study. The results demonstrated that the stress–strain curves are converted from a sigmoidal curve to a concave-down curve, which is caused by the preferentially and main deformation mechanism
{
10
1
¯
2
}
tension twinning gradually converting to simultaneously exist with the deformation mechanism of a non-basal slip at an elevated temperature, then completing with each other. Finally, the dynamic recrystallization (DRX) and non-basal slip are largely activated and enhanced by temperature elevated to weaken the
{
¯
2
}
tension twinning.
Keywords:
AZ31-TD
;
dynamic compression
;
deformation mechanism
;
CRSS
;
SF
1. Introduction
Mg is the eighth most common element in the crust of the earth, which is also extractable from seawater [ 1 ]. With the requirement of a lightweight, energy-efficient and environmentally benign system, the magnesium alloy was widely used in an environment where the science of material design processing could now address its complexities and offer up new possibilities [ 2 , 3 ]. Due to the hexagonal close-packed (HCP) crystalline structure, only limited independent slip systems of magnesium and its alloy could be initially activated at room temperature [ 4 ]. Hence, the mechanical properties of magnesium and its alloy were low formability, limited ductility and premature failure no mater quasi-static or dynamic deformation [ 5 , 6 , 7 ]. However, compared with room temperature conditions, the deformation mechanisms of magnesium and its alloys were significantly different and complex under high temperatures [ 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 ]. According to the extreme requirement of the magnesium alloy structure application, the knowledge of their mechanical response and microstructure evolution under a high strain rate and elevated temperature were significantly important [ 20 , 21 , 22 ].
In recent years, considerable effort has been made to research the deformation mechanisms of magnesium and its alloy under elevated temperature conditions, especially a wrought magnesium alloy. Generally, fracture strain (strain to failure) increases with increasing experimental temperature, whereas fracture strain decreases with the increasing experimental strain rate [
23
]. Hence, the temperature increase was known to effectively soften the mechanical properties of the magnesium alloy. The strain rate increase was known to enhance the flow stress and weaken the fracture strain. However, in the research of a solution-treated cast AM80 magnesium alloy with the strain rate ranging from 1100 to 5000 s
−1
at 298, 423 and 523 K, the effect of the strain rate on the fracture strain varied from enhanced to weakened as the strain rate increased to its critical value at all the temperature conditions [
16
]. It was found that the negative strain rate sensitivity was mainly caused by adiabatic shear bands (ASBs) and dynamic recrystallization (DRX). The ASBs were generated at 298 K under a strain rate of 5000 s
−1
. With elevated temperatures of 423 and 523 K, recrystallized microstructure forms were gradually generated on the basic of twins and dislocations, which were nucleated at the twins’ boundaries and extended between the twins’ boundaries and grains’ boundaries. As a typical wrought magnesium alloy, the mechanical properties of an AZ31 rolled sheet were strongly anisotropic, which was caused by typical
{
0002
}
texture [
5
,
24
,
25
]. During the dynamic compressive deformation in a strain rate range from 10
−4
to 3500 s
−1
at room temperature, the increased fracture strain was 30% in the transverse direction (TD) and 55% in the rolling direction (RD) under 3500 s
−1
as compared to 10
−4
s
−1
[
20
]. The twinning was the main deformation mechanism in the rolled direction, while the slipping seemed to be a significantly influenced participant in the 45° and normal direction. The flow stress behavior, strongly dependent on the strain rate, increased in the normal direction (ND). However, the strong strain rate dependence for compressive yield stress was not obviously exhibited in TD and RD [
26
]. For the AZ31 rolled sheet during the dynamic compression and tension behavior at the strain rates of ~10
3
s
−1
, the activation of
{
10
1
¯
2
}
tension twinning was extremely enhanced by the increased strain rate, while there was no significant strain rate dependence in contraction and secondary twinning [
27
]. In fact, the deformation behavior of the AZ31 rolled sheet was dependent on not only the strain rate but also the temperature. The typical result was shown that the anisotropy of the AZ31 rolled sheet, including the yield stress, peak stress and microstructure, was gradually weakened with the increased temperature [
28
]. Until the temperature was close to 350 °C, the anisotropy of the AZ31 rolled sheet almost disappeared. To sum up, most of the investigations on the anisotropy of an AZ31 rolled sheet were only focused on the activation and evolution of
{
10
1
tension twinning, non-basal slip and dynamic recrystallization mechanisms by changing temperatures. The detailed discussion about the relationship between twins and dynamic recrystallization mechanisms in a wrought AZ31 sheet were very limited, even unreported.
In our current study, the dynamic compression test of a wrought AZ31-TD sheet was conducted by split Hopkinson pressure bar (SHPB) and resistance-heated furnace at 1000 s
−1
strain rate under 20–350 °C temperature conditions. With the temperature elevated, the evolution of the microstructure mechanism was analyzed, especially the relationship between
tension twinning and dynamic recrystallization (DRX). Finally, the effect of temperature on the microstructural characteristics and subsequent soften mechanical responses of the wrought AZ31-TD sheet were systematically discussed by electron backscattered diffraction (EBSD), Schmid Factors (SF) and Critical Resolved Shear Stress (CRSS).
2. Experimental
2.1. Experimental Material
The wrought AZ31-TD sheet was offered by a Canada–China–USA collaborative research and development project, MAGNESIUM FRONT END RESEARCH AND DEVELOPMENT (MFERD), which was produced by Timminco Metals in Denver, CO, USA. The chemical composition of the AZ31 magnesium alloy is listed in Table 1 .
Table 1. Chemical composition of AZ31 magnesium alloy.
The wrought AZ31 sheet (with an average grain size ~25 μm) was proceeded by multi pass under 450 °C with a thickness of 8 mm. In order to avoid the negative effect on the microstructure mechanism analysis by the initial microstructure, the heat treatment process of detwinning was 300 °C × 2 h.
2.2. Experimental Method
The dynamic compression tests were conducted under 1000 s −1 strain rate with a temperature from 20 °C to 250 °C by combining SHPB apparatus and a resistance-heated furnace, which are shown in Figure 1 .
Figure 1. SHPB apparatus with resistance-heated furnace: ( a ) SHPB apparatus, ( b ) resistance-heated furnace.
The strain rate was controlled by impactive pressure and stroking on striker in pumping chamber. Additionally, the temperature was measured using a thermocouple in the resistance-heated furnace. The dynamic compression test experiment was conducted after 10 min of soaking time. The size of cylindrical sample was Φ6 × 6 mm, which was cut along the TD of the wrought AZ31 sheet by using an electrical discharged wire-cutter. At least 3 samples were repeated for every experimental condition to avoid error influence. After comparing the test result of every experiment, the stress–strain curves of the wrought AZ31-TD sheets were hardly influenced by the error. The cross sections of the cylindrical samples were polished using standard metallographic techniques, and then etched for 5~10 s in acetic picral (100 mL ethanol, 10 mL H
2
O, 6 g picric acid, 5 mL acetic acid). The optical microscope was conducted using a ZEISS metallographic microscope (Axio vert A1m). The microstructure and texture analysis were performed by using a field emission MERLIN Compact and scanning electron microscope (SEM), equipped with an EBSD detector system. In order to obtain a clear EBSD observation, it was necessary to conduct electrolysis treatment on the post impact samples. The etch solution was comprised of 4.2 g picric acid, 10 mL acetic acid, 10 mL H
2
O and 70 mL ethanol.
3. Result
3.1. Dynamic Mechanics Response
The stress–strain curves of the wrought AZ31-TD alloy with an elevated temperature under 1000 s −1 are presented in Figure 2 .
Figure 2. Stress–strain curves at different temperatures under 1000 s −1 .
The dynamic mechanics response of the wrought AZ31-TD alloy at room temperature is obviously highly anisotropic, which is shown by the sigmoidal curve. As the direction of impact loading is perpendicular to the normal direction of
texture plan, it is easier for a large number of
tension twinning to be activated, leading to the typical characteristic curve presence [
29
]. With the temperature increased, the critical strain, corresponding to the peak stress, gradually increases from 0.12 to 0.14. The peak stress decreases from 398.61 to 204.16 MPa with temperature increased. Finally, the evolution trend of stress–strain curves are from a sigmoidal curve to a concave-down curve. It is illustrated that the thermal softening has large effect on the wrought AZ31-TD dynamic deformation behavior. This phenomenon is caused by the reduced critical resolved shear stress (CRSS) of the non-basal slip and more activation of the non-basal glide systems, which is similarly reported by Liu et al. [
21
].
3.2. Microstructure Characteristic
The microstructures of the samples with an elevated temperature under 1000 s −1 are shown in Figure 3 .
Figure 3. Microstructure in elevated temperature under 1000 s −1 : ( a ) 20 °C, ( b ) 150 °C, ( c ) 250 °C.
In all the temperature conditions, a large number of twins are present at 1000 s
−1
, which partly consist of double twins and intersect twins. Meanwhile, the substructures are observed at 150 °C, which are randomly dispersed in the large grains. By comparing
Figure 3
a,b, it can be obviously seen that the twins gradually thickened and more dense with the increased temperature. Additionally, the grains are gradually separated by the twins. This phenomenon is usually caused by twinning dislocation spread on adjacent planes [
20
]. In addition, the c-axis, the normal direction of
plan, is perpendicular to the loading direction, which is also a benefit for
tension twinning activation. Additionally, the twins’ boundaries generated in the same grains are usually parallel to each other [
29
]. In
Figure 3
c, a large number of refinement grains are present, with grains of 3–4 μm radius size. On one hand, the twins completely disappeared as a result of detwinning occurring in some grains. On the other hand, the density and thickness of the twins are further increased. As fine grains induce slip deformation more easily, twinning is hardly activated. However, when the refinement grains are grown to be coarse grains by the elevated temperature, the formation of twinning is more easily activated [
28
]. Hence, the refinement grains may have been caused by dynamic recrystallized (DRX) as the temperature increased. Additionally, the twins in large grains may be present after the refinement grains.
4. Discussion
4.1. Effect of Temperature on Microstructure Evolution
The inverse pole figure (IPF) maps, pole figure (PF), boundaries misorientation (BM) and twins’ volume fraction (TVF) of the wrought AZ31-TD alloy after impact are shown in
Figure 4
, which was obtained from the EBSD data collected. In
Figure 4
, the black line is the grain boundary. The red line and green lines are the
tension twin boundary and
contraction twin boundary, respectively, which is illustrated and corresponds to the red line and green line in
Figure 4
h.
Figure 4. IPF maps, PF maps, BM maps and TVF of impacted wrought AZ31-TD alloy: ( a ) IPF at 20 °C, ( b ) BM at 20 °C, ( c ) IPF at 150 °C, ( d ) BM at 150 °C, ( e ) IPF at 250 °C, ( f ) BM at 250 °C, ( g ) twinning fraction under different temperature condition, ( h ) PF at 20 °C.
By combining
Figure 4
a,b,g, the TVF of the wrought AZ31-TD alloy at a temperature of 20 °C is 4.68%, which consists of
contraction twins and
tension twins. The three type of twins, such as
tension twins,
contraction twins and
double twins, are determined by the particular misorientation angles and rotation axis of twins [
30
]. In detail, the characteristics of a double twins-matrix, tension twins-matrix and contraction twins-matrix are the misorientation of 38° about
, 56° about
and 80° about
[
]. In order to further identify the type of twins, the misorientation angle distribution of the impacted wrought AZ31-TD alloy at different temperatures is shown in
Figure 5
.
Figure 5. Misorientation angle distribution of impacted wrought AZ31-TD alloy: ( a ) 20 °C, ( b ) 150 °C, ( c ) 250 °C.
It can been seen that the misorientation angle distributions are, respectively, concentrated in 38° about
56° about
and 80° about
. In addition, a little of the misorientation angle distribution is located in 38° about
;
double twins also exist in the matrix of the wrought AZ31-TD alloy. When the experimental temperature is increased to 150 °C, the most frequently observed boundaries are those with a misorientation of 80° about
. Additionally, almost none of 56° about
misorientation boundaries are found in
Figure 4
c,d, which also corresponds to the misorientation angle distribution in
Figure 5
b. Meanwhile, the TVF of the wrought AZ31-TD alloy is decreased to 2.98%, as shown in
Figure 4
g. This phenomenon may be caused by detwinning occurring at a high temperature, which has been addressed in previous research [
19
]. It is also illustrated that the predominant mechanism of non-uniform deformation with twinning is gradually weakened. As the stress is concentrated at a dislocation pile-up at the grain and twin boundaries, the non-basal slip, such as the pyramidal slip <a> and the pyramidal slip <c + a>, can be activated, including the boundary regions and the mantle region. Hence, the size of grain is relatively smaller. In this way, the stress concentration is relaxed, leading to the suppression of the
contraction twins and
tension twins [
31
]. Furthermore, when the experimental temperature is increased to 250 °C, almost all of the
double twins and
contraction twins disappear, as shown in
Figure 4
e–g. The TVF of the wrought AZ31-TD alloy is directly decreased to 2.66%. According to
Figure 4
f and
Figure 5
c, only a few of the
tension twins are located in the matrix of the wrought AZ31-TD alloy. Additionally, grains refinement is gradually present, which is caused by dynamic recrystallization. On one hand, as the large number of dislocations are easily slipped and piled up to the grain boundaries with an increased temperature, and the original grain boundaries act as the block, the DRX mechanism is initially activated at the grain boundaries due to the density of the dislocation rising to a threshold. Particularly, the stacking fault energy of the wrought AZ31-TD alloy is relatively lower. Then, the continuous DRX mechanism is enhanced by elevating the temperature beyond 250 °C [
32
]. On the other hand, the DRX can be also induced by strain under low temperature (110 °C) and medium temperature (210 °C) in two types of magnesium alloy during the compression process [
33
]. (i) When the numerous twins, dislocation and twin-twin intersection exist simultaneously at a low temperature, the DRX grains initially nucleate in the twins and the twin–twin intersection, then gradually expand outward from the inside of the original grains with an increased temperature. (ii) Compared with the DRX mechanism of a low temperature, the DRX grains initially nucleate around the original grain boundaries, which are induced by a larger strain. With the strain elevated, the DRX grains are expanded and even continuously distributed to the interior of the original grains.
4.2. Effect of Temperature on Dynamic Compressive Behavior
During the dynamic compressive deformation, the mechanical response of the wrought AZ31-TD alloy is directly determined by microstructure mechanism evolution. As the AZ31 magnesium alloy is the low symmetry of hexagonal close-packed (HCP) structure, five independent slip systems exist to satisfy the requirement of the critical stress in homogeneous deformation, especially
contraction twinning and
tension twinning. Generally,
tension twinning is induced by a tension loading direction parallel to the c-axis or a contraction loading direction perpendicular to the c-axis. However, the type of
contraction twinning induced is exactly opposite to the type of
tension twinning [
34
]. Additionally, the critical stress of the microstructure mechanism activation, which is almost dependent on the critical resolved shear stress (CRSS) and the Schmid factors (SF) [
28
,
35
,
36
], is given as follows:
τ
C
R
S
S
m
(1)
where
σ
stands for the critical stress of microstructure mechanism activation,
τ
C
R
S
S
stands for CRSS,
m
stands for SF. Additionally, the SF is established as follows:
m
=
cos
φ
⋅
cos
λ
(2)
where
φ
stands for the angle between the loading direction and the twinning (or slip) plane normal and
λ
stands for the angle between the loading direction and the twinning (or slip) direction. For the indices direction of the two-four-dimensional Miller–Bravais system, such as
{
h
,
k
,
i
,
l
}
−
〈
u
,
v
,
t
,
w
〉
, the twinning or slip plane normal can be calculated as follows:
[
u
,
v
,
t
,
w
]
=
[
h
,
k
,
i
,
3
l
2
(
c
a
)
2
]
(3)
where
a
and
c
are the lattice constants and, generally, the
c
/
a
axial ratio is 1.624 [
37
]. Finally, the
cos
φ
and
can be directly calculated using the follow equation:
V
c
a
(4)
where
V
1
,
v
t
1
,
w
1
]
is the twinning (slip) plane normal or twinning (slip) direction and
V
2
[
u
2
,
v
2
,
t
2
,
w
2
]
θ
about the different microstructure deformation mechanisms, such as the basal <a> slip, prismatic slip, pyramidal <a> slip, pyramidal <c + a> slip,
{
10
1
¯
2
}
tension
twinning and
{
10
1
¯
1
}
contraction twinning, can be calculated as shown in
Figure 6
.
Figure 6.
a
) basal <a> slip, (
b
) prismatic slip, (
c
) pyramidal <a> slip, (
d
) pyramidal <c + a> slip, (
e
)
{
10
1
¯
2
}
tension
twinning, (
f
)
{
¯
1
}
contraction twinning.
Additionally, the
θ
stands for the angle between the loading direction and the c-axis. The CRSS for the microstructure deformation mechanism of the wrought AZ31-TD alloy was predicted by Barnett, based on the Taylor model at 20, 150 and 250 °C, which is listed in
Table 2
[
38
,
39
,
40
,
41
].
Table 2. The CRSS of different microstructure deformation mechanism [ 38 , 39 , 40 , 41 ].
According to
Table 2
, the CRSS of the basal slip, prismatic slip, pyramidal <c + a> slip and
1
¯
1
contraction twinning presents its tendency to decrease with the temperature increasing from 20 to 250 °C. However, the evolution tendency of CRSS for
10
1
¯
2
tension twinning is the opposite. The PF maps of the wrought AZ31-TD alloy under different temperature conditions are shown in
Figure 7
.
Figure 7. The PF maps of wrought AZ31-TD alloy at 1000 s −1 under different temperatures: ( a ) 20 °C, ( b ) 150 °C, ( c ) 250 °C.
Hence, when the impact experiment is conducted at 20 °C, and the compressive impacting direction is perpendicular to the c-axis, the tension loading direction is particularly parallel to the c-axis. Moreover, the SF values of the prismatic slip, pyramidal <a> slip, pyramidal <c + a> slip and
¯
2
}
tension twinning are approximate to 0.5, according to a combination of
Figure 6
and
Figure 7
a. According to Equation (1) and
Table 2
, the
σ
values of the prismatic slip, pyramidal <c + a> and
{
10
1
¯
2
}
tension twinning are almost approximate to 180, 220 and 60 MPa, respectively. Hence, the
{
10
2
}
tension twinning is a priority to be activated. Additionally, the stress–strain curve presents a sigmoidal curve, as shown in
Figure 2
. When the temperature of the experiment is 150 °C, the direction of the c-axis partly departs from the normal direction of the wrought AZ31 alloy sheet after post impact, as shown in
Figure 7
b. Meanwhile, the CRSS values of the prismatic slip, pyramidal <c + a> and
10
1
¯
2
tension twinning are 60, 65 and 32 MPa, respectively. The
σ
of some prismatic slips and pyramidal <c + a> may be equivalent or even smaller than the
σ
of
{
10
1
tension twinning. Hence, the priority extent of
tension twinning is gradually weakened. It is illustrated that not only does the
tension twinning play an important role but the dislocation slip is also very important in the deformation mode during dynamic compression at 150 °C. In addition, the deformation mechanism is usually activated by twinning induced in a grain due to the following two reasons [
42
]: (i) The Hall–Petch effect and twinning-slip interaction are always enhanced by increased twin boundaries. Meanwhile, the twin boundaries are regarded as the barriers to certain slip systems. (ii) Compared to the parent grain under the same impact stress, the twinning form reoriented regions are easier to drive more slip or twin modes within twinned domains. Hence, the
tension twinning and non-basal slip simultaneously exist and compete with each other. When the temperature of the experiment is 250 °C, the direction of the c-axis is a completely departure from the normal direction of the wrought AZ31 alloy sheet after post impact, as shown in
Figure 7
c. Meanwhile, the CRSS of the prismatic slip and pyramidal <c + a> are directly dropped to be equivalent with
tension twinning, which is 40 MPa, as listed in
Table 2
. As the priority of CRSS and SF in
tension twinning almost disappeared, the non-basal slip and
tension twinning are activated almost at the same time. In addition, the grain refinement in gradually generated in the matrix of the wrought AZ31-TD alloy, as shown in
Figure 8
, which is caused by twin-induced dynamic recrystallization (TDRX) and continuous dynamic recrystallization (CDRX) [
43
].
Figure 8. Distribution maps of the recrystallized, substructured and deformed grains: ( a ) 20 °C, ( b ) 150 °C, ( c ) 250 °C.
In detail, the DRX can be induced by twins in the following three types: (i) the primary twin is mutually interacted, (ii) the secondary twin is initially nucleate and (iii) the twin is subdivided into nuclei, which is caused by the low angle grain boundaries inside coarse twin lamellae converting into high angle grain boundaries that depend on further increased strain. For CDRX, the rotational dynamic recrystallization (RDRX) of magnesium alloy is the most common mechanism. In the mechanism of RDRX, the local lattice rotation is completely activated, which is mainly caused by the transformation of the grain boundary from a low angle to a high angle grain boundary due to a dislocation accumulation. As a result, the stress–strain curve is a concave-down curve, as shown in
Figure 2
, which is caused by the effect of non-basal slip,
tension twinning and DRX simultaneously.
5. Conclusions
In the current paper, the effect of temperature (20–250 °C) on the dynamic compression behavior of the wrought AZ31-TD alloy under 1000 s
−1
is investigated using a SHPB test and EBSD observation. The mechanical responses are reflected by stress–strain curves. The deformation mechanism evolution is analyzed and discussed based on CRSS analysis, SF calculation and microstructure observation. Finally, the major conclusions can be summarized as follows:
With the temperature elevated from 20 to 250 °C, the curve is gradually converted from a sigmoidal curve to an approximate concave-down curve. As a result of the thermal soften effect, the critical plastic strain is increased from 0.12 to 0.14. Additionally, the peak stress is decreased from 398.61 to 204.16 MPa.
During the dynamic deformation with an elevated temperature,
tension twins,
contraction twins and
double twins are gradually decreased. Even the
double twins disappear at 150 °C. In addition, the refinement grains are initially nucleate at 150 °C and grow at 250 °C.
According to the combined CRSS and SF analysis,
tension twinning is the preferential and main deformation mechanism of the wrought AZ31-TD alloy due to the impact loading perpendicular to the c-axis at 25 °C. The deformation mechanism of non-basal slip and
tension twinning simultaneously exist and compete with each other at 150 °C. The DRX and non-basal slip are largely activated and enhanced at 250 °C, which is induced by
tension twinning.
Author Contributions
Conceptualization, M.Y. and W.Y.; methodology, M.Y.; software, F.Z.; validation, F.Z., W.Y. and Y.B.; formal analysis, M.Y.; investigation, M.Y.; resources, F.Z.; data curation, F.Z.; writing—original draft preparation, M.Y.; writing—review and editing, W.Y.; visualization, Y.B.; supervision, W.Y.; project administration, Z.L.; funding acquisition, Z.L. All authors have read and agreed to the published version of the manuscript.
Funding
The authors would like to acknowledge the financial support of the National Natural Science Foundation of China (No. 51571145), the Innovation Talent Program in Sciences and Technologies for Young and Middle-aged Scientists of Shenyang (No. RC180111) and the Doctoral Scientific Research Foundation of Liaoning Province (No. 20170520033).
Institutional Review Board Statement
Not applicable.
Informed Consent Statement
Not applicable.
Data Availability Statement
No new data were created or analyzed in this study. Data sharing is not applicable to this article.
Conflicts of Interest
The authors declare no conflict of interest.
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]
Tam, K.J.; Vaughan, M.W.; Shen, L.; Knezevic, M.; Karaman, I.; Proust, G. Modelling dynamic recrystallisation in magnesium alloy AZ31. Int. J. Plast. 2021 , 142 , 102995. [ Google Scholar ] [ CrossRef ]
Figure 1. SHPB apparatus with resistance-heated furnace: ( a ) SHPB apparatus, ( b ) resistance-heated furnace.
Figure 2. Stress–strain curves at different temperatures under 1000 s −1 .
Figure 3. Microstructure in elevated temperature under 1000 s −1 : ( a ) 20 °C, ( b ) 150 °C, ( c ) 250 °C.
Figure 4. IPF maps, PF maps, BM maps and TVF of impacted wrought AZ31-TD alloy: ( a ) IPF at 20 °C, ( b ) BM at 20 °C, ( c ) IPF at 150 °C, ( d ) BM at 150 °C, ( e ) IPF at 250 °C, ( f ) BM at 250 °C, ( g ) twinning fraction under different temperature condition, ( h ) PF at 20 °C.
Figure 5. Misorientation angle distribution of impacted wrought AZ31-TD alloy: ( a ) 20 °C, ( b ) 150 °C, ( c ) 250 °C.
Figure 6.
θ-maximum SF curves under different microstructure deformation mechanisms, (
a
) basal <a> slip, (
b
) prismatic slip, (
c
) pyramidal <a> slip, (
d
) pyramidal <c + a> slip, (
e
)
{
¯
2
}
tension
twinning, (
f
)
{
10
1
¯
1
}
contraction twinning.
Figure 7. The PF maps of wrought AZ31-TD alloy at 1000 s −1 under different temperatures: ( a ) 20 °C, ( b ) 150 °C, ( c ) 250 °C.
Figure 8. Distribution maps of the recrystallized, substructured and deformed grains: ( a ) 20 °C, ( b ) 150 °C, ( c ) 250 °C.
Table 1. Chemical composition of AZ31 magnesium alloy.
Al Mn Zn Fe Si Be Cu Mg 3.19 0.334 0.81 0.005 0.02 0.01 0.005 Bal.
Table 2. The CRSS of different microstructure deformation mechanism [ 38 , 39 , 40 , 41 ].
Mechanism Mode CRSS (MPa) 20 °C 150 °C 250 °C basal slip 5 4 3 prismatic slip 90 60 40 pyramidal <c + a> 110 65 40 { 10 1 ¯ 2 } tension twinning 30 32 40 { 10 1 ¯ 1 } contraction twinning 200 180 ≥130
© 2021 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 ( https://creativecommons.org/licenses/by/4.0/ ).
MDPI and ACS Style
Yang, M.; Zhang, F.; Yu, W.; Bai, Y.; Liu, Z. Microstructural Characteristics and Subsequent Soften Mechanical Response in Transverse Direction of Wrought AZ31 with Elevated Compression Temperature. Materials 2021, 14, 4055.
https://doi.org/10.3390/ma14144055
AMA Style
Yang M, Zhang F, Yu W, Bai Y, Liu Z. Microstructural Characteristics and Subsequent Soften Mechanical Response in Transverse Direction of Wrought AZ31 with Elevated Compression Temperature. Materials. 2021; 14(14):4055.
https://doi.org/10.3390/ma14144055
Chicago/Turabian Style
Yang, Mengmeng, Feng Zhang, Wei Yu, Yikui Bai, and Zheng Liu. 2021. "Microstructural Characteristics and Subsequent Soften Mechanical Response in Transverse Direction of Wrought AZ31 with Elevated Compression Temperature" Materials14, no. 14: 4055.
https://doi.org/10.3390/ma14144055
| https://www.mdpi.com/1996-1944/14/14/4055/htm |
Is styrofoam toxic for chickens? | Page 2 | BackYard Chickens - Learn How to Raise Chickens
I tend to be a messy housekeeper and there are occasionally a few styrofoam pellets of various sizes and colors on the floor before I manage to pick every...
Is styrofoam toxic for chickens?
I tend to be a messy housekeeper and there are occasionally a few styrofoam pellets of various sizes and colors on the floor before I manage to pick every last one of 'em up. Every single time a chicken gets into the house, it finds one of 'em and will either scarf it down right away before moving on to look for another or quickly run back outside with the prize as I try to snatch it away.
I used to stack the styrofoam clumps in packaging in their boxes next to the garbage and recycle cans until I felt like breaking down the boxes for recycling and putting the styrofoam into the trash. Well, I don't do THAT any more! The land-lady's 3 sheep nosh on the cardboard, exposing the styrofoam for the chickens, who go to town on it.
Apparently it goes right through them. Not wanting to run the risk of it clogging something up inside the chickens, I am trying much harder to keep it away from them.
They love the stuff! I don't know why, something about the texture. Geese love it too. It sounds really funny when geese eat it.
<here is a image 537a8289f4a9148a-f1eadab8359041d1>
My grand daughter covered a huge area of my yard with tiny piece of styrofoam once. The chickens went nuts, I was chasing and trying to catch them and running back to shoo them. I finally looking at all of it and there was no way I'd have gotten it up.
I waited for two days to see if I'd be burying birds. Did I mention there was a ton of the stuff??
No one got sick, no one died, but I just knew I was going to be picking them up and disposing of them.
Somehow packing peanuts made it into our composted pile. ( I think they were in the bottom of an old plant pot) the girls find pockets of them all the time. I go over and pick up what they find, but there always seems to be more. Generally it goes right through them. I have had one incident of what I think was packing peanut onset constipation. ( she loves them the most) the patient was isolated and given oatmeal w/ olive oil and her other favorite raisins. Afteran overnight in the infirmary and some "movement" she was fine.
DH raises quail, and this winter he surrounded their pens with sheets of styrofoam. He deliberately kept it several inches away, knowing how the chickens always go for it and taking it for granted that the quail would too. Sure enough, those little birds stretched their knecks as far as they could to get to the sheets, and made good sized holes in it. Funny thing was finding the white foamy looking poo in the trays under the pens.
Well, glad to know styrofoam does not appear to be toxic.
Which now brings on another lightbulb...
All that darn styrofoam I'm always getting in packing boxes...
Maybe I finally found a way to dispose of it.
<here is a image 84615ebf79b20797-f59a024f166911f1>
My chickens have eatin foam cups,foam cooler,foam insulation, foam packaging and its taking years to get it all away from them and they still find it somehow . as far as I know there as been no casualties due to Styrofoam consumption. One of my chicks ginger who is now decesed because she was almost 7 years old ,loved the stuff and never got sick ,I still wouldn't let them eat it tho.speaking of which I hear them eating some right now ,bye<here is a image 93949a96f8be0e46-8b67f6c92fbbe3af><here is a image ea46097285d08f6a-288b87d9d0a9abc3>
thank mercy for the lot of you.
I thought I was a terrible mother-hen that my babies keep FINDING it somehow. Now I know they are just smarter than we are and the stuff is their drug.
The ducks can remove siding to get at insulation. I keep telling my spouse to stop leaving the drill and hammers lying around, I think they can use tools.
It seems to be ok. One of my children left a large styrofoam bow target out last fall. They ate sooooooo very much of it. They all seemed fine and never missed a beat. They had to have eaten several crops full each.
Winter Creek Coop said:
It seems to be ok. One of my children left a large styrofoam bow target out last fall. They ate sooooooo very much of it. They all seemed fine and never missed a beat. They had to have eaten several crops full each.
I think one of us needs to taste it to find out WHY they love it so much, and someone needs to start making chicken feed in the shape of styrofoam.
| https://www.backyardchickens.com/threads/is-styrofoam-toxic-for-chickens.473648/page-2 |
Full text of Mid-Continent Banker : The Financial Magazine of the Mississippi Valley and Southwest : September 1964, Volume 60, No. 10 | FRASER | St. Louis Fed
Full text of Mid-Continent Banker : The Financial Magazine of the Mississippi Valley and Southwest :
September 1964, Volume 60, No. 10
d
bankers depart
m en t of M ercan
tile
Trust.
He
succeeds Jack J.
Scott,
assistant
v i c e president,
w ho le ft to b e
com e president of the n ew Citizens
B ank of Elizabethtow n, K y .
M r.
tional
N eb.
Trust
Fagot w as form erly w ith N a
B ank of Com m erce in Lincoln,
He w ill represent M ercantile
in Missouri and adjacent states.
N a tio n a l C harter Sought
ST. L O U IS — Application has been
filed w ith the C om ptroller o f the
C urrency for
the proposed W est
Side N ational B ank w hich w ould be
located at 9800 M anchester Road in
the W a r son W ood s Shopping Center.
no
https://fraser.stlouisfed.org
Federal Reserve Bank of St. Louis
St. Robert Bank O pens
ST. R O B E R T — The n ew First N a
tional Bank o f Pulaski County opened
for business here last m onth. V . L.
Long is president and A rd o Roberts
is executive vice president and cash
ier. The bank has $150,000 capital and
$100,000 surplus.
Two K.C. Fed Men Retire
K A N S A S C IT Y — Jam es T. W h ite,
vice president, and Jam es V . Fisler,
m on ey departm ent m anager, retired
June 30 fro m the Federal Reserve
here. M r. W h ite ’s career w ith the
bank spanned m ore than 46 years,
and M r. Fisler has alm ost 45 years
w ith the Federal Reserve System .
■ D E L M A R B A N K of U niversity City
has received authorization to exercise
trust powers. Rolla K . W etzel, as
sistant vice president and form erly
an assistant state bank exam iner, has
been nam ed trust officer. Joseph
G rand, vice president and general
counsel, w ill b e legal counsel to the
n ew trust departm ent.
■ M IC H A E L W . W R IG H T has been
elected assistant cashier, Brentw ood
Bank. H e has been a m em b er of the
instalm ent credit departm ent for the
past four years.
Missouri Deaths
B ank W a n ted !
Investor w ill p a y g oo d price and re ta in
m anagem ent. Prefers $3 m illio n to $6
m illio n d e p o s it ra ng e .
JEROM E I. CO O K
■ B R O O K F IE L D B A N K IN G CO. has
announced that construction on a new
building w ill begin this fall. Th e new
K A N S A S C IT Y
— D onald H. E ch
term eyer, assist
ant
cashier
of
Com m erce Trust,
has been nam ed
head
of
the
b an k’s credit de
partm ent.
He
joined
C om m erce Trust
in 1959 and since
D. H. ECHTERMEYER
June of 1960 has
traveled in Kansas for the corre
spondent departm ent. He is a gradu
ate of the U n iversity of Omaha.
S ervin g Banks S ince 1919
801 S. S kinke r Blvd., St. Louis, Mo.
H A R V E Y L. J E N K IN S , 71, one of the
founders o f Citizens Bank, Sparta,
and an officer of the bank until
his retirem ent in 1963.
G U S T A V R IE S M E Y E R JR., 80, vice
president of First N ational, St.
Louis, until his retirem ent 18 years
ago.
MID-CONTINENT BANKER for September, 1964
The Mercantile switchboard where more than 2 6 0 0 calls come in daily from customers and bankers throughout the nation.
r
v
W
W H Y YOUR M A N
FROM M ER C A N TILE
IS O N L Y
Thanks to modern communication, you are just a desklength away from the correspondent bank services you need
SECONDS
Lift your phone and in seconds you’re in touch with your
FROM
specialists waiting to help you. For any o f the more than 100
Man from Mercantile and our more than 1200 other bank
YOUR
DESK
correspondent services we provide—phone M ercantile.You’ll
get results almost quicker than you can cross your lobby!
*84 seconds—average time (based on telephone company
LA R G E S T B A N K IN M IS S O U R I
records) to reach your party on long distance calls by
operator. Only 30 seconds, average time, i f call is
placed by Direct Distance Dialing
AREA CODE 314
CEntra/ 1-3500
M E R C A N T IL E
S A I N T L O U IS . M O .
T R U S T
C O M P A N Y
MID-CONTINENT BANKER for September, 1964
https://fraser.stlouisfed.org
Federal Reserve Bank of St. Louis
rm
111
Smart,
Park Avenue Hotel
ONLY 8 MINUTES
FROM WALL STREET
Yes, you can enjoy the con
venience and comfort of a fine
mid-town hotel—and be on the
job in Wall Street on ten min
utes notice— when you stay at
the beautiful Manger Vander
bilt on Park Avenue at 34th
Street. The express subway to
Wall Street is practically at
your doorstep,— as are many of
M anhattan’s finest stores and
restaurants. And rates are rea
sonable for the Manger Vander
bilt’s 600 luxurious rooms, all
with radio and many with tele
vision. Next time you’re in New
York, try the Manger Vander
bilt. Y ou ’ll like it.
■ J A C K H O G A N has been nam ed
executive vice president and cashier
of Security National, Sikeston. Mr.
H ogan w as previously vice president
of First N ational, W est M em phis, A rk.
■ F IR S T
S T A T E , Rolla, has an
nounced plans for a new d rive-in
and w a lk -u p facility. The project is
being handled by B ank B uilding &
Equipm ent Co-rp., St. Louis.
■ A T S E C U R IT Y N A T IO N A L , Joplin,
Jam es R. Sanders has been advanced
from assistant vice president to* vice
president and cashier, and C. Stew art
Revenaugh has joined the bank as
assistant vice president. Mr. R ev e
naugh was form erly w ith M ercantile
N ational in Tulsa.
Lewis N am ed Asst. Cashier
THE
Wash Problem Ironed Out
BETH ANY, MO. — How to get
the family laundry done and still
work five and one-half days a week
is no longer a problem for 12 mar
ried women employes o f First Na
tional here.
The ladies formed a nonprofit cor
poration, obtained a loan from
First National, and installed an au
tomatic washer and dryer in the
bank’s boiler room!
■ B A N K OF H A Y T I is constructing
new quarters w hich w ill feature
drive-in facilities and am ple parking
space.
Sales Techniques
(C ontinued from p a g e 18)
by Empire o f S p ringfield
^ a n u L d tU lt'
PARK
HO TE l
AVENUE A T 34th STR E E T
NEW YORK CITY
S P R IN G F IE L D
,
¿S
~~
T e lety p e N o. 212 867-4234 (A rea C od e 2121
T el. M U 3-4000
r e s o r t liv in g
in fd b w n to w i
Los Angele!
D. C. LEWIS
— D avid C. Lew is
has been nam ed
assistant cashier
at Em pire Bank.
H e w ill retain
that title when
he m oves to the
new d riv e -in fa
cility that E m
pire is building
a fe w b l o c k s
from
its
M ain
O ffice.
Mr. Lew is was form erly in the loan
departm ent at First N ational, Joplin,
and had w orked in every departm ent
of that bank.
■ G R A V O IS B A N K in the St. Louis
suburb of A ffto n has relocated its
instalm ent loan departm ent in e x
panded quarters on the balcony.
POPULAR
RATES
$300
SINGLE ROOM
Slightly more
two persons
same room.
Children under
12 free.
1st of Neosho’s New Home
Luxury Living In the Heart
of Los Angeles— King-Size
Heated Swimming Pool—
With Food and Beverage
Service at Poolside. Adja
cent to Finest Shops, De
partment Stores and Busi
ness District. Excellent
Food in Coffee Shop, Din
ing Room and Jesters.
Nightly Entertainment.
I Name_
I SlICBL
I C lty_
112
https://fraser.stlouisfed.org
Federal Reserve Bank of St. Louis
.State.
Th e loyal custom er, w h o comes
back to do business with us tim e
after tim e, does so because o f three
reasons:
Products— He likes our product, re
gardless of price.
M ethods— He likes our service. He
likes doing business w ith our firm .
And
fin a lly — M en— he
believes
in
us and likes us.
O ne of the greatest handicaps in
the path of most of us is the habit
of procrastination. W e ’re constantly
putting o ff until tom orrow that which
w e should do today. A fte r all, hard
w ork is m erely an accum ulation of
easy things w e didn’t do when w e
One of the greatest explosives
kn ow n to m ankind is com m only called
“T .N .T .” If w e w ould put real e x
plosiveness into our daily selling,
let “ T .N .T .” in our little black book
stand for “ Today— N ot T om orrow .”
Do it today, not tom orrow .
HOTEL MAYFAIR
WRITE FOR
FREE COLOR FOLDER
People w ho are enthusiastic m ake
them selves that w ay. B ut w e can’t
be enthusiastic about anything we
don’t think is w orthw hile. W e have
to fire ourselves w ith enthusiasm
and generate that same enthusiasm
in our customers.
should have!
FREE LOCAL
• FREE TV AND RADIO
PHONE CALLS • FREE PARKING
LOS ANGELES 17, CALIFORNIA
pow er into us. It glow s and shines,
ligths up our faces, It’s the keynote
that m akes us sing and m akes m en
sing w ith us.
This new b u ild in g , scheduled fo r com ple tio n
a bo u t D ecem ber 15, w ill be the new home o f
First N a t'l in Neosho.
The 9 ,8 0 0 -s q u a re -fo o t
b u ild in g is b e in g constructed o f charcoal b ric k
and w h ite m a rble Crete. B ill B. Lee, tre a su re r
o f the M issouri Bankers A s so cia tio n , is p resid e nt
o f the N eosho bank.
A n ancient Chinese philosopher put
it this w a y : “ On the plains of hesi
tation bleach the bones of countless
m illions who, on the threshold of
victory, sat dow n to wait. A n d w a it
ing— they d ie d !”
MID-CONTINENT BANKER for September, 1964
•
^
In d e x to A d v e rtis e rs
Ralston Purina C o m p a n y ......................................................... 63
Recordak Corp o ratio n ..........................................................5 8 -5 9
R e lia b le S ta m p -O -M a tic C o rp .............................................. 17
•
A m erican G u a ra n te e Insurance G r o u p ............................
A m erica n N a tio n a l Bank and Trust C o ............................
2
89
Bank B u ild in g & Equipm ent C o rp o ra tio n .........................
79
Bank o f M o n tre a l........................................................................ 72
Bankers S e rvice C o m p a n y ...................................................... 20
Boatm en's N a tio n a l B a n k ....................................................
6
Business New s A sso cia te s, In c .......................................... 4 8 -5 4
C en tral Bank & Trust C o ........................................................ 56
C en tral States H ealth & Life C o ......................................... 68
C en tral Trust C o ............................................................................ 34
C hase M anhattan B a n k ........................................................... 51
C h e m ical Bank N ew Y o rk Trust C j .................................... 64
C itize n s F id e lity Bank & Trust C o ........................................ 91
C ity N a tio n a l Bank & Trust C o ., Kansas C it y ............. 37
Com m erce Trust C o ..................................................................... 15
C o ntine n tal Illin o is N a tio n a l Bank & Trust C o ...............
8
C o o k, Jerom e 1.......................................................................8 4 -1 1 0
C u m m in s-C h ica g o Corp oration ......................................... 50
-y 1
T
1
D e lb rid g e C a lc u la tin g System s, In c ................................. 20
De Lu xe C he ck Printers, In c ................................................... 76
D eposit G u a ra n ty Bank & Trust C o ....................................
7
D o u g la s-G u a rd ia n W arehou se C o rp ................................... 70
Downey C o ., C . L ......................................................................... 23
Drovers N a tio n a l B a n k ........................................................... 78
V
^
Eastm an
-*
'
V
^
H am ilton T a ilo rin g C o .............................................................
H arris Trust and S a v in g s B a n k ............................................
H egco In du stries, In c ................................................................
H ib e rn ia N a tio n a l B a n k .........................................................
74
27
21
97
Illin o is N a tio n a l B a n k ..............................................................
In d ia n a N a tio n a l B a n k ...........................................................
In d ia n a p o lis Bond and Sh a re C o rp ....................................
Insured C re d it S ervice s, In c .................................................
85
87
14
24
La Monte & S o n , G e o rg e ...................................................... 57
Le Febure C o rp ...................................................................... 3 3 -1 1 3
Lib e rty N a tio n a l Bank & Trust C o ........................................105
Liv e Stock N a tio n a l B a n k ...................................................... 81
Maco C o rp oration ...................................................................... 17
M anger V a n d e rb ilt H o te l.......................................................... 112
M anufacturers H an over Trust C o .........................................
5
M a y fa ir H o te l, Los A n g e le s .................................................. 112
M a y fa ir and Lennox H otels, St. L o u is ..........................
90
M ayo H o te l, T u ls a ................................................................... 98
M ercan tile Trust C o ....................................................................I l l
M erchants N a tio n a l Bank & Trust C o ............................... 86
M errill Lyn ch , P ierce, Fenner & S m it h ............................ 11
M issouri E n ve lop e C o ................................................................ 14
M cCou rtn ey-B recken rid ge & C o .............................................113
£
T alco tt, In c ., Ja m e s ...................................................................
Texas N a tio n a l Bank of C o m m e rce.................................
Third N a tio n a l B a n k ................................................................
TV Bank C o rp o ra tio n ................................................................
Union
Planters N a tio n a l
83
35
67
21
B a n k ............................................ 93
V a lle y N a tio n a l B a n k .............................................................. 22
V o lun te e r State Life Insurance C o ................................... 28
W a ssell O rg a n iza tio n ...........................................................
W estern and Southern Life Insurance C o .......................
W h ite , W e ld & C o ..................................................................
W h itn ey N a tio n a l B a n k ...........................................................
W o m eld o rff & L in d s e y ..............................................................
W orthern Bank & Trust C o ...................................................
17
22
32
96
14
99
Kod ak C o ................................................................. 5 8 -5 9
Farm Business C o u n c il, In c ................................................... 62
F in a n c ia l P u b lic R elation s A sso c ia tio n .......................... 49
First C ity N a tio n a l Bank of H o u sto n ...............................101
First N a tio n a l Bank of C in c in n a t i....................................... 80
First N a tio n a l Bank in D a lla s ..............................................
3
First N a tio n a l B ank, Kansas C it y ....................................... 29
First N a tio n a l B ank, Little R o c k ....................................... 98
First N a tio n a l Bank of M e m ph is..................................
4
First N a tio n a l B ank, S t. L o u is ............................................. 116
First N a tio n a l Bank & Trust C o ., T u ls a ..........................30
First N a tio n a l C ity B ank, N ew Y o r k ............................... 25
Ju n g Hotel ...................................................................................... 103
►
S t. Paul Fire & M arine Insurance C o ............................... 72
Sch a p iro & C o ., In c ., M. A ................................................. 36
S ch a rff & Jo n es, In c ................................................................ 14
S ecu rity Sea l C o .......................................................................... 17
Se d g w ick M achine W o rk s ...................................................... 17
Show -M e Bankers Se rvice C o ..............................................
9
Southw est N a tio n a l B a n k .......................................................... 102
Stern Bros. & C o ........................................................................ 77
S tu d le y , Shupert Trust Investm ent C o u n c il.................. 10
N a tio n a l Bank of Com m erce, M e m ph is.......................... 95
N a tio n a l Bank of D e tro it...................................................... 80
N a tio n a l Bank of T u ls a ........................................................... 47
N a tio n a l B oulevard Bank of C h ic a g o ............................ 71
N a tio n a l F id e lity Life Insurance C o ................................. 61
N a tio n a l Stock Yard s N a tio n a l B a n k ............................... 115
N ew Y o rk Term in al W arehouse C o ................................... 73
Northern Trust C o ........................................................................ 19
O za rk A ir
Lin es,
In c ..................................................................107
Puget Sound N a tio n a l Bank
82
Convention Calendar
New Mexico, June 10-12,
Palms Motor Hotel
Las
Cruces,
Oklahoma, May 5-7, Tulsa
N A T IO N A L (1965)
AIB, May 31-June 4, New Orleans, Hotel
Roosevelt
A BA Agricultural Credit Conference, Nov.
14-17, Denver, Denver-Hilton Hotel
ABA Automation Conference, March 8-10,
San Francisco
A BA Convention, Oct. 3-6, Chicago
ABA Credit Conference, Feb. 1-2, Dallas,
Sheraton-Dallas Hotel
ABA Instalment Credit Conference, March
29-31, Chicago, Conrad Hilton Hotel
ABA Mortgage Conference, May
Denver, Denver-Hilton Hotel
23-26,
ABA Personnel Conference, Oct, 17-20,
Washington, Sheraton-Park Hotel
A B A Savings Conference, April 26-28, New
York City, Hotel Roosevelt
FPRA, Oct. 24-28, New York City, New
York-Hilton Hotel
Independent Bankers Assn., April 8-10,
Hollywood, Fla., Diplomat Hotel
Robert Morris Associates, Oct. 27-30, Bos
ton, Hotel America
SCHOOLS (1965)
National Instalment Credit School,
7-19, University of Chicago
M ID -C O N T IN E N T AREA
Kentucky,
Hotel
Nov.
15-17,
Louisville,
Brown
Feb.
National Trust School, Aug. 9-27, Evans
ton, 111., Northwestern University
Stonier Graduate School of Banking, June
14-25, New Brunswick, N.J., Rutgers
University
N A T IO N A L
ABA Agricultural Credit Conference, Nov.
8-10, Memphis, Hotel Peabody
ABA Convention, Oct. 25-28, Miami Beach
A BA Personnel Conference, Nov. 15-17,
Chicago, Sheraton-Chicago Hotel
ABA Savings Automation Workshop, Sept.
14-15, Atlantic City, Chalfonte-Haddon
Hall
Consumer Bankers Assn., Oct. 14-17, Boca
Raton, Fla., Boca Raton Hotel
FPRA, Sept. 27-Oct. 1, St. Louis, ChasePark Plaza Hotel
NABAC, Sept. 28-30, New York, Americana
Hotel
B A N K EQ U IP M EN T
SALES OPPORTUNITY
Should have e xp e rie n ce in ban k e q u ip
m ent, o ffic e e q u ip m e n t, o r business m a
chines sales. Send b rie f resume. Several
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JOHN L. TALLEY, Gen. Sales Mgr.
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Cedar Rapids, Iowa 52406
National Assn, of Bank-W om en, Inc., Oct.
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IN STRICT
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Robert Morris Associates, Sept. 27-30, M on
treal, Queen Elizabeth Hotel
M ID -C O N T IN E N T AREA (1965)
Arkansas, May 17-19, Hot Springs, Arling
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Indiana, June 9-10, French Lick, French
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BANKER, 408 O liv e St., St. Louis, M o. 63102.
Y
MID-CONTINENT BANKER for September. 1964
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Federal Reserve Bank of St. Louis
Distributors and Underwriters of Investment Securities
Member Midwest Stock Exchange
1030 Boatm en’s Bank Building
CEntral 1-5730
St. Louis, Mo.
113
Kansas Bank Presents
A “Party Package”
on 25th A nniversary
X A / H E N Johnson County National, Prairie V illage, Kan., turned 25 years old last July, it
held a five-hour celebration that included a barbe
cue, home-state reunions, stage show, street danc
ing, a watermelon feed, prizes and fireworks (the
celebration was held just two days before Inde
pendence D a y ). The bank called the observance
“The Prairie Village Party Package.”
Many stores in the shopping center in which
the bank is located took part by remaining open
the night of the party.
TW O -H O U R STAGE SH O W in fro n t o f Johnson C ounty N a t'l was p a rt
o f b an k's 2 5 th -a n n ive rsa ry ce le b ra tio n .
A M O N G THOSE e n jo y in g stage show
was M. F. Barlow {4th fro m r. in 2nd row), ban k pres.
https://fraser.stlouisfed.org
Federal Reserve Bank of St. Louis
The barbecued chicken dinner was served under
a big tent near the bank, and $1 per person was
charged, with the proceeds going to the Prairie
Village Scholarship Foundation. The dinner was
followed by the stage show, street dancing and a
gigantic fireworks display.
SHIRLEY G O R D O N sings num ber
d u rin g stage show
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Federal Reserve Bank of St. Louis
Carroll F. Burton
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Leonard J. Schrewe
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Harry L. Smith
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| https://fraser.stlouisfed.org/title/mid-continent-banker-7027/september-1964-632209/fulltext |
Trump Trashes Another Treaty | Council on Foreign Relations
Even calculating for the rising threat from China, leaving the INF puts the United States in a worse strategic position than if it were to stay in.
Delegations, led by Russia's Defence Minister Sergei Shoigu (R) and U.S. National Security Adviser John Bolton (2nd L), meet in Moscow, Russia October 23, 2018. Reuters.
Even calculating for the rising threat from China, leaving the INF puts the United States in a worse strategic position than if it were to stay in.
Delegations, led by Russia's Defence Minister Sergei Shoigu (R) and U.S. National Security Adviser John Bolton (2nd L), meet in Moscow, Russia October 23, 2018. Reuters.
John Bolton, President Trump’s national security adviser, is in Moscow this week and reportedly plans to tell Vladimir Putin that, because of Russian cheating, the United States will withdraw from the treaty on intermediate-range nuclear forces (INF) signed by Ronald Reagan and Mikhail Gorbachev in 1987. Because Trump always disparages agreements reached by his predecessors, we might expect him to start tweeting that he’s saved America from yet another bad deal. But there’s a problem: the INF treaty may be the most one-sidedly good arms-control agreement any U.S. President has ever signed. And unless you start by recognizing this fact, you won’t make the right call about what to do next.
What made the INF treaty so good? It represented 100 percent Soviet acceptance of an American offer that almost no one in Washington thought could ever fly. Moscow agreed to scrap every single one of the new missiles, known as the SS-20, that it had been deploying for over a decade to intimidate European allies of the United States—plus all the missiles that the SS-20 was supposed to replace, plus any and all missiles of the same range deployed in Asia too. The Soviets accepted all this even though the U.S. counter-deployments that European allies had accepted on their territory were both less numerous and less powerful than the SS-20. Even more astoundingly, the INF treaty imposed no limits whatever on the main nuclear forces—both air- and sea-launched—on which the U.S. defense of Europe has rested ever since.
These one-sided terms do not mean, of course, that Russian violations of the treaty are unimportant. Both the Obama and Trump administrations have claimed that Moscow tested (and has now deployed) a cruise missile of illegal range. Even if information about these weapons is highly classified and therefore hard to discuss in public, and even if only a handful of them have actually been deployed, any U.S. President would feel obliged to respond. The crucial question is how.
One option—apparently Bolton’s preference—is to withdraw from the treaty and go forward with new U.S. deployments banned under INF. Another is to withdraw but stick to new missiles that the treaty allows (since no new INF-banned missiles will be ready for deployment for several years). A third would be to “suspend” the treaty in some way—declare that its terms no longer constrain us and prepare for withdrawal if Russia does not come into compliance. Finally, without either withdrawing from the treaty or suspending it, the United States could begin a build-up of the many weapon systems the INF treaty already allows.
There are surely things to be said for and against each of these options, and they should be debated fairly. What such a debate will make clear, however, is that only one option—the last one—both allows an increase in U.S. nuclear capabilities in and around Europe andkeeps Russian capabilities under legal limits. Yes, Moscow will probably keep nibbling at the edges of the INF deal, but the only way it can launch a big buildup is by withdrawing from the treaty itself—something it clearly hesitates to do.
By contrast, the United States is free under the treaty to move forward with a robust program of new deployments, all the while generating a steady stream of public accusations about Russian duplicity. Moscow’s cheating means this is not a viable long-term solution, but for the foreseeable future, the one-sidedness of the INF treaty gives us the military and the moral high-ground at the same time. Unlike the Russians, we don’t have to cheat to come out on top.
The Trump Administration does have a second complaint about the INF treaty that some officials suggest is becoming even more important than Russian cheating. Because the treaty only applies to U.S. and Russian forces, it allows China—without any restrictions whatever—to deploy the very missiles that Reagan and Gorbachev forswore. That was okay when the Chinese were our Cold War confederates against the Soviets, but when they seek (as they now do) to limit the ability of the United States to defend its East Asian allies, the arrangement suddenly seems a lot less advantageous. No surprise, then, that American military planners have begun to view the INF treaty as one-sided in a new way—favoring China.
Military competition between the China and the United States will obviously be the Pentagon’s top priority in coming years. But the idea that this need decisively devalues the INF treaty seems—at the very least—premature. Even more than it does in Europe, the United States protects allies in the Western Pacific through its navy and air force—and that includes both air- and sea-launched nuclear systems. It’s not impossible to imagine that over time we and our allies will come to think that medium-range, ground-based missiles—the kind the INF treaty keeps us from having—would add meaningfully to deterrence of China. NATO came to that same conclusion about the Soviet Union in the late 1970’s and early 1980’s. But this is not a near-term prospect. Today, in fact, virtually every U.S. ally in the region would reject the idea.
To embrace it, moreover, would involve a painful trade-off between the interests of America’s European allies and those of our friends in Asia. The United States may ultimately be driven to sacrifice a treaty that blocks a Russian nuclear buildup in Europe so as to be able to counter a Chinese nuclear buildup in Asia. But it would be foolish to do so when we still have so many ways of countering the latter and when the former has barely begun to take shape.
To date, the pushback against the Trump Administration’s handling of the INF treaty has come mainly from the professional arms-control community. Its spokesmen stress the value of “dialogue” and confidence building, of strategic “stability” and “win-win” solutions. None of this criticism is likely to have the slightest influence on John Bolton, who will treat it as so much peacenik hand-wringing. His view is that arms control agreements tie America’s hands and keep it from defending itself and its allies. He can make that ideological case if he wants to—and if he can find any agreements that prove him right. The INF Treaty is not one of them.
| https://www.cfr.org/article/trump-trashes-another-treaty |
Magazine Contents Lists: Page 2953
Previous — Magazine Issue Index — Table-of-Contents
Collier’s [Vol. 130 No. 1, July 5, 1952] (15¢, 10½″ x 13½″, cover by
Fred Ragsdale ) []
Details taken from eBay listing.
6 · The Week’s Mail · [The Readers] · lc
8 · 48 States of Mind · Walter Davenport · cl
12 · Summer Sonata · Don Tobin · ??
15 · Too Many Secrets Spoil the Atom ·
Dr. Ralph E. Lapp · ??
18 · Mt. Rushmore—Heritage in Granite · [uncredited] · ms
20 · Matthew Meets His Peer · Joseph Carroll · ss
22 · Taft Should Be Nominated ·
Senator Hugh Butler · ??
23 · Ike Should Be Nominated · Senator Leverett Saltonstall · ??
24 · Traffic James—How We Can Free Them Now · Bill Fay · ??
28 · The Gift of Cochise · Louis L’Amour
· ss
30 · The Case of Mario Bravo · Dr. Alberto Caride & John Lear · ??
32 · Sixpence · George Sumner Albee · vi
48 · Everything Tastes Better Outdoors · Harry Botsford · ??
54 · Voice of the Mule · Richard G. Hubler · ??
58 · Premature Babies · [uncredited] · ms
69 · The Mail for Today · Joseph Kiernan
· ??
70 · Saddle by Starlight [Part 5 of 7] ·
Luke Short · sl
82 · Editorial · [The Editor] · ed
Collier’s [Vol. 130 No. 2, July 12, 1952] (cover by Jack Lambert ) []
Details supplied by Bill Seabrook from contents listing at unz.org.
6 · 48 States of Mind · Walter Davenport · cl
8 · The Party · Bob Schroeter · ??
11 · How I Broke the Michigan Prison Riot · Dr. Vernon Fox & Bill Fay · ??
14 · The Sons of Cyrus Trask · John Steinbeck · nv
16 · Stanwyck · Frank S. Nugent · ??
18 · A Confession, a Cat, and a Canary · Joseph Petracca · ??
20 · Conventions: Party Time for Politicians · Robert Trout · ??
22 · Lopez and the Indian Signs · Tom Meany · ??
24 · Wolf’s Clothing · Allen Marple · ??
25 · Stalin’s Hungarian Hatchet Man ·
Seymour Freidin & William Richardson · ??
26 · Friendship Flight · Rep. Peter F. Mack, Jr. · ??
28 · Vendetta · James Atlee Phillips · ??
30 · Saddle by Starlight [Part 6 of 7] ·
Luke Short · sl
42 · A Dance Is Born · [uncredited] · ms
50 · Painting the Town: San Francisco ·
[uncredited] · ms
58 · Shakedown · [uncredited] · ms
62 · …Then Home to His Wife in Italy ·
[uncredited] · ms
70 · Editorial · [The Editor] · ed
Collier’s [Vol. 130 No. 3, July 19, 1952] (15¢, 82pp, 10½″ x 13½″, cover by
Sharland ) []
Details taken from eBay listing.
8 · Gangway—Fresh Corn! · Parke Cummings · ??
11 · 48 States of Mind · Walter Davenport · cl
13 · Most Important Room in America ·
Clarke Newlon · ??
16 · For Men Only · Willard H. Temple · ss
18 · Emergency Ward! · John Denson · ??
20 · Why I’m for Kefauver · Sen. Paul Douglas · ??
21 · Hot-Rock Pilot · Robert Dexter Neff
· ss
22 · The U.S. Male…Is He First-Class? ·
Dr. Judson T. & Mary G. Landis · ??
24 · How to Tie a Beau · [uncredited] · ms
26 · 10 Biggest Olympic Thrills · Dean Cromwell & H. Archie Richardson · ??
28 · Elodia · Mary Cooper · ss
34 · Saddle by Starlight [Part 7 of 7] ·
Luke Short · sl
42 · The Quarter-Pound Loss · Hazel Heckman · ss
49 · Photographer · Martha Blanchard · ??
50 · Film Fun Comes in Cannes ·
[uncredited] · ms
54 · The Family Next Door · Mildred &
Laurence Tilley · ??
66 · Wonder Earth · Jack Beardwood · ??
74 · Editorial · [The Editor] · ed
Collier’s [Vol. 130 No. 4, July 26, 1952] (15¢, 10½″ x 13½″, cover by
Jack Lambert ) []
Details taken from eBay listing.
8 · 48 States of Mind · Walter Davenport · cl
10 · Summer Storm · [uncredited] · ms
12 · New Sidewalk · Bob Schroeter · ??
15 · The Moslem Crescent · Seymour Freidin & William Richardson · ??
21 · Narcotics Ruined Me · Lila Leeds &
Bill Fay · ??
26 · Guinness—Man of Many Faces ·
Joseph Newman · ??
32 · Where Wind Works for Air Power ·
[uncredited] · ms
35 · His Job’s a Breeze · [uncredited] · ms
36 · Gal in the GI Kitchen · Jean Drew · ??
40 · Convention Time Again ·
[uncredited] · ms
42 · Sorry Spectacle · Hannibal Coons · ss
48 · The Package · Kurt Vonnegut, Jr. · ss
54 · William at the Bridge · Forrest Archer · ss
58 · City Woman · Bill Brownell · ss
64 · The Lost Million · Glenn F. Powers · ss
65 · Love Set · James Atlee Phillips · ss
70 · Editorial · [The Editor] · ed
Collier’s [Vol. 130 No. 5, August 2, 1952] (15¢, 11″ x 14″, cover by John Florea &
Fred Swartz ) []
Details taken from eBay listing.
8 · What Was That Word? · Parke Cummings · ??
10 · Ever See a Red Elephant? ·
[uncredited] · ms
12 · 48 States of Mind · Walter Davenport · cl
15 · Air-Crash Detective at Work ·
Richard Witkin · ??
19 · Montana’s Favorite Redhead ·
Huntington Smith · ??
24 · Hollywood Headache · Arthur Marx
· ??
28 · He Changes the Face of the Earth ·
Robert de Roos · ??
32 · String Pullers · [uncredited] · ms
34 · Insurance Companies: What Do They Do with All That Money? ·
Ben Merson · ??
38 · Something Lost · Jack Schaefer · ss; illustrated by Hardie Gramatky &
John McCormack
44 · Witness of Happiness · Hamlen Hunt · ss; illustrated by Milton Wolsky
48 · A Caboose Named Martin · Charles Einstein · ss; illustrated by Henry Luhrs
50 · There Is a Tide… · Jack Finney · ss; illustrated by David Stone Martin
54 · The Spartan Life · Willard H. Temple · ss; illustrated by Stan Ekman
58 · The Big Hunger · John Fante · ss; illustrated by Al Brule
62 · Their Playground Is Aloft ·
[uncredited] · ms
64 · Trieste—City Without a Country ·
Seymour Freidin & William Richardson · ??
70 · Editorial · [The Editor] · ed
Collier’s [Vol. 130 No. 6, August 9, 1952] (cover by John Florea ) []
Details supplied by Bill Seabrook from contents listing at unz.org.
8 · F.O.B. Back Yard · Stanley & Janice Berenstain · ??
10 · All Eyes on Doris Day ·
[uncredited] · ms
14 · 48 States of Mind · Walter Davenport · cl
17 · When an A-Bomb Misfires · Robert Cahn · ??
20 · All These People Help Cincinnati Play Ball · [uncredited] · ms
22 · You Can Tell Now How Tall Your Child Will Grow · Andrew Hamilton · ??
24 · Tete-a-Telephone · [uncredited] · ms
26 · Late Honeymoon · Harrison Kinney
· ??
34 · Who’s the Blonde? · John D. MacDonald · ss
40 · Decisions, Decisions! · Elmer Roessner · ??
42 · Thief of Time · Margery Sharp · ss
46 · Surrender · Mary Verdick · ??
52 · Political Pollsters: Can They Predict This Year’s Election? ·
Robert Bendiner · ??
57 · Canada Today · John Lear · ??
74 · Editorial · [The Editor] · ed
Collier’s [Vol. 130 No. 7, August 16, 1952] (cover by Charles Kerlee ) []
Details supplied by Bill Seabrook from contents listing at unz.org.
8 · 48 States of Mind · Walter Davenport · cl
10 · Week End with Major Ike ·
[uncredited] · ms
12 · Last Night on What Back Porch? ·
E. C. K. Read · ??
15 · Antivivisectionists—Are They Finished? · Bill Davidson · ??
19 · Pigs Have Wings [Part 1 of 6;
Blandings Castle ] · P. G. Wodehouse · n.
22 · Surf Fishing · Raymond R. Camp · ??
26 · Salad Days · Harry Botsford · ??
30 · Model Space Ship · [uncredited] · ms
32 · Beanie Takes a Look at the World ·
Elizabeth Bean · ??
36 · My Battle Inside the Korea Truce Tent ·
Vice-Admiral Charles Turner Joy, USN · ??
44 · Virginia · Gordon Forbes · ??
50 · The Unbeliever · Dorothy M. Johnson · ss
54 · Inside Call · Donald MacKenzie · ??
55 · Debt of Honor · John Savage · ??
60 · Gardening in the Sky · [uncredited]
· ms
66 · “Let the Fire Fall!” · [uncredited] · ms
68 · A Place for a Beginning · Valeria Winkler Griffith · ??
74 · Editorial · [The Editor] · ed
Collier’s [Vol. 130 No. 8, August 23, 1952] (cover by Philippe Halsman ) []
Details supplied by Bill Seabrook from contents listing at unz.org.
8 · 48 States of Mind · Walter Davenport · cl
10 · Some Pops Stay Tops ·
[uncredited] · ms
13 · Duel Without Pistols · John Steinbeck · ar
16 · Words Are Weapons, Too ·
[uncredited] · ms
18 · Safer Highways—The Massachusetts Way · Joseph F. Dinneen
· ??
22 · Around the World on $80 · Robert Christopher · ??
26 · A Deadly Game of Tit-for-Tat · Vice-Admiral Charles Turner Joy, USN · ??
32 · The Rams Run on “Crazylegs” · Bill Fay · ??
35 · Hand Me a Bent Pin · John Keasler · ??
36 · Woman’s Man · Frances Ensign Greene · ??
42 · The Hardhearted Kid · Margaret Chase · ??
47 · It’s a Pleasure · Caskie Stinnett · ??
48 · The Boy Who Wasn’t Chicken ·
William R. Scott · ??
54 · Bianco · Giovanni Guareschi · ??
56 · Pigs Have Wings [Part 2 of 6;
Blandings Castle ] · P. G. Wodehouse · n.
62 · A Fathom of Pearls · F. H. Young &
James Atlee Phillips · ??
66 · They’re Raising 24 Problem Children · Joseph P. Blank · ??
70 · Editorial · [The Editor] · ed
Collier’s [Vol. 130 No. 9, August 30, 1952] (10½″ x 13½″, cover by
Paul Annixter ) []
Details taken from Table of Contents.
6 · The Week’s Mail · [The Readers] · lc
8 · 48 States of Mind · Walter Davenport · cl
9 · Wrong Cue · Ray Helle · ??
10 · Damsels Preparing for Distress ·
[uncredited] · ms
13 · Beauty on the Bench · Gladwin Hill
· ??
16 · Francis Wallace’s 13th Football Preview · [uncredited] · ms
26 · “The Soul and Guts of France” ·
John Steinbeck · ??
32 · They’re Adding Years to Your Life ·
Frank Holeman · ??
36 · Last Cover · Paul Annixter · ss
Argosy (UK) December 1946
42 · Baseball Ain’t Cricket · Tom Meany
· ??
44 · Unlucky Tiger · Ray K. Robinson · vi
46 · Smile When You Call Me Pocahontas · Wauhillau La Hay · ??
48 · The Angle of a Bullet · Paul Horgan
· ss
54 · Campus Cues for Clothes · Bert Bacharach · ??
56 · Pigs Have Wings [Part 3 of 6;
Blandings Castle ] · P. G. Wodehouse · n.
65 · The Big Regatta · Will Stanton · ss
70 · The Critical Prisoner-of-War Problem ·
Vice-Admiral Charles Turner Joy, USN · ??
74 · Editorial · [The Editor] · ed
Collier’s [Vol. 130 No. 10, September 6, 1952] (The Crowell-Collier Publishing Company, 15¢, 10½″ x 13½″, cover by
Philippe Halsman ) []
Details supplied by Steve Scott.
8 · Anniversary · Martha Blanchard · ??
10 · Lions Club Luncheon—Kenya Style · [uncredited] · ms
12 · 48 States of Mind · Walter Davenport · cl
15 · The Koje Snafu · Peter Kalischer · ??
20 · What You Don’t Know About Your Eyes · Carle Hodge · ??
24 · “14,000 Uses and 2¢ per Pound” ·
Robert Froman · ar; illustrated by
Lowell Hess
28 · Gabbing with the Gabors ·
[uncredited] · ms
32 · The Windfall · John D. Weaver · ss; illustrated by Milton Wolsky
36 · Pigs Have Wings [Part 4 of 6;
Blandings Castle ] · P. G. Wodehouse · n.; illustrated by Robert Fawcett
44 · Baseball’s Biggest Bargain · Tom Meany · ??
47 · Daddy’s Boy · Stan Fine · ??
48 · Blood Money · Owen Cameron · ss; illustrated by Saul Tepper
52 · Ninety Saddles for Kengtu ·
Edmund G. Love · ss; illustrated by
William Reusswig
58 · Indian Factory · [uncredited] · ms
59 · First or Nothing · Carl D. Halbak · ss; illustrated by W. David Shaw
60 · History Hinges on These Two Rivers · [uncredited] · ms
64 · Ike Is My Boy · Sergeant Marty Maher & Nardi Reeder Campion · ar
67 · Inch and a Half to Go · H. Allen Smith · ??
70 · Editorial · [The Editor] · ed
Next — Magazine Issue Index — Table-of-Contents | http://www.philsp.com/homeville/fmi/k02/k02953.htm |
(PDF) Genomic and transcriptomic analysis unveils population evolution and development of pesticide resistance in fall armyworm Spodoptera frugiperda
PDF | The fall armyworm (FAW), Spodoptera frugiperda, is a destructive pest native to America and has recently become an invasive insect pest in China.... | Find, read and cite all the research you need on ResearchGate
Genomic and transcriptomic analysis unveils population evolution and development of pesticide resistance in fall armyworm Spodoptera frugiperda
Authors:
Abstract
The fall armyworm (FAW), Spodoptera frugiperda, is a
destructive pest native to America and has recently
become an invasive insect pest in China. Because of its
rapid spread and great risks in China, understanding of
FAW genetic background and pesticide resistance is
urgent and essential to develop effective management
strategies. Here, we assembled a chromosome-level
genome of a male FAW (SFynMstLFR) and compared resequencing
results of the populations from America,
Africa, and China. Strain identification of 163 individuals
collected from America, Africa and China showed that
both C and R strains were found in the American populations,
while only C strain was found in the Chinese
and African populations. Moreover, population genomics
analysis showed that populations from Africa and
China have close relationship with significantly genetic
differentiation from American populations. Taken together,
FAWs invaded into China were most likely originated
from Africa. Comparative genomics analysis
displayed that the cytochrome p450 gene family is
extremely expanded to 425 members in FAW, of which
283 genes are specific to FAW. Treatments of Chinese
populations with twenty-three pesticides showed the
variant patterns of transcriptome profiles, and several
detoxification genes such as AOX, UGT and GST specially
responded to the pesticides. These findings will be
useful in developing effective strategies for management
of FAW in China and other invaded areas.
R ESEARCH ARTICLE
Genomic and transcriptomic analysis unveils
population evolution and development
of pesticide resistance in fall armyworm
Spodoptera frugiperda
Furong Gui
1,12
, Tianming Lan
2,9
, Yue Zhao
1
, Wei Guo
3,15
, Yang Dong
1,12
, Dongming Fang
2
,
Huan Liu
2,9
, Haimeng Li
2
, Hongli Wang
2
, Ruoshi Hao
12
, Xiaofang Cheng
5
, Yahong Li
16
,
Pengcheng Yang
4
, Sunil Kumar Sahu
2
, Yaping Chen
1
, Le Cheng
7
, Shuqi He
1
, Ping Liu
5
, Guangyi Fan
6
,
Haorong Lu
8,10
, Guohai Hu
8,10
, Wei Dong
2
, Bin Chen
1
, Yuan Jiang
18
, Yongwei Zhang
18
, Hanhong Xu
17
,
Fei Lin
17
, Bernard Slipper
19
, Alisa Postma
19
, Matthew Jackson
19
, Birhan Addisie Abate
20
,
Kassahun Tesfaye
20,21
, Aschalew Lemma Demie
20
, Meseret Destaw Bayeleygne
20
, Dawit Tesfaye Degefu
22
,
Feng Chen
5
, Paul K. Kuria
23
, Zachary M. Kinyua
23
, Tong-Xian Liu
13
, Huanming Yang
10,11
,
Fangneng Huang
14 &
, Xin Liu
2,10 &
, Jun Sheng
1,12 &
, Le Kang
3,4,15 &
1
State Key Laboratory for Conservation and Utilization of Bioresources in Yunnan, Yunnan Agricultural University, Kunming
650201, China
2
State Key Laboratory of Agricultural Genomics, BGI-Shenzhen, Shenzhen 518083, China
3
State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of
Sciences, Beijing 100101, China
4
Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing 100101, China
5
MGI, BGI-Shenzhen, Shenzhen 518083, China
6
BGI-Qingdao, BGI-Shenzhen, Qingdao 266555, China
7
BGI-Yunnan, No. 389 Haiyuan Road, High-tech Development Zone, Kunming 650106, China
8
China National GeneBank, Jinsha Road, Dapeng New District, Shenzhen 518120, China
9
Department of Biology, University of Copenhagen, 2100 Copenhagen, Denmark
10
Guangdong Provincial Key Laboratory of Genome Read and Write, BGI-Shenzhen, Shenzhen 518120, China
11
Guangdong Provincial Academician Workstation of BGI Synthetic Genomics, BGI-Shenzhen, Shenzhen 518120,China
12
Yunnan Plateau Characteristic Agriculture Industry Research Institute, Kunming 650201, China
13
College of Plant Health and Medicine, Qingdao Agricultural University,Qingdao 266109, China
14
Department of Entomology, Louisiana State University Agricultural Center, Baton Rouge, LA 70803, USA
15
CAS Center for Excellence in Biotic Interactions, University of Chinese Academy of Sciences, Beijing 100101, China
16
Yunnan Plant Protection and Quarantine Station, Kunming 650034, China
17
State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, South ChinaAgricultural University,
Guangzhou 510642, China
18
BGI-Americas, One Broadway, 14th Floor, Cambridge, MA 02142, USA
19
Department of Biochemistry, Genetics and Microbiology, Forestry and Agricultural Biotechnology Institute, University of
Pretoria, Pretoria, South Africa
20
Ethiopian Biotechnology Institute, Addis Ababa, Ethiopia
21
College of Natural Science, Addis Ababa University, Addis Ababa, Ethiopia
22
Melkassa Agricultural Research Center, Ethiopian Institute of Agricultural Research, Melkassa, Addis Ababa, Ethiopia
23
Kenya Agricultural and Livestock Research Organization, P.O. Box 57811, Nairobi 00800, Kenya
& Correspondence: [email protected] (Fangneng Huang), [email protected] (X. Liu), [email protected]
(J. Sheng), [email protected] (L. Kang)
Received June 3, 2020Accepted September 15, 2020
© The Author(s) 2020
Protein Cell
https://doi.org/10.1007/s13238-020-00795-7 Protein & Cell
Protein &Cell
ABSTRACT
The fall armyworm (FAW), Spodoptera frugiperda ,isa
destructive pest native to America and has recently
become an invasive insect pest in China. Because of its
rapid spread and great risks in China, understanding of
FAW genetic background and pesticide resistance is
urgent and essential to develop effective management
strategies. Here, we assembled a chromosome-level
genome of a male FAW (SFynMstLFR) and compared re-
sequencing results of the populations from America,
Africa, and China. Strain identi fi cation of 163 individuals
collected from America, Africa and China showed that
both C and R strains were found in the American pop-
ulations, while only C strain was found in the Chinese
and African populations. Moreover, population geno-
mics analysis showed that populations from Africa and
China have close relationship with signi fi cantly genetic
differentiation from American populations. Taken toge-
ther, FAWs invaded into China were most likely origi-
nated from Africa. Comparative genomics analysis
displayed that the cytochrome p450 gene family is
extremely expanded to 425 members in FAW, of which
283 genes are speci fi c to FAW. Treatments of Chinese
populations with twenty-three pesticides showed the
variant patterns of transcriptome pro fi les, and several
detoxi fi cation genes such as AOX , UGT and GSTspe-
cially responded to the pesticides. These fi ndings will be
useful in developing effective strategies for manage-
ment of FAW in China and other invaded areas.
KEYWORDS Spodoptera frugiperda , chromosome-level
genome, population differentiation, cytochrome p450,
pesticides
INTRODUCTION
The fall armyworm (FAW), Spodoptera frugiperda , is a dev-
astating and highly migratory insect herbivore native to
tropical and sub-tropical areas in America, and was first
reported more than 100 years ago in the USA as a damaging
pest to maize and other crops (Hinds and Dew, 1915).
Currently, FAW invasion has been reported in more than 100
countries worldwide (Fig. S1). FAW larvae mayattack more
than 350 host plant species belonging to 76 plant families
(Montezano et al., 2018 ), causing serious damage to crops
including maize, rice, sugarcane, sorghum, and cotton
(Sparks, 1979 ). The strongmigrationcapacity of FAW adults
has led to its recently rapid and wide spread throughout
Africa, the Middle East, and several Asian countries includ-
ing India, Bangladesh, Sri Lanka, Thailand, Yemen, Myan-
mar and China since their fi rst appearance in west Africa in
early 2016 (Goergen et al., 2016 ; Mallapur et al., 2018;
CABI, 2019 ; Farmer, 2019 ). In January 2019, FAW was first
reported in Yunnan Province of China (Jing et al., 2019 ), and
then rapidly spread to 13 provinces and cities (Yunnan,
Guizhou, Sichuan, Chongqing, Guangxi, Guangdong, Hai-
nan, Hunan, Hubei, Fujian, Zhejiang, Jiangxi and Henan) of
China within only four months (Wu et al., 2019 ). With the fast
dispersal rates and available suitable habitats in the south-
west, central and northern regions of China, the pest had
already attacked 1,366 counties (cities and districts) across
24 provinces of China until August 17, 2019 (Xiao et al.,
2020 ). The recent FAW invasion in China has caused
tremendous losses of agricultural production in the invaded
regions and has become a great threat to the corn produc-
tion in eastern China, the major regions of corn production in
China (Li et al., 2019).
The FAW consists of two morphological identical but
genetically distinct strains, the corn strain (C strain) and rice
strain (R strain) (Pashley, 1986 ; Juárez et al., 2014 ; Nagoshi
et al., 2018 ). The C strain is the major type that widely
spreads around the world. Each strain shows speci fic
physiological traits thereby exhibiting strain-speci fic
response to biological and chemical agents (Nagoshi and
Meagher, 2004 ; Meagher and Nagoshi, 2012 ; Unbehend
et al., 2014 ). The C strain larvae are more tolerant to pesti-
cides methyl parathion, cypermethrin and Bacillus
thuringiensis ( Bt ) ∂ -endotoxins than the R strain (Adamczyk
et al., 1997 ). Therefore, the con firmation of FAW strain type
(s) invading China is critical for the effective management of
the pest.
FAW management would bene fi t from detailed and com-
prehensive genomic analysis. However, the FAW genomes
from its cell lines or strains are fragmented without anchoring
on chromosomes before the year 2019 (Gouin et al., 2017 ;
Kakumani et al., 2014 ; Nam et al., 2018 , 2019 ; Nandakumar
et al., 2017 ). With the advancement in genome sequencing
and assembly technology, three chromosome-level genome
assemblies of FAW have been published or pre-printed
(Nam et al., 2019 ; Zhang et al., 2019 , 2020 ; Xiao et al.,
2020 ). Nevertheless, only two of them are available to the
public (Xiao et al., 2020 ; Zhang et al., 2020 ). In addition, the
genome sizes of the three assemblies varied dramatically
from 384 to 486 Mb, even considering the sequencing
technologies and potential strain differences. The quality of
the genome assemblies is the foundation of population
genetic analysis; therefore, more accurate FAW genome
assembly and population genomes are urgently needed.
In this study, we comprehensively analyzed the results
from de novo genome sequences, re-sequencing data of
America, Africa, and China populations, as well as tran-
scriptomic pro fi les after pesticide treatments. We assembled
a chromosome-level genome using one male FAW collected
from Yunnan, the fi rst place of the pest occurred in China.
Furong Gui, Tianming Lan, Yue Zhao, and Wei Guo have
contributed equally to this work.
Electronic supplementary material The online version of this
article ( https://doi.org/10.1007/s13238-020-00795-7 ) contains sup-
plementary material, which is available to authorized users.
© The Author(s) 2020
Protein &Cell
RESEARCH ARTICLE Furong Gui et al.
We also analyzed the strain types of the FAW population that
invaded Yunnan, and also discussed the possible origin of
the invaded FAW populations in China. In addition, we
screened expanded gene families in FAW to determine key
genes associated with the function of polyphagia and
resistance to pesticides. The results provide essential infor-
mation for managing FAW invaded in China.
RESULTS
Genome assembly, evaluati on and annotation
A total of 110.93 Gb high-quality single tube long fragment
read (stLFR) sequencing data was generated from a male
individual from Yunnan Province (Table S1 and Fig. 1 A). The
size of the primary genome assembled by the stLFR data is
542.42 Mb, and the scaffold N50 is 507.12 kb. Using the
High-throughput chromosome conformation capture (Hi-C)
technology, the scaffolds were fi nally concatenated to 31
chromosomes, whereby scaffold N50 is 14.16 Mb. Genomes
size assembled in this study fell within the scope of 246 Mb
to 809 Mb of the Lepidopteran species (Triant et al., 2018).
However, the size of the genome reported in the current
study is larger than that of the previously assembled FAW
genomes (Kakumani et al., 2014 ; Gouin et al., 2017 ; Nam
et al., 2018 , 2019 ; Nandakumar et al., 2017; Zhang et al.,
2019 ,2020 ; Xiao et al.,2020 ) (Table 1 ). The extra regions of
0
10
20
0
10
20
0
1 0
0
10
0
10
0
10
0
10
0
10
0
10
0
10
0
10
0
10
0
10
0
10
0
10
0
10
0
10
0
10
0
10
0
10
0
10
0
10
0
10
0
10
0
0
10
123456789
123456789101112131415161718
19 20 21 2223 24252627 2829 3031
10 1112 13 14 15 16 17 181920 2122 23
24
2526
27
28
29
30
31
C
B
A
chr1
chr2
chr3
chr13
chr14
chr15
c hr16
chr17
chr18
chr19
chr20
chr21
chr22
chr23
chr24
chr25
chr26
chr27
chr28
chr29
chr30
chr31
collected in Yunnan used for genome assembly. (B) Genomic characterization of FAW genome, it shows the GC content, gene
number, repeat content, Single NucleotidePolymorphism (SNP)density and chromosomefrom the center tothe edge. (C) Synteny
between FAW and Spodoptera litura genome. The gray lines reveal the genome-wide collinearity, and the red lines reveal the
Cytochrome P450 ( CYP ) gene collinearity.
Genomic and transcriptomic analysis of fall armyworm RESEARCH ARTICLE
© The Author(s) 2020
Protein &Cell
our FAWgenome compared with that published by Xiao
(Xiao et al., 2020 ) are evenly distributed on 31 chromosomes
(Fig. S2). We mapped the raw data(raw reads used for
assembly of our genome and Xiao ’ s genome) to those
regions, and the mapping rates are more than 30%, sug-
gesting the validity of the extra regions. Besides, 1,494
genes were identi fi ed in the extra regions, of which 1,421
genes were expressed gene (average FPKM value of con-
trol>0)(Fig. S3) and 512 genes were differential expression
genes (DEGs) in 23 pesticide treatments (Fig. S4), indicating
the assembled extra regions might be genuine and
functional.
The GC content of FAW genome is 36.52% (Fig. 1B)
which fell within the scope of 31.6% to 37.7% of its closely
related Lepidopteran species, Bicyclus anynana(Nowell
et al., 2017 ). The genome covers 95% for complete BUSCO
genes with duplicated BUSCO components of 9.8%
(Table S2). The quality of these data was largely improved,
because of more information available from other published
FAW genomes (PRJNA380964, PRJNA257248, PRJEB
13110, and PRJNA344686) (Table 1 ), including the recently
published FAW assembled using the Pacbio RSIItechnology
(Xiao et al., 2020 ). The sequencing data generated from
libraries for Hi-C, WGS, RNA-seq were also mapped to the
assembled genome, and all the mapping rates and
sequencing coverage were above 90% (Tables S3 and S4),
indicated that most of the sequencing data can be mapped
back to the genome, and the K-mer analysis showed that the
inferred genome size were various, indicating the possibly
big differences on genome size between different individuals
(Fig. S5 and Table S5). Moreover, the FAW expressed
sequence tags (EST) and transcripts from NCBI were per-
fectly mapped to the genome with>90% and>80% mapping
ratios, respectively (Table S6).
Combining de novo and homology-based search, we
identi fi ed 153 Mb repeat elements, accounting for 28.24% of
the FAW genome (Fig. 1 B). A total of 22,201 genes were
annotated using the repeat-masked genome based on de
novo , RNA-seq and homology-based methods (Tables S7
and S8). The gene set covered 94.2% of complete BUSCO
genes, which presented a more complete gene set than
previously published FAW genome (Table S9). Totally,
93.48% of the identi fi ed genes in the gene set were identi fied
as functional genes (Table S8). The FAW genome estab-
lished in this study revealed a high sequence coverage and
identity with its closely related species, Spodoptera litura
(Fig. 1 C), another important insect pest on vegetable and
horticultural plants.
Comparative genomics revealed the possible genetic
basis of pesticides resistance
Based on the 4,056,205 bp fourfold degenerate synonymous
site (4DTv) sequences across the genomes of FAW and
other seven Lepidopteran species, the phylogenetic analysis
showed that FAW is closely related with S . litura (Fig. 2).
Branch-site likelihood ratio test was performed to identify
positively selected genes (PSGs) based on 20,051 single-
copy orthologous genesof FAW and Bombyx moriabstrac-
ted by syntenic alignment, and a total of 363 PSGs were
identi fi ed, which were enriched in reverse transcriptase
domain (IPR000477), endonuclease/exonuclease/phos-
phatase (IPR005135), zinc fi nger, CCHC-type (IPR001878),
fructose-2,6-bisphosphatase (IPR003094), etc. (Table S10).
Of them, ABCC4 , UGT and ChuaMOX genes were related to
detoxi fi cation function.
Several insect gene families are supposed to be associ-
ated with detoxi fi cation function, including ATP-binding cas-
sette ( ABC ) (Koenig et al., 2015 ), Carboxyl esterase ( CES)
(Satoh and Hosokawa, 2009 ), Cytochrome P450 ( CYP ) (Zhu
et al., 2013 ), Glutathione S-transferase ( GST ) (Hayes and
Pulford, 2008 ), UDP-glucuronosyl transferase ( UGT ) (Bock,
2016 ), Aldehyde Oxidase ( AOX ) (Chang et al.,2010 ),
Chitinase Acidic ( CHIA ) (Downing et al., 2000 ), Epoxide
Hydrolase ( EPHX ) (Iarmarcovai et al., 2008 ), PIF1 5 ′ -to-3 ′
DNA helicase ( PIF ) (Erlandson 2009 ), Patched Domain
Table 1.Comparison of SFynMstLFR and other published Spodoptera frugiperda genome assemblies.
AssemblyASM221328v1SF_CORN_1Sf-RVN WGSASM75363v2SFynMstLFR
BioprojectPRJNA380964 PRJEB13110 PRJNA344686PRJNA257248 –
Assembly approachCanu – CLC NGS CellSOAPdenovosupernovo
Sequencing platformPacBio – Illumina-HiSeq 2500Illumina/454/SOLiDMGISEQ-2000
Number of contigs2,84450,01489,958119,77729,584
Contig N50 (bp)516,06721,39010,1706,27691,970
Number of scaffolds2,39641,56266,31837,23531+21809
Scaffold N50 (bp)601,12752,31712,37953,77914,162,803
Total gap length (bp)890,87011,379,1362,171,00527,684,48637,953,553
Total bases (bp)514,225,903436,269,483391,647,540358,047,567543,659,128
Ungapped bases (bp)513,335,033424,890,347389,476,535330,363,081505,705,575
RESEARCH ARTICLE Furong Gui et al.
© The Author(s) 2020
Protein &Cell
Containing ( PTCHD ) and Protein Tyrosine Phosphatase
( PTP ) (Herraiz et al., 2006 ) gene families. Here, we scanned
all of these genes or gene families to detect expanded
detoxi fi cation-related genes (Fig. 2 and Table S11). A total of
1,256 CYP genes were detected from these eight insect
species, and 425 CYP genes were identi fi ed in the FAW
genome, indicating that they are extremely expanded in
FAW than the other seven Lepidopteran species. The sig-
ni fi cant expansion trend is similar with the published FAW
genome (Xiao et al., 2020 ). Besides, the expanded CYP
genes from FAW shows quite short-time divergence, and
283 genes are speci fi c to FAW (Fig. 3 A, 3C and Table S12).
D. melanogaster
2 n = 8
P. xylostella
2 n = 60
M. sexta
2 n = 56
B.mori
2 n = 56
D. plexippus
2 n = 60
H. armigera
2 n = 62
S. litura
2 n = 62
1cm
S. frugiperda
2 n = 62
ABC
CES
CYP450
GST
UGT
AOX
CHIA
EPHX
PIF
PTCHD
PTP
Gene family
Gene number
0100 200300400
1.4
0.0
0.6
0.6
100 0.1
100
0.1
0.9
0.8
100
0.3
100
100
0.1 0.2
0.2
0.3
0.5
0.4
Figure 2. Phylogenetic relationships among seven lepidopteran and D. melanogaster genomes. Below: the gene family
number of ATP-binding cassette ( ABC ), Carboxylesterase ( CES ), Cytochrome P450 ( CYP ), Glutathione S-transferase ( GST ), UDP-
glucuronosyl transferase ( UGT ), Aldehyde Oxidase ( AOX ), Chitinase Acidic ( CHIA ), Epoxide Hydrolase ( EPHX ), PIF1 5 ′ -to-3 ′DNA
helicase ( PIF ), Patched Domain Containing ( PTCHD ) and protein tyrosine phosphatase ( PTP) genes.
Genomic and transcriptomic analysis of fall armyworm RESEARCH ARTICLE
© The Author(s) 2020
Protein &Cell
According to the DNA sequence identity, the 425 CYPgenes
of FAW were merged into 152 gene clusters (Fig. 3D).
Furthermore, the MEME software veri fi ed the accuracy of
the CYP gene family for the FAW-speci fi c CYP gene set
based on the control CYP genes from B . mori and S . litura.
The conservation of motif and 10 bp fl anking sequences is
shown as a seq-logo plot (Fig. 3 B). From the highlighted seq-
logo plot, the conservation of motifs in the three species
(FAW, B . mori , and S . litura ) displayed a striking variant. The
motif sequence in FAW is more conserved than in the other
two species.
Whole genome resequencing
Variation discovery
To assess the genetic diversity among FAWaccessions, 163
individuals from America ( n = 39), Africa ( n = 24) and China
( n = 100) (Table S20) were mapped totheFAW assembly
(Fig. 4 A). The average mapping rate and sequencing cov-
erage were 95.60% ± 3.34% and 90.41% ± 2.38%, respec-
tively (Table S4). After fi ltration (See “ METHODS ” ), we
identi fi ed 45,569,102 single nucleotide polymorphism
(SNPs) and 11,391,362 short genomic insertions and
B. mori
S. litura
S. frugiperda
B
D
Tree scale: 0.1
Inner colored ranges:
Species
B.mori
D.melanogaster
D.plexippus
H.armigera
M.sexta
P.xylostella
S.frugiperda
S.litura
Outer colored bar:
CYP gene family
mito
CYP2
CYP4
CYP3
Sfr_specific CYP
A
C
Colored histogram:
FPKM value of control
Tree scale: 0.1
DEGs in all 23 pesticides treatments
DEGs in Bttreatment
Tree scale: 0.1
Figure 3.The gene tree of Cytochrome P450 gene family. (A) 1,256 Cytochrome P450 (CYP) genes in 8 species, the label color
shows different species, the bar color shows different CYP gene sub-families. (B) The seq-logo plot of the motif and 10 bp flanking
sequences of CYP genes in 3 species. (C) The 425 CYP genes of FAW, the bar color shows different CYP gene sub-families, 107
differential expression genes (DGEs) between all treatments and control are shown as orange triangle, 37 DGEs between Bt
treatment and control are shown as red star, and the histogram means CYP gene FPKM value of control. (D) The 152 CYP genes
fi ltered by CD-HIT, the bar color shows different CYP gene sub-families.
RESEARCH ARTICLE Furong Gui et al.
© The Author(s) 2020
Protein &Cell
deletions (InDels) (less than 40 bp) with a minor allele fre-
quency (MAF) > 0.01. About 71.71% of the SNPs are located
in the intergenic regions, whereas 3.99% of them are in the
coding sequences. The non-synonymous-to-synonymous
substitution ratio for the SNPs in the coding regions is 0.242,
indicating high quality of the SNP call sets. Moreover,
72.94% of the InDels are located in the intergenic regions,
whereas 0.38% of them in the coding regions. About 68.77%
of the InDels in the coding regions were estimated to cause
frame shift mutations. The SNP density is shown in Figs. 1B
and S6.
African origin of FAW populations in China
The core set of SNPs were used to analyze the phylogeny and
population structure of FAW. Principal component analysis
(PCA) showed substantial genetic diversity among the six
FAWpopulations, PC1, PC2 and PC3 revealing a total genetic
variance of 5.49%, 5.34% and 2.70%, respectively (Fig. 4B).
PC1 separated American FAW from other fi ve accessions,
PC2 evidently separated the four American accessions and
PC3 separated AA accessions from the rest. American pop-
ulations showed relatively large genetic divergence within
populations, compared to Chinese and African populations.
Maximum likelihood (ML) phylogenetic analysis revealed
distinct monophyletic clades for Ethiopia (ET), Kenya (KE),
America (A), South Africa (SA), Guangxi (GX), and Yunnan
(YN) FAW populations (Fig. 4 C). This ML-tree further illus-
trated that the American group could be marginally divided
into subgroups AA and AB-AC-AD (Fig. 4 C). Chinese (YN,
GX) and African (ET, KE, SA) clades displayed close phy-
logenetic relationship (Fig. 4 C). Structure analysis showed
that populations in China and Africa comprise accordant
components (Fig. 4 D and 4E, K = 5). Varying the number of
K (presumed ancestral populations) revealed genetic dis-
tinctions between American and other accessions. When
K = 2, we observed two separate clusters: American (A) and
other accessions, and when K = 3, three separate clusters
were exhibited: AA, AB-AC-AD and other accessions. Sim-
ilar patterns are also supported by the PCA and ML-tree
analyses (Fig. 4 B and 4C), suggesting that Chinese acces-
sions (YN and GX) shared much closer genetic relationships
with African accessions (SA, ET, KE) than that of America
(AA, AB, AC, AD). Taken together, FAW populations in China
(YN, GX) migrated directly from Africa, because the genetic
structure of these populations is highly mixed. Besides, we
estimated admixture graphs of different geographically
de fi ned groups using TreeMix. Extensive gene flow
(45.17%) were found from AB to AC when m = 1 (Fig. S7).
Additional gene fl ow from KE to ET (14.66%) and YN
(15.17%) were also found when setting the parameter m = 2
and m = 3, respectively. These fi ndings proved that Ameri-
can accessions are deep divergent from other accessions,
further supporting that Chinese accessions was derived from
Africa, rather than directly from America.
All the samples were identi fi ed as C strain in FAW
| https://www.researchgate.net/publication/354332543_Genomic_and_transcriptomic_analysis_unveils_population_evolution_and_development_of_pesticide_resistance_in_fall_armyworm_Spodoptera_frugiperda |
Sensors | Free Full-Text | A Bandwidth-Efficient Dissemination Scheme of Non-Safety Information in Urban VANETs
The recent release of standards for vehicular communications will hasten the development of smart cities in the following years. Many applications for vehicular networks, such as blocked road warnings or advertising, will require multi-hop dissemination of information to all vehicles in a region of interest. However, these networks present special features and difficulties that may require special measures. The dissemination of information may cause broadcast storms. Urban scenarios are especially sensitive to broadcast storms because of the high density of vehicles in downtown areas. They also present numerous crossroads and signal blocking due to buildings, which make dissemination more difficult than in open, almost straight interurban roadways. In this article, we discuss several options to avoid the broadcast storm problem while trying to achieve the maximum coverage of the region of interest. Specifically, we evaluate through simulations different ways to detect and take advantage of intersections and a strategy based on store-carry-forward to overcome short disconnections between groups of vehicles. Our conclusions are varied, and we propose two different solutions, depending on the requirements of the application.
A Bandwidth-Efficient Dissemination Scheme of Non-Safety Information in Urban VANETs †
by Estrella Garcia-Lozano , Celeste Campo * , Carlos Garcia-Rubio and Alicia Rodriguez-Carrion
Department of Telematic Engineering, University Carlos III of Madrid, Avda. de la Universidad 30, Leganes, Madrid 28911, Spain
This paper is an extended version of our paper published in Garcia-Lozano, E.; Campo, C.; Garcia-Rubio, C.; Rodriguez-Carrion,A.Adaptingabandwidth-efficientinformationdisseminationschemeforurbanVANETs. In Ubiquitous Computing and Ambient Intelligence. Sensing, Processing, and Using Environmental Information; Garcia-Chamizo, J.M., Fortino, G., Ochoa, S.F., Eds.; Springer International Publishing: Heidelberg, Germany, 2015; pp. 72–83.
Sensors 2016 , 16 (7), 988; https://doi.org/10.3390/s16070988
Received: 28 April 2016 / Revised: 21 June 2016 / Accepted: 22 June 2016 / Published: 27 June 2016
(This article belongs to the Special Issue Selected Papers from UCAmI, IWAAL and AmIHEALTH 2015 )
Abstract
:
The recent release of standards for vehicular communications will hasten the development of smart cities in the following years. Many applications for vehicular networks, such as blocked road warnings or advertising, will require multi-hop dissemination of information to all vehicles in a region of interest. However, these networks present special features and difficulties that may require special measures. The dissemination of information may cause broadcast storms. Urban scenarios are especially sensitive to broadcast storms because of the high density of vehicles in downtown areas. They also present numerous crossroads and signal blocking due to buildings, which make dissemination more difficult than in open, almost straight interurban roadways. In this article, we discuss several options to avoid the broadcast storm problem while trying to achieve the maximum coverage of the region of interest. Specifically, we evaluate through simulations different ways to detect and take advantage of intersections and a strategy based on store-carry-forward to overcome short disconnections between groups of vehicles. Our conclusions are varied, and we propose two different solutions, depending on the requirements of the application.
Keywords:
VANETs
;
dissemination
;
urban scenarios
;
broadcast suppression scheme
;
With the aim of avoiding collisions and saving lives, the USA government started a series of actions to standardize and deploy a short-range communications system for vehicles. Other powers, like the European Union (EU) and Japan, have followed and developed their own standards over the last decade. This was the origin of VANETs (vehicular ad hoc networks).
In this type of network, we expect to require the delivery of information (for example, warnings or advertising) to groups of vehicles at more than one hop from the sender. This kind of communication is generally referred to as dissemination of information. In fact, the authors of [
1
] point out that these two communication patterns will be common in VANETs:
Geo-broadcast: The sender wants to immediately inform all of the vehicles in a larger area about a sudden event. For example, a vehicle that suddenly brakes needs to inform coming vehicles about it. Depending on the message, it may be repeated from time to time and have more relaxed time and delivery requirements, like in the case of work zone warning. The forwarding scheme may be optimized to reduce overhead in cases of high node density.
Advanced information dissemination: The goal is to provide information among vehicles in a given area during a certain time, bridging network partitions. In this case, a wide coverage and the persistence during the intended period are more important than a low latency. Thus, this type of communication usually applies store-carry-forward mechanisms, in which a relay node awaits the appearance of new nodes in its communication range, also called neighbors, before forwarding the message one or more times.
We have focused on creating a dissemination scheme that fits both the relaxed geo-broadcast and the advanced information dissemination patterns: it should minimize the overhead in dense traffic situations (large connected network) and reach as many vehicles as possible in sparse traffic (disconnected small networks). Such a scheme could be useful for public service, improved driving and, especially, business/entertainment applications. As an example, it could be used for disseminating warnings about a blocked road or announcements of scenery overlooks in the route or sales in the downtown area.
According to renowned researchers [
2
], we must first distinguish between two types of target scenarios, due to their differences in connectivity patterns: roadways and urban areas. In [
3
], the same authors present a list of challenges that are present in the latter, but not in roadways, that we summarize here:
Direction of the message and determination of the region of interest (ROI). The authors consider that the definition of the ROI depends on the type of application and the vehicles that may be interested in the information. Furthermore, the direction of the message should correspond to the direction of the targets, so defining it may pose a privacy risk.
Changes of vehicle direction. A vehicle may change its current direction at any intersection. This is a problem for choosing nodes for store-carry-forwarding: the selected relay may not go towards the desired direction at some point. The conclusion they reach is that typical mechanisms for roadways are not applicable to this type of scenario.
Multiple points to enter or exit the ROI. As there will be several streets going through the bi-dimensional ROI, vehicles can enter or exit them at different points around the edge. The main implication is that we cannot consider that a dissemination is complete when the message reaches the edge, because it may have covered only a sector of the area of interest.
The coverage of a vehicle depends on its location. The authors point out that vehicles at intersections can connect with vehicles in other streets, while others can only reach vehicles behind or in front of them. They suggest that routing and dissemination protocols should bear in mind this difference in order to take advantage of it.
In addition, they extract two important observations about the special connectivity conditions in urban VANETs from their study. First, the existence of path redundancy is usual: there are multiple ways to connect one vehicle with another. This can help to improve the robustness of routing or dissemination protocols. Second, the broadcast storm and the disconnected network problems are present at the same time. The reason is that vehicles are not evenly distributed in the scenario, forming dense groups disconnected from the others. Urban scenarios are especially sensitive to broadcast storms because of the high density of vehicles in downtown areas. On the other hand, disruptions in propagation caused by buildings and other obstacles accentuate the problem of network partitioning.
Broadcast storms are usually avoided by using broadcast suppression schemes. They consist of a set of rules that prevent some nodes from retransmitting the message. In order to combat network partitioning, a popular type of mechanism is store-carry-forward. One or more vehicles get in charge of keeping a copy of the message and forwarding it after some time (for example, when they encounter other vehicles).
We use both techniques in our search for a dissemination scheme that is useful in urban settings. In this article, we discuss several alternatives that we have considered and present our conclusions about the results achieved. In particular, we develop our work on urban adaptations to the roadway broadcast suppress scheme, which we presented in the original paper. In addition, we design and evaluate different ways to incorporate a specific store-carry-forward mechanism in our solution. We also compare the resulting formula with a protocol from the state of the art, Urban Vehicular Broadcast (UV-CAST). The article is structured as follows: First, in
Section 2
, we present some of the most relevant work to our approach, as well as our solution for roadway environments. In
Section 3
, we discuss the design alternatives and the main parameters that affect their performance. Next, in
Section 4
, we present the metrics that we use, the simulation configuration and the results of the comparative evaluations that we have carried out. Finally, we summarize our conclusions in
Section 5
.
2. Related Work
We divide the contents of this section into two parts. First, we give an overview of the selection of dissemination schemes for urban areas that are relevant to our work. This part concludes with some thoughts about their principal strengths and the mechanisms that they use to achieve them. In the second part, we briefly present our dissemination scheme for roadways, which we use as the base for our version for urban spaces.
2.1. Dissemination Schemes for Urban VANETs
Many authors have been interested in the topic of information dissemination in vehicular ad hoc networks (VANETs), and a compilation of relevant works can be found in [
4
]. There are different techniques that are traditionally used as a base for vehicular multi-hop dissemination. A simple flooding can be used, but it is likely to cause a broadcast storm if the road is heavily populated with vehicles. Most authors use broadcast suppression techniques so that vehicles are able to spread a message through a given area with a lower number of retransmissions. For example, vehicles may construct groupings or clusters a priori with the available information about one-hop neighbors. Then, the pre-selected cluster heads or gateways act as relays when a dissemination occurs. A posteriori techniques usually consist of a contention based on the distance to the previous sender, in order to minimize the number of hops. Others are based on different aspects, entirely probabilistic or a mix of them.
The European Telecommunications Standards Institute (ETSI), who is responsible for developing the Intelligent Transportation Systems (ITS) standards for Europe, has defined GeoNetworkingas the routing protocol intended for ad hoc communications in the 5-GHz band. In particular, we are interested in the GeoBroadcastpacket handling mode; it relies on geo-addressing for a multi-hop dissemination, and it is used for Decentralized Environmental Notification Messages (DENM), i.e., event-triggered updates, among other applications. The forwarding algorithms can be found in the standard specification ETSI EN 302 636-4-1 [
5
], and they are three: the SimpleGeoBroadcastforwarding algorithm with line forwarding, the Contention-based forwarding (CBF) algorithm for GeoBroadcast, and the AdvancedGeoBroadcast forwarding algorithm. They use the notions of distance-based and location-based contentions, in order to arrive at the destination area in the minimum number of hops and with the idea to avoid the broadcast storm inside it, hence improving the reliability and the speed of the dissemination. They do not apply any special technique that takes into consideration the characteristics that are specific to urban environments.
Given the routing challenges typical of urban areas mentioned above, the research community has identified a necessity to create specific solutions for this type of scenario. Now, we present a selection of works in chronological order that consists of tailored schemes (TAF, ABSM and eMDR), adaptations of general schemes that are better suited for roadways (UV-CAST), and holistic solutions (AMB/UMB).
Urban Multihop Broadcast (UMB) is part of a global solution together with Ad Hoc and Multihop Broadcast (AMB) [
6
]. It is a MAC level solution that addresses the broadcast storm, hidden nodes and reliability problems in a multi-hop dissemination of messages. It is made up of two phases: directional broadcast and intersection broadcast. Depending on the presence of infrastructure to manage junctions, the intersection broadcast is done by applying AMB (in the absence of it) or UMB (when there is a managing device). UMB is supposed to be used in urban areas because the authors expect that they will be supplied with assisting infrastructure first. The devices located at intersections are responsible for initiating a dissemination branch per every possible direction (except the one that is already covered).
Urban Vehicular Broadcast (UV-CAST) [ 3 ] is a version of Distributed Vehicular Broadcast (DV-CAST) [ 7 ] adapted to urban environments. It is intended to work in either well-connected or disconnected vehicular networks without help from fixed infrastructure. Depending on the received beacons, a vehicle can determine if it is inside a connected region or not. If it is, it will act according to the well-connected regime, applying a broadcast suppression scheme. Otherwise, be it a boundary node or a totally disconnected node, it will enter the disconnected regime and store-carry-forward the message.
Two Angles Forwarding (TAF), along with two other variations [
8
], intend to disseminate information in an urban area while meeting the following goals: to be beacon-less, to depend just on the current position and not to make use of any infrastructure. The three algorithms rely on a distance-based contention and on the Triangle Forwarding Rule. This rule is based on the idea that when a vehicle receives the same message from two different neighbors, they form a triangle. By calculating the corresponding angles, a vehicle is able to estimate if it is in a different street than the latest relay. In that case, it becomes a candidate for relay, as well, as it would help the dissemination in a different direction.
In [
9
], we find Acknowledged Broadcast from Static to Highly Mobile (ABSM), an adaptation of the Parameterless Broadcast in Static to Highly mobile Ad hoc Networks (PBSM) protocol. It is based on the formation of connected dominating sets (CDS) as in PBSM. Vehicles use the beacons from one-hop neighbors to decide whether they belong to a CDS or not. Vehicles at intersections (among others) happen to be in CDSs. These beacons also contain the identifiers of the last received messages, as implied acknowledgments. With the information from beacons and the CDS, every vehicle can construct two lists: neighbors that must have received the message and neighbors that must have not. Then, it forwards the message if the latter is not empty. During the message lifetime, new vehicles that do not acknowledge its reception in their beacons may appear. They are put in the list of ignorant neighbors, and the vehicle will forward again, until the list becomes empty again. This constitutes an implicit store-carry-forward mechanism. This is another totally distributed approach, and the way it solves the problem is similar to UV-CAST.
The goal for the authors of Enhanced Message Dissemination Based on Roadmaps (eMDR) [
10
] is to reduce the latency. They work on this objective by making vehicles at intersections become relays. This is achieved with the support of GPS and digital roadmaps. A vehicle forwards any new message if its distance to the previous relay is above a threshold or if it is in a different street. This last condition is also true if it is in the same street, but located at an intersection. The vehicle that is closest to the center of the intersection forwards first, inhibiting the rest. The source of the warning emits it periodically, changing the sequence number (that identifies each dissemination). The authors claim that this makes store-carry-forward unnecessary.
A summary of the presented works is in
Table 1
. There, we can see that the focus is generally set on the efficiency. This is due to the high density of vehicles in cities, together with usually lower speeds. Because of this, most solutions use a distance-based contention or clustering, to select as few relays as possible. There are other works that have their focus on a fast dissemination. These use location-based solutions and binary thresholds in order to take advantage of junctions and to avoid a time-consuming contention. A good portion of them also considers some kind of acknowledgment in order to improve the reliability.
Inside urban areas, buildings are the main problem. The selection of works explained in this section uses different methods for detecting junctions or other streets: digital maps, reception angles and the relative location of neighbors.
There is a discussion regarding disconnected areas that result from buildings blocking the dissemination. Some authors propose using mechanisms to overcome disconnections, while others argue that it should be the source who repeats its message periodically.
Finally, cities are expected to have some infrastructure deployed in them over time. Therefore, dissemination solutions are still capable of working without the aid of any fixed device, but some consider this possibility, as well.
2.2. Our Dissemination Scheme for Roadways
We presented in [
11
] a dissemination scheme that is valid for roadways. Its broadcast suppression algorithm relies on a distance-based contention. Whenever a vehicle hears a new message, it waits a short time,
W
, for an almost simultaneous duplicate of the same message. The distance to the closest vehicle from which it received the same message is stored as
d
m
i
n
. Then, it assigns itself a forwarding priority based on this distance. This priority is given by the amount of time it waits before forwarding,
t
w
, described by Equation (
1
):
t
w
=
T
m
a
x
×
(
1
-
d
m
i
n
/
r
)
(1)
Here,
r
is the communication range and
is the maximum per-hop delay. The latter is a very important parameter, because it affects the latency of the scheme and it helps to prevent several vehicles from trying to forward almost at the same time. In addition, it has to be small enough to consider the scenario as almost static during the contention. The same value should work properly in very different traffic situations.
This equation lets the vehicle that is furthest from the last relay to forward first. This way, the number of hops (and hence, the number of retransmissions) is minimized.
A vehicle may hear a duplicate of the same message before the wait times out. We assume that messages include a time to live (TTL) field, so any duplicate with a lower value than what the vehicle observed in the first reception indicates that the message is old. Hence, the vehicle aborts the contention. If the duplicate comes in the opposite direction of the first message, that means that another vehicle’s timer expired sooner and got to forward first. In such a case, this vehicle does not have to forward the message. If it comes from a vehicle located over the previous relay, it is ignored because it belongs to the dissemination in the opposite direction. If no other duplicates are received, this vehicle is the one who forwards the message.
In addition, this scheme has a store-carry-forward mechanism to handle isolated groups of vehicles. The scheme does not rely on beacons from other vehicles, and this, in turn, is the cause of its main characteristics: First, the way for a relay to determine if another vehicle has taken its role after its retransmission is to hear a new duplicate with a lower TTL. If it does not hear any new duplicate in a time interval of
after it forwarded the message, it concludes that there is not any new relay, and so, it must store the message and try to find one later on.
3. Design of a Scheme for Urban Dissemination
Our starting point is the dissemination scheme that we have just explained in
Section 2.2
. According to our previous research [
11
], it achieves a redundancy level close to the optimum in dense roadway environments. However, given the different nature of urban scenarios, we will try to adapt the broadcast suppression scheme in accordance with their singularities in order to obtain good results. The store-carry-forward scheme will also have to respond to the challenges that we summarized in
Section 1
: the omni-directionality of the message and the difficulty of selecting a suitable relay for carrying, according to [
2
].
We depict a typical situation in a city in Figure 1 to illustrate the case. In this figure, vehicle “src” sends a message that needs to be disseminated. If we apply our roadway scheme, the next relay will be vehicle “B”, because it is the furthest from “src”. However, due to the shadowing effect of buildings, vehicle “C” will not receive the message from “src”, nor from “B”. Vehicle “A” is the only one in the line-of-sight of “C”. Thus, vehicle “A” should be the next relay, so that “C” can also receive the message.
We have broken the problem down into two necessities:
an omni-directional and circular approach in the dissemination, because targets may be moving in any direction around the source and
an effort to reach neighbors that may be hiding around corners.
We propose to tackle both problems by increasing the chances of forwarding at intersections. Therefore, in order to achieve this, a vehicle that receives a new message first tries to determine if it is at an intersection. We are going to explore two different approaches for this. The first one is using a digital map together with their location coordinates. The other one is interpreting the angle between its direction and the imaginary segment that connects it to the sender. We will describe each one thoroughly below.
Then, vehicles located in an intersection take part in a specific time contention, given by a waiting time called
t
j
. The equation that determines its value is related to each of the detection techniques that we are going to use. While vehicles located at intersections use this timer, the others apply the distance-based scheme, waiting
t
w
(see Equation (
1
)). That is, the intersection contention only affects the vehicles in the same intersection. Conversely, a vehicle located at an intersection will ignore any duplicate coming from outside it.
3.1. Broadcast Suppression Mechanism
Basically, the map-based and the angle-based modifications of the base roadway scheme only differ in the method applied to decide if a vehicle or another relay is at a junction.
3.1.1. Map-Based Adaptation for Cities
The first method for detecting junctions that we are considering is the use of a digital map. At the moment of receiving a new packet, a vehicle checks its coordinates to determine if it is at an intersection or not. Given the case, it will use the map again to find out the distance to the junction center,
c
e
n
t
e
r
. It will use this distance to compute a different contention delay, as shown in Equation (
2
):
t
j
=
T
j
×
(
d
c
e
n
t
/
r
j
u
n
c
t
i
o
n
)
(2)
Here,
T
j
is the maximum waiting time for vehicles at junctions and
r
j
u
n
c
o
n
is the radius of the given intersection. This radius can be obtained from the digital map, as well. In this case, we want to prioritize the vehicle that is closest to the intersection center, in order to reach as many other vehicles as possible.
We mentioned above that a vehicle located at an intersection will ignore every duplicate, except if it comes from the same intersection. If it is using the map-based method, it will be easy to check the other’s location and its own in the map and see if they belong to the same intersection.
3.1.2. Angle-Based Adaptation for Cities
As a different alternative, we propose that vehicles pay attention to the angle of the previous sender with respect to their own trajectory. We assume that if it is more or less close to a right angle to either side, the message comes from another street. A problem of urban scenarios is that the signal may bounce of and be redirected by buildings, parked cars, street signs, etc. Therefore, learning the reception angle from the antenna may be misleading. To avoid this, we calculate it based on the other’s reported location and the receiver knowledge of its own trajectory. We will use two threshold angles,
α
m
i
n
and
α
m
a
x
, in order to set a range for the condition evaluation. If the reception angle falls between the two of them, the vehicle is considered to be at an intersection. It cannot determine the distance to the intersection center, unlike in the map-based adaptation, so next, it waits a random amount of time,
t
j
′
, from the distribution in Equation (
3
).
t
j
′
∼
U
(
0
,
T
j
)
(3)
Again, the first vehicle to forward inhibits the rest at the intersection to do the same. When using the angle-based method, it will need to use a generic threshold distance,
d
j
. If the other vehicle is closer than this distance, we assume that it is located at the same intersection.
3.2. Store-Carry-Forward Mechanism
A fact that we must take into account is that we will face frequent disconnections in the vehicular network. The many obstacles that are present in cities artificially break the network, and low traffic densities lead to the same outcome. With the current scheme, the message dissemination stops there.
Depending on the application of the information, this can pose a problem or not. The source may opt to emit the message periodically, and so, vehicles entering the area of interest later on can receive it, as well. In other cases, though, it may be interesting to overcome eventual disconnections. We discuss about how to integrate a store-carry-forward mechanism in our solution for cities in this section.
Being a totally different scenario, we cannot apply our store-carry-forward approach for roadways to an urban scenario. First of all, vehicles’ relative locations are not only behind or in front of another anymore. The message travels omni-directionally, and so do the vehicles. Hence, many of the measures we considered for our scheme for roadways [ 11 ] cannot be applied here. However, there are two design principles from the roadway approach that we intend to include in this design, that we proceed to explain.
3.2.1. Acknowledging and Taking over as Relay
When a vehicle forwards a message, it may reach new recipients or none at all. If there is any, it will start a new contention, and there will eventually be a retransmission. Otherwise, no one will forward the message again. Therefore, if disconnections cannot be ignored and we need to apply a healing mechanism, silence after a retransmission will be the sign that it did not reach any new node. A relay that does not hear a subsequent retransmission will have to forward again in the future in the hopes of finding new neighbors. This retransmission will happen at some point in the following interval:
(
W
,
W
+
m
a
x
(
t
w
,
t
j
)
]
=
(
W
,
W
+
m
a
x
(
T
m
a
x
,
T
j
)
]
=
(
W
,
W
+
T
m
a
x
]
(4)
After the assessment time for receiving almost simultaneous duplicates,
W
, nearby vehicles will start one of two types of contention, depending on the applied algorithm and their position: a regular distance-based contention (given by
t
w
in Equation (
1
)) or an intersection contention (given by
t
j
in Equation (
2
) or Equation (
3
)). Both of them have a maximum length of
T
m
a
x
and
T
j
, respectively. We want vehicles in intersections to wait, at most, the same as vehicles applying the general distance-based contention equation. Thus,
T
j
must be less than or equal to
T
m
a
x
. Hence, the maximum time a relay will wait for a new one is
W
+
T
m
a
x
.
Conversely, a new duplicate with lower TTL in said interval acts as an implicit acknowledgment of reception and taking over as the relay.
3.2.2. Waiting before Forwarding Again
When we discussed the case of roadways in [
11
], we adopted
two measures
about how much to wait before forwarding for a second time or more:
As we do not use beacons in our scheme, we would not rely on receiving them from vehicles that do not appear in each vehicle’s neighbor database.
The best time to forward again is after the vehicle has moved out of the area that it covered with its first retransmission. In order to suit the speed of not only the relay, which may be slow, but also the nearby vehicles, we opted to use the maximum allowed speed,
v
l
i
m
i
t
. Then, the right time to forward again was every
r
/
v
l
i
m
i
t
, being
r
our communication range.
Measure 1 is still applicable to the urban scenario, as our adapted scheme does not relay on a neighbor database. In regard to Measure 2, we are going to try different approaches to finding the best delay between repeated retransmissions from the same vehicle. We have come up with three different alternatives:
Speed-Adaptive
A possibility is to modify the equation above in order to adapt the interval to the vehicle’s speed:
r
/
v
r
e
l
a
y
(5)
r
is the vehicle’s communication range and
v
r
e
l
a
y
, its current speed. The reasoning is that vehicles in cities halt frequently, due to traffic lights, yieldings, pedestrian crossings or jams. It would not make sense to forward at a fixed interval if the vehicles in that spot are not moving or doing so very slowly. If
v
r
e
l
a
y
is 0 km/h, it must be checked again after a few seconds in order to compute a finite delay.
Fixed Interval
This would be the most similar option to what we included in the mechanism for roadways because the period is fixed. The delay given by Equation ( 5 ) might be too long, as the speed limit in urban areas is significantly lower than in roadways. We are going to test a wide range of values, from short intervals (every 0.5 s) up to the long ones that would result in applying the speed-adaptive method at 5 km/h. This range includes the period used in roadways and the corresponding value to the speed limit in urban areas.
Map Polling
Finally, we can make the retransmissions happen when the relay is passing through an intersection. This could help the message spread in other directions than the forwarding vehicle’s. Our way to implement this will be via a “map polling”: the vehicle checks its coordinates in the digital map at a fixed interval. If at the time, it is in an intersection, it forwards. Otherwise, it waits for the next check. This will let us test if we can avoid forwarding at every junction (that will surely happen with a low frequency) or not (by using a short period).
The reasoning for the speed-adaptive approach brings the case for a third measure : not forwarding if the vehicle has not moved since the last retransmission. If the vehicle has remained stopped, probably the vehicles around it are still the same, and the retransmission would be useless.
4. Parameter Tuning and Evaluation through Simulations
In this section, we use realistic simulations for four different goals. First, we perform sweeps on the values for the configuration parameters of the proposed broadcast suppression algorithms. We will use two different city maps so that we can choose the most convenient values for almost any scenario. Second, we will be able to compare the performance of each alternative in its best configuration, in order to choose the final form of our dissemination scheme for urban environments. Third, we want to compare the three different alternatives for store-carry-forwarding and see how much they improve the performance of the scheme. Lastly, we simulate UV-CAST in the same conditions in order to find out how our solution compares to a well-known protocol that has been selected for many other comparisons in the state of the art.
Now, we are going to present the metrics that we will be measuring to compare the results of each algorithm. Next, we detail the configuration details of our simulations, so that they could be replicated. Finally, we present and comment on the results.
4.1. Metrics
We can group the metrics we use in this study into three categories: success, overhead and latency.
Success
: The final goal of a multi-hop broadcast is to reach as many nodes as possible in a given area. We define the success with two different metrics. The
long-reach success
is the proportion of cases where the dissemination goes further than the second hop, i.e., the message leaves the source area. It is normalized to that of simple flooding in the same situation. The other metric is the
coverage
, or the number of vehicles that received the message in the long-reach cases.
Overhead
: A high overhead is undesirable, as it occupies the limited shared bandwidth with useless data. It can be measured with the
redundancy ratio
, which we define as the ratio of vehicles that act as relays from the total number of receivers. Another metric that echoes the overhead is the
number of lost packets
, as congestion leads to this effect.
Latency
: The third performance indicator is the latency of the scheme. We may use the per-hop delay or the end-to-end delay. The
per-hop delay
accounts for distance-based and MAC contention and for propagation time. The
end-to-end delay
is averaged over all of the receivers, be they one or several hops away from the source.
4.2. Simulations Configuration
As in our preliminary studies [ 12 , 13 ], we have used Veins [ 14 ] as our simulation framework because it offers the possibility of importing real maps through OpenStreetMap [ 15 ], realistic movements thanks to SUMO [ 16 ], an implementation of 802.11p for OMNeT++ [ 17 ] and the Simple Obstacle Shadowing [ 18 ] propagation model for building shadowing. We have also used VACaMobil [ 19 ] in order to maintain a constant traffic density throughout every run of the simulations. The traffic densities go in the range from 25 to 100 vehicles per square kilometer.
As discussed in [ 3 , 10 ], the results can be quite different depending on the urban scenario in which the dissemination happens. We have used two different areas of 2 km × 2 km, shown in Figure 2 . The Manhattan, New York, map is almost a grid, while the area around Castellana Street in Madrid is more irregular.
After running the simulations, we could appreciate a clear difference in absolute values, which confirms what the mentioned works had already found out: different scenarios yield different results. However, we could also see that the tendency of the curves and the inflection points were always the same for both scenarios. We have already discussed this finding previously in [ 12 ]. Therefore, we can extrapolate conclusions from one scenario that will be valid for the rest. Therefore, for the sake of brevity, we only show the results of the New York scenario in this article.
The origin of the message is a fixed unit in the center of the scenario. The preset radius of interest (the ROI) is 1 km. Finally, we have configured the network parameters according to typical values described in [ 20 ]. The specific overall configuration is listed in Table 2 .
4.3. Results
4.3.1. Parameters for Broadcast Suppression
According to the descriptions in
Section 3.1
, there are three key parameters:
T
m
a
x
,
T
j
and
Δ
α
.
T
m
a
x
is the maximum per-hop delay for a vehicle that is not located at a junction. This parameter is important because it helps to prevent situations in which several vehicles try to forward almost simultaneously. In addition, it has to be small enough to consider the scenario almost static during the contention. The same value should work properly in very different traffic situations. Furthermore, it directly affects the latency of the scheme.
T
j
is the maximum wait for vehicles at junctions. It must be less than or equal to
T
m
a
x
, and it affects the performance in a similar way.
Δ
α
is the difference between
α
m
a
x
and
α
m
i
n
. It defines what is considered a junction, given that a vehicle determines its position at one by comparing the reception angle with these two thresholds. As explained above, the reception angle is calculated by using the relay’s reported location and the receiver knowledge of its own trajectory.
From the descriptions above, the reader can note that the base roadway scheme only depends on
T
m
a
x
; the map-based scheme depends on
T
m
a
x
and
T
j
; and the angle-based scheme depends on the three parameters. Hence, to isolate their effects, the first step will be to tune
T
m
a
x
with simulations of the roadway scheme. Then, we will fix the resulting value for the map-based scheme to find out
T
j
. Last, we will configure the angle-based scheme with those values and make a sweep of
Δ
α
.
It did not make sense to try to adjust
d
j
by simulations because it is highly dependent on the given city, and we would only overfit it to our scenario. Instead, we have studied the widest diagonal at junctions from a set of four different city maps: New York (USA), Madrid (Spain), Rome (Italy) and Cologne (Germany), available via OpenStreetMap. The results are shown in
Table 3
. The median, the most usual value, was, respectively, 9.89 m, 9.24 m, 9.64 m and 9.61 m. Accordingly, we have set
d
j
=
10
m.
The results of the simulations to find the best
T
m
a
x
using the base roadway scheme are shown in
Figure 3
. We show the 95% confidence interval together with the values represented in these graphs and the rest that follow.
The first thing we notice is that the long-reach success (
Figure 3
a) and the coverage (
Figure 3
b) remain constant for every traffic density considered in our study. Apart from that, we can see that the redundancy ratio in
Figure 3
c descends when the maximum wait is longer. The reason is that, when the wait is short, there is a high probability that several vehicles will pass the message to the MAC layer almost simultaneously. This leads to the high number of lost packets that we see in
Figure 3
d for values of
T
m
a
x
under 350 ms. Regarding the average per-hop delay (
Figure 3
e) and the end-to-end delay (
Figure 3
f), they are proportional to
T
m
a
x
, as expected. Given that this parameter does not affect the success, we search for a good trade-off between overhead and latency. The former is improved when the value is greater than or equal to 350 ms, while the latency worsens as the value gets higher. Therefore, we choose
T
m
a
x
=
350
ms. This is a rather large value when compared to our chosen value for the roadway scenario,
T
m
a
x
=
18
ms. The reason is that the broadcast storm problem is very pronounced in urban areas, as pointed out in [
2
]. Apart from the higher traffic density, there are multiple paths that connect the source of the message to any vehicle that is in the same connected network. The access to the channel is more difficult, especially if we face collisions due to several relays forwarding at the same time.
We use the value we found above,
T
m
a
x
=
350
ms, in the map-based variant to study the effect of
T
j
alone. This parameter is the maximum wait for vehicles at junctions. We want vehicles at intersections to wait, at most, the same as vehicles applying the general distance-based contention equation. Thus, it must be less than or equal to
T
m
a
x
. In order to better understand the simulated points, the
x
-axis of the graphs in
Figure 4
represents the relation between
T
j
and
T
m
a
x
instead of absolute values. There, we can see that the success, be it in terms of long reach (
Figure 4
a) or delivery ratio (
Figure 4
b), is not related to this waiting time either. We also find a very limited effect in the redundancy ratio from
Figure 4
c. The slight rise is caused by vehicles at a junction that are also the furthest from the previous relay. They wait so much that another vehicle forwards first, though it does not inhibit them. It is almost balanced out by the slightly higher number of vehicles that forward from junctions (
Figure 4
d) when their wait is shorter. Again, a very short maximum delay has the same problems of redundancy and losses as
T
m
a
x
did, and that we can see in
Figure 4
e. The average per-hop delay, shown in
Figure 4
f, is clearly influenced by the vehicles that have to wait less because they are at intersections. However, this effect is hidden in the average end-to-end delay, as we can appreciate in
Figure 4
g. Following a similar reasoning to that for
a
x
, we find that
T
j
/
T
m
a
x
=
0.6
is the best compromise between losses and delay. This corresponds to
T
j
=
210
ms.
Now, we set to find out the angle thresholds,
α
m
and
α
m
a
x
. They will let us determine if a vehicle is receiving a message from a different street, by comparing the reception angle with these two thresholds. The reception angle is calculated by using the relay’s reported location and the receiver knowledge of its own trajectory. We define
Δ
α
as the difference between
α
m
a
x
and
α
m
i
n
.
We can observe the effect of this parameter in
Figure 5
. When
α
is a flat angle to either side, every reception angle indicates that the vehicle is at an intersection. Hence, all of the retransmissions are assumed to be done from intersections, because every vehicle believes it is at one. Additionally, when
Δ
α
is 0 °, no one considers itself inside a junction, so none of the retransmissions is done from one.
Δ
α
does not affect the success of the scheme, as we can see in the graphs that represent the long-reach success (
Figure 5
a) and the delivery ratio (
Figure 5
b). However, it does have a strong impact on the forwarding ratio, as shown in
Figure 5
c. When the parameter’s value is a wide angle, many vehicles consider themselves inside a junction. We can see this in
Figure 5
d. Because of this, the number of retransmissions grows significantly. This leads to many lost packets, as seen in
Figure 5
e, especially for values bigger than 60. Regarding the latency, we see quite flat curves for the average per-hop (
Figure 5
f) and end-to-end (
Figure 5
g) delays. The reduction in latency that we could expect when most vehicles have a shorter waiting time is compensated with the long MAC contentions. All in all, given the high packet loss and latency with wide angles, we limit this parameter to
α
=
60
.
4.3.2. Comparative Evaluation of the Broadcast Suppression Schemes
In this section, we compare the base roadway scheme and the two urban variants with their chosen configuration. For reference, we have included the simulation results of a simple flooding scheme with a random jitter before forwarding.
The flooding scheme is configured so that when a vehicle receives a new message, it selects a random delay from a uniform distribution. We have selected the maximum value of the delay distribution so that the mean would approximately match the average per-hop delay of the other schemes in the comparison. This way, the dissemination through the whole ROI takes a similar time for all of them. This is important because, as time passes by, vehicles will be entering the ROI (becoming new targets) or leaving it (becoming unreachable). By keeping the end-to-end delays comparable, the number of reachable targets is consistent, as well.
Again, the traffic densities go in the range from 25 to 100 vehicles per square kilometer. The origin of the message is a fixed unit in the center of the scenario, and the preset radius of the ROI is 1 km.
The simulation results can be seen in Figure 6 . The long-reach success of each one, normalized to that achieved by simple flooding, is shown in Figure 6 a. The three studied schemes are close to the flooding, being the two urban adaptations the ones with the highest ratios. We see similar results for the delivery ratio ( Figure 6 b).
In return for the higher coverage, the urban schemes require more duplicates. This can be noticed in the forwarding ratio in
Figure 6
c, as well as in the number of lost packets in
Figure 6
e. As the forwarding ratio tends to one, like in simple flooding, the rising number of duplicates causes a more severe broadcast storm and a higher number of losses. We can see that the angle-based scheme is the worst in this sense, with high ratios of forwarders per receiver even in high densities. We can see in
Figure 6
d that this is due to the greater number of vehicles forwarding from junctions. An important factor for this is the definition of intersection in each urban scheme. In the angle-based scheme, a vehicle may be physically close to a junction rather than in it, but it will consider itself inside it, whilst the map-based scheme will not allow this. In addition, a map does not account for sidewalks and other open spaces that let the signal travel. Another factor is the distance threshold used in the angle-based scheme to decide if a neighboring relay is in the same intersection as a waiting vehicle. In wide junctions like a big roundabout, it may be too short, letting two or more vehicles in the same intersection forward the message.
Lastly, Figure 6 f,g shows the latency of the schemes. Together with the average value, we show the maximum end-to-end delay. Due to the shorter wait for vehicles at intersections, the two urban schemes have a slightly shorter average per-hop delay, though this effect is softened in the average end-to-end delay.
In general, our conclusion is that the adaptations for urban environments improve the success in the dissemination with regard to the roadway scheme, though the latter also offers reasonably good results and with a lower redundancy. Between the two adapted schemes, the angle-based variation achieves a slightly higher coverage than the map-based one at the cost of a relevant overhead. Hence, we think that the map-based option offers a good compromise between gains and losses and that any of the roadway or the map-based schemes would be a good choice for the urban environment.
4.3.3. Comparative Evaluation of the Store-Carry-Forward Strategies
Given that store-carry-forward achieves a higher coverage over time by increasing the number of duplicates, we show the evolution of the performance along the first 450 s since the source emits the message. We use the X axis to represent the time after the emission, and we have chosen four instants to measure each metric: after 1 s, 5 s, 250 s and 450 s. The first milestone corresponds to the first moments of the dissemination, before store-carry-forward can be applied. The next three show the evolution until all of the vehicles that were in the scenario at the beginning of the dissemination have left it.
In this lapse, vehicles keep entering and leaving the scenario (though the density is kept constant thanks to the VACaMobil extension). At each milestone, we need to take into account the activity of the vehicles that have been in the scenario up until that point. The graphs that show the performance results in the following sections reflect this facet.
Speed-Adaptive Approach
Figure 7 , Figure 8 and Figure 9 contain the simulation results when using Equation ( 5 ) in Section 3.2.2 to compute the interval between subsequent retransmissions. In this case, we have included the results of applying the store-carry-forward mechanism to the map-based urban scheme, as well. It is worth noticing that the results of the roadway distance-based and map-based adapted schemes are practically the same in the long run. We have cut down on the number of graphs for brevity, but this aspect is also true for the fixed interval and the map polling strategies.
In
Figure 7
, we can see the delivery ratio along with the portion of vehicles that acted as relays, as well as how many of them applied store-carry-forward.
Figure 7
a,b correspond to a low traffic density, and thus, they show a higher proportion of relays than what we see in
Figure 7
c,d. We observe that the portion of relays applying store-carry-forward is 0% until after 5 s since the beginning of the dissemination. The reason is that the speed-adaptive period is larger than that. Given our configured communication range, vehicles should be traveling at more than 167 km/h in order to compute a shorter delay. The absolute portion of relays that apply store-carry-forward after 450 s is slightly higher in the scenarios with 100 vehicles/km
2
. This is, in fact, relatively much lower than in the sparse traffic situations. We could expect this effect, given that large gaps are more prone to occur in the latter.
In Figure 8 , we can see the average number of duplicates that were necessary for the dissemination of a single message, together with how many of them were the second or more retransmission from the same relay. As we could already appreciate in the previous set of graphs, the proportion of messages due to store-carry-forward is reduced. The number of messages shows a predictable rise in time as new vehicles enter the ROI and become targets and relays.
Finally, we see the general efficiency at a glance in Figure 9 . The ratio of duplicates by receivers goes up slowly, and the number of retransmissions does not reach the accumulated number of targets after 450 s. We will be able to put this information in context when we compare this approach with the other two.
Fixed Interval Approach
In Figure 10 , Figure 11 and Figure 12 , we show the simulation results of applying store-carry-forward to the roadway dissemination scheme with this approach. From all of the tested values, we have selected for representation the three smaller ones (every 0.5, 5 and 10 s).
First, we can see that the aspects we have discussed about the speed-adaptive interval are present in these results, as well. Therefore, we proceed to evaluate how the configured interval length affects the performance.
If we look at Figure 10 , we can see that changing the actual configured value does not have a significant impact on the delivery ratio. However, the number of duplicates observed in Figure 11 is clearly higher when the retransmissions due to store-carry-forward are more frequent. All this leads to the higher ratios of retransmissions per reached vehicle that we can see in Figure 10 a,b when compared to the other two.
Map Polling Approach
We can see the simulation results for this strategy in Figure 13 , Figure 14 and Figure 15 . The number of reached vehicles, as seen in Figure 13 , is slightly lower when the polling period is longer. This is due to the consequent reduction in retransmissions, which we can verify in Figure 14 . Additionally, we can see that the highest polling frequency causes a higher proportion of duplicates caused by store-carry-forwarding, up to a half of the duplicates. This contrasts with the results of the other two considered values, which are in the line of the two previous options. This is very clearly seen in Figure 15 , where the line for a 0.5-s period rapidly rises above one retransmission per receiver, while the other two remain below during the first 450 s.
Comprehensive Comparison
We focus especially on the graphs in Figure 9 , Figure 12 and Figure 15 , so that we can compare the results from each approach easily. They offer a summary of the performance, as they relate the number of reached vehicles with the total number of duplicates.
First, we have confirmed that, the lower the density, the worse the overhead. Store-carry-forwarding is needed more often, and hence, the number of duplicates increases. However, we have seen that the number of receivers still does not reach the same value as in a higher traffic density.
The speed-adaptive strategy shows a good performance, keeping the ratio under one duplicate per receiver during the 450 s of the experiments. Map polling also offers very good results, as long as the interval is long enough. Checking the map every 5 s yields approximately the same outcome as the speed-adaptive approach. Doing the check every 10 s improves it slightly because the compromise between the number of reached nodes and duplicates is more balanced. The fixed interval strategy, configured with a 10-s retransmission period, also shows very similar results. However, increasing the period for any of these two strategies would not imply better results. The store-carry-forward mechanism would cause less retransmissions at the cost of reaching fewer vehicles.
Regarding the other metrics, the fixed interval approach achieves a higher coverage at the cost of a large number of duplicates, as it almost doubles the speed-adaptive overhead. The map polling option, on the other hand, caused a slightly lower number of messages than the speed-adaptive one, but its coverage was also slightly lower. Therefore, we choose the speed-adaptive strategy, as it is the approach that achieves the best compromise on the different metrics.
4.3.4. Comparison with UV-CAST
We compare the roadway scheme and the map-based urban scheme, together with the store-carry-forward mechanism for cities, with a well-known work from the state of the art, UV-CAST [
3
]. It is a version of DV-CAST [
7
] adapted to urban environments. It is intended to work in either well-connected or disconnected vehicular networks without help from fixed infrastructure. From the received beacons, a vehicle can determine if it is inside a connected region or not according to the angles to all of its neighbors. If it is, it will act according to the well-connected regime, applying a broadcast suppression scheme. It consists of a distance-based contention to forward the message first. The waiting time for vehicle
i
,
τ
i
, is calculated using Equation (
6
):
τ
i
=
1
2
1
-
d
i
,
j
R
τ
m
a
x
if
i
is
at
an
intersection
1
2
2
-
d
i
,
j
R
τ
m
a
x
if
i
otherwise
(6)
where
d
i
,
j
is the distance from the relay, vehicle
j
,
R
is the maximum transmission range and
τ
m
a
x
is the maximum waiting time. It follows that vehicles that are located at intersections wait half of the maximum wait at most. The authors do not clarify how the vehicle gets knowledge about intersections, but we could assume it gets the information from a digital map. At the end of the wait, if it did not receive any new duplicate, it forwards the message and inhibits the rest. Then, all of the participants become idle again.
If it is a boundary node or a totally disconnected node, it will enter the disconnected regime and store-carry-forward the message. Whenever it receives a new beacon, it forwards the stored message. This is repeated until it exits the area of interest associated with the message.
In the evaluation by the authors, its parameter
τ
m
a
x
=
500
ms. We modify it to
τ
m
a
x
=
350
ms, to match our
T
m
a
x
value.
The graphs in Figure 16 , Figure 17 and Figure 18 show the performance results of our simulations. According to the graphs showing the involved vehicles ( Figure 16 a,b), we can see that UV-CAST reaches a low number of vehicles in the first stage of the dissemination. However, it achieves an almost total coverage in the long run, even in low traffic densities. Our solutions, on the other hand, get to a higher number of vehicles in the first few seconds, especially in high densities, but the increase over time is limited. The cause of UV-CAST’s high coverage is its overhead, as we can verify in Figure 17 a,b. We can see that the vast majority of duplicates when using UV-CAST are due to its store-carry-forward mechanism. This is what lets the protocol reach such a high number of targets.
Finally, the ratio graphs in Figure 18 a,b summarize what we have just observed. Our alternatives’ ratios grow together and slowly towards the one duplicate per receiver reference. UV-CAST, for its part, starts with a low ratio, which justifies the low coverage in the early dissemination stage, and rises fast to several duplicates per receiver. It is significant that it causes relatively more overhead as the density is higher, as opposed to our schemes.
5. Conclusions
In this article, we have explored how to adapt our distance-based dissemination scheme for roadways to the special characteristics of the urban environment. Our intuition was to add some mechanism that would let vehicles detect when they are passing through an intersection and increase their chance to forward if so. This way, we would increase the chances of the message to be disseminated in other directions and reach more vehicles.
In order to do this, we compared it with two different approaches. One of them is checking the location coordinates in a digital map when a new message arrives. The other is finding out if the reception angle is more or less close to a straight angle or not. Vehicles that estimate that they are in an intersection take part in a different time contention to gain precedence. We have tested the three algorithms thoroughly via simulations.
Our conclusions are varied. First, we have found the most suitable values for the maximum per-hop waiting time, the maximum junction-specific waiting time and the threshold angles. Furthermore, we have discovered that the angle-based approach detects intersections very well and incurs a high overhead due to the intensive forwarding at corners. Finally, we have learned that the adaptation to urban scenarios does not achieve a significantly better performance than the roadway scheme. They do reach more vehicles, but the number of necessary duplicates is also higher.
We still had to try adding a store-carry-forward mechanism for cities, so that we could weigh the extra coverage achieved by the urban scheme. We have created a custom store-carry-forward following the same principles that guided us for the roadway version [ 11 ]: We use the reception of a new duplicate with a different TTL as an implicit acknowledgment of reception and taking over as relay. We base the delay before retransmitting for a second time or more on a timer instead of an event. Finally, vehicles must skip forwarding if they are halted.
The timer for retransmissions could be set in different ways, and we have considered three: with a fixed interval, based on the current vehicle’s speed and by polling the position of the vehicle in a digital map to check if it is at an intersection. Again, we have tested the different options via simulations. The performance results we have obtained show that the map-polling and the speed-adaptive approaches are good candidates, though the latter offers a better compromise on coverage and overhead. In addition, we have observed that, no matter the initial coverage of the scheme, in the long run, it gets to the same point in coverage and overhead, depending only on the approach for the retransmissions timer. When compared to UV-CAST, we see that we achieve a better coverage in the first stages with either of the two options, but UV-CAST gets an almost total coverage later, thanks to the high amount of duplicates its store-carry-forward mechanism issues.
Therefore, our final conclusion is that we can apply two different schemes depending on the requirements of the application. If the source will repeat the message periodically, then using store-carry-forward does not make sense, and the map-based urban adaptation should be applied. Otherwise, it is a good idea to use the roadway scheme with the addition of the store-carry-forward for cities.
Acknowledgments
This work was partially founded by the Spanish Ministry of Science and Innovation within the framework of projects TEC2010-20572-C02-01 “CONSEQUENCE” and TEC2014-54335-C4-2-R “INRISCO” and by the Regional Government of Madrid within the “eMadrid” project under Grants S2009/TIC-1650 and S2013/ICE-2715, including the costs to publish in open access.
Author Contributions
This article is the product of joined efforts. All the authors contributed to the conception, design and performance of the experiments, the analysis of the data and the writing of the paper.
Conflicts of Interest
The authors declare no conflict of interest. The founding sponsors had no role in the design of the study; in the collection, analyses or interpretation of data; in the writing of the manuscript; nor in the decision to publish the results.
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Figure 1. The shadowing problem in urban environments.
Figure 1. The shadowing problem in urban environments.
Figure 2. Simulation scenarios for the urban environment.
Figure 2. Simulation scenarios for the urban environment.
Figure 3. Simulation results of the base roadway scheme with different T max values in the New York scenario: ( a ) long-reach success rate; ( b ) delivery ratio; ( c ) forwarding ratio; ( d ) number of lost packets; ( e ) average per-hop delay; ( f ) average end-to-end delay.
Figure 3. Simulation results of the base roadway scheme with different T max values in the New York scenario: ( a ) long-reach success rate; ( b ) delivery ratio; ( c ) forwarding ratio; ( d ) number of lost packets; ( e ) average per-hop delay; ( f ) average end-to-end delay.
Figure 4. Results of the map-based scheme with fixed T max and different T j values in the New York scenario: ( a ) long-reach success rate; ( b ) delivery ratio; ( c ) forwarding ratio; ( d ) portion of relays from junctions; ( e ) number of lost packets; ( f ) average per-hop delay; ( g ) average end-to-end delay.
Figure 4. Results of the map-based scheme with fixed T max and different T j values in the New York scenario: ( a ) long-reach success rate; ( b ) delivery ratio; ( c ) forwarding ratio; ( d ) portion of relays from junctions; ( e ) number of lost packets; ( f ) average per-hop delay; ( g ) average end-to-end delay.
Figure 5. Results of the angle-based scheme with fixed T max and T j , and varying Δ α in the New York scenario: ( a ) long-reach success rate; ( b ) delivery ratio; ( c ) forwarding ratio; ( d ) portion of relays from junctions; ( e ) number of lost packets; ( f ) average per-hop delay; ( g ) average end-to-end delay.
Figure 5. Results of the angle-based scheme with fixed T max and T j , and varying Δ α in the New York scenario: ( a ) long-reach success rate; ( b ) delivery ratio; ( c ) forwarding ratio; ( d ) portion of relays from junctions; ( e ) number of lost packets; ( f ) average per-hop delay; ( g ) average end-to-end delay.
Figure 6. Comparison of the different schemes with the final values in the New York scenario: ( a ) long-reach success rate, normalized to the simple flooding’s rate. ( b ) delivery ratio; ( c ) forwarding ratio; ( d ) portion of relays from junctions; ( e ) number of lost packets; ( f ) average per-hop delay; ( g ) average and maximum end-to-end delay.
Figure 6. Comparison of the different schemes with the final values in the New York scenario: ( a ) long-reach success rate, normalized to the simple flooding’s rate. ( b ) delivery ratio; ( c ) forwarding ratio; ( d ) portion of relays from junctions; ( e ) number of lost packets; ( f ) average per-hop delay; ( g ) average and maximum end-to-end delay.
Figure 7. Involved vehicles with the speed-adaptive approach for store-carry-forward in the New York scenario: ( a ) roadway scheme, 25 vehicles/km 2 ; ( b ) map-based scheme, 25 vehicles/km 2 ; ( c ) roadway scheme, 100 vehicles/km 2 ; ( d ) map-based scheme, 100 vehicles/km 2 .
Figure 7. Involved vehicles with the speed-adaptive approach for store-carry-forward in the New York scenario: ( a ) roadway scheme, 25 vehicles/km 2 ; ( b ) map-based scheme, 25 vehicles/km 2 ; ( c ) roadway scheme, 100 vehicles/km 2 ; ( d ) map-based scheme, 100 vehicles/km 2 .
Figure 8. Sent duplicates with the speed-adaptive approach for store-carry-forward in the New York scenario: ( a ) roadway scheme, 25 vehicles/km 2 ; ( b ) map-based scheme, 25 vehicles/km 2 ; ( c ) roadway scheme, 100 vehicles/km 2 ; ( d ) map-based scheme, 100 vehicles/km 2 .
Figure 8. Sent duplicates with the speed-adaptive approach for store-carry-forward in the New York scenario: ( a ) roadway scheme, 25 vehicles/km 2 ; ( b ) map-based scheme, 25 vehicles/km 2 ; ( c ) roadway scheme, 100 vehicles/km 2 ; ( d ) map-based scheme, 100 vehicles/km 2 .
Figure 9. Forwarding ratio or the relation between sent duplicates and receivers with the speed-adaptive approach for store-carry-forward in the New York scenario: ( a ) roadway scheme. ( b ) map-based scheme.
Figure 9. Forwarding ratio or the relation between sent duplicates and receivers with the speed-adaptive approach for store-carry-forward in the New York scenario: ( a ) roadway scheme. ( b ) map-based scheme.
Figure 10. Involved vehicles with the fixed interval approach for store-carry-forward in the New York scenario: ( a ) roadway scheme, 25 vehicles/km 2 ; ( b ) roadway scheme, 100 vehicles/km 2 .
Figure 10. Involved vehicles with the fixed interval approach for store-carry-forward in the New York scenario: ( a ) roadway scheme, 25 vehicles/km 2 ; ( b ) roadway scheme, 100 vehicles/km 2 .
Figure 11. Sent messages with the fixed interval approach for store-carry-forward in the New York scenario: ( a ) roadway scheme, 25 vehicles/km 2 ; ( b ) roadway scheme, 100 vehicles/km 2 .
Figure 11. Sent messages with the fixed interval approach for store-carry-forward in the New York scenario: ( a ) roadway scheme, 25 vehicles/km 2 ; ( b ) roadway scheme, 100 vehicles/km 2 .
Figure 12. Forwarding ratio or the relation between sent messages and receivers with the fixed interval approach for store-carry-forward in the New York scenario: ( a ) roadway scheme, 25 vehicles/km 2 ; ( b ) roadway scheme, 100 vehicles/km 2 .
Figure 12. Forwarding ratio or the relation between sent messages and receivers with the fixed interval approach for store-carry-forward in the New York scenario: ( a ) roadway scheme, 25 vehicles/km 2 ; ( b ) roadway scheme, 100 vehicles/km 2 .
Figure 13. Involved vehicles with the map polling approach for store-carry-forward in the New York scenario: ( a ) roadway scheme, 25 vehicles/km 2 ; ( b ) roadway scheme, 100 vehicles/km 2 .
Figure 13. Involved vehicles with the map polling approach for store-carry-forward in the New York scenario: ( a ) roadway scheme, 25 vehicles/km 2 ; ( b ) roadway scheme, 100 vehicles/km 2 .
Figure 14. Sent duplicates with the map polling approach for store-carry-forward in the New York scenario: ( a ) roadway scheme, 25 vehicles/km 2 ; ( b ) roadway scheme, 100 vehicles/km 2 .
Figure 14. Sent duplicates with the map polling approach for store-carry-forward in the New York scenario: ( a ) roadway scheme, 25 vehicles/km 2 ; ( b ) roadway scheme, 100 vehicles/km 2 .
Figure 15. Forwarding ratio or the relation between sent messages and receivers with the map polling approach for store-carry-forward in the New York scenario: ( a ) roadway scheme, 25 vehicles/km 2 ; ( b ) roadway scheme, 100 vehicles/km 2 .
Figure 16. Involved vehicles in comparison with UV-CAST in the New York scenario: ( a ) 25 vehicles/km 2 ; ( b ) 100 vehicles/km 2 .
Figure 16. Involved vehicles in comparison with UV-CAST in the New York scenario: ( a ) 25 vehicles/km 2 ; ( b ) 100 vehicles/km 2 .
Figure 17. Sent duplicates in comparison with UV-CAST in the New York scenario: ( a ) 25 vehicles/km 2 ; ( b ) 100 vehicles/km 2 .
Figure 17. Sent duplicates in comparison with UV-CAST in the New York scenario: ( a ) 25 vehicles/km 2 ; ( b ) 100 vehicles/km 2 .
Figure 18. Forwarding ratio or the relation between sent messages and receivers in comparison with UV-CAST in the New York scenario: ( a ) 25 vehicles/km 2 ; ( b ) 100 vehicles/km 2 .
Figure 18. Forwarding ratio or the relation between sent messages and receivers in comparison with UV-CAST in the New York scenario: ( a ) 25 vehicles/km 2 ; ( b ) 100 vehicles/km 2 .
Table 1. Summary of the main works for urban dissemination. UMB, Urban Multihop Broadcast; UV-CAST, Urban Vehicular Broadcast; TAF, Two Angles Forwarding; ABSM, Acknowledged Broadcast from Static to Highly Mobile; CDS, connected dominating sets; eMDR, Enhanced Message Dissemination Based on Roadmaps.
Table 1. Summary of the main works for urban dissemination. UMB, Urban Multihop Broadcast; UV-CAST, Urban Vehicular Broadcast; TAF, Two Angles Forwarding; ABSM, Acknowledged Broadcast from Static to Highly Mobile; CDS, connected dominating sets; eMDR, Enhanced Message Dissemination Based on Roadmaps. Goal Relay Selection ACKed Junction Detection Store-Carry-Forward Needs Infrastructure Needs Beacons UMB, 2007 fast distance-based hand-shake digital map no yes no UV-CAST, 2011 efficient, resilient to disconnections distance-based in beacons digital map yes no yes TAF, 2012 efficient distance-based no reception angles no no no ABSM, 2012 reliable, efficient clustering (CDS construction) in beacons - yes no yes eMDR, 2012 fast location-based + distance thresholds no digital map no no yes
Table 2. Network parameters in the simulations.
Table 2. Network parameters in the simulations. Parameter Value MAC 802.11p Frequency band (10 MHz channel) 5.900 GHz Propagation model Simple Obstacle Shadowing Transmission power 1 W Sensitivity −77 dBm SNR 13 dBm Thermal noise −104 dBm LOS communication range ( r ) 232 m Modulation QPSK Bitrate 6 Mbps
Table 3. Statistics of the widest diagonal at junctions in several cities.
© 2016 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
Garcia-Lozano, E.; Campo, C.; Garcia-Rubio, C.; Rodriguez-Carrion, A. A Bandwidth-Efficient Dissemination Scheme of Non-Safety Information in Urban VANETs. Sensors 2016, 16, 988.
https://doi.org/10.3390/s16070988
Garcia-Lozano E, Campo C, Garcia-Rubio C, Rodriguez-Carrion A. A Bandwidth-Efficient Dissemination Scheme of Non-Safety Information in Urban VANETs. Sensors. 2016; 16(7):988.
https://doi.org/10.3390/s16070988
Garcia-Lozano, Estrella, Celeste Campo, Carlos Garcia-Rubio, and Alicia Rodriguez-Carrion. 2016. "A Bandwidth-Efficient Dissemination Scheme of Non-Safety Information in Urban VANETs" Sensors16, no. 7: 988.
https://doi.org/10.3390/s16070988
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Charlie Sheen, Dr. Drew, Prostitutes, and the Recovery Mafia
American entertainment figures cycle in and out of addiction rehab, stardom, prison - and, ultimately, Dr. Drew's Celebrity Rehab, for which he is constantly recruiting by analyzing whichever star addict is in the news.
Charlie Sheen, Dr. Drew, Prostitutes, and the Recovery Mafia
TV gossip shows are fed by a revolving band of recovered guys boasting about their recovery and discussing the relapses of other of their members.
CNN interviewed Tom Sizemore about Charlie Sheen, whom Sizemore said he had been unsuccessfully trying to reach. Sizemore is a man whose own acting career was derailed by drugs - he first underwent treatment for addiction in 1998. TheDaily Beastsays he was sober from 1997-2002, but then developed a meth addiction and beat girlfriend Heidi Fleiss - for which he was convicted in 2003 and served 17 months in prison. Sizemore entered Celebrity Rehab with Dr. Drewand then Sober House, and now at 47, he has been sober for 17 months. According to the Beast, Sizemore is hotter than ever and is now awash in projects.
CNN interviewed Sizemore about Charlie Sheen since they couldn't get anyone who actually had talked to him. He droppedRobert Downey's name as someone who was likewise trying to reach out to Charlie. So is Charlie's father, whose name Sizemore also drops, since he too is in recovery: "Marty knows all about it." Of course, Dr. Drew made his usual claims, "He needs to be in recovery, rather than going back to work - it is impossible to work and do rehab, in my opinion." Dr. Drew predicted doom if Sheen doesn't enter treatment: "We haven't learned from Michael Jackson and other cases that we are seeing someone who is seriously, seriously ill" - although so far it is the women in Sheen's life who have had the most to fear. Meanwhile, Sizemore fantasized about Charlie getting a heart attack but not dying, and being paralyzed!
Dr. Drew suggests a media vulture, circling the latest carrion. In a famous recent example, he recommended that Lindsay Lohan's father plant drugs in Lohan's car, then call the police, in order toget her into treatment. This, despite his acknowledgement that Lohan "has had excellent treatment in the past at outstanding treatment programs." So why should we expect better results this time? As I have suggested, Lohan and others may bereceiving the wrong treatmentsince they respond so poorly to - and regularly relapse following - standard 12-step programs. Don't years of futility dictate attempting something new?
Like Lohan, Sizemore, Martin Sheen, and so many others who have cycled through treatment, Charlie himself knows all about rehab - he had a well-chronicled stay for his addiction to cocaine and pills in 1998. Then again, he had been in rehab before that, following which then-girlfriend Brittany Ashland filed charges that he beat her. But, after his second stint in '98, Sheen described how rehab saved him. In this period Sizemore says that Sheen tried to get him into treatment - it seems one is always attempting to get the other into rehab - a rotating crew of sobriety-addiction buffs.
There is a deep sexual-violence undercurrent to Sheen's substance use. CNN reviewed Denise Richards' accusations that Charlie was accessing porn sites about prepubescent girls, which provoked one of his outbursts towards her. He also put a knife to the throat of Brooke Mueller, the wife he is currently divorcing, when both were drunk. Bothentered treatment, bringing along their two children. In terms of violence towards the women in his life, Sheen previously accidentally shot girlfriend Kelly Preston in the arm.
Not every man who becomes intoxicated strikes out at women (just as all drunks don't disparage Jews). The latest Charlie Sheen story involves an alleged prostitute at the Plaza Hotel whom he threatened in a violent outburst. Whether the woman in this case is a prostitute, Sheen's predilection for that profession and for porn stars has constantly erupted throughout his career - including his avid involvement with Fleiss' call girl business.
The character Sheen plays in his incredibly popular television series, Two and a Half Man, has non-stop women - and he doesn't have to pay for sex. What's the difference between Sheen the wealthy actor-family man (Richards was in the Plaza hotel with their two daughters for a family reunion when Sheen trashed his room, while Sheen also has two children with Mueller and another child from a prior relationship) and the single bon vivant he plays on television?
Well, Sheen can't control his prostitute habit, while the character he plays shows enough respect for his nephew that he doesn't go there (although he does parade women in and out of his bedroom on the show, sometimes several at once). One episode had Sheen and his brother in the series, Jon Cryer, being taken to Las Vegas where they were offered the services of prostitutes. On television, this inspired the men to reflect on the impact their mother's active sex life - with men revolving in and out of their home - had on them, leading to valuable self-insight. But we have never seen such introspection emanating from the actor behind the series - how do his frequent excursions with prostitutes impact his kids, like the two children staying in the Plaza?
Certainly, Sheen's repeated treatments haven't resolved his violent tendencies towards women. In his CNN interview, Sizemore excuses Sheen's anger with the woman in his room and the damage he did there because Sheen was reportedly upset over losing his watch - an anger Sizemore indicated was understandable, since he had had similar experiences himself. Perhaps Sheen and Sizemore need a different kind of treatment than one that convinces them they have an uncontrollable disease caused by external substances.
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<p>Most classification tasks rely on a source dataset of known labels and a target dataset of unknown labels. There might exist multiple variabilities between the source and the target; this is the case, for instance, in our application (classification of physiological data). This is one of the situations tackled by transfer learning, the improvement of the classification performances on a target dataset (of unknown labels) by considering the knowledge acquired on a (known) source dataset. We previously introduced two kernel-based methods of transferring knowledge: Quadratic Loss Transfer Learning (QLTL) and Kernel-Cross Alignment Transfer Learning (KCATL). The latter has been introduced in an applicative paper (currently submitted to a journal) and one of the perspectives was the improvement of the method through the centring of the cross- Gram matrix.</p>
<p>In this paper, we focus on data centring; we show that, for our criteria, only the source centre impacts the detector's Receiver Operating Characteristics (ROC) curve. We also compare two centring strategies, in the Reproducing-Kernel Hilbert Space (RKHS) <i>H</i> and in the input space χ, with joint optimisation on the sought target labels <i>Y<sub>T</sub>
</i> . As shown in this paper, Kernel- Cross Polarisation (KCP) and its normalised equivalent, the Kernel-Cross Alignment (KCA), are optimised by the same <i>Y<sub>T</sub>
</i> . Considering the expressions of the gradients of our criteria w.r.t., first, the unknown labels and second, the centres, we propose an alternate directions optimisation scheme.</p>
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{{Audio|Ar-muhammad.ogg|
'''Muhammad''' }}
({{lang-ar|محمد}}, also Arabic transliterated '''Mohammad''', '''Mohammed''', '''Muhammed''', and sometimes '''Mahomet''', following the Latin
or Turkish), is considered
the final prophet
of [[Islam]] by mainstream Muslims, and the founder of Islam -
the world's second largest religion - by many non-Muslims
. Some Muslims dislike the English term religion, which implies a private belief whereas Islam, for many Muslims, includes government and legal aspects
. Some non-Muslims do accept that God stands behind Islam, thus recognizing with Muslims the genuiness of Muhammad's spiritual experiences and leadership. Although they do not accept every aspect of Muslim belief, they reject the view that Muhammad was insincere or that he invented Islam (which has no connection with God). Some non-Muslims recognize Muhammad
as a successful political leader but think that his religious claims are bogus
.
+
'''Muhammad''' ({{lang-ar| '''
محمد '''
}}, also Arabic transliterated '''Mohammad''', '''Mohammed''', '''Muhammed''', and sometimes '''Mahomet''', following the
[[
Latin ]]
or [[
Turkish language|Turkish]]
), is the founder
of [[Islam]] —
the world's second largest religion.
<ref>
Some Muslims dislike the English term religion, which implies a private belief ,
whereas Islam, for many Muslims, includes government and legal aspects as well
.
</ref>
−
According to traditional Muslim biographers, Muhammad was born ca
. 570 C.E.
in Mecca (Makkah) and died June 8, 632 in Medina (Madinah) ; both
Mecca and Medina are cities in the Hejaz region of present day [[Saudi Arabia]].
Muhammad's legacy lives on
in the minds and hearts
of billions of Muslims throughout the world
, for whom he represents
the best model of human conduct. Non-Muslim opinion on Muhammad has often been less favorable
,
stressing his political
and military achievements rather than his role
as a religious leader
. However, few disagree
that his life must be numbered among one of
the most influential and significant ever lived. One
of the greatest and geographically widespread civilizations in the world owes its existence
to him
.
Islam, as
a religio-cultural-social-political system or way
of life represents God's ideal, or will,
for billions of people. This way of life stresses that all life must be lived in harmony with God
, holds all aspects of life - sacred
and secular -
in
balance
and encourages people
to live as if God sees everything they do
. Islam seeks to replace human will with God's will. It teaches
the equality
of all people and anticipates that day when
the whole world will be obedient to God, when peace
('' salam
'', from which
the word
'' islam
'' is derived) will exist in
the vertical (
between all people
and God)
and in the horizontal (among all people) and when the earth, given humanity as a trust from God, will be properly valued and respected. Above all, Muhammad taught that without inner piety, external displays
of devotion are worthless
. From
the point
of view of those who see God
's hand within history
, Muhammad's life cannot be understood providentially in other than positive terms
.
+
According to traditional Muslim biographers, Muhammad was born c
. 570 <small>C.E.</small>
in [[
Mecca ]]
(Makkah) and died June 8, 632 in [[
Medina ]]
(Madinah) . Both
Mecca and Medina are cities in the Hejaz region of present day [[Saudi Arabia]].
He was a merchant in Mecca when,
in 610<small> C.E.</small> at about
the age
of 40, while meditating in a cave
, Muhammad experienced a vision from
the angel [[Gabriel]]
, who commanded him to memorize
and recite the verses subsequently collected
as
the ''[[Qur'an]]''
. Gabriel told him
that God (''Allah'' in Arabic) had chosen him as
the last
of the prophets
to
mankind
. He began publicly preaching a strict [[monotheism]] and predicting
a ''Qiyamah'' (Day
of
Judgement)
for sinners and idol-worshippers
, such as his tribe
and neighbors
in Mecca. For this was persecuted
and
ostracized by the Meccan establishment, who depended on income from pilgrims
to its polytheistic shrine, the [[Kaaba]]
. In 622 Muhammad accepted an invitation from believers in the city of Yathrib, where he became
the
leader
of the first avowedly Muslim community
( Yathrib ever after become known as
'' Medina-al-Naby
'', City of the Prophet, or Medina for short). This journey is known as
the '' Hijra
'' , or migration; the event marked the beginning of
the Islamic calendar. War
between Mecca
and Medina followed, in which Muhammad
and his followers were eventually victorious. The military organization honed
in
this struggle was then set to conquering
the other [[paganism|pagan]] tribes
of [[Arabia]]
. By
the time
of
Muhammad
's death, he had unified Arabia and launched a few expeditions to the north
, towards [[Syria]] and [[Palestine]]
.
− ==Summary== + Under Muhammad's immediate [[caliph|successors]] the [[Islam]]ic empire expanded into Palestine, Syria, [[Mesopotamia]], [[Iran|Persia]], [[Egypt]], [[North Africa]], and [[Spain]]. Although there were many battles against the pagans, some of whom became Muslim, the primary method by which Islam as a [[faith]] spread around much of the globe was commercial contact between Muslims and non-Muslims, and missionary activity. Islamic rule, on the other hand, was extended by conquest. Many people did not convert but lived as subject of Islamic rule, although as time passed the majority did embrace Islam. As Muhammad taught the unity of all aspects of life, a whole civilization developed from his teaching, with its own art, literature, philosophy, science and theology, but also governmental and legal systems.
−
[[Image:Muhammad callig.gif|thumb| left
|The name "Muhammad" written in Arabic [[calligraphy]] as a form of devotion]] + {{toc}}
+ Muhammad's legacy lives on in the minds and hearts of billions of Muslims throughout the world, for whom he represents the best model of human conduct. Non-Muslim opinion on Muhammad has often been less favorable—however, few disagree that his life must be numbered among one of the most influential and significant ever lived, as one of the greatest and geographically widespread [[civilization]]s in the world owes its existence to him. Islam, as a religio-cultural-social-political system or way of life, represents God's ideal or will for billions of people. This way of life stresses that all life must be lived in harmony with God, holds all aspects of life—sacred and secular—in balance and encourages people to live as if God sees everything they do. Islam teaches the equality of all people and anticipates that day when the whole world will be obedient to God, when peace (''salam'', from which the word ''islam'' is derived) will exist in the vertical (between all people and God) and in the horizontal (among all people) and when the earth, given humanity as a trust from God, will be properly valued and respected. Above all, Muhammad taught that without inner piety, external displays of devotion are worthless. From the point of view of those who see God's hand within history, Muhammad's life cannot be understood in other than positive terms.
+
[[Image:Muhammad callig.gif|thumb| 150 px|right
|The name "Muhammad" written in Arabic [[calligraphy]] as a form of devotion
. Many Muslims believe that Islam prohibits art depicting humans or animals; much Islamic art is decorative calligraphy or [[arabesque]].]]
+ ==Sources for Muhammad's Life ==
+
The sources available to us for information about Muhammad are the [[Qur'an
]] , ''sira'' biographies, and the ''[[hadith]]'' (sayings and deeds of Muhammad) collections. Technically ''hadith'' refers to a single saying (the plural is ''ahadith'') but in English it is customary to use the singular. While the ''Qur'an'' is not a biography of Muhammad, it does provide some information about his life; on the other hand, knowledge of Muhammad's life provides Muslims with the 'situation of revelation' (''Asbab al-nuzul'', or reasons of revelation) without which understanding the Qur'an becomes problematical. Zakaria (1991) suggests that “it is impossible for even Muslims, let alone non-Muslims, to understand the Qur'an without an acquaintance with the circumstances in which each revelation descended on Muhammad” (''tanzir'', or descent, is used to describe the 'sending down' of the Qur'an, together with the term ''wahy'', or revelation). The Qur'an does refer to incidents in Muhammad's life, including both public and private circumstances, so it does contain information about him.
−
Born Muhammad ibn Abdullah
, he is said to have been a merchant who traveled widely
. He is also said to have spent some time working as a shepherd
, ' because there is no prophet who has not shepherded the flock
' ( Guillaume: 72
) . Muslims say that in 610, at about the age
of forty, while meditating in a cave near Mecca,
Muhammad experienced a vision
. Later he described the experience
to those close to him as a visit from
the Angel Gabriel
, who commanded him to memorize and recite the verses subsequently collected as
the '' [[
Qur'an ]]
'' . Gabriel told him that God (
'' Allah
'' in Arabic) had chosen him as
the last
of the prophets to mankind
. His mission eventually expanded as he began publicly preaching a strict
[[ monotheism
]] and
predicting a
'' Qiyamah
'' ( Day of Judgement
) for sinners and idol-worshippers, such as his tribe and neighbors in Mecca
. He was
a successful leader
on both religious and political levels
. He did not completely reject
[[ Judaism]] and [[Christianity
]], the two other monotheistic faiths that were known to the Arabs and which are
referred to in the Qur'an; he said to have been sent
by God in order to complete
and perfect their teachings
. He soon acquired a following by some
and rejection and hatred by others in the region
. In 622 he accepted an inviation from believers in
the City of Yathrib where he became the leader of the first avowedly Muslim community
( Yathris now became known as Medina
-al- Naby, or City of the Prophet
) . This journey is known as the
'' Hijra'
', or migration, this event marked
the beginning
of the Islamic calendar. War between Mecca and Medina followed, in which
Muhammad and his followers were eventually victorious. The military organization honed in this struggle was then set to conquering
the other [[paganism|pagan]] tribes
of [[Arabia]]
. By the time of Muhammad's death
, he had unified Arabia and launched a few expeditions to the north
, towards [[Syria]]
and [[Palestine]]
.
+ ===The Sira: Biographical Literature===
+
The earliest surviving biographies are the ''Life of the Apostle of God''
, by Ibn Ishaq (d
. 768) (see Guillaume 1955)
, edited by Ibn Hisham (d. 833); and al-Waqidi's (d. 822) biography
''( sira
) ''
of Muhammad. Ibn Ishaq wrote his biography some 120
to 130 years after Muhammad's death. The third source,
the ''hadith'' collections
, like
the ''Qur'an'' , are not a biography
'' per se
'' . In the [[Sunni]] belief, they are
the accounts
of the words and actions of Muhammad and his companions
. In the
[[ Shi'a
]] belief, they are the accounts of the words and actions of Muhammad, of the Household of the Prophet ''(Ahl al-Bayt)''
and their companions, the
'' sahabah
'' ( see below
).
Lings (1983) gives us
a modern ''sira'', based
on the above
.
+
+ ===The Hadith Literature===
+
Six collections of ''hadith'' are recognized by most Sunni as especially trustworthy: those by
[[ Bukhari
]] (d. 870)
,
Muslim Ibn al-Hajjaj (d. 875) (
referred to above
by Cook
and Crone), Tirmidhi (d. 892), Nasa'i (d. 915), Ibn Majah (d
.
885),
and Abu Da'ud (d. 888)
. Together these are called
the "six books" ''
( al
- kutub
al- sitta
)'' . Shi
' a use the above but also have their own collections
, which include sayings of
the Imams (male descendants
of Muhammad );
the
collections
of al-Kulayni (d
. 940)
, Ibn Babuya (d. 991)
, and
Al Tusi (d. 1058) who authored two collections (making four) have special status
.
−
Under Muhammad
' s immediate [[caliph|successors]]
the [[Islam]]ic empire expanded into Palestine
, Syria
, [[Mesopotamia]]
, [[Iran|Persia]], [[Egypt]], North Africa
, and [[Spain]]
. Although there were many battles against
the pagans
,
some
of whom became Muslim, the primary method by which [[Islam]] as
a
faith spread around much
of the globe
was commercial contact between Muslims and non-Muslims
, and missionary activity
. Islamic rule
, on
the other hand
, was extended by conquest
. Many people
did not convert but lived as subject of Islamic rule
, although as time passed
the majority did embrace Islam. As Muhamamd taught
the unity
of all aspects
of life, a whole civilization developed from
his teaching
, with its own art, literature, philosophy, science and theology but also governmental and legal systems
.
+
Many Muslims believe that the whole of Bukhari is authentic, although even in that collection the various ''hadith'
' are given different categories depending on
the
reliability of their transmitter
, ranging from the highest
,
''sahih''
, to the lowest
, da`îf (weak)
. Rules concerning ''hadith'' include that all transmitters (
the ''isnad''
, or chain
of transmission must trace back to
a close companion
of
Muhammad) must be pious, their content ''(matn)'' must not contradict
the Qur'an or what
was commonly accepted to have been Muhammad's opinion, any penalty prescribed must not be disproportionate to the offense or crime involved
, and they must not depict Muhammad as predicting the future or performing miracles
. With reference to the latter
, many ''hadith'' do depict Muhammad predicting
the future and performing miracles (see Bennett 1998
, 49-54)
. On the latter point, several Qur'anic verses, such as Q29:50 and Q2:23 suggest that Muhammad
did not perform miracles
, since
the Qur'an alone was
the only confirmation needed
of the genuineness
of his mission. However
, Q13:38 can be understood to imply that Muhammad could perform miracles "by Allah's leave
. "
−
== How do we know about
Muhammad ? == +
== =Critical scholarship regarding the sources for
Muhammad 's life
===
− ===The Sira: Biographical Literature
=== +
Muslim and non-Muslim scholars alike agree that there
are
many inauthentic traditions concerning
the life of Muhammad in
the ''hadith'' collections. Muslims have always been free
to question
the authenticity
of '' hadith
'', even of those contained
in the above
- mentioned collections
. A very small minority called
the “Quran Alone Muslims” considers all
''hadith'' as unreliable
.
−
The sources available to us for information about Muhammad
are
the ''sira'' biographies, and
the ''hadith'' (sayings and deeds of Muhammad)
collections.
Technically ''hadith'' refers
to a single saying (the plural is ''ahadith'') but in English it is customary to use the singular. While the ''Qur'an'' is not a biography of Muhammad, it does provide some information about his life; on
the other hand, knowledge
of Muhammad
' s life provides Muslims with the
' situation of revelation' (''Asbab al-nuzul
'', or reasons of revelation) without which understanding the Qur'an becomes problematical. Zakaria (1991) suggests that 'it is impossible for
even Muslims, let alone non-Mulsims, to understand the Qur'an without an acquaintance with the circumstances in which each revelation descended on Muhammad' (''tanzir'', or descent, is used to describe the 'sending down'
of the Qur'an, togetehr with the term ''wahy'', or revelation). The Qur'an does refer to incidents
in Muhammad's life, including both public and private circumstances, so it does contain information about him. The earliest surviving biographies are
the ''Life of the Apostle of God'', by Ibn Ishaq (d. 768) (see Guillaume, 1955), edited by Ibn Hisham (d. 833); and al
-
Waqidi's (d. 822) biography (''sira'') of Muhammad. Ibn Ishaq wrote his biography some 120 to 130 years after Muhammad's death
. The third source,
the ''hadith'' collections, like the ''Qur'an'', are not a biography ''per se''. In the Sunni belief, they are the accounts of the words and actions of Muhammad and his companions. In the Shia belief, they are the accounts of the words and actions of Muhammad, of the Household of the Prophet (''Ahl al-Bayt'') and their companions, the ''sahabah'' (see below). Lings (1983) gives us a modern ''sira'', based on the above
.
− ===
Non-Muslim Skepticism=== +
Non-Muslim scholars, though
, are much more skeptical
about the reliability of ''hadith'' literature
. Joseph Schacht, John Wansbrough, Michael Cook, Patricia Crone, and others
argue that by the time the oral traditions were being collected, the Muslim community had fractured into rival schools of thought. Each sect and school had its own sometimes -
conflicting traditions of what Muhammad and his companions had done and said. Traditions multiplied
. While later
Muslim compilers of the ''hadith'' collections
made strenuous efforts
to weed out what they felt were spurious stories , and traditionalists
rely on their efforts; the skeptics feel that the question must be revisited, using modern methods.
−
Some skeptical
scholars such as John Wansbrough
, Michael Cook
, Patricia Crone, and others have raised doubts
about the reliability of these sources, especially the
''hadith'' collections
. They
argue that by the time the oral traditions were being collected, the Muslim community had fractured into rival schools of thought. Each sect and school had its own sometimes conflicting traditions of what Muhammad and his companions had done and said. Traditions multiplied , and
Muslim scholars
made a
strenuous effort
to weed out what they felt were spurious stories . Traditionalists
rely on their efforts; the skeptics feel that the question must be revisited, using modern methods
. Other scholars, such as Joseph Schacht (1902-1969), have been pessimistic about the reliablity of the ''hadith'' but Cook and Crone go further, doubting the whole chronology of Muhammad's life which they regard as a post-638 fabrication, a ''heilgeschichte'' invented after the conquest of Jerusalem to lend religious sanction to Arab territorial expansion. They regard this creation as owing most to Jewish sources and legend, with Mecca serving as an Arab Sinai, thus making Moses a fore-type of Muhammad (1977: 25). There is, they argue, 'no indication of the existence of the Koran before the end of the 7th century'(18) and that what emerged as 'Islam', a mix of Arab (Hagarite) and Samaritan legends, 'can plausibly' be dated from 'the reign of [[Abd al-Malik]]' (646-705) (29), who built the Dome. The Qur'an's composition possibly involved Muslim Ibn al-Hajjaj (810-75), editor of the second most authoratative collection of ''hadith'' for Sunni Muslims. Commenting that the inscriptions on the Dome of the Rock in Jerusalem 'attest the existence, at the end of the seventhc entury, of materials immediately recognisable as Koranic' they add that this does not give any indication 'of the literary form in which those materials normally appeared at the time' (18). Wansbrough argued that it was more likely that the Qur'an's recession followed rather than preceded the codification of the ''hadith'', which took place in the ninth century; the Qur'anic revelation could only have been effected within the community once its concent could be related to that of the prophetic Sunna and, perhaps more important, to the historical figure delineated therein' (1977: 52). Following Schacht, he thinks it significant that 'with very few exceptions, Muslim jurisprudence was not derived from the contents of the Qur'an' (44). Thus, the traditional Muslim account of the recession of the Qur'an under the third caliph, Uthman (580-656)is fictitious. Earlier, Abraham Geiger (1896) the German Reform Jewish scholar had explained Islam as in the main derived from Judaism:
− :In general he was in favour of borrowing from earlier religions. He desired no peculiarity, no new religion which should oppose all that had gone before; he sought rather to establish one founded on the ancient creeds purified from later changes and additions, one which should adopt this or that new idea, and which should above all things acknowledge him as a divinely commissioned prophet. He let all that was already established stand good ... (21-22)
.
− ===The Hadith Literature=== +
Schacht (1964) argued that in the years after Muhammad's death, competing factions
invented ''hadith'' to justify their own claims and also to accuse anyone who
disagreed
with their views of illegitimacy
, even
apostasy or
[[
heresy ]]
. However from an Islamic standpoint, Muhammad M al-Azami
( 1996
) has systematically repudiated
Schacht' s scholarship
of the ' 'hadith''.
Sir William Muir (1894) believed that “pious fraud”
and
“perverted tradition”
was the “chief
instrument employed to accomplish”
different parties' goals, thus “traditions
were colored
, distorted and fabricated. ”
He believed that the tendency was to idealize Muhammad by surrounding him with mystique and by attributing miracles and futuristic predictions to him , hence
material that reflects less favorably on Muhammad (his supposed moral failings) was more likely to be authentic.
Bennett (1998) suggested that the issue is not whether Muslims attributed Muhammad with mystique but whether he deserved this reverence or not, thus:
−
Muslim and non-Muslim scholars alike agree that there are many inauthentic traditions concerning the life of Muhammad in the ''hadith'' collections. A very small minority called the "Quran Alone Muslims" consider all ''hadith'' as unreliable. Non-Muslims scholars, though, are much more skeptical about the reliablity of ''hadith'' literature.
Schacht (1964) argued that each faction
invented ''hadith'' to justify their own claims and also to accuse
anyone who
diagreed
with their views of ilegitimacy, that is
, apostasy or heresy. Coulson
( 1994
) agreed with
Schacht that,
' the vast majority
of legal dicta attributed to
the prophet are apocryphaal
' (64), while
Sir William Muir (1894) had it that since the sword was used to silence any doubt, 'absence of candid and free investigation into the origin and early incidents of Islam ... charcterises the Muslim mind even to the present day' (xxxviii-ix). Muir
believed that 'pious fraud'
and 'perverted tradition'
was the 'chief
instrument employed to
accomplish'
different parties' goals, thus 'traditions
were coloured
, distorted and fabricated '
.
He believed that the tendency was to idealize Muhammad by surrounding him with mystique ,
and by attributing miracles and futuristic predictions to him but that
material that reflects less favorably on Muhammad (his supposed moral failings) was more likely to be authentic.
−
The historicity of the biographical material about
Muhammad presented in the summary above is less contested than legal material,
with the exception of such scholars as Wansbrough
, Cook and Crone. Ibn Warrack
( 1995) points out that historical
and legal material was handled, collected and codified by the same people, which must raise questions about
the authenticity
of the whole corpus (69-70
) . Many non-Muslim scholars think that 570 C.E. as Muhammad's birth is
a back-projection to make him 40 when
he received his first revelation
,
emphasising
the parralel with Moses (Bennett
, 1998: 18)
. Most think that 622 C.E. for the ''hijrah'' is a safe date
( which marks the beginning of the Islamic calendar
) . Other dates and the sequence of some events are also contested.
+
<blockquote>Admitting that 'myths' were created, I am interested in why. Was it to surround
Muhammad with a mystique he neither had nor deserved
, or was it to depict metaphorically
(and in
the idiom
of the day
) a mystique
he
really had? If the former
, we may impute insincerity to the compilers; if
the latter, this seems to be an inappropriate judgment, however far fetched, by today’s standards
, the myths seem to be
. ( 54
) </blockquote>
− ==Canonical Hadith== +
Material
on [[miracle]]s surrounding
Muhammad's birth may
be examples of back-projection
, although scholars
have pointed out similarity between
this material and stories associated
with the births
of other religious teachers and founders including [[Jesus]] and
the
[[Buddha]]
.
−
Six collections of ''hadith'' are recognised by most Sunni as especially trustworthy - those by Bukhari (d. 870), Muslim Ibn al-Hajjaj (d.875) (referred to above by Cook and Crone), Tirmidhi (d. 892), Nasa'i (d. 915), Ibn Majah (d.885), and Abu Da'ud (d.888). Together these are called the "six books" (''al-kutub al-sitta''). Shi'a use the above but also have their own collections which include sayings of the Imams (male descendants of Muhammad); the collections of al-Kulayni (d. 940), Ibn Babuya (d. 991), Al Tusi (d. 1058) who authored two collections (making four) have special status. Many Muslims believe that the whole of Buckari is authentic although ''hadith'' are given different catergories, depending
on the reliablity of their transmitter ranging from the highest, ''sahih'', to the lowest, da`îf (weak). Rules concerning ''hadith'' include that all transmitters (the ''isnad'', or chain of transmission must trace back to a close companion of Muhamamd) must be pious, their content (''matn'') must not contradict the Qur'an or what was commonly accepted to have been
Muhammad's opinion, any penalty prescribed must not
be disproprortionate to the offence or crime involved, they must not depict Muhammad as predicting the future or performing miracles. With reference to the latter, many ''hadith'' do depict Muhammad predicting the future and performing miracles (see Bennett, 1998: 49-54 for
examples and discussion
of this issue). Several Qur'anic verses
, such as 29: 50 and 2: 23 suggest that Muhammad did not perform miracles, since the Qur'an was the only confirmation needed of the genuiness of his mission. Q13: 38 can be understood to imply that Muhammad could perform miracles 'by Allah's leave'. However, Muslims
have always been free to question the authenticity of ''hadith'', even of those contained in the above mentioned collections. Bennett (1998) suggested that the issue is not whether Muslims attributed Muhammad with mystique but whether he deserved
this reverence or not, thus:
−
:admitting that 'myths' were created, I am interested in why. Was it to surround Muhammad
with a mystique he neither had nor deserved, or was it to depict metaphorically (and in
the idom
of the day) a mystique he really had? If the former, we may impute insincerity to the compilers; if the latter, this seems to be an inappropriate judgement, however farfetched, by toaday's standards, the myths seem to be (54)
.
−
Material on miracles surrounding
Muhammad's birth may be examples of back
-
projection, although scholars have pointed out similarity betweeen this material and stories associated with
the births
of other
religious teachers and founders including Jesus and the Buddha
.
Muhammad M al
- Azami
( 1996
) systematically repudiates Schact's scholarship of
the '' hadith
''.
+
The historicity of the biographical material about Muhammad presented in the summary above is less contested than legal material of the ''hadith''. However, Cook and Crone doubt the chronology of
Muhammad's life as presented in the ''Sira'', which they regard as a post
-
638 fabrication—a ''heilgeschichte'' invented after
the conquest
of Jerusalem to lend
religious sanction to Arab territorial expansion. Many non-Muslim scholars think that 570 <small>C.E
. </small> as
Muhammad 's birth is a back
- projection to make him 40 years old when he received his first revelation, emphasizing the parallel with Moses
( Bennett 1998, 18
) . Most think that 622 <small>C.E.</small> for
the '' hijrah
'' is a safe date. Other dates and the sequence of some events are also contested
.
−
==Muhammad's life according to Sira== +
==Muhammad's life according to ''
Sira ''
==
===Muhammad's genealogy===
===Muhammad's genealogy===
+ According to tradition, Muhammad traced his genealogy back as far as Adnan, whom the northern [[Arab]]s believed to be their common ancestor. Adnan in turn is said to be a descendant of ''Ismail'' ([[Ishmael]]), son of ''Ibrahim'' ([[Abraham]]) though the exact genealogy is disputed. Muhammad's genealogy up to Adnan is as follows:
− According to tradition, Muhammad traced his genealogy back as far as Adnan, whom the northern [[Arab]]s believed to be their common ancestor. Adnan in turn is said to be a descendant of Ismaeel ([[Ishmael]]), son of Ibrahim ([[Abraham]]) though the exact genealogy is disputed. Muhammad's genealogy up to Adnan is as follows: +
Muhammad ibn Abd Allah ibn Abd al-Muttalib (Shaiba) ibn Hashim (Amr) ibn Abd Manaf (al-Mughira) ibn Qusai (Zaid) ibn Kilab ibn Murra ibn Ka`b ibn Lu'ay ibn Ghalib ibn Fahr ( Quraysh
) ibn Malik ibn an-Nadr (Qais) ibn Kinana ibn Khuzaimah ibn Mudrikah (Amir) ibn Ilyas ibn Mudar ibn Nizar ibn Ma`ad ibn Adnan. <ref>
''ibn'' = "son of" in Arabic; alternate names of people with two names are given in brackets. </ref>
−
−
Muhammad ibn Abd Allah ibn Abd al-Muttalib (Shaiba) ibn Hashim (Amr) ibn Abd Manaf (al-Mughira) ibn Qusai (Zaid) ibn Kilab ibn Murra ibn Ka`b ibn Lu'ay ibn Ghalib ibn Fahr ( Quraish
) ibn Malik ibn an-Nadr (Qais) ibn Kinana ibn Khuzaimah ibn Mudrikah (Amir) ibn Ilyas ibn Mudar ibn Nizar ibn Ma`ad ibn Adnan. (
''ibn'' = "son of" in Arabic; alternate names of people with two names are given in brackets. )
−
His nickname was ''Abul-Qasim'', "father of Qasim" ,
after his short-lived first son. +
His nickname was ''Abul-Qasim'', "father of Qasim ,
" after his short-lived first son.
===Childhood===
===Childhood===
+ Muhammad was born into a well-to-do family settled in the northern Arabian town of [[Mecca]]. Some calculate his birth date as April 20, 570 ([[Shi'a]] Muslims believe it to be April 26), and some as 571; tradition places it in the Year of the Elephant. Muhammad's father, Abd Allah ibn Abd al-Muttalib, had died before he was born, and the young boy was brought up by his paternal grandfather Abd al-Muttalib, of the tribe of Quraysh (or Quraish). Tradition says that as an infant, he was placed with a [[Bedouin]] wet nurse, Halima, as desert life was believed to be safer and healthier for children. At the age of six, Muhammad lost his mother Amina, and at the age of eight his grandfather Abd al-Muttalib. Muhammad now came under care of his uncle Abu Talib, the new leader of the Hashim clan of the Quraysh tribe, the most powerful in Mecca.
− Muhammad was born into a well-to-do family settled in the northern Arabian town of Mecca. Some calculate his birthdate as April 20, 570 (Shia Muslims believe it to be April 26), and some as 571; tradition places it in the Year of the Elephant. Muhammad's father, Abd Allah ibn Abd al-Muttalib, had died before he was born and the young boy was brought up by his paternal grandfather Abd al-Muttalib, of the tribe of Quraysh (or Quraish). Tradition says that as an infant, he was placed with a Bedouin wetnurse, Halima, as desert life was believed to be safer and healthier for children. At the age of six, Muhammad lost his mother Amina, and at the age of eight his grandfather Abd al-Muttalib. Muhammad now came under care of his uncle Abu Talib, the new leader of the Hashim clan of the Quraysh tribe, the most powerful in Mecca. +
Mecca was a thriving commercial center, due in great part to a stone temple called the [[
Ka'bah ]]
that housed many different idols, possibly numbering
365. Merchants from different tribes would visit Mecca during the pilgrimage season, when all inter-tribal warfare was forbidden and they could trade in safety.
−
−
Mecca was a thriving commercial center, due in great part to a stone temple called the Ka'bah that housed many different idols, possibly 365. Merchants from different tribes would visit Mecca during the pilgrimage season, when all inter-tribal warfare was forbidden and they could trade in safety.
−
As a teenager Muhammad began accompanying his uncle on trading journeys to [[Syria]]. He thus became well- travelled
and gained some knowledge of life beyond Mecca.
He earned a reputation for honesty and the nick-name
, ''al-amin'' ( the trust-worthy
).
During the rebuilding of the Ka'bah after a flood (some sources say fire), a fight almost broke out over who
would have the honor of putting the Black Stone back in its place.
Abu Umayyah, Makkah's oldest man, suggested that the first man to enter the gate of the mosque the next morning would decide the matter. That man was the
Muhammad. The Makkans were ecstatic. "This
is the trustworthy one ( Al
- Amin
), "
they shouted in a chorus . "This
is Muhammad "
.
+
As a teenager ,
Muhammad began accompanying his uncle on trading journeys to [[Syria]]. He thus became well-
traveled
and gained some knowledge of life beyond Mecca. He earned a reputation for honesty and the
nickname
, ''al-amin'' ( “the trustworthy”
). During the rebuilding of the Ka'bah after a [[
flood ]]
(some sources say [[
fire ]]
), a fight almost broke out over whom
would have the honor of putting the Black Stone back in its place. Abu Umayyah, Makkah's oldest man, suggested that the first man to enter the gate of the [[
mosque ]]
the next morning would decide the matter. That man was Muhammad. The Makkans were ecstatic. “This
is the trustworthy one ''
( al
- amin
) ''
, ”
they shouted in a chorus , “this
is Muhammad. ”
He came to them and they asked him to decide on the matter.
He came to them and they asked him to decide on the matter.
−
Muhammad
proposed a solution that all agreed to -
putting the Black Stone on a cloak, the elders of each of the clans held on to one edge of the cloak and carried the stone to its place. The Prophet then picked up the stone and placed it on the wall of the Ka'ba.
The precise date of this incident is not known.
+
Muhammad proposed a solution that all agreed to —
putting the Black Stone on a cloak, the elders of each of the clans held on to one edge of the cloak and carried the stone to its place. The Prophet then picked up the stone and placed it on the wall of the Ka'ba. The precise date of this incident is not known.
===Middle years===
===Middle years===
+ One of Muhammad's employers was [[Khadija]]h, a rich widow then 40 years old. The young 25-year-old Muhammad so impressed Khadijah that she offered him [[marriage]] in the year 595 <small>C.E.</small> He became a wealthy man through this marriage. By Arab custom minors did not inherit, so Muhammad had received no inheritance from either his father or his grandfather.
− One of Muhammad's employers was [[Khadija]]h, a rich widow then forty years old. The young twenty-five-year old Muhammad so impressed Khadijah that she offered him marriage in the year 595 C.E. He became a wealthy man through this marriage. By Arab custom minors did not inherit, so Muhammad had received no inheritance from either his father or his grandfather. +
Ibn Ishaq records that Khadijah bore Muhammad five children, one son and four daughters. All of Khadija's children were born before Muhammad started preaching about [[Islam]]. His son Qasim died at the age of two. The four daughters are said to be Zainab bint Muhammad, Ruqayyah bint Muhammad, Umm Kulthum bint Muhammad, and [[Fatimah|
Fatima Zahra ]]
.
−
−
Ibn Ishaq records that Khadijah bore Muhammad five children, one son and four daughters. All of Khadija's children were born before Muhammad started preaching about [[Islam]]. His son ''
Qasim ''
died at the age of two.
The four daughters are said to be Zainab bint Muhammad, Ruqayyah bint Muhammad, Umm Kulthum bint Muhammad, and Fatima Zahra.
The Shi'a say that Muhammad had only the one daughter, Fatima, and that the other daughters were either children of Khadijah by her previous marriage, or children of her sister.
The Shi'a say that Muhammad had only the one daughter, Fatima, and that the other daughters were either children of Khadijah by her previous marriage, or children of her sister.
Line 67: Line 67:
|-
|-
|align="right">|''c''. 570
|align="right">|''c''. 570
−
|Possible birth (April 20): Mecca +
|Possible birth (April 20): [[
Mecca ]]
|-
|-
|align="right">|570
|align="right">|570
Line 73: Line 73:
|-
|-
|align="right">|570
|align="right">|570
−
|Unsuccessful Abyssinian
attack on Mecca +
|Unsuccessful [[Abyssinia]]n
attack on Mecca
|-
|-
|align="right">|576
|align="right">|576
Line 88: Line 88:
|-
|-
|align="right">|610
|align="right">|610
−
|First reports of Qur' anic
revelation: Mecca +
|First reports of [[
Qur' an]]ic
revelation: Mecca
|-
|-
|align="right">|''c''. 610
|align="right">|''c''. 610
Line 102: Line 102:
|Emigration of Muslims to Abyssinia
|Emigration of Muslims to Abyssinia
|-
|-
−
|align="right">|616 ] +
|align="right">|616
|Banu Hashim clan boycott begins
|Banu Hashim clan boycott begins
|-
|-
Line 112: Line 112:
|-
|-
|align="right">|''c''. 620
|align="right">|''c''. 620
−
|Isra ( Night Journey
) and Miraj ( Ascent
) +
| ''
Isra ''
( night journey
) and ''
Miraj ''
( ascent
)
|-
|-
|align="right">|''c''. 620
|align="right">|''c''. 620
Line 118: Line 118:
|-
|-
|align="right">|622
|align="right">|622
−
|Emigrates to Medina (Hijra) +
|Emigrates to Medina ''
(Hijra) ''
|-
|-
|align="right">|622
|align="right">|622
−
|Takes leadership of Medina (Yathrib) +
|Takes leadership of Medina ''
(Yathrib) ''
|-
|-
|align="right">|''c''. 622
|align="right">|''c''. 622
Line 168: Line 168:
|Gains access to Mecca shrine Ka'ba
|Gains access to Mecca shrine Ka'ba
|-
|-
−
|align="right">|628 ] +
|align="right">|628
|Conquest of the Battle of Khaybar oasis
|Conquest of the Battle of Khaybar oasis
|-
|-
|align="right">|629
|align="right">|629
−
|First hajj pilgrimage +
|First [[
hajj ]]
pilgrimage
|-
|-
|align="right">|629
|align="right">|629
−
|Attack on [[Byzantine empire
]] fails: Battle of Mu'ta +
|Attack on [[Byzantine Empire
]] fails: Battle of Mu'ta
|-
|-
|align="right">|630
|align="right">|630
−
|Attacks and bloodlessly
captures Mecca +
|Attacks and captures Mecca without bloodshed
|-
|-
|align="right">|''c''. 630
|align="right">|''c''. 630
Line 190: Line 190:
|-
|-
|align="right">|''c''. 631
|align="right">|''c''. 631
−
|Subjugates Arabian peninsula
tribes +
|Subjugates Arabian Peninsula
tribes
|-
|-
|align="right">|''c''. 632
|align="right">|''c''. 632
Line 205: Line 205:
|-
|-
|align="right">|''c''. 632
|align="right">|''c''. 632
−
|[[Abu Bakr]] ( Caliph
) reimposes
rule by divine law +
|[[Abu Bakr]] ( [[caliph]]
) re-imposes
rule by divine law
|}
|}
<!-- END TIMELINE —>
<!-- END TIMELINE —>
===The first revelations===
===The first revelations===
+ Muhammad routinely spent nights in a cave (Hira) near [[Mecca]] in [[meditation]] and thought. Muslims believe that around the year 610, while meditating, Muhammad had a vision of the [[angel]] [[Gabriel]] and heard a voice saying to him (in rough translation): "Read in the name of your Lord the Creator. He created man from something that clings. Read, and your Lord is the Most Honored. He taught man with the pen; taught him all that he knew not" (See ''surat'' ''Al-Alaq'', Q96). Muslims stress that Muhammad had never taken part in [[idol]] worship (just as [[Abraham]] kept himself apart from idolatry in Ur; see Q6:79). This experience took place on what became known as the "Night of Power and Excellence," (the night worth a thousand months, Q97:1-5) in the month of Ramadan (the month of the fast). It was his unhappiness with the ethics and religious practices of his peers that compelled him to seek spiritual retreat in the cave.
−
Muhammad routinely spent nights in
a cave (Hira) near Mecca in [[meditation]]
and thought
. Muslims believe that around the year 610
, while meditating
,
Muhammad had a vision
of the Angel Gabriel and heard a voice saying to him
( in rough translation
) "Read in the name of your Lord the Creator. He created man from something which clings. Read
, and your Lord is the Most Honored. He taught man with the pen; taught him all
that he knew not
. " (See
' 'surat'' ''Al
-
Alaq''
, Q96.) Muslims stress that Muhammad had never taken part in idol worship (just as Abraham kept himself apart from idolatry in Ur; see Q6: 79). This experience took place on what became known as the (the "Night of Power
and Excellence
, " the night worth a thousand months, Qur
' an 97:1-5) in the month of Ramadan (the month of the fast)
. It was his unhappiness with
the
ethics and religious practices
of his peers that compelled him to seek spiritual retreat in the cave
.
+
The first vision of Gabriel disturbed
Muhammad , but Khadijah reassured him that it was
a true vision
and
became his first follower
. She is said to have consulted her relative
, Warakah
, renowned for his knowledge
of
scripture
( Christian scripture
), who was also convinced
that God was choosing Muhammad as a Prophet
. She was soon followed by Muhammad
' s ten-year
- old cousin [[Ali ibn Abi Talib]]
, and [[Abu Bakr]]
, whom Sunnis assert to have been Muhammad
' s closest friend
. Some sources reverse
the order
of their conversion
.
−
The first vision
of Gabriel disturbed
Muhammad, but Khadijah reassured him that it
was a true vision and became his
first follower
. She is said to have consulted her relative
, Warakah
, renowned for his knowledge of scripture (Christian scripture)
, who
was also convinced that Muhammad was being chosen as
a Prophet by God
. She was soon followed by Muhammad's ten-year-old cousin [[Ali ibn Abi Talib]]
, and [[Abu Bakr]]
, whom Sunnis assert to have been
Muhammad' s closest friend
. Some sources reverse
the order
of their conversion
.
+ ===Muhammad's experience
of revelation===
+
Until his death,
Muhammad received frequent [[revelation]]s
, although there
was a relatively long gap after the
first revelation
. This silence worried him, until he received ''surat'' ''ad-Dhuha''
, whose words provided comfort and reassurance. The ''hadith'' tell us more about how Muhammad experienced revelation. Often
, he saw Gabriel. Sometimes
, revelation
was preceded by what sounded like the ringing of
a bell
. The words seemed as if they were burnt into his heart
, and he had no choice but to proclaim them. Even on bitterly cold nights
, the experience left him dripping with sweat. Tradition says that before
Muhammad died, Gabriel recited the whole of the Qur
' an again to ensure that no content was lost and that all the verses were correctly remembered
. He often wrapped himself in his cloak during
the experience
of
receiving revelation
.
− ===Muhammad's Experience of Revelation=== +
According to tradition, Muhammad was unlettered. He is described as the ''al-nabiyy-al-ummiy'' (Q7:157; 62:2) ,
which is usually understood to mean that he was illiterate. This safeguards the Qur'an's integrity for Muslims as completely divine, containing no human content. Non-Muslims, who often claim that Muhammad wrote the Qur'an ,
dispute this —
but Muslims argue that even if Muhammad was not entirely [[
illiterate ]]
, no human could have composed the Qur'an ,
which is a miracle
of language and incomparable as a work in Arabic. Muslims often dislike calling the Qur'an a 'text ,
' since this compares it with human creations while it has no human author. S. H .
Nasr (1994) compares the unletteredness
of Muhammad with Mary's [[
virginity ]]
:
− Until his death, Muhammad received frequent revelations, although there was a relatively long gap after the first revelation. This silence worried him, until he received ''surat'' ''ad-Dhuha'', whose words provided comfort and reassurance. The ''hadith'' tell us more about how Muhammad experienced revelation. Often, he saw Gabriel. Sometimes, revelation was preceded by what sounded like the ringing of a bell. The words seemed as if they were burnt into his heart, and he had no choice but to proclaim them. Even on bitterly cold nights, the experience left him dripping with sweat. Tradition says that before Muhammad died, Gabreil recited the whole of the Qur'an again to ensure that no content was lost and that all the verses was correctly remembered. He often wrapped himself in his cloak during the experience of receiving revelation.
According to tradition, Muhammad was unlettered. He is described as the ''al-nabiyy-al-ummiy'' (Q7: 157; 62: 2) which is usually understood to mean that he was illiterate.
This safeguards the Qur'an's integrity for Muslims as completely divine, containing no human content.
Non-Muslims, who often claim that Muhammad wrote the Qur'an dispute this but Muslims argue that even if Muhammad was not entirely illiterate, no human could have composed the Qur'an which is a mircale
of language and incomparable as a work in Arabic.
Muslims often dislike calling the Qur'an a 'text' ,
since this compares it with human creations while it has no human author. S. H Nasr (1994) compares the unletterdness
of Muhammad with Mary's virginity:
−
:the
human vehicle of a Divine Message must be pure and untainted ... If this word is in the form of flesh, the purity is symbolised
by the virginity of the mother ... if it is in the form of a book this purity is symbolized by the unlettered nature of the person who is chosen to announce this word (44). +
<blockquote>The
human vehicle of a Divine Message must be pure and untainted ... If this word is in the form of flesh, the purity is symbolized
by the virginity of the mother ... if it is in the form of a book this purity is symbolized by the unlettered nature of the person who is chosen to announce this word (44). </blockquote>
−
Around 613, Muhammad began to spread his message amongst the people. Most of those who heard his message ignored it. A few mocked him. Some, however, believed and joined his small following of companions (called the believers,''al-mu'minum'').
Many of these supporters were from the poorest and most oppressed classes, although some were powerful and influential
. Others mocked and made fun of him, calling him a magician, a soothsayer, a poet (the Qur'an is rhymed prose but Muhamamd always rejected the accusation that he was a poet)
.
+
Around 613, Muhammad began to spread his message amongst the people. Most of those who heard his message ignored it. A few mocked him
, calling him a magician, a soothsayer, a poet (the Qur'an is rhymed prose but Muhammad always rejected the accusation that he was a poet)
. Some, however, believed —
and joined his small following of companions (called the believers, ''al-mu'minum''). Many of these supporters were from the poorest and most oppressed classes, although some were powerful and influential.
===Rejection===
===Rejection===
+ As the ranks of Muhammad's followers swelled, he became a threat to the local tribes and the rulers of the city. Their wealth rested on the Ka'bah, a sacred house of idols and the focal point of Meccan religious life. If they threw out their idols, as Muhammad preached, there would be no more pilgrims, no more trade, and no more wealth. Muhammad’s denunciation of [[polytheism]] was especially offensive to his own tribe, the Quraysh, as they were the guardians of the Ka'bah. Muhammad and his followers were persecuted. Muhammad's enemies boycotted his supporters' businesses and sometimes attacked them in the streets. Poets denounced him. His own prestigious pedigree protected him from physical harm. Concerned for the safety of his small following, Muhammad sent a group to [[Abyssinia]] and founded a small colony there. The Christian ruler received them with courtesy.
−
As the ranks of
Muhammad's followers swelled, he became a threat to the local tribes and the rulers of the city. Their wealth rested on the Ka'bah
, a sacred house of idols and the focal point of Meccan religious life. If they threw out their idols
, as
Muhammad preached
, there would
be no more pilgrims, no more trade,
and no more wealth. Muhammad’s denunciation of [[polytheism]] was especially offensive to his own tribe
, the Quraysh, as they were the guardians of
the Ka'bah . Muhammad and his followers were persecuted. Muhammad's enemies boycotted his supporters' businesses and sometimes atacked them
in
the streets
. Poets denounced
him . His own prestigious pedigree protected him from physical harm.
+ ===
Muhammad's message in Mecca===
−
Concerned for the saftey of his small following
, Muhammad sent a group to [[Abyssinia]]
and founded a small colony there. The Christian ruler received them with courtesy
.
+
The one just [[God]]
, Allah
, whose existence
Muhammad
proclaimed was incomparable
, could not
be represented
and, unlike
the gods and goddesses surrounding
the Ka'bah , Allah (God
in Arabic, a masculine form) has neither partners nor offspring
. The Arabs did revere Allah but thought
him remote and aloof
, while impersonal
and
arbitrary time ''(zaman)'' controlled human destiny
.
− ==Muhammad's Message== +
As well as fearing that their income stream was under threat, the polytheists were also alarmed by the egalitarian message that Muhammad proclaimed. The nobility controlled justice, to their own advantage, and they had no desire to relinquish their elite
privileges. Several ''suras'' (chapters) and parts of ''suras'' are said to date from this time, and reflect its circumstances: see for example ''al-Masadd'', ''al-Humaza'', parts of ''Maryam'' and ''Al-Anbiya'', ''al-Kafirun'', and ''Abasa''
.
− The one, just God, Allah, whose existence Muhammad proclaimed was incomparable, could not be represented and, unlike the gods and goddesses surrounding the Ka'bah, Allah (God in Arabic, a masculine form) has neither partners nor offsprng. The Arabs did revere Allah but thought him remote and aloof, while impersonal and arbitrary time (''zaman'') controlled human destiny.
As well as fearing that their income stream was under threat, the polytheists were also alarmed by the egalitarian message that Muhammad proclaimed. The nobility controlled justice, to their own advantage, and they had no desire to relinquish their elite priviliges
.
−
Several ''suras'' (chapters) and parts of ''suras'' are said to date from this time, and reflect its circumstances: see for example ''al-Masadd'', ''al-Humaza'', parts of ''Maryam'' and ''Al-Anbiya'', ''al-Kafirun'', and ''Abasa''.
It was during this period that the episode known as the Satanic Verses may have occurred. Some non-Muslims think that Muhammad was briefly tempted to relax his condemnation of Meccan polytheism and buy peace with his neighbors, but later recanted his words and repented (see Q53: 19-22 and also Q22: 52-3 which says that whenever Muhammad received relevation
, Satan tried to substitute his words for the divine words. The incident is reported in only a few sources (see Guillaume, 1955:
146- 8 for Ibn Ishaq's account
), and Muslims disagree as to its authenticity.
+
It was during this period that the episode known as the
"
Satanic Verses "
may have occurred. Some non-Muslims think that Muhammad was briefly tempted to relax his condemnation of Meccan polytheism and buy peace with his neighbors, but later recanted his words and repented (see Q53:19-22 and also Q22:52-3 which says that whenever Muhammad received revelation
, Satan tried to substitute his words for the divine words. The incident is reported in only a few sources (see Guillaume 1955
, 146-
148
), and Muslims disagree as to its authenticity.
In 619, both Muhammad's wife Khadijah and his uncle Abu Talib died. It was known as ''"the year of mourning."'' Muhammad's own clan withdrew their protection of him. Muslims patiently endured hunger and persecution. It was a bleak time.
In 619, both Muhammad's wife Khadijah and his uncle Abu Talib died. It was known as ''"the year of mourning."'' Muhammad's own clan withdrew their protection of him. Muslims patiently endured hunger and persecution. It was a bleak time.
===Isra and Miraj===
===Isra and Miraj===
+ [[Image:Miraj2.jpg|thumb|250 px|right|A sixteenth-century [[Persian Empire|Persian]] miniature painting celebrating Muhammad's ascent into the Heavens, a journey known as the [[Miraj]]; Muhammad's face is veiled]]
+ About 620, Muhammad went on the ''Isra'' and ''Miraj'' (night journey and ascension), a two-part journey he took in one night. ''Isra'' is the Arabic word referring to what it regarded as Muhammad's miraculous night journey from [[Mecca]] to [[Jerusalem]], specifically, to the site of the ''Masjid al-Aqsa'', the [[al-Aqsa Mosque]]. It is believed to have been followed by the ''Miraj'', his ascension to heaven, where he toured [[heaven]] and [[hell]], and spoke with Allah and earlier prophets (including Moses, Abraham and Jesus) and received the instruction that his followers should pray five times daily. Non-Muslims are skeptical about the authenticity of this event, while some Muslims suggest that it was a spiritual and not a physical experience (see Asad 1981, 187).<ref>Muhammad Asad (1900-1992) was a converted [[Jew]], named Leopold Weiss at birth, who became an important scholar of Islam.</ref> Certainly, this experience gave Muhammad great encouragement and comfort at a critical period in his career.
−
About 620
, Muhammad went on
the '' Isra
'' and ' 'Miraj''
, ( Night Journey
and
Ascension
) a two-part journey he took in one night
. '' Isra
'' is
the Arabic word referring
to what it regarded as Muhammad
' s miraculous night journey from
[[Mecca]] to
[[ Jerusalem
]], specifically, to the site
of Masjid al-Aqsa
. It is believed to have been followed by the ''Miraj''
, his ascension to heaven
, where he toured
[[ heaven
]] and [[hell]]
, and spoke with Allah
and earlier prophets
( including Moses, Abraham
and Jesus
) and received
the instruction
that his followers should pray five times daily
. Non-Muslims are skeptical about
the
authenticity
of this event, while some Muslims suggest that it was a spiritual
and not
a phyisical experience
( see Asad, 1981
: 187
). Muhammad Asad
( 1900-92
) was
a converted Jew
, named Leopold Weiss at birth who became an important scholar of Islam. Certainly, this experience gave Muhammad great encouragement and comfort at a critical period in his career
.
+ ===Hijra===
+
By 622, life in the small Muslim community of [[Mecca]] was becoming not only difficult, but also dangerous. Muslim traditions say that there were several attempts to assassinate Muhammad. Muhammad then resolved to emigrate to [[Medina]], then known as Yathrib, a large [[agriculture|agricultural]] oasis where there were a number of Muslim converts. By breaking the link with his own tribe
, Muhammad demonstrated that tribal and family loyalties were insignificant compared to the bonds of [[Islam]], a revolutionary idea in
the tribal society of Arabia. This
'' Hijra
'' or emigration (traditionally translated into English as "flight") marks the beginning of the Islamic calendar. The Muslim calendar counts dates from the Hijra, which is why Muslim dates have the suffix A.H. (After Hijra). Only after the Hijrah were the believers called Muslims, the religion Islam (Q5:3)
and the five daily prayers established. There has been some speculation whether the migration was voluntary or forced. Not all of Muhammad
' s followers fled
, though those who stayed behind may have been compelled to remain by the Quraysh. Others belonged to split families
( which had Muslim
and non-Muslim members
) and could not freely leave.
+
+
Muhammad came to Medina as a mediator, invited to resolve the feud between the Arab factions of Aws and Khazraj. He ultimately did so by absorbing both factions into his Muslim community, and forbidding bloodshed among Muslims. However, Medina was also home to
a
number of Jewish tribes (whether they were ethnically as well as religiously Jewish is an open question, as is the depth of their “Jewishness”). Muhammad had hoped that they would recognize him as a prophet, but they did not do so
. Some academic historians suggest that Muhammad abandoned hope of recruiting Jews as allies or followers at this time, and thus the
'' qibla
'' , the Muslim direction of prayer, was changed from the site of
the former [[Temple of Jerusalem]]
to the Ka
' bah in
[[Mecca]] . Muhammad built a
[[ mosque
]], which also contained his living quarters and those
of his wives
. Later, he would teach
, preach
, receive
[[ diplomacy|diplomatic delegations
]] and adjudicate disputes in the mosque, where he was also buried.
+
+
While at Mecca, the Qur'anic revelations had in the main preached justice, fair treatment of the poor
, and worship of the one God
and condemnation of idolatry. Now, more detailed legal content was revealed The Muslim community ''(ummah)'' was to be the best community
( Q3:110) and Muslims were to be a people who forbid the wrong
and invite goodness (Q3:104
) . The primacy of God's will over human will
and the need to submit the whole of one's life to God are dominant themes. The unity ''(tawhid)'' of the ''ummah'' should reflect
that of Allah, holding different qualities in balance— leisure, work and prayer, for example—in equal measure. Inner piety must accompany outward conformity to religious ritual
. The created world is beloved of God; the sun, the moon, the trees and
the hills praise God (Q22:18), thus Islam recognizes no absolute ownership
of property
and
regards human domination of the planet as
a sacred trust ''
( amana)''. All is eventually to be returned to the true owner (Q23
: 115
). The rich must care for the less fortunate, thus ''zakat''
( a tithe given to the disadvantaged
) is one of
a Muslim's obligations (''fard''
,
duties)
.
−
=== Hijra
=== +
=== Muhammad and followers of other monotheistic faiths
===
+ Muhammad did not completely reject [[Judaism]] and [[Christianity]], the two other [[monotheism|monotheistic]] faiths that were known to the Arabs and which are referred to in the Qur'an; he said to have been sent by God in order to complete and perfect their teachings. He soon acquired a following by some and rejection and hatred by others in the region.
−
By 622, life in
the small Muslim community of Mecca was becoming not only difficult
, but dangerous.
Muslim traditions say that there
were several attempts to assassinate Muhammad
. Muhammad then resolved to emigrate to [[Medina]], then
known as Yathrib, a large agricultural oasis where there were a number
of Muslim converts
. By breaking
the link with his own tribe
,
Muhammad demonstrated that tribal and family loyalties were insignificant compared to
the bonds of
[[ Islam
]], a revolutionary idea in
the tribal society
of
Arabia
. This ''Hijra'' or emigration (traditionally translated into English as "flight") marks
the beginning
of the Islamic calendar
. The Muslim calendar counts dates from the Hijra
, which is why Muslim dates have
the suffix AH (After Hijra). Only after
the Hijrah were
the believers called Muslims
, the
religion Islam (Q5: 3)
and the five daily prayers established. There has been some speculation whether the migration was voluntary or forced. Not all of Muhammad's followers fled
, though those who stayed behind may have been compelled
to remain by
the Quraish. Others belonged to split families
( which had Muslim
and non-Muslim members
) and could not freely leave
.
+
In contrast to the [[paganism|pagans]] who were given
the
stark choice to convert or be expelled
, Jewish and Christian settlements within
Muslim territories
were
tolerated and taxed
. Muhammad drafted a document now
known as the ''Constitution
of Medina'' (c
. 622-623), which laid out
the terms on which the different factions
,
specifically
the [[ Jew
]] s, could exist within the new state. In this system
, the Jews and other "Peoples
of the Book" were allowed to keep their religions as long as they paid tribute
. This
system would come to typify Muslim relations with their non-believing subjects and that tradition was one reason for
the stability
of the later Muslim [[caliph]]ate
. In this
, the Islamic empire was more tolerant than
the other great powers of
the area
, the [[Byzantine Empire|Byzantine]]
and [[Sassanid Empire|Sassanid]] empires
, which were actively hostile
to any religions or sects other than
the state-sponsored religions
( [[Orthodox Christianity]]
and [[Zoroastrianism]]
).
− Muhammad came to Medina as a mediator, invited to resolve the feud between the Arab factions of Aws and Khazraj. He ultimately did so by absorbing both factions into his Muslim community, and forbidding bloodshed among Muslims. However, Medina was also home to a number of Jewish tribes (whether they were ethnically as well as religiously Jewish is an open question, as is the depth of their "Jewishness"). Muhammad had hoped that they would recognize him as a prophet, but they did not do so. Some academic historians suggest that Muhammad abandoned hope of recruiting Jews as allies or followers at this time, and thus the ''qibla'', the Muslim direction of prayer, was changed from the site of the former [[Temple]] in [[Jerusalem]] to the Ka'bah in [[Mecca]]. Muhammad built a Mosque, which also contained his living quarters and those of his wives. Later, he would teach, preach, receive diplomatic delegations and adjudicate disputes in the Mosque, where he was also buried. While at Mecca, the Qur'anic revelations had in the main preached justice, fair treatment of the poor, worship of the one God and condemnation of idolatry. Now, more detailed legal content was revealed The Muslim community (''ummah'') was to be the best community (3:110) and Muslims were to be a people who forbid the wrong and invite goodness (Q3: 104). The primacy of God's will over human will and the need to submit the whole of one's life to God are dominant themes. The unity ''tawhid'') of the ''ummah'' should reflect that of Allah, holding different qualities in balance - leisure, work and prayer, for example, in equal measure. Inner piety must accompany outward conformity to religious ritual. The created world is beloved of God; the sun, the moon, the trees and the hills praise God (Q22: 18), this Islam recognizes no absolute ownership of property and regards human domination of the planet as a sacred trust (''amana''). All is eventually to be returned to the true owner (Q23: 115). The rich must care for the less fortunate, thus ''zakat'' (a tithe given to the disadvantaged) is one of a Muslim's obligations (''fard'', duties). +
Although Islam supercedes or completes
the earlier religions of Judaism and Christianity (see Q3:1-2) ,
Muslims recognize a family relationship between all three Abrahamic faiths. [[
Abraham ]]
is an important character in the Qur’an,
which describes him as neither a Jew nor a Christian but a Muslim (see Q2
:134). Christians and Jews are criticized
for claiming that only they are saved ( Q2
:111) and for corrupting the originally pure messages they had received. Christians are wrong to make [[
Jesus of Nazareth|Jesus]]
into God (or God's son) since he had pointed to God, not to himself ( Q3
:51). The category of protected minority '' (
dhimmi )
'' established by Muhammad
was permitted
to retain their faith in return for relinquishing arms and payment of a [[
tax ]]
( Muhammad
stipulated that they should not be taxed too heavily). Muhammad said that whoever harms a ''dhimmi'', harmed him. On one occasion
, when a Christian delegation from Najran visited
him in Medina
, he allowed them to pray in his own mosque,
as there was no church
available (see Guillaume 1955
, 271).
− ===Muhammad and Followers of Other Monotheistic Faiths===
−
Non-Muslim settlements within Muslim territories were taxed rather than expelled. Muhammad drafted a document now known as the ''Constitution of Medina'' (ca. 622-623), which laid out the terms on which the different factions, specifically the [[Jews]], could exist within the new state. In this system, the Jews and other "Peoples of the Book" were allowed to keep their religions as long as they paid tribute. This system would come to typify Muslim relations with their non-believing subjects and that tradition was one reason for the stability of the later Muslim caliphate. In this, the Islamic empire was more tolerant than the other great powers of the area, the [[Byzantine Empire|Byzantine]] and [[Sassanid]] empires, which were actively hostile to any religions or sects other than the state-sponsored religions ([[Orthodox Christianity]] and [[Zoroastrianism]]).
Although Islam supercedes or complates
the earlier religions of Judaism and Christianity (see Q3: 1-2)
Muslims recognize a family relationship between all three Abrahamic faiths.
Abraham is an important character in the Qur'an
which describes him as neither a Jew nor a Christian but a Muslim (see 2
: 134). Christians and Jews are criticised
for claiming that only they are saved ( 2
: 111) and for corrupting the originally pure messages they had received.
Christians are wrong to make Jesus into God (or God's son) since he had pointed to God, not to himself ( 3
: 51).
The category of protected minority (
''dhimmi'' )
established by Muhammad were permiited
to retain their faith in return for relinquishing arms and payment of a tax ( Muhamamd
stipulated that they should not be taxed too heavily).
Muhammad said that whoever harms a ''dhimmi'', harmed him.
On one occassion
, when a Christian delegation from Najran visted
him in Madina
, he allowed them to pray in his own Mosque
as there was no Church
available (see Guillaume, 271).
===War===
===War===
+ Relations between [[Mecca]] and [[Medina]] rapidly worsened (see ''surat'' ''al-Baqara''). Meccans confiscated all the property that the Muslims had left in Mecca. From Medina, Muhammad signed treaties of alliance and mutual help with neighboring tribes.
−
Relations between
[[ Mecca
]] and [[ Medina
]] rapidly worsened (see
' 'surat'' ''al-Baqara'')
. Meccans confiscated all
the property that
the Muslims had left in Mecca
. From
Medina, Muhammad signed treaties
of alliance
and mutual help
with neighboring tribes
.
+
At a certain point, Muhammad began to engage in the old
[[ Arab
]] ian practice of raiding caravans bound for Mecca. Some have criticized this decision
and practice, but others insist that it is justified by the circumstances. Meccan-Muslim relations had degenerated virtually to a state of
[[ war
]] . As such it is argued that Islam
' s very survival depended on such action. Muslims owned no land in Medina and absent such raids they would have to live on charity and on sparse chances for wage labor.
+
+
In March of 624, Muhammad led some three hundred warriors in a raid on a Meccan merchant caravan
. The
Meccans successfully defended
the caravan, and then decided to teach
the Medinans a lesson
. They sent a small army against
Medina . On March 15
, 624, near a place called [[Battle
of Badr|Badr]], the Meccans
and the Muslims clashed. Though outnumbered eight hundred to three hundred in the battle, the Muslims met
with success, killing at least 45 Meccans and taking 70 prisoners for ransom; only 14 Muslims died. This marked the real beginning of Muslim military achievement and followed from a verse of the Qur'an that gave them permission to fight against persecution (Q 22:39). Previously, all resistance to oppression had been non-violent
.
−
At a
certain point
, Muhammad began
to engage in the old Arabian practice of raiding caravans bound for Mecca. Some
have criticised
this decision and practice
, but others insist that it is justified by
the circumstances
. Meccan-
Muslim relations had degenerated virtually
to a state of
war . As such it is argued that
Islam's very survival depended on such action
. Muslims owned no land in Medina
and absent such raids they would have
to live on charity and on sparse chances for wage labor
.
+
The verse that allowed Muslim men to marry, in
certain
circumstances
, up to four wives (Q4:3) is widely believed
to have been revealed shortly after
this battle
, which left some widows without protection. Other revelations became known as
the "sword verses," such as Q9:5 and Q2:216
. Muslim rulers subsequently used these verses to justify aggressive war
to extend the borders of the Islamic empire; however when these verses were first revealed the Muslim community was already engaged in
a war for
Islam's very survival. Defenders of these verses' subsequent use to justify conquest remark that it was a time when many empires were competing for supremacy
and used force
to do so
.
− In March of 624, Muhammad led some 300 warriors in a raid on a Meccan merchant caravan. The Meccans successfully defended the caravan, then decided to teach the Medinans a lesson. They sent a small army against Medina. On March 15, 624 near a place called [[Battle of Badr|Badr]], the Meccans and the Muslims clashed. Though outnumbered 800 to 300 in the battle, the Muslims met with success, killing at least forty-five Meccans and taking seventy prisoners for ransom; only fourteen Muslims died. This marked the real beginning of Muslim military achievement and followed from a verse of the Qur'an that gave them permission to fight against persecution (Q22: 39). Previously, all resistance to oppression had been non-violent. The verse that allowed Muslim men to marry, in certain circumstances, up to four wives (Q4: 3) is widely believed to have been revealed shortly after this battle, which left some widows without protection. Other revelations became known as the sword verses, such as Q 9: 5 and Q2: 216 which Muslim rulers subsequently used to justify aggressive war to extend the borders of the Islamic empire, although some Muslims argue that these texts refer to situations in which Muslims were already engaged as defendants in a war for Islam's very survival. Others simply point out that at the time, many Empires were competing for supremacy and used force to do so. Thus,
Islam, while no different from other contemporary powers in using force to spread its empire, nonetheless set out strict rules for the conduct of war that protected civilians, places of worship, crops and animals from harm.
The accusation that Islam spread by means of the sword, forcing to convert at the point of a sword, is hotly contested by Muslims who argue that what spread was Muslim rule while embracing the faith was voluntary.
Evidence is that large portions of the Empire
remained non-Muslim for centuries, although over time the non-Muslims became minorities in many regions. It is, however, documented that over zealous
Muslim conquerors sometimes did use force to convert the vanguished
but this should not be taken as the norm.
+
Islam, while no different from other contemporary powers in using force to spread its empire, nonetheless set out strict rules for the conduct of war that protected civilians, places of worship, crops and animals from harm. The accusation that Islam spread by means of the sword, forcing to convert at the point of a sword, is hotly contested by Muslims who argue that what spread was Muslim rule ,
while embracing the faith was voluntary. Evidence is that large portions of the empire
remained non-Muslim for centuries, although over time the non-Muslims became minorities in many regions. It is, however, documented that overzealous
Muslim conquerors sometimes did use force to convert the
vanquished
but this should not be taken as the norm.
===Muhammad's rule consolidated===
===Muhammad's rule consolidated===
+ To the Muslims, the victory in Badr appeared as a divine vindication of Muhammad's [[prophet]]hood, and he and all the Muslims rejoiced greatly. Following this victory, after minor skirmishes, and the breaking of a treaty that risked the security of the [[city-state]], the victors expelled a local Jewish clan, the Banu Qainuqa. Virtually all the remaining Medinans converted, and Muhammad became ''de facto'' ruler of the city. Alongside the Qur'an, his own edicts ''(sunnah)'' became part of the sacred regulations that governed the life of the community. Many Muslims regard this as the ideal for all human society—to be governed by an individual whose life is centered on God and who has no self-interest. Others suggest that Muhammad’s temporal or political authority resulted from the particular circumstances in which he found himself.
−
To the Muslims, the victory in Badr appeared as a divine vindication of Muhammad's prophethood, and he and all
the Muslims rejoiced greatly. Following this victory, after minor skirmishes,
and the breaking
of a treaty that risked the security of the city state, the victors expelled a local Jewish clan, the Banu Qainuqa. Virtually all the remaining Medinans converted, and Muhammad became ''de facto'' ruler of the city. Alongside the Qur'an, his own edicts (''sunnah'') became part of the sacred regulations that governed the life of the community. Many Muslims regard this as the ideal for all human society - to be governed by an individual whose life is centered on God, who has no self-interest. Others suggest that Muhammad'a temporal or political authority resulted from the particular circumstances in which he found himself. While this
helped to ensure Islam's survival it does
not represent a precedent
for all times and places. Muslims , however,
are careful to ascertain whether Muhammad intended a particular edict to be universally binding, or not
before they deem it to be mandatory for all Muslims.
The most important tool here is what is called the 'circumstance
of revelation'
although the technical term also carries the meaning of 'reason'
(to reason).
Knowledge ,
or information ,
about the context in which a verse of the Qur'an or a saying of Muhammad was first uttered depends on the witness statements of Muhammad's companions.
These accounts describe the context and whether or not the revelation addressed a general situation, or responded to a particular question asked by someone, or to a specific issue.
If the former, the verse or saying becomes universally binding.
If either of the latter, the witness (who must be a close companion or relative of Muhammad) will detail whether, in their view, the verse was only intended to speak to the specific situation, or applies to all Muslims.
Some debate, clearly, can result and there is a strong tradition in Islam that all such rulings are tentative.
However, the ''ijma'' or consensus rule, based on Muhammad's advice that his people would not agree in error, often results in agreement.
+
While measures promulgated during
the war with Mecca
and the consolidation
of Islamic rule
helped to ensure Islam's survival , they may
not necessary
represent
precedents
for all times and places. Muslims are careful to ascertain whether Muhammad intended a particular edict to be universally binding, before they deem it to be mandatory for all Muslims. The most important tool here is what is called the “circumstance
of revelation”
although the technical term also carries the meaning of “reason”
(to reason). Knowledge or information about the context in which a verse of the Qur'an or a saying of Muhammad was first uttered depends on the witness statements of Muhammad's companions. These accounts describe the context and whether or not the revelation addressed a general situation, or responded to a particular question asked by someone, or to a specific issue. If the former, the verse or saying becomes universally binding. If either of the latter, the witness (who must be a close companion or relative of Muhammad) will detail whether, in their view, the verse was only intended to speak to the specific situation, or applies to all Muslims. Some debate, clearly, can result and there is a strong tradition in Islam that all such rulings are tentative. However, the ''ijma'' or consensus rule, based on Muhammad's advice that his people would not agree in error, often results in agreement.
−
The commonly accepted view is that any material that 'attaches
solely to the historical event'
must be distinguished from that which 'although
attached to the historical event, also has wider implications'
(Denffer, 1989:
103).
For
exampple
, Q5: 41 which says that the penalty for theft is amputation, was revealed 'concerning
a specific person who had stolen a piece of armour
, and had been punished accordingly'
is taken to be universally binding, although some Muslims understand this ''hudud'' (extreme) punishment to be translatable into an alternative but equally stern penalty.
Others insist that any Muslim state that substitutes an alternative penalty departs from true Islam
. Some sayings of Muhammad are taken as mandatory, others as only advisory but major difference in practice and consequecnes for policing Islamic faithfulness may result. For example, Muslims who believe that men must wear beards (that it is ''haram'', prohibited, to shave) and also that beards must be long not short may enforce this rule by publically humiliating shaved men [http://www.islam.tc/beard/beard.html]. Similarly, dispute about whether the head-covering for women is optional or mandatory also leads to disciplinary action in parts of the Muslim world. Other Muslims strongly reject such actions as petty and obscurantist, totally contrary to Islam's concern for human upliftment, charity and godliness
.
+
The commonly accepted view is that any material that
“attaches
solely to the historical event”
must be distinguished from that which “although
attached to the historical event, also has wider implications”
(Denffer
1989
, 103). For example
, Q5:41 ,
which says that the penalty for theft is amputation, was revealed “concerning
a specific person who had stolen a piece of armor
, and had been punished accordingly”
is taken to be universally binding, although some Muslims understand this ''hudud'' (extreme) punishment to be translatable into an alternative but equally stern penalty. Others insist that any Muslim state that substitutes an alternative penalty departs from true Islam.
−
After Khadija's death,
Muhammad married again
, to [[Aisha]] daughter of his friend [[Abu Bakr]] (who later emerged
as the first leader of the Muslims after Muhammad's death)
. In Medina
, he married Hafsah, daughter of [[Umar ibn al-Khattab|Umar]]
( who would eventually become Abu Bakr
' s successor
) . These marriages sealed relations between Muhammad
and his top-ranking followers
.
These men played imortant roles
, advising Muhammad, who always consulted on important matters
.
+
Some sayings of
Muhammad are taken as mandatory
,
others
as only advisory but major difference in practice and consequences for policing Islamic faithfulness may result
. For example
, Muslims who believe that men must wear beards
( that it is ''haram'
' , prohibited to shave
) and
also that beards must be long not short may enforce this rule by publicly humiliating shaved men
. <ref>Mufti Afzal Elias
, [http://www.islam
. tc/beard/beard
. html “What Islam says About
the Beard
, ”
] Islam.tc
. Retrieved August 10
,
2007.</ref> Similarly
, dispute about whether the head covering for women is optional or mandatory also leads
to
disciplinary action in parts
of the Muslim world
. Other
Muslims strongly reject such actions
as petty and obscurantist, totally contrary to Islam
' s concern for human betterment
, charity and godliness
.
−
−
Muhammad's daughter [[Fatima]] married [[Ali ibn Abi Talib|Ali]], Muhammad's cousin
. According to
the Sunni, another daughter, Umm Kulthum
, married [[Uthman ibn Affan|Uthman]
]. Each of these men
, in later years
, would emerge as successors
to Muhammad and political leaders of the Muslims. Thus all four
of the first four [[caliphs]] were linked to Muhammad by blood, marriage, or both
. Sunni
Muslims regard these caliphs
as the ''Rashidun'
', or ''Rightly Guided''
.
===Continued warfare===
===Continued warfare===
+ In 625 the [[Mecca]]n general [[Abu Sufyan]] marched on [[Medina]] with three thousand men. The ensuing Battle of Uhud took place on March 23, ending in a stalemate. The Meccans claimed victory, but they had lost too many men to pursue the Muslims into Medina.
−
In 625 the [[Mecca]]n general [[
Abu Sufyan ]] marched on [[
Medina ]] with 3,000 men
. The ensuing
Battle of Uhud took place on March 23, ending in a stalemate. The Meccans claimed victory, but they had lost too many men to pursue
the Muslims into Medina
.
+
In April 627,
Abu Sufyan (whose wife, Hind, was among Muhammad's most vocal and bitter opponents) led another strong force against
Medina. But Muhammad had dug a trench around Medina and successfully defended the city in the
Battle of the Trench
.
− In April 627 Abu Sufyan (whose wife, Hind, was among Muhammad's most vocal and bitter opponents)led another strong force against Medina. But Muhammad had dug a trench around Medina and successfully defended the city in the Battle of the Trench. +
Many of the Muslims believed that Abu Sufyan had been aided by sympathizers among Jewish residents of Medina
of the clan
Banu Qurayza . As
soon as the battle was over, reprisals commenced against
the Banu Qurayza. After the Banu Qurayza were defeated, all the adult men and
one woman were beheaded by the order of Saad ibn Muadh, head of the Aws clan, an arbiter chosen by the Banu Qurayza. The remaining women and children were taken as slaves or for ransom. Some critics of Islam feel that this was unjust; Muslims believe that this was necessary. Reeves (2000) states
that ibn Muadh applied “the
law of Moses to the followers of Moses (Deuteronomy, 20:12-14) ”
(38).
−
−
Many of the Muslims believed that Abu Sufyan had been aided by sympathizers among the Medinans, the
Jewish tribe
of the Banu Qurayza and as
soon as the battle was over, reprisals commenced agains
the Banu Qurayza . After the Banu Qurayza were defeated, all the adult men as well as
one woman ,
were beheaded by the order of Saad ibn Muadh, head of the Aws clan, an arbiter chosen by the Banu Qurayza. The remaining women and children were taken as slaves or for ransom. Some critics of Islam feel that this was unjust; Muslims believe that this was necessary. Reeves (2000) says
that ibn Muadh applied 'the
law of Moses to the followers of Moses (Deuteronomy, 20: 12-14) '
(38).
Following the Battle of the Trench, the Muslims were able, through conversion and conquest, to extend their rule to many of the neighboring cities and tribes.
Following the Battle of the Trench, the Muslims were able, through conversion and conquest, to extend their rule to many of the neighboring cities and tribes.
===The conquest of Mecca===
===The conquest of Mecca===
+ By 628 the Muslim position was strong enough that Muhammad decided to return to [[Mecca]], this time as a pilgrim. In March of that year, he set out for Mecca, followed by 1,600 men. After some negotiation, a treaty was signed at the border town of al-Hudaybiyah. While Muhammad would not be allowed to finish his pilgrimage that year, hostilities would cease and the Muslims would have permission to make a pilgrimage to Mecca in the following year. The same year, correspondence occurred between Muhammad, who described himself as the 'slave of Allah' and the Byzantine emperor, [[Heraclius]] (610–641 <small>C.E.</small>) who had met Abu Sufyan and questioned him about the prophet. Reportedly, Abu Sufyan converted following this encounter, since he was convinced that if even the Byzantine emperor feared Muhammad, he would soon conquer all.<ref>See T. A. Cengia, [http://www.southcom.com.au/~cengiata/politik.htm#6 “Society and the State,”] for Muhammad's letters to various kings and emperors (including the Negus of Ethiopia and Heraclius).</ref>
− By 628, the Muslim position was strong enough that Muhammad decided to return to [[Mecca]], this time as a pilgrim. In March of that year, he set out for Mecca, followed by 1,600 men. After some negotiation, a treaty was signed at the border town of al-Hudaybiyah. While Muhammad would not be allowed to finish his pilgrimage that year, hostilities would cease and the Muslims would have permission to make a pilgrimage to Mecca in the following year. The same year correspondence occured between Muhammad, who described himself as the 'slave of Allah' and the Byzantine Emperor, Heraclius (610-641
C.E. ) who had met Abu Sufyan and questioned him about the prophet. Reportedly, Abu Sufyan converted following this encouner, since he was convinced that if even the Byzantine Emperor feared Mumammad, he would soon conquer all. See [http://www.southcom.com.au/~cengiata/politik.htm#6] for Muhammad's letters to various kings and emperors (including the Negus of Ethiopia and Heraclius).
+
The agreement lasted only two years, however, as war broke out again in 630. Muhammad marched on Mecca with an enormous force, said to number ten thousand
men. Eager to placate the powerful Muslims and anxious to regain their lucrative tribal alliances, the Meccans submitted without a fight. Muhammad ,
in turn ,
promised a general amnesty (from which a small number of people were specifically excluded). Hind begged forgiveness, and was pardoned. Most Meccans converted to [[Islam]] and Muhammad destroyed the idols in the Ka'bah. Henceforth the pilgrimage would be a Muslim pilgrimage and the shrine a Muslim shrine.
−
−
The agreement lasted only two years, however, as war broke out again in 630. Muhammad marched on Mecca with an enormous force, said to number
10,000
men. Eager to placate the powerful Muslims and anxious to regain their lucrative tribal alliances, the Meccans submitted without a fight. Muhammad in turn promised a general amnesty (from which a small number of people were specifically excluded).
Hind begged forgiveness, and was pardoned. Most Meccans converted to [[Islam]] and Muhammad destroyed the idols in the Ka'bah. Henceforth the pilgrimage would be a Muslim pilgrimage and the shrine a Muslim shrine.
===Unification of Arabia===
===Unification of Arabia===
+ The capitulation of Mecca and the defeat of an alliance of enemy tribes at Hunayn effectively brought the greater part of the Arabian world under Muhammad's authority. This authority was not enforced by any formal governments, however, as he chose instead to rule through personal relationships and tribal treaties. For his followers, Muhammad combined temporal and spiritual leadership and recognized no distinction between the sacred and the secular. Islam aims to bring the whole of life into harmony with God's will and regards the live centered on God, the life of ''taqwa'' (God-consciousness) as the ideal. Muhammad once described the whole earth as a mosque, and in its widest sense any permitted act is a form of worship. Even at the height of his power, Muhammad only ever used the title 'messenger' ''(rasul)'' or prophet ''(naby)'' and always lived very modesty (when he died he left almost no personal property). He recited, “I am just a human being like you,” except “to me is given the revelation that your God is God alone” (Q18:110). He dressed modestly and disliked ostentatious clothes.
− The capitulation of Mecca and the defeat of an alliance of enemy tribes at Hunayn effectively brought the greater part of the Arabian world under Muhammad's authority. This authority was not enforced by any formal governments, however, as he chose instead to rule through personal relationships and tribal treaties. For his followers, Muhammad combined temporal and spiritual leadership and recognized no distinction between the sacred and the secular. Islam aims to bring the whole of life into harmony with God's will and regards the live centered on God, the life of ''taqwa'' (God-consciousness) as the ideal. Muhammad once described the whole earth as a mosque, and in its widest sense any permitted act is a form of worship. Even at the height of his power, Muhammad only ever used the title 'messenger' (''rasul'') or propeht (''naby'') and always lived very modesty (when he died he left almost no personal property). He recited, 'I am just a human being like you', except 'to me is given the reveltion that your God is God alone' (Q18: 110). He dressed modestly and disliked ostentatious clothes. +
[[Image:ArabianpeninsulaAL.png|thumb| px|300
right|By his death in 632, Muhammad had consolidated his rule over the entire Arabian peninsula]]
−
−
[[Image:ArabianpeninsulaAL.png|thumb|right|By his death in 632, Muhammad had consolidated his rule over the entire Arabian peninsula .
]]
The Muslims were clearly the dominant force in Arabia, and most of the remaining tribes and states hastened to submit to Muhammad.
The Muslims were clearly the dominant force in Arabia, and most of the remaining tribes and states hastened to submit to Muhammad.
−
===Muhammad as a warrior
=== +
===Muhammad 's family life
===
+ From 595 to 619, Muhammad had only one wife, [[Khadijah]]. She was Muhammad's first wife and the mother of the only child to survive him, his daughter [[Fatima]].
−
For most
of the sixty-three years
of his life
, Muhammad
was a merchant
, then
a prophet
. He took up the sword late
in his life
. He was a warrior for only ten years
.
+
After Khadija's death, Muhammad married again, to [[Aisha]], daughter
of his friend [[Abu Bakr]] (who later emerged as
the first leader
of the Muslims after Muhammad's death). In Medina, he married Hafsah
,
daughter of [[Umar ibn al-Khattab|Umar]] (who would eventually become Abu Bakr's successor). Later he
was to marry more wives
, for
a total of 11 (nine or ten living at the time of his death)
. Some of these women were recent widows of warriors
in battle. Others were daughters of
his
close allies or tribal leaders
. These marriages sealed relations between Muhammad and his top-ranking followers. These men played important roles, advising Muhammad, who always consulted on important matters
.
−
Much criticism has been leveled at Muhammad for engaging in caravan raids and wars of conquest. Critics
say that his wars went well beyond self
- defense. Muslim commentators
, however, argue that he fought only
to defend his community against
the Meccans
, and that he insisted on humane rules of warfare
.
+
Some
say that he also married
his slave girl [[Maria al
-
Qibtiyya]]
, but other sources speak
to the contrary. She bore him a son, Ibrahim
, who died in infancy
.
− ===
Muhammad's family life=== +
Muhammad's daughter [[Fatima]] married [[Ali ibn Abi Talib|Ali]], Muhammad's cousin. According to the Sunni, another daughter, Umm Kulthum, married [[Uthman]]. Each of these men, in later years, would emerge as successors to Muhammad and political leaders of the Muslims. Thus all four of the first four [[caliph|caliphs]] were linked to Muhammad by blood, marriage, or both. [[Sunni]] Muslims regard these caliphs as the ''Rashidun'', or “Rightly Guided.”
−
From 595
to 619
, Muhammad had
only one wife,
[[ Khadijah
]] . After her death he married Aisha
, then Hafsa
. Later he was
to marry
more wives, for a total of eleven
( nine or ten living at the time of his death
). Some say
that he also married
his slave girl [[Maria al-Qibtiyya]], but other sources speak to
the
contrary
. She bore him
a son, Ibrahim, who died in infancy
.
+
His marriage
to [[Aisha]] is often criticized today
, citing traditional sources that state she was
only nine years old when he consummated the marriage.<ref>See
[[ Aisha
]]
for a discussion of other, conflicting
, traditions
. </ref> Critics also question his marriage
to his adopted son's ex-wife, Zaynab bint Jahsh, and his alleged violation of the Qur'anic injunction against marrying
more than four
wives
alleging that he fabricated the verses that allowed this
,
which also abolished adoption
( Q33:4-5; 37
). Such criticism is almost exclusively non-Muslim. Muslims take a different view, believing that Muhammad was protected as a prophet from any major error and
that his life represents
the highest standard of human behavior
. It is
a noble ''(hasan)'' ''sunnah'' (Q33:21)
.
−
Khadija was
Muhammad's first wife and the mother
of the only child to survive him
, his daughter [[Fatima]]
. He married his other
wives after
the death of Khadija. Some of these women were recent widows of warriors
in battle. Others were daughters of
his close allies or tribal leaders. One of the later unions resulted in a son
, but the child died when he was ten months old
.
+
Muhammad's multiple marriages do not match some understandings
of the ideal family as one husband and one wife. However
, special conditions may apply (as Muslims argue) given the circumstances
. The relationship between Muhammad's
wives was sometimes strained (see Q66) but they are all known as 'mothers of
the believers' and gave Muhammad great comfort and support
in his
domestic life
, enabling him to perform his public functions
.
− His marriage to [[Aisha]] is often criticized today citing traditional sources that state she was only nine years old when he consummated the marriage. (See [[Aisha]] for a discussion of other, conflicting, traditions). Critics also question his marriage to his adopted son's ex-wife, Zaynab bint Jahsh, and his alleged violation of the ''Qur'anic'' injunction against marrying more than four wives alleging that he fabricated the verses that allowed this, which also abolished adoption (Q33: 4-5; 37). Such criticism is almost exclusively non-Muslim. Muslims take a different view, believing that Muhamamd was protected as a prophet from any major error and that his life represents the highest standard of human behavior. It is a noble (''hasan'') ''sunnah'' (Q33: 21). Muhammad's multiple marriages do not match some understandings of the ideal family as one husband and one wife. However, special conditions may apply (as Muslims argue) given the circumstances. The relationship between Muhammad's wives was sometimes strained (see Q66) but they are all known as 'mothers of the believers' and gave Muhammad great comfort and support in his domestic life, enabling him to perform his public functions.
Muslim feminists contend that Muhammad was a champion of women's rights but that most of his male followers were unprepared to accept this aspect of his teaching, and subsequently altered it.
Mernissi (1991) described her ''The Veil and the Male Elite'' as
+
Muslim feminists contend that Muhammad was a champion of women's rights but that most of his male followers were unprepared to accept this aspect of his teaching, and subsequently altered it. Mernissi (1991) described her ''The Veil and the Male Elite'' as
−
:
a vessel journeying back in time in order to find a fabulous wind that will swell our sails and send us gliding towards new worlds, towards the time both far away and near the beginning of the Hejira, when the Prophet could be a lover and a leader hostile to all hierarchies, when women had their place as unquestioned partners in a revolution that made the mosque as open place and the household a temple of debate (10) .
+
<blockquote>...
a vessel journeying back in time in order to find a fabulous wind that will swell our sails and send us gliding towards new worlds, towards the time both far away and near the beginning of the Hejira, when the Prophet could be a lover and a leader hostile to all hierarchies, when women had their place as unquestioned partners in a revolution that made the mosque as open place and the household a temple of debate .
(10)
</blockquote>
−
Muslims are not embarrassed by the fact that Muhammad liked women or indeed sex, regarding this as healthy and also as providing guidance on how men should treat women, indeed on how they should engage in intimacy (praying before doing so). Muslims point out in response to Christian criticism that
Jesus does not provide them with any advice in this area. One Muslim woman comments that Jesus 'never
married, so he could not become an ideal husband and father '
, he 'did
not rise to power '
, so can not
serve 'as
a model of a benevolent just ruler and judge' -
indeed unlike Muhammad, 'his
life and character are shrouded in mystery'
(Ulfat Aziz Us-Samad, 1979:
26). In
contrast, Muhammad's life 'offers
us the perfect example in all walks of life'.
He give
us 'the
picture of an ideally happy and pious married life and of a wise, just and benevolent ruler working for the material and moral amelioration of his people
' ( ''
ibid'' )
. Reeves (2000) refers to Muhammad's love of children and says that his household was 'a
model husband -
gentle, generous, considerate and courteous'
(49). His wives were 'precious companions'
with whom he 'could
talk and on whom he could rely for frank opinions and wise advice'
(49).
Aisha, certainly, felt free to speak her mind, even in criticism.
+
Muslims are not embarrassed by the fact that Muhammad liked women or indeed sex, regarding this as healthy and also as providing guidance on how men should treat women, indeed on how they should engage in intimacy (praying before doing so). Muslims point out in response to Christian criticism that Jesus does not provide them with any advice in this area. One Muslim woman comments that Jesus “never
married, so he could not become an ideal husband and father, ” and
he “did
not rise to power, ”
so cannot
serve “as
a model of a benevolent just ruler and
judge”—
indeed unlike Muhammad, “his
life and character are shrouded in mystery”
(Ulfat Aziz Us-Samad
1979
, 26). By
contrast, Muhammad's life “offers
us the perfect example in all walks of life…[
He gives
us ] “the
picture of an ideally happy and pious married life and of a wise, just and benevolent ruler working for the material and moral amelioration of his people” '
'(ibid )
''. Reeves (2000) refers to Muhammad's love of children and says that his household was “a
model husband —
gentle, generous, considerate and courteous”
(49). His wives were
“precious companions”
with whom he “could
talk and on whom he could rely for frank opinions and wise advice”
(49). Aisha, certainly, felt free to speak her mind, even in criticism.
===Companions of Muhammad===
===Companions of Muhammad===
− +
The term '''companions''' '' (
sahabah )
'' refers to anyone who met three criteria. First, he must have been a contemporary of Muhammad. Second, he must have seen or heard Muhammad speak on at least one occasion. Third, he must have converted to Islam. Companions are responsible for the transmission of ''hadith'', as each ''hadith'' must have as its first transmitter a companion. There were many other companions in addition to the ones listed here.
−
The term '''companions''' (
''sahabah'' )
refers to anyone who met three criteria.
First, he must have been a contemporary of Muhammad.
Second, he must have seen or heard Muhammad speak on at least one occasion.
Third, he must have converted to Islam.
Companions are responsible for the transmission of ''hadith'', as each ''hadith'' must have as its first transmitter a companion. There were many other companions in addition to the ones listed here.
List in alphabetic order:
List in alphabetic order:
Line 321: Line 327:
* Talha
* Talha
* [[Umar ibn al-Khattab]]
* [[Umar ibn al-Khattab]]
−
* [[Uthman|Uthman ]
ibn Affan]] +
* [[Uthman|Uthman ibn Affan]]
* Zubair
* Zubair
===The death of Muhammad===
===The death of Muhammad===
+ After a short illness, Muhammad died around noon on Monday, June 8, 632, in the city of Medina at the age of 63.
− After a short illness, Muhammad died around noon on Monday 8 June 632, in the city of Medina at the age of sixty-three. +
According to [[
Shi'a ]]
Islam, Muhammad had appointed his son-in-law Ali as his successor, in a public sermon at Ghadir Khumm. But Abu Bakr and Umar intrigued to oust Ali and make Abu Bakr the leader or ''[[caliph]]''. The majority, the Sunni, disputes
this, and say that the leaders of the community conferred and freely chose Abu Bakr, who was pre-eminent among the followers of Muhammad. However it happened, Abu Bakr became the new leader. He spent much of his short reign suppressing rebellious tribes in the Ridda Wars.
−
−
According to Shi'a Islam, Muhammad had appointed his son-in-law Ali as his successor, in a public sermon at Ghadir Khumm. But Abu Bakr and Umar intrigued to oust Ali and make Abu Bakr the leader or ''[[caliph]]''. The majority, the Sunni, dispute
this, and say that the leaders of the community conferred and freely chose Abu Bakr, who was pre-eminent among the followers of Muhammad. However it happened, Abu Bakr became the new leader. He spent much of his short reign suppressing rebellious tribes in the Ridda Wars.
With unity restored in Arabia, the Muslims looked outward and commenced the conquests that would eventually unite the Middle East under the caliphs.
With unity restored in Arabia, the Muslims looked outward and commenced the conquests that would eventually unite the Middle East under the caliphs.
===Muhammad's descendants===
===Muhammad's descendants===
+ Muhammad was survived only by his daughter [[Fatima]] and her children (some say that he had a daughter, Zainab bint Muhammad, who had borne a daughter, Amma or Umama, who survived him as well).
− Muhammad was survived only by his daughter [[Fatima]] and her children. (Some say that he had a daughter, Zainab bint Muhammad, who had borne a daughter, Amma or Umama, who survived him as well.) +
In [[Shi'a Islam]], it is believed that Fatima's husband 'Ali and his descendants are the rightful leaders of the faithful. The Sunni do not accept this view, but they still honor Muhammad's descendents.
−
−
In [[ Shia|
Shi'a Islam]], it is believed that Fatima's husband 'Ali and his
descendants are the rightful leaders of the faithful. The Sunni do not accept this view, but they still honor Muhammad's descendents.
−
Descendents of Muhammad are known by many names, such as ''sayyids'', ''syeds'' سيد, and ''sharifs'' شريف (plural: ِأشراف Ashraaf). Many rulers and notables in Muslim countries, past and present, claim such descent, with various degrees of credibility, such as the [[Fatimid]] dynasty
of [[North Africa]], the Idrisis, the current royal families of [[Jordan]] and [[Morocco]], and the [[Agha Khan]] Imams of the [[Ismaili]] branch of Islam. In various Muslim countries, there are societies that authenticate claims of descent; some societies are more credible than others.
+
Descendents of Muhammad are known by many names, such as ''sayyids'', ''syeds'' سيد, and ''sharifs'' شريف (plural: ِأشراف Ashraaf). Many rulers and notables in Muslim countries, past and present, claim such descent, with various degrees of credibility, such as the [[
Fatimids Caliphate|
Fatimid dynasty
]] of [[North Africa]], the Idrisis, the current royal families of [[Jordan]] and [[Morocco]], and the [[Agha Khan]] Imams of the [[Ismaili]] branch of Islam. In various Muslim countries, there are societies that authenticate claims of descent; some societies are more credible than others.
==Muhammad's historical significance==
==Muhammad's historical significance==
+ Before his death in 632, Muhammad had established Islam as a social and political force and had unified most of Arabia. A few decades after his death, his successors had united all of Arabia, and conquered [[Iran]], [[Iraq]], [[Egypt]], [[Palestine]], [[Syria]], [[Armenia]], and much of [[North Africa]]. By 750, Islam had emerged as the spiritual counterpart to the two great monotheistic belief systems, Judaism and Christianity, and as the geopolitical successor to the [[Roman Empire]]. The rest of North Africa had come under Muslim rule, as had the southern part of [[Spain]] and much of Central Asia (including Sind, in the Indus Valley).
−
Before his death
in 632
, Muhammad had established
Islam as a social and political force and had unified most of Arabia. A few decades after his death, his successors had united all of Arabia, and conquered
[[ Iran
]] ,
[[ Iraq
]], [[ Egypt
]], [[ Palestine (region)|Palestine]], [[Syria]], [[Armenia]], and much of [[North Africa
]]. By 750,
Islam had emerged as
the spiritual counterpart to
the
two great monotheistic belief systems
, Judaism
and Christianity, and as the geopolitical successor
to the [[Roman Empire]]. The rest of north Africa had come under Muslim rule, as had the southern part
of [[Spain]] and much of Central Asia (including Sind, in
the Indus Valley)
.
+
Under the Ghaznavids,
in the tenth century
, Islam was spread to the
[[ Hindu
]] principalities east of the Indus by conquering armies in what is now northern
[[ India
]] . Even later
, Islam expanded peacefully into much of
[[ Africa
]]
and Southeast Asia
, where today
[[ Indonesia
]] has the largest Muslim population
. Islam is now
the faith of well over a billion people all over
the globe
, and believed
to be
the second-largest religion
of the present day
.
−
Under the Ghaznavids
, in
the tenth century, Islam was spread to
the [[Hindu]] principalities east
of the Indus by conquering armies in what is now northern [[India]]
. Even later
, Islam expanded peacefully into much
of [[Africa]]
and
Southeast Asia where Indonesia today has
the largest Muslim population
. Islam
is now
the faith
of well over a billion people all over the globe
, and believed
to
be the second largest religion of the present day.
+ ==Muhammad's Legacy==
− + ===Muslim reverence for Muhammad===
− ==Muslim reverence of Muhammad== +
For all Muslims
, Muhammad is
the final prophet or
the
''khatm'' (seal
of prophecy, Q33: 40) after whom there are no more prophets
. However
, they regard him as the successor
of numerous prophets (tradition says between 124,000
and 125,000 are named in
the Qur'an)
. All prophets are equal but Muhammad
is distinguished from all others by
the nature
of his message
, which was universal whereas their messages were limited
to
particular places
or people
.
− <div style="float:right">
− <gallery>
−
Image:Muhammad callig.gif|The name "Muhammad" written in Arabic [[calligraphy]]. Many Muslims believe that Islam prohibits art depicting humans
or animals; much Islamic art is decorative calligraphy or [[arabesque]] (abstract pattern)
.
−
Image:Miraj2
. jpg|A
[[ 16th century
]] [[ Persians|Persian
]] miniature painting celebrating Muhammad'
s ascent into the Heavens
, a journey known as the
[[ Miraj
]]. Muhammad' s face is veiled
.
+
Because his example was understood to represent the highest ideal for human conduct, many details of his life, his likes and dislikes were preserved so that a great deal of information is available to anyone who is interested to know what his opinions were on a range of topics
. We know that he loved
[[ cat
]] s and
[[ horse
]]s, hated bad smells, disliked
[[ music
]] and loved the color green (hence it is the color for Islam)
. Muslims believe that he was inspired when acting in his capacity as prophet but that when he was not fulfilling that role he did so as a fallible human, so for example when he advised on farming he might not necessarily have given sound advice. Asked what
Muhammad was like, his wife [[Aisha]] once said, “read the Qur
' an,” suggesting that Muhammad lived by what he preached
.
− </gallery>
− </div>
Most Muslims feel a great love and reverence for Muhammad, and express this in many ways, although no Muslim worships him or regards him as other than human.
Most Muslims feel a great love and reverence for Muhammad, and express this in many ways, although no Muslim worships him or regards him as other than human.
−
* When speaking or writing, Muhammad's name is preceded by the title " Prophet
" and is followed by the phrase, ''Peace
be upon him ''
, or ''Peace
be upon him and his descendents
' ' by Shias
; in English often abbreviated as
''
"pbuh" ''
and ''
"pbuh&hd" '',
or just simply as "p" .
+
* When speaking or writing, Muhammad's name is preceded by the title " prophet
" and is followed by the phrase, “Peace
be upon him, ”
or “Peace
be upon him and his descendents” by Shi
' a
; in English often abbreviated as "pbuh" and "pbuh&hd ,
" or just simply as "p .
"
−
* Concerts of Muslim and especially [[Sufi]] devotional music include songs praising Muhammad, known as ''[[Qawwali]]''). +
* Concerts of Muslim and especially [[Sufi]] devotional music include songs praising Muhammad, known as ''[[Qawwali]]'').
−
* Some Muslims celebrate the birthday of Muhammad (
''[[Mawlid]]'' )
with elaborate festivities. Others do not, believing that such festivities are modern innovations, including the dominant school in Saudi Arabia. +
* Some Muslims celebrate the birthday of Muhammad '' (
[[Mawlid]] )
'' with elaborate festivities. Others do not, believing that such festivities are modern innovations, including the dominant school in Saudi Arabia.
* Criticism of Muhammad is often equated with [[blasphemy]], which is punishable by death in some Muslim states.
* Criticism of Muhammad is often equated with [[blasphemy]], which is punishable by death in some Muslim states.
* Muhammad is often referenced with titles of praise.
* Muhammad is often referenced with titles of praise.
* Muhammad's relics, such as his grave, his sword, his clothing, even strands of his hair, are revered by some.
* Muhammad's relics, such as his grave, his sword, his clothing, even strands of his hair, are revered by some.
−
* Even non-iconic representations of Muhammad are traditionally discouraged. From the 16th
century however, [[ Persians
|Persian]] and [[Ottoman]] art frequently represented Muhammad in miniatures, albeit with his
his face either veiled, or emanating radiance.
+
* Even non-iconic representations of Muhammad are traditionally discouraged. From the sixteenth
century ,
however, [[ Persian Empire
|Persian]] and [[ Ottoman Empire|
Ottoman]] [[
art ]]
frequently represented Muhammad in miniatures, albeit with his face either veiled, or emanating radiance.
* Beyond the stories accepted as [[canon]]ical by Islamic scholars of ''hadith'', or oral traditions, there are many folktales praising Muhammad and recounting miraculous stories of his birth, upbringing and life.
* Beyond the stories accepted as [[canon]]ical by Islamic scholars of ''hadith'', or oral traditions, there are many folktales praising Muhammad and recounting miraculous stories of his birth, upbringing and life.
−
== Muhammad's Legacy
== +
== =Non-Muslim Assessments=
==
−
=== Muslim Assessment
=== +
=== =Traditional Western animus=
===
−
For all
Muslims, Muhammad is the final prophet or the ''khatm'' (seal of prophecy, Q33: 40) after whom
there are
no more prophets
. However
, they regard him as
the successor
of numerous prophets
( tradition says 124
, 000
- 25 are named in the Qur'an
). All prophets are equal but
Muhammad is distinguished from all others by
the nature
of his message, which was universal whereas their messages were limited to particular places or people
. Because his example was understood to represent the highest ideal for human conduct, many details of his life, his likes and dislikes were preserved so that a great deal
of information is available to anyone who is interested to know what
his
opinions were
on a range of topics
. We know that he loved cats
and horses
,
hated bad smells
, disliked music and loved
the color green (hence it is the color for Islam). Muslims believe
that he was inspired when acting in his capacity as prophet but that when he was not fulfilling that role he did so as
a fallible human
, so for example when he advised on farming he may not necessarily have given sound advice
. Asked what Muhammad was like
, his wife [[Aisha]] once said, 'read the Qur'
an ', suggesting that Muhamamd lived
by what he preached
.
+
Few non-Muslims doubt Muhammad's achievement in terms of uniting Arabia, establishing an embryonic empire and leaving behind him a faith tradition that developed into the second largest religion in the world. They have been less inclined to accept the religious claims made about him.
For Muslims, Muhammad is the perfect man and
there is
no question that he was sincere, moral, righteous and God revealed that Islam to him
. Indeed
,
Muslims believe that God guided and directed the birth of Islam and
the affairs
of the early community. God is intimately involved in His creation, sustaining it daily
( Q13:17, 15:16-23, 20:50, 30:40, 43:11
, 56:63
- 74
). Non-Muslims have often taken a much more critical view, and many have regarded
Muhammad as self-serving, insincere, immoral,
the inventor
of Islam
. Christians have long accused Muhammad
of making up
his religion based
on borrowed material
. Early accounts report meetings between Muhammad
and a Christian monk, Bahira (see Guillaume
, 79-82)
, while Q16:103 may respond to
the
charge
that he was coached by
a young Christian called Jabr (see Guillaume
, 180)
. He has been called a fake prophet
, a charlatan and worse. Some have attributed
his
"revelations" to epilepsy or some form of mental illness. Early writers even portrayed him as
an idol worshiped
by
Muslims. His name was invariably misspelled
.
− ===Non-Muslim Assessment=== +
Many Europeans, though critical
of his motives
,
nonetheless credited Muhammad with political
and military success. Even
in this
there have been skepics
, notably Aloys Sprenger (1951)
, who depicted
him as a tool in
the
hands
of greater men such as Abu Bakr
and Umar
.
However
, William Muir
( 1894
), whose biography of
Muhammad is one of
the earliest
and most detailed biographies by
a non-Muslim based on the best sources
,
while he echoed many
of the above criticisms (indeed, as a Christian he suggests a satanic origin for Muhammad
' s inspiration), concluded
that Muhammad, not those around him, “formed Islam”
( lxxxvi
).
−
Few doubt Muhammad's achievement in terms
of uniting Arabia
, establishing an embryonic empire
and leaving behind him a faith tradition that developed into the second largest religion
in the world. For Muslims, Muhammad is the perfect man and
there is no question that he was sincere
, moral
, righteous and that Islam was revealed to
him by God. Indeed, Muslims believe that God guided and directed
the birth
of Islam
and the affairs of the early community
.
God is intimately involved in His creation
, sustaining it daily
( Q13:17, 15:16-23, 20:50, 30:40, 43:11, 56:63-74
) . Non-Muslims have often taken a much more critical view
, regarding
Muhammad as self-serving, insincere, immoral,
the
inventor
and author of Islam. He has been called
a fake prophet
, a charlatan and worse. Early writers even portrayed him as an idol worshiped by Muslims. His name was invariably misspelled.
−
Epilepsy or some form
of mental illness has been used to explain
the ' fits'
that
accompanied the receipt of revelation. Christians have long accused
Muhammad of making up his religion based on borrowed material. Early accounts report meetings between Muhammad and a Christian monk
, Bahira (see Guillaume: 79-82) while Q16: 103 may respond to the charge that he was coached by a young Christian called Jabr
( see Guillaume: 180
).
− Many, though critical of his motives, nonetheless credit him with political and military success. One excepting was Aloys Sprenger (1813-97) who depicted him as a tool in the hands of greater men, such as Abu Bakr and Umar. William Muir (1819-1905), whose biography of Muhammad is one of the earliest and most detailed biographies by a non-Muslim based on the best sources, echoes many of the above criticisms (indeed, as a Christian he suggests a satanic origin for Muhammad's inspiration) yet he concluded that Muhammad, not those around him, 'formed Islam' (1984: lxxxvi).
Minou Reeves' ''Muhammad in Europe: A Thousand Years of Mythmaking'' (2000) traces the story of how non-Muslims in Europe have depicted, evaluated
,
understood
, insulted and
mythologized and demonized the life and character of Muhammad:
+
Minou Reeves' ''Muhammad in Europe: A Thousand Years of Mythmaking'' (2000) traces the story of how non-Muslims in Europe have depicted, misunderstood
, insulted
, mythologized and demonized the life and character of Muhammad:
− :In the works of an overwhelming majority of European writers Muhammad was portrayed as a man of deep moral faults. Churchmen, historians, orientalists, biographers, dramatists, poets and politicians alike had sought to attribute to Islam and especially to Muhammad fanatical and disreputable, even demonic characteristics (x).
− QUOTES: + <blockquote>In the works of an overwhelming majority of European writers Muhammad was portrayed as a man of deep moral faults. Churchmen, historians, Orientalists, biographers, dramatists, poets and politicians alike had sought to attribute to Islam and especially to Muhammad fanatical and disreputable, even demonic characteristics. (x)</blockquote>
− "Mohammad
's Message for Muslims & People on Earth" + ====Western appreciation for Muhammad====
+
Reeves' book, however, also uncovers another tradition—that of such writers as Roger Bacon and William Montgomery Watt—who have tried to “understand Muhammad's cause, Muhammad's message, Muhammad's social and political reforms, Muhammad
's
personality and character in the context of his times and with an open mind, [seeking to] “dispel the myths and the stereotypes and to show how Islam embraces values dear to religions that have regarded it as their sworn enemy” (300).
−
When God created human beings
, each individual was to be an object
of joy to Him
.
+
Muir followed others in seeing Muhammad at Mecca as sincerely searching for the truth but alleged a moral decline at Medina where worldly ambition mingled with his original goal
, and robbed him
of any virtue he may have had at Mecca. Muir singles out many events in Muhammad's life for moral censure yet even he praises his simple life-style, his “urbanity and kindness of disposition [and] magnanimity towards his enemies” (although he accuses him of murdering some of his critics, such as the poet Ka'b ibn Ashraf (see Lings, 160 for a Muslim explanation) (see Muir 1858, vol. 4, 304-310)
.
+ In recent years, Christian writers Kenneth Cragg (1984), William Montgomery Watt (1961) and Clinton Bennett (1998) have attempted to find ways of affirming that he was a prophet of God while remaining loyally Christian. Watt, asking whether Muhammad was a prophet, concluded:
+ <blockquote>…not all the ideas he preached [from Watt's Christian perspective] are true and sound, but by God's grace he has been enabled to provide billions of men [and women] with a better religion than they had before they testified that there is no God but God and that Muhammad is the messenger of God (240).</blockquote>
+ In today's interfaith climate, more and more non-Muslims have come to resonate with these views; they accept that God stands behind Islam, thus recognizing with Muslims the genuineness of Muhammad's spiritual experiences and leadership. Although they do not accept every aspect of Muslim belief, they reject the view that Muhammad was insincere or that he invented Islam.
−
Reeves' book
, however, also uncovers
' another tradition' - that
of such writers
as Roger Bacon
and William Montgomery Watt who have tried
to 'understand
Muhammad's cause
, Muhammad
's message, Muhammad
's social and political reforms
, Muhammad's personality and character in
the context
of his times
and with an open mind
', seeking
to ' dispel the myths
and the stereotypes and to show how
Islam embraces values dear to religions that have regarded it as their sworn enemy' (300)
.
+
For secular historians
, the question of Muhammad
' s sincerity or authorship of Islam is irrelevant. His legacy in terms
of a worldwide civilization is sufficient. For those who believe in God
as the prime mover behind
and within history, the issue of whether Muhammad was really inspired by God cannot be avoided. Either he was not, and despite political success he was a charlatan, or he was inspired and so was used by God to spread faith in him and to teach the importance of obedience
to God. Islam is either
Muhammad's creation
, or God
's . If God
's, then
the
binding
of people together in a common faith across race
and nationality,
with a single hope in God
' s ultimate perfecting of the world
, is providential not accidental. Muslims are the first
to admit that they have not always lived up to the ideal. The ''ummah'
' has not remained united yet Muslims aspire towards unity, and all know that equality, justice
and fairness are of
the essence of
Islam.
− Muir followed others in seeing Muhamamd at Mecca as sincerely searching for the truth but alleged a moral decline at Madina where worldly ambition mingled with his original goal, and robbed him of any virtue he may have had at Mecca. Muir singles out many events in Muhammad's life for moral censure yet even he praises his simple life-style, his 'urbanity and kindness of disposition' and 'magnanimity towards his enemies' (although he accuses him of murdering some of his critics, such as the poet Ka'b ibn Ashraf (see Lings: 160 for a Muslim explanation)(see Muir, 1858, V4: 304-10). Muslims and non-Muslims are likely to differ in their appraisal of Muhammad, since many of the latter deny the genuiness of Muhammad's religious experience. Some non-Muslims have attempted to re-evaluate Muhammad and among these such Christians writers as Kenneth Cragg (1984), William Montgomery Watt (1961) and Clinton Bennett (1998) have attempted to find ways of affirming that he was a prophet of God while remaining loyally Christian. Watt, asking whether Muhammad was a Prophet, concluded: + ==Notes==
− : not all the ideas he preached [from Watt's Christian perspective] are true and sound, but by God's grace he has been enabled to provide billions of men [and women] with a better religion than they had before they testified that there is no God but God and that Muhamamd is the messenger of God' (240). For secular historians, the question of Muhammad's sincerity or authorship of Islam is irrelevant. His legacy in terms of a worldwide civilization is sufficient. For those who believe in God as the prime mover behind and within history, the issue of whether Muhammad was really inspired by God cannot be avoided. Either he was not, and despite political success he was a charlatan, or he was inspired and so was used by God to spread faith in him and to teach the importance of obedience to God. Islam is either Muhammad's creation, or God's. If God's, then the binding of people together in a common faith across race and nationality, with a single hope in God's ultimate perfecting of the world, is providential not accidental. Muslims are the first to admit that they have not always lived up to the ideal. The ''ummah'' has not remained united yet Muslims aspire towards unity, and all know that equality, justice and fairness is of the essence of Islam. + <references/>
−
− QUOTES:
==References==
==References==
−
*Armstrong, Karen ''Muhammad: A Biography of the Prophet'' ,
San Francisco: Harper, 1993 ISBN 0062508865 +
*Armstrong, Karen .
''Muhammad: A Biography of the Prophet .
'' San Francisco: Harper, 1993 .
ISBN 0062508865
−
*Asad, Mohammed ''Sahih-al-Buckari: The Early Years of Islam'' , Gibralter,
Dar-al-Andalus, 1981 original 1932 ISBN 0317524585 +
*Asad, Mohammed .
''Sahih-al-Buckari: The Early Years of Islam .
'' Gibraltar:
Dar-al-Andalus, 1981 (
original 1932 ).
ISBN 0317524585
−
*al-Azami, Muhammad M On Schacht's ''Origins
of Muhammadan Jurisprudence'' ,
Cambridge: Islamic Texts Society, 1996 ISBN 0946621462
+
*al-Azami, Muhammad M . ''
On Schacht's “Origins
of Muhammadan Jurisprudence .”
'' Cambridge: Islamic Texts Society, 1996 .
ISBN 0946621462
−
*Bennett, Clinton ''In Search of Muhammad'' , NY
: Continuum, 1998 ISBN 0304704016 +
*Bennett, Clinton .
''In Search of Muhammad .
'' New York
: Continuum, 1998 .
ISBN 0304704016
−
*Coulson, Noel C A History of Islamic Law ,
Edinburgh: Edinburgh University Press, 1994 ISBN 0748605142 +
*Coulson, Noel C . ''
A History of Islamic Law .''
Edinburgh: Edinburgh University Press, 1994 .
ISBN 0748605142
−
*Cragg, Kenneth ''Muhammad and the Christian: A Question of Response'' ,
London: Darton, Longman and Todd, 1984 new
edition Oxford: Oneworld, 1999 ISBN 1851681795 +
*Cragg, Kenneth .
''Muhammad and the Christian: A Question of Response .
'' London: Darton, Longman and Todd, 1984 . New
edition ,
Oxford: Oneworld, 1999 .
ISBN 1851681795
−
*Crone, Patricia and Cook , Michael
''Hagarism'' ,
Cambridge: Cambridge University Press, 1977 ISBN 0521211336 +
*Crone, Patricia and Michael
Cook .
''Hagarism .
'' Cambridge: Cambridge University Press, 1977 .
ISBN 0521211336
−
*Denffer, von , Ahmed
''Ulum al Qur'an'' ,
Leicester: The Islamic Foundation,1989 ISBN 0860371093
electronically at [http://www
. youngmuslims.ca/online%5Flibrary/books/ulum%5Fal%5Fquran/]
+
*Denffer, Ahmed
von .
''Ulum al Qur'an .
'' Leicester: The Islamic Foundation, 1989 .
ISBN 0860371093.
−
*Geiger, Abraham Judaism and Islam , translated by Young,
F. M ,
Bangalore, India, 1896 [http://www.bible.ca/islam/library/Geiger/Judaism/index.htm] +
*Geiger, Abraham . ''
Judaism and Islam '' (trans.
F. M . Young).
Bangalore, India, 1896 .
[http://www.bible.ca/islam/library/Geiger/Judaism/index.htm
Available online.
] Retrieved August 10, 2007.
−
*Guillaume, Alfred ''The Life of Muhammad: A Translation of Ibn Ishaq's Sirat Rasul Allah'' ,
Oxford: Oxford University Press, 1955 (reprinted 2002) ISBN 0196360331 +
*Guillaume, Alfred .
''The Life of Muhammad: A Translation of Ibn Ishaq's Sirat Rasul Allah .
'' Oxford: Oxford University Press, 1955 (reprinted 2002) .
ISBN 0196360331
−
*Haykal, Muhammad Husayn ,
''The Life of Muhammad'' ,
New Delhi: Islamic Book Service
Year, 1995 ,
ISBN 1577311957
+
*Haykal, Muhammad Husayn .
''The Life of Muhammad .
'' New Delhi: Islamic Book Service Year, 1995 .
ISBN 1577311957
−
*Lings, Martin ''Muhammad: His Life Based on Earliest Sources'' ,
Bombay: Inner Traditions International, Limited, 1987 ISBN 0892811706 }}
+
*Lings, Martin .
''Muhammad: His Life Based on Earliest Sources .
'' Bombay: Inner Traditions International, Limited, 1987 .
ISBN 0892811706
− *Rodinson, Maxime, Muhammad, NY: New Press, Year, 2002 ISBN 1565847520 +
*Mernissi, Fatima .
''The Veil and the Male Elite: A Feminist Interpretation of Women's Rights in Islam'' . New York:
Perseus, 1991 .
ISBN 0201523213
− *Nasr, Seyyed Hossain ''Ideas and Realities of Islam'', London: Thorsons/HarperCollins, 1994 ISBN 1855384094 +
*Muir, Sir William . ''
Life of Mahomet ''
(4 vols
) .
London: Smith, Elder & Co, 1858- 1922.
[http://www.answering-islam.org/Books/Muir/index.htm Available online.
]
Retrieved August 10, 2007.
−
*Mernissi, Fatima ''The Veil and the Male Elite: A Feminist Interpretation of Women's Rights in Islam'' , NY,
Perseus, 1991 ISBN 0201523213
+
*Muir, Sir William . ''
Life of Mahomet ''
(abridged edition) .
London: Smith, Elder & Co, 1894 .
−
*Muir, Sir William Life of Mahomet (4 Vols
) ,
London: Smith, Elder & Co, 1858- 22
[http://www.answering-islam.org/Books/Muir/index.htm]
+ *Nasr, Seyyed Hossain. ''Ideas and Realities of Islam.'' London: Thorsons/HarperCollins, 1994. ISBN 1855384094
−
*Muir, Sir William Life of Mahomet (abridged edition) ,
London: Smith, Elder & Co, 1894 +
*Reeves, Minou .
''Muhammad in Europe: A Thousand Years of Mythmaking .
'' New York
: New York University Press
, 2000 .
ISBN 0814775330
−
*Reeves, Minou ''Muhammad in Europe: A Thousand Years of Mythmaking'' , NY
: New York University Pres
, 2000 ISBN o 8147 7533 0
+ *Rodinson, Maxime. ''Muhammad.'' New York: New Press, 2002. ISBN 1565847520
−
*Schacht, Joseph ''An Introduction to Islamic Law'' , NY
: Oxford Univesity
Press, 1964 reprinted 1983 ISBN 0198254737 +
*Schacht, Joseph .
''An Introduction to Islamic Law .
'' New York
: Oxford University
Press, 1964 (
reprinted 1983 ).
ISBN 0198254737
−
*Sprenger, Aloys ''The Life of Mohammed from Original Sources'' ,
Allahabad ,
The Presbyterian Mission Press, 1851
+
*Sprenger, Aloys .
''The Life of Mohammed from Original Sources .
'' Allahabad :
The Presbyterian Mission Press, 1851 .
−
*Us-Samad, Ulfat Aziz ''Islam and Christianity'' ,
Lahore: Kazi Publishers, 1979 +
*Us-Samad, Ulfat Aziz .
''Islam and Christianity .
'' Lahore: Kazi Publishers, 1979 .
−
*Warraq, Ibn ''Why I am Not a Muslim'' ,
Amherst, NY: Prometheous, 1995 ISBN 0879759844 +
*Warraq, Ibn .
''Why I am Not a Muslim .
'' Amherst, NY: Prometheous, 1995 .
ISBN 0879759844
−
*Warraq, Ibn The Quest for the Historical Muhammad'' Italic text'',
Amherst, NY: Prometheus Books,
2000 ISBN 1573927872 }}
+
*Warraq, Ibn . ''
The Quest for the Historical Muhammad .
'' Amherst, NY: Prometheus Books, 2000 .
ISBN 1573927872
−
*Wansborough, John ''Quranic Studies'' ,
Oxford: Oxford University Press, 1977 ISBN 0197135 889 +
*Wansborough, John .
''Quranic Studies .
'' Oxford: Oxford University Press, 1977 .
ISBN 0197135 889
−
*Watt, William Monthomery
''Muhammad: Prophet and Statesman'' ,
Oxford: Oxford University Press, 1961 ISBN 0198810784 +
*Watt, William Montgomery.
''Muhammad: Prophet and Statesman .
'' Oxford: Oxford University Press, 1961 .
ISBN 0198810784
−
*Zakaria, Rafiq ''Muhammad and the Quran'' ,
London: Penguin, 1991 ISBN 0140147234 +
*Zakaria, Rafiq .
''Muhammad and the Quran .
'' London: Penguin, 1991 .
ISBN 0140147234
==External links==
==External links==
+ All links retrieved November 10, 2022.
+ * [http://www.pbs.org/muhammad Muhammad: Legacy of a Prophet] from PBS
− Non-sectarian biography: + ;
Sunni
− * [http://www.pbs.org/muhammad Public Broadcasting System program on Muhammad] +
* [http://www.muhammad.net/ Twenty
- Nine Traits
of
Prophet’s Great Character
] –
The Islamic Circle
of
North America
− * [http://encarta.msn.com/encyclopedia_761553918/Muhammad_(prophet).html/ Encarta Encyclopedia]
− * [http://31.1911encyclopedia.org/M/MA/MAHOMET.htm 1911 Encyclopedia article of Muhammad]
−
−
Sunni biography:
− *[http://www.al-sunnah.com/nektar/ Ar-Raheeq Al-Makhtum (The Sealed Nectar)- Memoirs of the Noble Prophet]
− * [http://www.witness-pioneer.org/vil/Books/MH_LM/default.htm The Life of Muhammad] Muhammad Husayn Haykal Translated by Isma'il Razi A. al-Faruqi
− * [http://www.islamonline.net/English/In_Depth/mohamed/1424/index.shtml Islamonline]
− * [http://www.usc.edu/dept/MSA/fundamentals/prophet/ About Muhammad]
−
* [http://www.muhammad.net/ Muhammad Biography and more]
−
− Shia biography:
−
* [http://www.al
- islam.org/restatement/ A Restatement
of the History of Islam and Muslims by Sayed Ali Asgher Razwy
]
−
* [http://al-islam.org/lifeprophet/ The Life of Muhammad
The Prophet by Syed Saeed Akhtar Rizvi]
− * [http://al-islam.org/beacons/title.htm Beacons
of Light by Abu Ali al Fadl]
− Critical perspectives: + ;Shi'a
−
* [http://www. answering
-islam.org .uk
/ Books
/ Jeffery
/ historical_mhd
. htm The Quest for
the Historical Mohammed
]
+
* [http://www. al
-islam.org/ restatement
/ “A Restatement of the History of Islam and Muslims”] by Sayed Ali Asgher Razwy
−
* [http:// debate
.org .uk
/ topics
/ theo/muhbiog
.htm Trends in Biographies
of
Muhammad
]
+
* [http:
/ /al-islam
. org/lifeprophet/ “The Life of Muhammad
the Prophet”
] by Syed Saeed Akhtar Rizvi
+
* [http:// al-islam
.org/ beacons
/ title
.htm “Beacons
of Light”
]
by Abu Ali al Fadl
−
[[Category: History
and biography
]] + [[category:Islam]]
+ [[Category: Religion]]
+
[[Category: Philosophy
and religion
]]
{{credit1|Muhammad|25607460}}
{{credit1|Muhammad|25607460}}
Latest revision as of 01:48, 11 March 2023
Part of the series on
Islam
History of Islam
Beliefs and practices
Oneness of God
Profession of Faith
Prayer · Fasting
Pilgrimage
· Charity
Major figures
Muhammad
Ali
· Abu Bakr
Companions of Muhammad
Household of Muhammad
Prophets of Islam
Texts & law
Qur'an
· Hadith · Sharia
Jurisprudence
Biographies of Muhammad
Branches of Islam
Sunni
· Shi'a
· Sufi
Sociopolitical aspects
Art · Architecture
Cities · Calendar
Science · Philosophy
Religious leaders
Women in Islam
Political Islam · Jihad
Liberal Islam
See also
Vocabulary of Islam
Index of articles on Islam
Muhammad
(Arabic: محمد
, also Arabic transliterated
Mohammad
,
Mohammed
,
Muhammed
, and sometimes
Mahomet
, following the Latin or Turkish), is the founder of Islam
—the world's second largest religion. [1]
According to traditional Muslim biographers, Muhammad was born c. 570 C.E.
in
Mecca
(Makkah) and died June 8, 632 in Medina (Madinah). Both Mecca and Medina are cities in the Hejaz region of present day
Saudi Arabia
. He was a merchant in Mecca when, in 610 C.E.
at about the age of 40, while meditating in a cave, Muhammad experienced a vision from the angel
Gabriel
, who commanded him to memorize and recite the verses subsequently collected as the Qur'an
. Gabriel told him that God ( Allah
in Arabic) had chosen him as the last of the prophets to mankind. He began publicly preaching a strict monotheism
and predicting a
Qiyamah
(Day of Judgement) for sinners and idol-worshippers, such as his tribe and neighbors in Mecca. For this was persecuted and ostracized by the Meccan establishment, who depended on income from pilgrims to its polytheistic shrine, the
Kaaba
. In 622 Muhammad accepted an invitation from believers in the city of Yathrib, where he became the leader of the first avowedly Muslim community (Yathrib ever after become known as
Medina-al-Naby
, City of the Prophet, or Medina for short). This journey is known as the Hijra
, or migration; the event marked the beginning of the Islamic calendar. War between Mecca and Medina followed, in which Muhammad and his followers were eventually victorious. The military organization honed in this struggle was then set to conquering the other pagan
tribes of Arabia
. By the time of Muhammad's death, he had unified Arabia and launched a few expeditions to the north, towards Syria
and Palestine
.
Under Muhammad's immediate successors
the Islamic
empire expanded into Palestine, Syria, Mesopotamia, Persia
,
Egypt
, North Africa
, and Spain
. Although there were many battles against the pagans, some of whom became Muslim, the primary method by which Islam as a
faith
spread around much of the globe was commercial contact between Muslims and non-Muslims, and missionary activity. Islamic rule, on the other hand, was extended by conquest. Many people did not convert but lived as subject of Islamic rule, although as time passed the majority did embrace Islam. As Muhammad taught the unity of all aspects of life, a whole civilization developed from his teaching, with its own art, literature, philosophy, science and theology, but also governmental and legal systems.
Contents
1 Sources for Muhammad's Life
1.1 The Sira: Biographical Literature
1.2 The Hadith Literature
1.3
Critical scholarship regarding the sources for Muhammad's life
2 Muhammad's life according to Sira
2.1 Muhammad's genealogy
2.2 Childhood
2.3 Middle years
2.4 The first revelations
2.5
Muhammad's experience of revelation
2.6 Rejection
2.7 Muhammad's message in Mecca
2.8 Isra and Miraj
2.9 Hijra
2.10
Muhammad and followers of other monotheistic faiths
2.11 War
2.12 Muhammad's rule consolidated
2.13 Continued warfare
2.14 The conquest of Mecca
2.15 Unification of Arabia
2.16 Muhammad's family life
2.17 Companions of Muhammad
2.18 The death of Muhammad
2.19 Muhammad's descendants
3 Muhammad's historical significance
4 Muhammad's Legacy
4.1 Muslim reverence for Muhammad
4.2 Non-Muslim Assessments
4.2.1 Traditional Western animus
4.2.2
Western appreciation for Muhammad
5 Notes
6 References
7 External links
8 Credits
Muhammad's legacy lives on in the minds and hearts of billions of Muslims throughout the world, for whom he represents the best model of human conduct. Non-Muslim opinion on Muhammad has often been less favorable—however, few disagree that his life must be numbered among one of the most influential and significant ever lived, as one of the greatest and geographically widespread civilizations
in the world owes its existence to him. Islam, as a religio-cultural-social-political system or way of life, represents God's ideal or will for billions of people. This way of life stresses that all life must be lived in harmony with God, holds all aspects of life—sacred and secular—in balance and encourages people to live as if God sees everything they do. Islam teaches the equality of all people and anticipates that day when the whole world will be obedient to God, when peace ( salam
, from which the word islam
is derived) will exist in the vertical (between all people and God) and in the horizontal (among all people) and when the earth, given humanity as a trust from God, will be properly valued and respected. Above all, Muhammad taught that without inner piety, external displays of devotion are worthless. From the point of view of those who see God's hand within history, Muhammad's life cannot be understood in other than positive terms.
The name "Muhammad" written in Arabic
calligraphy
as a form of devotion. Many Muslims believe that Islam prohibits art depicting humans or animals; much Islamic art is decorative calligraphy or arabesque.
Sources for Muhammad's Life
The sources available to us for information about Muhammad are the Qur'an
, sira
biographies, and the hadith
(sayings and deeds of Muhammad) collections. Technically hadith
refers to a single saying (the plural is ahadith
) but in English it is customary to use the singular. While the
Qur'an
is not a biography of Muhammad, it does provide some information about his life; on the other hand, knowledge of Muhammad's life provides Muslims with the 'situation of revelation' ( Asbab al-nuzul
, or reasons of revelation) without which understanding the Qur'an becomes problematical. Zakaria (1991) suggests that “it is impossible for even Muslims, let alone non-Muslims, to understand the Qur'an without an acquaintance with the circumstances in which each revelation descended on Muhammad” ( tanzir
, or descent, is used to describe the 'sending down' of the Qur'an, together with the term wahy
, or revelation). The Qur'an does refer to incidents in Muhammad's life, including both public and private circumstances, so it does contain information about him.
The Sira: Biographical Literature
The earliest surviving biographies are the
Life of the Apostle of God
, by Ibn Ishaq (d. 768) (see Guillaume 1955), edited by Ibn Hisham (d. 833); and al-Waqidi's (d. 822) biography (sira)
of Muhammad. Ibn Ishaq wrote his biography some 120 to 130 years after Muhammad's death. The third source, the hadith
collections, like the
Qur'an
, are not a biography per se
. In the
Sunni
belief, they are the accounts of the words and actions of Muhammad and his companions. In the Shi'a
belief, they are the accounts of the words and actions of Muhammad, of the Household of the Prophet (Ahl al-Bayt)
and their companions, the sahabah
(see below). Lings (1983) gives us a modern sira
, based on the above.
The Hadith Literature
Six collections of hadith
are recognized by most Sunni as especially trustworthy: those by Bukhari (d. 870), Muslim Ibn al-Hajjaj (d. 875) (referred to above by Cook and Crone), Tirmidhi (d. 892), Nasa'i (d. 915), Ibn Majah (d. 885), and Abu Da'ud (d. 888). Together these are called the "six books"
(al-kutub al-sitta)
. Shi'a use the above but also have their own collections, which include sayings of the Imams (male descendants of Muhammad); the collections of al-Kulayni (d. 940), Ibn Babuya (d. 991), and Al Tusi (d. 1058) who authored two collections (making four) have special status.
Many Muslims believe that the whole of Bukhari is authentic, although even in that collection the various hadith
are given different categories depending on the reliability of their transmitter, ranging from the highest, sahih
, to the lowest, da`îf (weak). Rules concerning hadith
include that all transmitters (the isnad
, or chain of transmission must trace back to a close companion of Muhammad) must be pious, their content (matn)
must not contradict the Qur'an or what was commonly accepted to have been Muhammad's opinion, any penalty prescribed must not be disproportionate to the offense or crime involved, and they must not depict Muhammad as predicting the future or performing miracles. With reference to the latter, many hadith
do depict Muhammad predicting the future and performing miracles (see Bennett 1998, 49-54). On the latter point, several Qur'anic verses, such as Q29:50 and Q2:23 suggest that Muhammad did not perform miracles, since the Qur'an alone was the only confirmation needed of the genuineness of his mission. However, Q13:38 can be understood to imply that Muhammad could perform miracles "by Allah's leave."
Critical scholarship regarding the sources for Muhammad's life
Muslim and non-Muslim scholars alike agree that there are many inauthentic traditions concerning the life of Muhammad in the hadith
collections. Muslims have always been free to question the authenticity of hadith
, even of those contained in the above-mentioned collections. A very small minority called the “Quran Alone Muslims” considers all
hadith
as unreliable.
Non-Muslim scholars, though, are much more skeptical about the reliability of
hadith
literature. Joseph Schacht, John Wansbrough, Michael Cook, Patricia Crone, and others argue that by the time the oral traditions were being collected, the Muslim community had fractured into rival schools of thought. Each sect and school had its own sometimes-conflicting traditions of what Muhammad and his companions had done and said. Traditions multiplied. While later Muslim compilers of the hadith
collections made strenuous efforts to weed out what they felt were spurious stories, and traditionalists rely on their efforts; the skeptics feel that the question must be revisited, using modern methods.
Schacht (1964) argued that in the years after Muhammad's death, competing factions invented hadith
to justify their own claims and also to accuse anyone who disagreed with their views of illegitimacy, even apostasy or heresy. However from an Islamic standpoint, Muhammad M al-Azami (1996) has systematically repudiated Schacht's scholarship of the hadith
. Sir William Muir (1894) believed that “pious fraud” and “perverted tradition” was the “chief instrument employed to accomplish” different parties' goals, thus “traditions were colored, distorted and fabricated.” He believed that the tendency was to idealize Muhammad by surrounding him with mystique and by attributing miracles and futuristic predictions to him, hence material that reflects less favorably on Muhammad (his supposed moral failings) was more likely to be authentic. Bennett (1998) suggested that the issue is not whether Muslims attributed Muhammad with mystique but whether he deserved this reverence or not, thus:
Admitting that 'myths' were created, I am interested in why. Was it to surround Muhammad with a mystique he neither had nor deserved, or was it to depict metaphorically (and in the idiom of the day) a mystique he really had? If the former, we may impute insincerity to the compilers; if the latter, this seems to be an inappropriate judgment, however far fetched, by today’s standards, the myths seem to be. (54)
Material on miracles
surrounding Muhammad's birth may be examples of back-projection, although scholars have pointed out similarity between this material and stories associated with the births of other religious teachers and founders including Jesus
and the Buddha
.
The historicity of the biographical material about Muhammad presented in the summary above is less contested than legal material of the hadith
. However, Cook and Crone doubt the chronology of Muhammad's life as presented in the Sira
, which they regard as a post-638 fabrication—a heilgeschichte
invented after the conquest of Jerusalem to lend religious sanction to Arab territorial expansion. Many non-Muslim scholars think that 570 C.E.
as Muhammad's birth is a back-projection to make him 40 years old when he received his first revelation, emphasizing the parallel with Moses (Bennett 1998, 18). Most think that 622
C.E.
for the hijrah
is a safe date. Other dates and the sequence of some events are also contested.
Muhammad's life according to
Sira
Muhammad's genealogy
According to tradition, Muhammad traced his genealogy back as far as Adnan, whom the northern Arabs
believed to be their common ancestor. Adnan in turn is said to be a descendant of Ismail
( Ishmael
), son of
Ibrahim
( Abraham
) though the exact genealogy is disputed. Muhammad's genealogy up to Adnan is as follows:
Muhammad ibn Abd Allah ibn Abd al-Muttalib (Shaiba) ibn Hashim (Amr) ibn Abd Manaf (al-Mughira) ibn Qusai (Zaid) ibn Kilab ibn Murra ibn Ka`b ibn Lu'ay ibn Ghalib ibn Fahr (Quraysh) ibn Malik ibn an-Nadr (Qais) ibn Kinana ibn Khuzaimah ibn Mudrikah (Amir) ibn Ilyas ibn Mudar ibn Nizar ibn Ma`ad ibn Adnan. [2]
His nickname was Abul-Qasim
, "father of Qasim," after his short-lived first son.
Childhood
Muhammad was born into a well-to-do family settled in the northern Arabian town of Mecca
. Some calculate his birth date as April 20, 570 ( Shi'a
Muslims believe it to be April 26), and some as 571; tradition places it in the Year of the Elephant. Muhammad's father, Abd Allah ibn Abd al-Muttalib, had died before he was born, and the young boy was brought up by his paternal grandfather Abd al-Muttalib, of the tribe of Quraysh (or Quraish). Tradition says that as an infant, he was placed with a Bedouin
wet nurse, Halima, as desert life was believed to be safer and healthier for children. At the age of six, Muhammad lost his mother Amina, and at the age of eight his grandfather Abd al-Muttalib. Muhammad now came under care of his uncle Abu Talib, the new leader of the Hashim clan of the Quraysh tribe, the most powerful in Mecca.
Mecca was a thriving commercial center, due in great part to a stone temple called the Ka'bah
that housed many different idols, possibly numbering 365. Merchants from different tribes would visit Mecca during the pilgrimage season, when all inter-tribal warfare was forbidden and they could trade in safety.
As a teenager, Muhammad began accompanying his uncle on trading journeys to Syria
. He thus became well-traveled and gained some knowledge of life beyond Mecca. He earned a reputation for honesty and the nickname, al-amin
(“the trustworthy”). During the rebuilding of the Ka'bah after a flood
(some sources say fire
), a fight almost broke out over whom would have the honor of putting the Black Stone back in its place. Abu Umayyah, Makkah's oldest man, suggested that the first man to enter the gate of the mosque
the next morning would decide the matter. That man was Muhammad. The Makkans were ecstatic. “This is the trustworthy one (al-amin)
,” they shouted in a chorus, “this is Muhammad.”
He came to them and they asked him to decide on the matter.
Muhammad proposed a solution that all agreed to—putting the Black Stone on a cloak, the elders of each of the clans held on to one edge of the cloak and carried the stone to its place. The Prophet then picked up the stone and placed it on the wall of the Ka'ba. The precise date of this incident is not known.
Middle years
One of Muhammad's employers was Khadijah, a rich widow then 40 years old. The young 25-year-old Muhammad so impressed Khadijah that she offered him
marriage
in the year 595 C.E.
He became a wealthy man through this marriage. By Arab custom minors did not inherit, so Muhammad had received no inheritance from either his father or his grandfather.
Ibn Ishaq records that Khadijah bore Muhammad five children, one son and four daughters. All of Khadija's children were born before Muhammad started preaching about Islam
. His son Qasim died at the age of two. The four daughters are said to be Zainab bint Muhammad, Ruqayyah bint Muhammad, Umm Kulthum bint Muhammad, and Fatima Zahra
.
The Shi'a say that Muhammad had only the one daughter, Fatima, and that the other daughters were either children of Khadijah by her previous marriage, or children of her sister.
Timeline of Muhammad
Important dates and locations in the life of Muhammad
c . 570
Possible birth (April 20):
Mecca
570 End of ancient South Arabian high culture
570 Unsuccessful Abyssinian attack on Mecca
576 Mother dies
578 Grandfather dies
c . 583
Takes trading journeys to
Syria
c . 595
Meets and marries
Khadijah
610
First reports of
Qur'anic
revelation: Mecca
c . 610 Appears as Prophet of Islam: Mecca
c . 613 Begins public preaching: Mecca
c . 614 Begins to gather following: Mecca
c . 615 Emigration of Muslims to Abyssinia
616 Banu Hashim clan boycott begins
c . 618 Medinan Civil War: Medina
619 Banu Hashim clan boycott ends
c . 620
Isra (night journey) and
Miraj (ascent)
c . 620 Converts tribes to Islam: Medina
622 Emigrates to Medina (Hijra)
622 Takes leadership of Medina
(Yathrib)
c . 622 Preaches against Ka'aba pantheon: Mecca
622 Meccans attack Muhammad
c . 622 Confederation of Muslims and other clans
c . 623 Constitution of Medina
624 Battle of Badr - Muslims defeat Meccans
625 Battle of Uhud
c . 625 Expulsion of Banu Nadir tribe
626 Attacks Dumat al-Jandal: Syria
c . 627 Opponents' unsuccessful siege: Medina
627 Battle of the Trench
627 Destruction of the Banu Qurayza tribe
c . 627 Bani Kalb subjugation: Dumat al-Jandal
c . 627 Unites Islam: Medina
628 Treaty of Hudaybiyya
c . 628 Gains access to Mecca shrine Ka'ba
628 Conquest of the Battle of Khaybar oasis
629
First hajj
pilgrimage
629
Attack on
Byzantine Empire
fails: Battle of Mu'ta
630 Attacks and captures Mecca without bloodshed
c . 630 Battle of Hunayn
c . 630 Siege of al-Ta'if
630 Establishes rule by divine law (nomocracy): Mecca
c . 631 Subjugates Arabian Peninsula tribes
c . 632 Attacks the Ghassanids: Tabuk
632 Farewell hajj pilgrimage
632 Dies (June 8): Medina
c . 632 Tribal rebellions throughout Arabia
c . 632
Abu Bakr
( caliph ) re-imposes rule by divine law
The first revelations
Muhammad routinely spent nights in a cave (Hira) near Mecca
in
meditation
and thought. Muslims believe that around the year 610, while meditating, Muhammad had a vision of the angel
Gabriel
and heard a voice saying to him (in rough translation): "Read in the name of your Lord the Creator. He created man from something that clings. Read, and your Lord is the Most Honored. He taught man with the pen; taught him all that he knew not" (See surat
Al-Alaq
, Q96). Muslims stress that Muhammad had never taken part in idol worship (just as
Abraham
kept himself apart from idolatry in Ur; see Q6:79). This experience took place on what became known as the "Night of Power and Excellence," (the night worth a thousand months, Q97:1-5) in the month of Ramadan (the month of the fast). It was his unhappiness with the ethics and religious practices of his peers that compelled him to seek spiritual retreat in the cave.
The first vision of Gabriel disturbed Muhammad, but Khadijah reassured him that it was a true vision and became his first follower. She is said to have consulted her relative, Warakah, renowned for his knowledge of scripture (Christian scripture), who was also convinced that God was choosing Muhammad as a Prophet. She was soon followed by Muhammad's ten-year-old cousin
Ali ibn Abi Talib
, and Abu Bakr
, whom Sunnis assert to have been Muhammad's closest friend. Some sources reverse the order of their conversion.
Muhammad's experience of revelation
Until his death, Muhammad received frequent revelations, although there was a relatively long gap after the first revelation. This silence worried him, until he received
surat ad-Dhuha
, whose words provided comfort and reassurance. The
hadith
tell us more about how Muhammad experienced revelation. Often, he saw Gabriel. Sometimes, revelation was preceded by what sounded like the ringing of a bell. The words seemed as if they were burnt into his heart, and he had no choice but to proclaim them. Even on bitterly cold nights, the experience left him dripping with sweat. Tradition says that before Muhammad died, Gabriel recited the whole of the Qur'an again to ensure that no content was lost and that all the verses were correctly remembered. He often wrapped himself in his cloak during the experience of receiving revelation.
According to tradition, Muhammad was unlettered. He is described as the
al-nabiyy-al-ummiy
(Q7:157; 62:2), which is usually understood to mean that he was illiterate. This safeguards the Qur'an's integrity for Muslims as completely divine, containing no human content. Non-Muslims, who often claim that Muhammad wrote the Qur'an, dispute this—but Muslims argue that even if Muhammad was not entirely illiterate
, no human could have composed the Qur'an, which is a miracle of language and incomparable as a work in Arabic. Muslims often dislike calling the Qur'an a 'text,' since this compares it with human creations while it has no human author. S. H. Nasr (1994) compares the unletteredness of Muhammad with Mary's
virginity
:
The human vehicle of a Divine Message must be pure and untainted ... If this word is in the form of flesh, the purity is symbolized by the virginity of the mother ... if it is in the form of a book this purity is symbolized by the unlettered nature of the person who is chosen to announce this word (44).
Around 613, Muhammad began to spread his message amongst the people. Most of those who heard his message ignored it. A few mocked him, calling him a magician, a soothsayer, a poet (the Qur'an is rhymed prose but Muhammad always rejected the accusation that he was a poet). Some, however, believed—and joined his small following of companions (called the believers, al-mu'minum
). Many of these supporters were from the poorest and most oppressed classes, although some were powerful and influential.
Rejection
As the ranks of Muhammad's followers swelled, he became a threat to the local tribes and the rulers of the city. Their wealth rested on the Ka'bah, a sacred house of idols and the focal point of Meccan religious life. If they threw out their idols, as Muhammad preached, there would be no more pilgrims, no more trade, and no more wealth. Muhammad’s denunciation of polytheism
was especially offensive to his own tribe, the Quraysh, as they were the guardians of the Ka'bah. Muhammad and his followers were persecuted. Muhammad's enemies boycotted his supporters' businesses and sometimes attacked them in the streets. Poets denounced him. His own prestigious pedigree protected him from physical harm. Concerned for the safety of his small following, Muhammad sent a group to Abyssinia and founded a small colony there. The Christian ruler received them with courtesy.
Muhammad's message in Mecca
The one just God
, Allah, whose existence Muhammad proclaimed was incomparable, could not be represented and, unlike the gods and goddesses surrounding the Ka'bah, Allah (God in Arabic, a masculine form) has neither partners nor offspring. The Arabs did revere Allah but thought him remote and aloof, while impersonal and arbitrary time
(zaman)
controlled human destiny.
As well as fearing that their income stream was under threat, the polytheists were also alarmed by the egalitarian message that Muhammad proclaimed. The nobility controlled justice, to their own advantage, and they had no desire to relinquish their elite privileges. Several suras
(chapters) and parts of suras
are said to date from this time, and reflect its circumstances: see for example al-Masadd
, al-Humaza
, parts of Maryam
and Al-Anbiya
, al-Kafirun
, and Abasa
.
It was during this period that the episode known as the "Satanic Verses" may have occurred. Some non-Muslims think that Muhammad was briefly tempted to relax his condemnation of Meccan polytheism and buy peace with his neighbors, but later recanted his words and repented (see Q53:19-22 and also Q22:52-3 which says that whenever Muhammad received revelation, Satan tried to substitute his words for the divine words. The incident is reported in only a few sources (see Guillaume 1955, 146-148), and Muslims disagree as to its authenticity.
In 619, both Muhammad's wife Khadijah and his uncle Abu Talib died. It was known as "the year of mourning."
Muhammad's own clan withdrew their protection of him. Muslims patiently endured hunger and persecution. It was a bleak time.
Isra and Miraj
A sixteenth-century Persian miniature painting celebrating Muhammad's ascent into the Heavens, a journey known as the Miraj; Muhammad's face is veiled
About 620, Muhammad went on the Isra
and Miraj
(night journey and ascension), a two-part journey he took in one night. Isra
is the Arabic word referring to what it regarded as Muhammad's miraculous night journey from Mecca
to Jerusalem
, specifically, to the site of the
Masjid al-Aqsa
, the al-Aqsa Mosque. It is believed to have been followed by the Miraj
, his ascension to heaven, where he toured heaven and hell
, and spoke with Allah and earlier prophets (including Moses, Abraham and Jesus) and received the instruction that his followers should pray five times daily. Non-Muslims are skeptical about the authenticity of this event, while some Muslims suggest that it was a spiritual and not a physical experience (see Asad 1981, 187). [3]
Certainly, this experience gave Muhammad great encouragement and comfort at a critical period in his career.
Hijra
By 622, life in the small Muslim community of Mecca
was becoming not only difficult, but also dangerous. Muslim traditions say that there were several attempts to assassinate Muhammad. Muhammad then resolved to emigrate to Medina, then known as Yathrib, a large agricultural
oasis where there were a number of Muslim converts. By breaking the link with his own tribe, Muhammad demonstrated that tribal and family loyalties were insignificant compared to the bonds of Islam
, a revolutionary idea in the tribal society of Arabia. This Hijra
or emigration (traditionally translated into English as "flight") marks the beginning of the Islamic calendar. The Muslim calendar counts dates from the Hijra, which is why Muslim dates have the suffix A.H. (After Hijra). Only after the Hijrah were the believers called Muslims, the religion Islam (Q5:3) and the five daily prayers established. There has been some speculation whether the migration was voluntary or forced. Not all of Muhammad's followers fled, though those who stayed behind may have been compelled to remain by the Quraysh. Others belonged to split families (which had Muslim and non-Muslim members) and could not freely leave.
Muhammad came to Medina as a mediator, invited to resolve the feud between the Arab factions of Aws and Khazraj. He ultimately did so by absorbing both factions into his Muslim community, and forbidding bloodshed among Muslims. However, Medina was also home to a number of Jewish tribes (whether they were ethnically as well as religiously Jewish is an open question, as is the depth of their “Jewishness”). Muhammad had hoped that they would recognize him as a prophet, but they did not do so. Some academic historians suggest that Muhammad abandoned hope of recruiting Jews as allies or followers at this time, and thus the
qibla
, the Muslim direction of prayer, was changed from the site of the former
Temple of Jerusalem
to the Ka'bah in
Mecca
. Muhammad built a mosque
, which also contained his living quarters and those of his wives. Later, he would teach, preach, receive diplomatic delegations and adjudicate disputes in the mosque, where he was also buried.
While at Mecca, the Qur'anic revelations had in the main preached justice, fair treatment of the poor, and worship of the one God and condemnation of idolatry. Now, more detailed legal content was revealed The Muslim community (ummah)
was to be the best community (Q3:110) and Muslims were to be a people who forbid the wrong and invite goodness (Q3:104). The primacy of God's will over human will and the need to submit the whole of one's life to God are dominant themes. The unity (tawhid)
of the ummah
should reflect that of Allah, holding different qualities in balance— leisure, work and prayer, for example—in equal measure. Inner piety must accompany outward conformity to religious ritual. The created world is beloved of God; the sun, the moon, the trees and the hills praise God (Q22:18), thus Islam recognizes no absolute ownership of property and regards human domination of the planet as a sacred trust (amana)
. All is eventually to be returned to the true owner (Q23:115). The rich must care for the less fortunate, thus zakat
(a tithe given to the disadvantaged) is one of a Muslim's obligations ( fard
, duties).
Muhammad and followers of other monotheistic faiths
Muhammad did not completely reject
Judaism
and Christianity, the two other
monotheistic
faiths that were known to the Arabs and which are referred to in the Qur'an; he said to have been sent by God in order to complete and perfect their teachings. He soon acquired a following by some and rejection and hatred by others in the region.
In contrast to the pagans
who were given the stark choice to convert or be expelled, Jewish and Christian settlements within Muslim territories were tolerated and taxed. Muhammad drafted a document now known as the Constitution of Medina
(c. 622-623), which laid out the terms on which the different factions, specifically the Jews
, could exist within the new state. In this system, the Jews and other "Peoples of the Book" were allowed to keep their religions as long as they paid tribute. This system would come to typify Muslim relations with their non-believing subjects and that tradition was one reason for the stability of the later Muslim caliphate
. In this, the Islamic empire was more tolerant than the other great powers of the area, the Byzantine
and Sassanid
empires, which were actively hostile to any religions or sects other than the state-sponsored religions (Orthodox Christianity and
Zoroastrianism
).
Although Islam supercedes or completes the earlier religions of Judaism and Christianity (see Q3:1-2), Muslims recognize a family relationship between all three Abrahamic faiths. Abraham
is an important character in the Qur’an, which describes him as neither a Jew nor a Christian but a Muslim (see Q2:134). Christians and Jews are criticized for claiming that only they are saved (Q2:111) and for corrupting the originally pure messages they had received. Christians are wrong to make Jesus
into God (or God's son) since he had pointed to God, not to himself (Q3:51). The category of protected minority (dhimmi)
established by Muhammad was permitted to retain their faith in return for relinquishing arms and payment of a tax (Muhammad stipulated that they should not be taxed too heavily). Muhammad said that whoever harms a
dhimmi
, harmed him. On one occasion, when a Christian delegation from Najran visited him in Medina, he allowed them to pray in his own mosque, as there was no church available (see Guillaume 1955, 271).
War
Relations between Mecca
and Medina rapidly worsened (see surat al-Baqara
). Meccans confiscated all the property that the Muslims had left in Mecca. From Medina, Muhammad signed treaties of alliance and mutual help with neighboring tribes.
At a certain point, Muhammad began to engage in the old Arabian
practice of raiding caravans bound for Mecca. Some have criticized this decision and practice, but others insist that it is justified by the circumstances. Meccan-Muslim relations had degenerated virtually to a state of
war
. As such it is argued that Islam's very survival depended on such action. Muslims owned no land in Medina and absent such raids they would have to live on charity and on sparse chances for wage labor.
In March of 624, Muhammad led some three hundred warriors in a raid on a Meccan merchant caravan. The Meccans successfully defended the caravan, and then decided to teach the Medinans a lesson. They sent a small army against Medina. On March 15, 624, near a place called Badr
, the Meccans and the Muslims clashed. Though outnumbered eight hundred to three hundred in the battle, the Muslims met with success, killing at least 45 Meccans and taking 70 prisoners for ransom; only 14 Muslims died. This marked the real beginning of Muslim military achievement and followed from a verse of the Qur'an that gave them permission to fight against persecution (Q 22:39). Previously, all resistance to oppression had been non-violent.
The verse that allowed Muslim men to marry, in certain circumstances, up to four wives (Q4:3) is widely believed to have been revealed shortly after this battle, which left some widows without protection. Other revelations became known as the "sword verses," such as Q9:5 and Q2:216. Muslim rulers subsequently used these verses to justify aggressive war to extend the borders of the Islamic empire; however when these verses were first revealed the Muslim community was already engaged in a war for Islam's very survival. Defenders of these verses' subsequent use to justify conquest remark that it was a time when many empires were competing for supremacy and used force to do so.
Islam, while no different from other contemporary powers in using force to spread its empire, nonetheless set out strict rules for the conduct of war that protected civilians, places of worship, crops and animals from harm. The accusation that Islam spread by means of the sword, forcing to convert at the point of a sword, is hotly contested by Muslims who argue that what spread was Muslim rule, while embracing the faith was voluntary. Evidence is that large portions of the empire remained non-Muslim for centuries, although over time the non-Muslims became minorities in many regions. It is, however, documented that overzealous Muslim conquerors sometimes did use force to convert the vanquished but this should not be taken as the norm.
Muhammad's rule consolidated
To the Muslims, the victory in Badr appeared as a divine vindication of Muhammad's prophethood
, and he and all the Muslims rejoiced greatly. Following this victory, after minor skirmishes, and the breaking of a treaty that risked the security of the city-state, the victors expelled a local Jewish clan, the Banu Qainuqa. Virtually all the remaining Medinans converted, and Muhammad became de facto
ruler of the city. Alongside the Qur'an, his own edicts
(sunnah)
became part of the sacred regulations that governed the life of the community. Many Muslims regard this as the ideal for all human society—to be governed by an individual whose life is centered on God and who has no self-interest. Others suggest that Muhammad’s temporal or political authority resulted from the particular circumstances in which he found himself.
While measures promulgated during the war with Mecca and the consolidation of Islamic rule helped to ensure Islam's survival, they may not necessary represent precedents for all times and places. Muslims are careful to ascertain whether Muhammad intended a particular edict to be universally binding, before they deem it to be mandatory for all Muslims. The most important tool here is what is called the “circumstance of revelation” although the technical term also carries the meaning of “reason” (to reason). Knowledge or information about the context in which a verse of the Qur'an or a saying of Muhammad was first uttered depends on the witness statements of Muhammad's companions. These accounts describe the context and whether or not the revelation addressed a general situation, or responded to a particular question asked by someone, or to a specific issue. If the former, the verse or saying becomes universally binding. If either of the latter, the witness (who must be a close companion or relative of Muhammad) will detail whether, in their view, the verse was only intended to speak to the specific situation, or applies to all Muslims. Some debate, clearly, can result and there is a strong tradition in Islam that all such rulings are tentative. However, the
ijma
or consensus rule, based on Muhammad's advice that his people would not agree in error, often results in agreement.
The commonly accepted view is that any material that “attaches solely to the historical event” must be distinguished from that which “although attached to the historical event, also has wider implications” (Denffer 1989, 103). For example, Q5:41, which says that the penalty for theft is amputation, was revealed “concerning a specific person who had stolen a piece of armor, and had been punished accordingly” is taken to be universally binding, although some Muslims understand this hudud
(extreme) punishment to be translatable into an alternative but equally stern penalty. Others insist that any Muslim state that substitutes an alternative penalty departs from true Islam.
Some sayings of Muhammad are taken as mandatory, others as only advisory but major difference in practice and consequences for policing Islamic faithfulness may result. For example, Muslims who believe that men must wear beards (that it is haram
, prohibited to shave) and also that beards must be long not short may enforce this rule by publicly humiliating shaved men. [4]
Similarly, dispute about whether the head covering for women is optional or mandatory also leads to disciplinary action in parts of the Muslim world. Other Muslims strongly reject such actions as petty and obscurantist, totally contrary to Islam's concern for human betterment, charity and godliness.
Continued warfare
In 625 the Meccan
general Abu Sufyan
marched on Medina with three thousand men. The ensuing Battle of Uhud took place on March 23, ending in a stalemate. The Meccans claimed victory, but they had lost too many men to pursue the Muslims into Medina.
In April 627, Abu Sufyan (whose wife, Hind, was among Muhammad's most vocal and bitter opponents) led another strong force against Medina. But Muhammad had dug a trench around Medina and successfully defended the city in the Battle of the Trench.
Many of the Muslims believed that Abu Sufyan had been aided by sympathizers among Jewish residents of Medina of the clan Banu Qurayza. As soon as the battle was over, reprisals commenced against the Banu Qurayza. After the Banu Qurayza were defeated, all the adult men and one woman were beheaded by the order of Saad ibn Muadh, head of the Aws clan, an arbiter chosen by the Banu Qurayza. The remaining women and children were taken as slaves or for ransom. Some critics of Islam feel that this was unjust; Muslims believe that this was necessary. Reeves (2000) states that ibn Muadh applied “the law of Moses to the followers of Moses (Deuteronomy, 20:12-14)” (38).
Following the Battle of the Trench, the Muslims were able, through conversion and conquest, to extend their rule to many of the neighboring cities and tribes.
The conquest of Mecca
By 628 the Muslim position was strong enough that Muhammad decided to return to Mecca
, this time as a pilgrim. In March of that year, he set out for Mecca, followed by 1,600 men. After some negotiation, a treaty was signed at the border town of al-Hudaybiyah. While Muhammad would not be allowed to finish his pilgrimage that year, hostilities would cease and the Muslims would have permission to make a pilgrimage to Mecca in the following year. The same year, correspondence occurred between Muhammad, who described himself as the 'slave of Allah' and the Byzantine emperor, Heraclius (610–641 C.E.
) who had met Abu Sufyan and questioned him about the prophet. Reportedly, Abu Sufyan converted following this encounter, since he was convinced that if even the Byzantine emperor feared Muhammad, he would soon conquer all. [5]
The agreement lasted only two years, however, as war broke out again in 630. Muhammad marched on Mecca with an enormous force, said to number ten thousand men. Eager to placate the powerful Muslims and anxious to regain their lucrative tribal alliances, the Meccans submitted without a fight. Muhammad, in turn, promised a general amnesty (from which a small number of people were specifically excluded). Hind begged forgiveness, and was pardoned. Most Meccans converted to Islam
and Muhammad destroyed the idols in the Ka'bah. Henceforth the pilgrimage would be a Muslim pilgrimage and the shrine a Muslim shrine.
Unification of Arabia
The capitulation of Mecca and the defeat of an alliance of enemy tribes at Hunayn effectively brought the greater part of the Arabian world under Muhammad's authority. This authority was not enforced by any formal governments, however, as he chose instead to rule through personal relationships and tribal treaties. For his followers, Muhammad combined temporal and spiritual leadership and recognized no distinction between the sacred and the secular. Islam aims to bring the whole of life into harmony with God's will and regards the live centered on God, the life of taqwa
(God-consciousness) as the ideal. Muhammad once described the whole earth as a mosque, and in its widest sense any permitted act is a form of worship. Even at the height of his power, Muhammad only ever used the title 'messenger' (rasul)
or prophet (naby)
and always lived very modesty (when he died he left almost no personal property). He recited, “I am just a human being like you,” except “to me is given the revelation that your God is God alone” (Q18:110). He dressed modestly and disliked ostentatious clothes.
By his death in 632, Muhammad had consolidated his rule over the entire Arabian peninsula
The Muslims were clearly the dominant force in Arabia, and most of the remaining tribes and states hastened to submit to Muhammad.
Muhammad's family life
From 595 to 619, Muhammad had only one wife, Khadijah
. She was Muhammad's first wife and the mother of the only child to survive him, his daughter Fatima
.
After Khadija's death, Muhammad married again, to Aisha
, daughter of his friend Abu Bakr
(who later emerged as the first leader of the Muslims after Muhammad's death). In Medina, he married Hafsah, daughter of Umar
(who would eventually become Abu Bakr's successor). Later he was to marry more wives, for a total of 11 (nine or ten living at the time of his death). Some of these women were recent widows of warriors in battle. Others were daughters of his close allies or tribal leaders. These marriages sealed relations between Muhammad and his top-ranking followers. These men played important roles, advising Muhammad, who always consulted on important matters.
Some say that he also married his slave girl Maria al-Qibtiyya, but other sources speak to the contrary. She bore him a son, Ibrahim, who died in infancy.
Muhammad's daughter Fatima
married Ali
, Muhammad's cousin. According to the Sunni, another daughter, Umm Kulthum, married Uthman
. Each of these men, in later years, would emerge as successors to Muhammad and political leaders of the Muslims. Thus all four of the first four
caliphs
were linked to Muhammad by blood, marriage, or both. Sunni
Muslims regard these caliphs as the Rashidun
, or “Rightly Guided.”
His marriage to Aisha
is often criticized today, citing traditional sources that state she was only nine years old when he consummated the marriage. [6]
Critics also question his marriage to his adopted son's ex-wife, Zaynab bint Jahsh, and his alleged violation of the Qur'anic injunction against marrying more than four wives alleging that he fabricated the verses that allowed this, which also abolished adoption (Q33:4-5; 37). Such criticism is almost exclusively non-Muslim. Muslims take a different view, believing that Muhammad was protected as a prophet from any major error and that his life represents the highest standard of human behavior. It is a noble
(hasan) sunnah
(Q33:21).
Muhammad's multiple marriages do not match some understandings of the ideal family as one husband and one wife. However, special conditions may apply (as Muslims argue) given the circumstances. The relationship between Muhammad's wives was sometimes strained (see Q66) but they are all known as 'mothers of the believers' and gave Muhammad great comfort and support in his domestic life, enabling him to perform his public functions.
Muslim feminists contend that Muhammad was a champion of women's rights but that most of his male followers were unprepared to accept this aspect of his teaching, and subsequently altered it. Mernissi (1991) described her
The Veil and the Male Elite
as
...a vessel journeying back in time in order to find a fabulous wind that will swell our sails and send us gliding towards new worlds, towards the time both far away and near the beginning of the Hejira, when the Prophet could be a lover and a leader hostile to all hierarchies, when women had their place as unquestioned partners in a revolution that made the mosque as open place and the household a temple of debate. (10)
Muslims are not embarrassed by the fact that Muhammad liked women or indeed sex, regarding this as healthy and also as providing guidance on how men should treat women, indeed on how they should engage in intimacy (praying before doing so). Muslims point out in response to Christian criticism that Jesus does not provide them with any advice in this area. One Muslim woman comments that Jesus “never married, so he could not become an ideal husband and father,” and he “did not rise to power,” so cannot serve “as a model of a benevolent just ruler and judge”—indeed unlike Muhammad, “his life and character are shrouded in mystery” (Ulfat Aziz Us-Samad 1979, 26). By contrast, Muhammad's life “offers us the perfect example in all walks of life…[He gives us] “the picture of an ideally happy and pious married life and of a wise, just and benevolent ruler working for the material and moral amelioration of his people” (ibid)
. Reeves (2000) refers to Muhammad's love of children and says that his household was “a model husband—gentle, generous, considerate and courteous” (49). His wives were “precious companions” with whom he “could talk and on whom he could rely for frank opinions and wise advice” (49). Aisha, certainly, felt free to speak her mind, even in criticism.
Companions of Muhammad
The term companions (sahabah)
refers to anyone who met three criteria. First, he must have been a contemporary of Muhammad. Second, he must have seen or heard Muhammad speak on at least one occasion. Third, he must have converted to Islam. Companions are responsible for the transmission of hadith
, as each hadith
must have as its first transmitter a companion. There were many other companions in addition to the ones listed here.
List in alphabetic order:
Aamir
Abdullah ibn Abbas
Abdulrahman
Abu Bakr
Ali ibn Abi Talib
Hamza
Sa'd
Sa'eed
Sad Ibn Abi Waqqas
Salman the Persian
Talha
Umar ibn al-Khattab
Uthman ibn Affan
Zubair
The death of Muhammad
After a short illness, Muhammad died around noon on Monday, June 8, 632, in the city of Medina at the age of 63.
According to Shi'a
Islam, Muhammad had appointed his son-in-law Ali as his successor, in a public sermon at Ghadir Khumm. But Abu Bakr and Umar intrigued to oust Ali and make Abu Bakr the leader or caliph
. The majority, the Sunni, disputes this, and say that the leaders of the community conferred and freely chose Abu Bakr, who was pre-eminent among the followers of Muhammad. However it happened, Abu Bakr became the new leader. He spent much of his short reign suppressing rebellious tribes in the Ridda Wars.
With unity restored in Arabia, the Muslims looked outward and commenced the conquests that would eventually unite the Middle East under the caliphs.
Muhammad's descendants
Muhammad was survived only by his daughter Fatima
and her children (some say that he had a daughter, Zainab bint Muhammad, who had borne a daughter, Amma or Umama, who survived him as well).
In Shi'a Islam
, it is believed that Fatima's husband 'Ali and his descendants are the rightful leaders of the faithful. The Sunni do not accept this view, but they still honor Muhammad's descendents.
Descendents of Muhammad are known by many names, such as sayyids
, syeds
سيد, and sharifs
شريف (plural: ِأشراف Ashraaf). Many rulers and notables in Muslim countries, past and present, claim such descent, with various degrees of credibility, such as the Fatimid dynasty
of
North Africa
, the Idrisis, the current royal families of Jordan
and Morocco
, and the Agha Khan Imams of the Ismaili branch of Islam. In various Muslim countries, there are societies that authenticate claims of descent; some societies are more credible than others.
Muhammad's historical significance
Before his death in 632, Muhammad had established Islam as a social and political force and had unified most of Arabia. A few decades after his death, his successors had united all of Arabia, and conquered Iran
, Iraq
, Egypt
, Palestine
,
Syria
, Armenia
, and much of North Africa
. By 750, Islam had emerged as the spiritual counterpart to the two great monotheistic belief systems, Judaism and Christianity, and as the geopolitical successor to the
Roman Empire
. The rest of North Africa had come under Muslim rule, as had the southern part of Spain
and much of Central Asia (including Sind, in the Indus Valley).
Under the Ghaznavids, in the tenth century, Islam was spread to the Hindu
principalities east of the Indus by conquering armies in what is now northern
India
. Even later, Islam expanded peacefully into much of Africa
and Southeast Asia, where today Indonesia
has the largest Muslim population. Islam is now the faith of well over a billion people all over the globe, and believed to be the second-largest religion of the present day.
Muhammad's Legacy
Muslim reverence for Muhammad
For all Muslims, Muhammad is the final prophet or the khatm
(seal of prophecy, Q33: 40) after whom there are no more prophets. However, they regard him as the successor of numerous prophets (tradition says between 124,000 and 125,000 are named in the Qur'an). All prophets are equal but Muhammad is distinguished from all others by the nature of his message, which was universal whereas their messages were limited to particular places or people.
Because his example was understood to represent the highest ideal for human conduct, many details of his life, his likes and dislikes were preserved so that a great deal of information is available to anyone who is interested to know what his opinions were on a range of topics. We know that he loved cats
and horses
, hated bad smells, disliked music
and loved the color green (hence it is the color for Islam). Muslims believe that he was inspired when acting in his capacity as prophet but that when he was not fulfilling that role he did so as a fallible human, so for example when he advised on farming he might not necessarily have given sound advice. Asked what Muhammad was like, his wife Aisha
once said, “read the Qur'an,” suggesting that Muhammad lived by what he preached.
Most Muslims feel a great love and reverence for Muhammad, and express this in many ways, although no Muslim worships him or regards him as other than human.
When speaking or writing, Muhammad's name is preceded by the title "prophet" and is followed by the phrase, “Peace be upon him,” or “Peace be upon him and his descendents” by Shi'a; in English often abbreviated as "pbuh" and "pbuh&hd," or just simply as "p."
Concerts of Muslim and especially
Sufi devotional music include songs praising Muhammad, known as
Qawwali ).
Some Muslims celebrate the birthday of Muhammad (Mawlid) with elaborate festivities. Others do not, believing that such festivities are modern innovations, including the dominant school in Saudi Arabia.
Criticism of Muhammad is often equated with blasphemy , which is punishable by death in some Muslim states.
Muhammad is often referenced with titles of praise.
Muhammad's relics, such as his grave, his sword, his clothing, even strands of his hair, are revered by some.
Even non-iconic representations of Muhammad are traditionally discouraged. From the sixteenth century, however, Persian and
Ottoman art frequently represented Muhammad in miniatures, albeit with his face either veiled, or emanating radiance.
Beyond the stories accepted as
canonical by Islamic scholars of hadith , or oral traditions, there are many folktales praising Muhammad and recounting miraculous stories of his birth, upbringing and life.
Non-Muslim Assessments
Traditional Western animus
Few non-Muslims doubt Muhammad's achievement in terms of uniting Arabia, establishing an embryonic empire and leaving behind him a faith tradition that developed into the second largest religion in the world. They have been less inclined to accept the religious claims made about him. For Muslims, Muhammad is the perfect man and there is no question that he was sincere, moral, righteous and God revealed that Islam to him. Indeed, Muslims believe that God guided and directed the birth of Islam and the affairs of the early community. God is intimately involved in His creation, sustaining it daily (Q13:17, 15:16-23, 20:50, 30:40, 43:11, 56:63-74). Non-Muslims have often taken a much more critical view, and many have regarded Muhammad as self-serving, insincere, immoral, the inventor of Islam. Christians have long accused Muhammad of making up his religion based on borrowed material. Early accounts report meetings between Muhammad and a Christian monk, Bahira (see Guillaume, 79-82), while Q16:103 may respond to the charge that he was coached by a young Christian called Jabr (see Guillaume, 180). He has been called a fake prophet, a charlatan and worse. Some have attributed his "revelations" to epilepsy or some form of mental illness. Early writers even portrayed him as an idol worshiped by Muslims. His name was invariably misspelled.
Many Europeans, though critical of his motives, nonetheless credited Muhammad with political and military success. Even in this there have been skepics, notably Aloys Sprenger (1951), who depicted him as a tool in the hands of greater men such as Abu Bakr and Umar. However, William Muir (1894), whose biography of Muhammad is one of the earliest and most detailed biographies by a non-Muslim based on the best sources, while he echoed many of the above criticisms (indeed, as a Christian he suggests a satanic origin for Muhammad's inspiration), concluded that Muhammad, not those around him, “formed Islam” (lxxxvi).
Minou Reeves' Muhammad in Europe: A Thousand Years of Mythmaking
(2000) traces the story of how non-Muslims in Europe have depicted, misunderstood, insulted, mythologized and demonized the life and character of Muhammad:
In the works of an overwhelming majority of European writers Muhammad was portrayed as a man of deep moral faults. Churchmen, historians, Orientalists, biographers, dramatists, poets and politicians alike had sought to attribute to Islam and especially to Muhammad fanatical and disreputable, even demonic characteristics. (x)
Western appreciation for Muhammad
Reeves' book, however, also uncovers another tradition—that of such writers as Roger Bacon and William Montgomery Watt—who have tried to “understand Muhammad's cause, Muhammad's message, Muhammad's social and political reforms, Muhammad's personality and character in the context of his times and with an open mind, [seeking to] “dispel the myths and the stereotypes and to show how Islam embraces values dear to religions that have regarded it as their sworn enemy” (300).
Muir followed others in seeing Muhammad at Mecca as sincerely searching for the truth but alleged a moral decline at Medina where worldly ambition mingled with his original goal, and robbed him of any virtue he may have had at Mecca. Muir singles out many events in Muhammad's life for moral censure yet even he praises his simple life-style, his “urbanity and kindness of disposition [and] magnanimity towards his enemies” (although he accuses him of murdering some of his critics, such as the poet Ka'b ibn Ashraf (see Lings, 160 for a Muslim explanation) (see Muir 1858, vol. 4, 304-310).
In recent years, Christian writers Kenneth Cragg (1984), William Montgomery Watt (1961) and Clinton Bennett (1998) have attempted to find ways of affirming that he was a prophet of God while remaining loyally Christian. Watt, asking whether Muhammad was a prophet, concluded:
…not all the ideas he preached [from Watt's Christian perspective] are true and sound, but by God's grace he has been enabled to provide billions of men [and women] with a better religion than they had before they testified that there is no God but God and that Muhammad is the messenger of God (240).
In today's interfaith climate, more and more non-Muslims have come to resonate with these views; they accept that God stands behind Islam, thus recognizing with Muslims the genuineness of Muhammad's spiritual experiences and leadership. Although they do not accept every aspect of Muslim belief, they reject the view that Muhammad was insincere or that he invented Islam.
For secular historians, the question of Muhammad's sincerity or authorship of Islam is irrelevant. His legacy in terms of a worldwide civilization is sufficient. For those who believe in God as the prime mover behind and within history, the issue of whether Muhammad was really inspired by God cannot be avoided. Either he was not, and despite political success he was a charlatan, or he was inspired and so was used by God to spread faith in him and to teach the importance of obedience to God. Islam is either Muhammad's creation, or God's. If God's, then the binding of people together in a common faith across race and nationality, with a single hope in God's ultimate perfecting of the world, is providential not accidental. Muslims are the first to admit that they have not always lived up to the ideal. The ummah
has not remained united yet Muslims aspire towards unity, and all know that equality, justice and fairness are of the essence of Islam.
Notes
↑ Some Muslims dislike the English term religion, which implies a private belief, whereas Islam, for many Muslims, includes government and legal aspects as well.
↑ ibn = "son of" in Arabic; alternate names of people with two names are given in brackets.
↑ Muhammad Asad (1900-1992) was a converted Jew , named Leopold Weiss at birth, who became an important scholar of Islam.
↑ Mufti Afzal Elias, “What Islam says About the Beard,”
Islam.tc. Retrieved August 10, 2007.
↑ See T. A. Cengia, “Society and the State,”
for Muhammad's letters to various kings and emperors (including the Negus of Ethiopia and Heraclius).
↑ See Aisha for a discussion of other, conflicting, traditions.
References
ISBN links support NWE through referral fees
Armstrong, Karen. Muhammad: A Biography of the Prophet.
San Francisco: Harper, 1993.
ISBN 0062508865
Asad, Mohammed. Sahih-al-Buckari: The Early Years of Islam.
Gibraltar: Dar-al-Andalus, 1981 (original 1932).
ISBN 0317524585
al-Azami, Muhammad M. On Schacht's “Origins of Muhammadan Jurisprudence.”
Cambridge: Islamic Texts Society, 1996. ISBN 0946621462
Bennett, Clinton. In Search of Muhammad.
New York: Continuum, 1998. ISBN 0304704016
Coulson, Noel C. A History of Islamic Law.
Edinburgh: Edinburgh University Press, 1994. ISBN 0748605142
Cragg, Kenneth. Muhammad and the Christian: A Question of Response.
London: Darton, Longman and Todd, 1984. New edition, Oxford: Oneworld, 1999. ISBN 1851681795
Crone, Patricia and Michael Cook.
Hagarism. Cambridge: Cambridge University Press, 1977.
ISBN 0521211336
Denffer, Ahmed von. Ulum al Qur'an.
Leicester: The Islamic Foundation, 1989. ISBN 0860371093 .
Geiger, Abraham. Judaism and Islam
(trans. F. M. Young). Bangalore, India, 1896. Available online. Retrieved August 10, 2007.
Guillaume, Alfred. The Life of Muhammad: A Translation of Ibn Ishaq's Sirat Rasul Allah.
Oxford: Oxford University Press, 1955 (reprinted 2002). ISBN 0196360331
Haykal, Muhammad Husayn. The Life of Muhammad.
New Delhi: Islamic Book Service Year, 1995.
ISBN 1577311957
Lings, Martin. Muhammad: His Life Based on Earliest Sources.
Bombay: Inner Traditions International, Limited, 1987. ISBN 0892811706
Mernissi, Fatima. The Veil and the Male Elite: A Feminist Interpretation of Women's Rights in Islam
. New York: Perseus, 1991. ISBN 0201523213
Muir, Sir William. Life of Mahomet (4 vols). London: Smith, Elder & Co, 1858-1922. Available online. Retrieved August 10, 2007.
Muir, Sir William. Life of Mahomet
(abridged edition). London: Smith, Elder & Co, 1894.
Nasr, Seyyed Hossain. Ideas and Realities of Islam.
London: Thorsons/HarperCollins, 1994.
ISBN 1855384094
Reeves, Minou. Muhammad in Europe: A Thousand Years of Mythmaking.
New York: New York University Press, 2000.
ISBN 0814775330
Rodinson, Maxime. Muhammad.
New York: New Press, 2002. ISBN 1565847520
Schacht, Joseph. An Introduction to Islamic Law.
New York: Oxford University Press, 1964 (reprinted 1983). ISBN 0198254737
Sprenger, Aloys. The Life of Mohammed from Original Sources.
Allahabad: The Presbyterian Mission Press, 1851.
Us-Samad, Ulfat Aziz. Islam and Christianity.
Lahore: Kazi Publishers, 1979.
Warraq, Ibn. Why I am Not a Muslim.
Amherst, NY: Prometheous, 1995. ISBN 0879759844
Warraq, Ibn. The Quest for the Historical Muhammad.
Amherst, NY: Prometheus Books, 2000.
ISBN 1573927872
Wansborough, John. Quranic Studies.
Oxford: Oxford University Press, 1977. ISBN 0197135 889
Watt, William Montgomery.
Muhammad: Prophet and Statesman.
Oxford: Oxford University Press, 1961.
ISBN 0198810784
Zakaria, Rafiq. Muhammad and the Quran. London: Penguin, 1991. ISBN 0140147234
External links
All links retrieved November 10, 2022.
Muhammad: Legacy of a Prophet
from PBS
Sunni
Twenty-Nine Traits of Prophet’s Great Character
– The Islamic Circle of North America
Shi'a
“A Restatement of the History of Islam and Muslims”
by Sayed Ali Asgher Razwy
“The Life of Muhammad the Prophet” by Syed Saeed Akhtar Rizvi
“Beacons of Light” by Abu Ali al Fadl
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ENB:05:02
ENB:05:02
A BRIEF HISTORY OF THE CSD
The idea of a Commission on Sustainable Development emerged from
within the negotiating chambers at UN Headquarters just over one
year ago at UNCED PrepCom IV. While most of Chapter 38 of Agenda 21
went "unbracketed" to Rio, the PrepCom forwarded two options for
the international institutional follow-up to UNCED: 1) a high-level
Commission on Sustainable Development that would report to the
General Assembly on matters of substance and to ECOSOC on matters
of coordination; or 2) the use of a revitalized ECOSOC with a
subsidiary mechanism such as a third sessional committee or the
utilization of its high-level coordination segments. During UNCED,
in meetings of the contact group on institutions led by Amb. Razali
Ismail of Malaysia, a compromise was reached that called for the
establishment of a high-level Commission on Sustainable Development
that would be a functional commission of ECOSOC. The compromise
text also recommended that the 47th session of the General Assembly
take the decisions on the specific organizational modalities of the
Commission, including the number of members and matters related to
the frequency, venue and duration of meetings.
During the 47th Session of the General Assembly (GA) the Second
Committee decided to establish a special ad-hoc working group under
the guidance of Amb. Razali to deal with the list of specific
recommendations made by UNCED to be considered by the GA, including
the establishment of the Commission on Sustainable Development.
After one month of intense negotiations, the group negotiated a
34-paragraph resolution that set out the terms of reference of the
Commission, its composition, the participation of NGOs, the
organization of work, the CSD's relationship with other UN bodies,
the high-level advisory board and Secretariat- support
arrangements.
This resolution, A/RES/47/191 "Institutional arrangements to follow
up the United Nations Conference on Environment and Development,"
was adopted by the General Assembly on 23 December 1992. In this
resolution the GA requested that the Economic and Social Council,
at its organizational session in 1993, set up the CSD as a
functional commission and that the Secretary-General submit to the
1993 ECOSOC organizational session his proposals on the rules of
procedure applicable to the Commission. The resolution also
recommended that the Commission hold a short organizational session
in New York to establish the Bureau and decide on the agenda for
its first substantive session. It also called on the
Secretary-General to establish, within the new Department for
Policy Coordination and Sustainable Development (DPCSD), a
Secretariat to provide support to the CSD.
The ECOSOC organizational session, which was supposed to meet from
2-5 February, ended up lasting for two weeks. The ECOSOC
negotiations on the CSD took much longer than anticipated to reach
agreement on the procedural arrangements for the participation of
the European Economic Community. ECOSOC was able to take four
decisions related to the CSD that: 1) established the CSD; called
for election of the 53 members to be held on 16 February; set the
dates for the organizational and first substantive session, and
agreed on the provisional agenda for the organizational session; 2)
established the rules of procedure for the CSD as a functional
commission of ECOSOC, including supplementary arrangements
regarding the participation of specialized agencies, IGOs and NGOs;
3) decided to conduct a review of current arrangements for
consultations with NGOs; and 4) requested that the regional
economic commissions submit reports to the CSD by 1994 on their
plans to implement Agenda 21.
The CSD held its organizational session from 24-26 February 1993 at
UN Headquarters in New York where the members elected the Chair and
other members of the Bureau; discussed the provisional agenda and
organization of work of the Commission at its first substantive
session; and approved an outline of a multi-year thematic programme
of work. Ambassador Razali Ismail of Malaysia was elected the first
Chair of the Commission. The Commission also elected the other four
members of the Bureau who will serve as Vice-Chairs and Rapporteur:
Rodney Williams, Antigua and Barbuda's Minister for Economic
Development, Tourism, Industry (and Environment); Hamadi Khouini,
Tunisia's Ambassador to the UN; Bedrich Moldan, Director of the
Charles University Centre for Environmental Scholarship and
formerly of the Czech Ministry of the Environment; and Arthur
Campeau, Canada's Ambassador for Environment and Sustainable
Development.
The organizational session adopted three decisions. The first is
the provisional agenda of the first substantive session. The second
is a series of decisions relating to the future work of the
Commission. These include: the Commission will establish informal
negotiating groups as needed at each session; the Commission will
decide which reports it will consider when preparing the agendas
for future meetings and how it will consider contributions from
entities outside the UN system, including NGOs; and the Commission
requested the Chair to hold informal consultations on its work.
These consultations took place in late March and were chaired by
CSD Vice-Chair Hamadi Khouini. The last decision recommended a
clustering of Agenda 21 chapters as the basis for the multi-year
thematic programme of work of the Commission.
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17/073-08:11:13.590 ON ON ON OFF ON ON ON OFF ON OFF | https://lasp.colorado.edu/maven/sdc/public/data/sites/site-20191226T201211/anc/eng/sasm2/sci_anc_sasm217_070_074.drf |
Policy R13: Site of former Gas Holder at Gas Hill | GNLP
Policy R13: Site of former Gas Holder at Gas Hill
2.269
The site was allocated in the previous Local Plan but has not yet been developed. The gas holder previously on site has been decommissioned and removed. The principle of development on the site has already been accepted, and it is expected that development will take place within the new local plan time-period up to 2038. The site is re-allocated for residential development. As an existing allocation it has been considered in the calculation of the housing requirement.
2.270
The site is located to the east of the city centre, on the steep slope of Gas Hill. It is 0.3 hectares in size. The site, consisting of the disused gas holder itself and small areas of incidental land, is flat. It is within an area with a mix of uses. It lies below the Thorpe wooded ridge, which includes the remains of the Benedictine St Leonards Priory to its east. It is topographically above a pub, furniture store and housing to the west and south. There is also housing to the north of the site.
2.271
The site is between the St Matthews Conservation Area and the Thorpe Hamlet Conservation Area. The steepness of the chalk escarpment east of the site has prevented any major development, resulting in a ‘green wedge’ of trees and greenery, creating an important refuge for wildlife and open space. The ridge provides excellent views to and from the city centre, though there is no public access to the Thorpe wooded ridge at this point.
2.272
This brownfield site is in an accessible location for housing, close to Bishop Bridge local centre, the city centre, bus routes and the railway station.
2.273
Design will have to take account of the site’s topography and development must not have a negative impact on geodiversity or on views to and from the Thorpe wooded ridge.
2.274
The development will have to address specific on site constraints relating to its former uses. Removal of the hazardous substance consent will be required. Ground conditions and contamination assessments will also be necessary.
2.275
As a minimum, protection and enhancement of geodiversity will include recording of geological features on site.
2.276
Access to the site will be via the existing access from Gas Hill.
2.777
Development needs to ensure that the water environment is protected. The site falls within Source Protection Zone 1, designated to protect water supplies, and therefore the water environment is particularly vulnerable in this location. Detailed discussions over this issue will be required with the Environment Agency to ensure that proposals are appropriate for the site and that the site is developed in a manner which protects the water environment.
2.278
Policy R13
Site of former Gas Holder at Gas Hill, Norwich (approx. 0.30ha) is allocated for residential development. This will accommodate a minimum of 15 homes.
The development will achieve the following site-specific requirements:
Achievement of a high quality, locally distinctive design of a scale and form which reflects and responds to its prominent location on the hillside east of the city centre adjacent to Thorpe wooded ridge. Development should blend in with the existing pattern of development in this location
Development should respect the heritage significance and setting of the adjacent Thorpe Hamlet Conservation Area and of the scheduled remains of St Leonards Priory. The site is in close proximity to Cow Tower scheduled monument, design of development on this site should preserve and enhance the setting of adjacent heritage assets.
Protection and enhancement of key green infrastructure, biodiversity and geodiversity assets within the site;
Ensures a high level of flood resilience and incorporates appropriate mitigation measures addressing identified risks from surface water flooding);
Development will not take place prior to the revocation of the hazardous substance consent.
Site contamination arising from the former gas storage use should be addressed and mitigated.
Car free or low car development in accordance with policy 2 is appropriate in this location.
Policy Map
| https://www.gnlp.org.uk/regulation-19-publication-part-2-sites-2-norwich-existing-allocations-be-carried-forward/policy-r13 |
UNIPROT:Q96P95 - FACTA Search
Poly(ADP-ribose) polymerase activity in nuclei isolated from differentiating cardiac muscle of the rat has been characterized and its activity measured during development. Optimum enzyme activity is observed at pH 8.5. Poly(ADP-ribose) polymerase is inhibited by ATP, thymidine, nicotinamide , theophylline, 3-isobutyl-1-methylxanthine and caffeine and stimulated by actinomycin D. The activity measured under optimal assay conditions increases during differentiation of cardiac muscle and is inversely related to the rate of DNA synthesis and to the activities of DNA polymerase alpha and thymidine kinase. When DNA synthesis and the activity of DNA polymerase alpha are inhibited in cardiac muscle of the 1-day-old neonatal rat by dibutyryl cyclic AMP or isoproterenol, the specific activity of poly(ADP-ribose) polymerase measured in isolated nuclei is increased. The concentration of NAD+ in cardiac muscle increases during postnatal development. In the adult compared with the 1-day-old neonatal rat the concentration of NAD+ relative to fresh tissue weight, DNA or protein increased 1.7-fold, 5.2-fold or 1.4-fold respectively. The concentration of NAD+ in cardiac muscle of the 1-day-old neonatal rat can be increased by approx. 20% by dibutyryl cyclic AMP. These data suggest that NAD+ and poly(ADP-ribose) polymerase may be involved with the repression of DNA synthesis and cell proliferation in differentiating cardiac muscle.
...
PMID:Poly(adenosine diphosphate ribose) polymerase activity and nicotinamide adenine dinucleotide in differentiating cardiac muscle. 18 Sep 77
Poly(ADP-ribose) polymerase with a high specific activity was obtained from Ehrlich ascites tumor cells by extraction of nuclei with 175 mM potassium phosphate, followed by chromatography on DNA-agarose. Electrophoretic analysis indicated that the preparation contained two proteins, one of which was shown to catalyze the synthesis of poly(ADP-ribose). As expected from results obtained by other workers, the synthesis was inhibited by nicotinamide and thymidine, and stimulated by DNA. Addition of histones gave inhibition of the synthesis, unless DNA was present in the reaction mixture.
...
PMID:Purification of poly(ADP-ribose) polymerase from Ehrlich ascites tumor cells by chromatography on DNA-agarose. 18 48
Poly(ADP-ribose) polymerase activity was measured in bleomycin (BLM)-resistant HeLa (HeLa-BLMr) and the parental HeLa cells after BLM treatment. HeLa-BLMr cells, which had been subcultured in growth medium containing 1 micrograms/ml of BLM, showed a 3.75-fold higher enzyme activity than did HeLa cells, but this activity was decreased to the same level as that of HeLa cells after 48 h of BLM-free cultivation. When HeLa and HeLa-BLMr cells after a 48-h cultivation in BLM-free growth medium were treated with BLM, the enzyme activity was induced at a higher level (2.5-3.8 times) in HeLa-BLMr than in HeLa cells and was inhibited markedly in HeLa-BLMr and slightly in HeLa cells by nicotinamide , an inhibitor of this enzyme. The BLM-induced cell killing by nicotinamide was highly potentiated (about 18 times) in HeLa-BLMr as compared to HeLa cells.
...
PMID:High induction of poly(ADP-ribose) polymerase activity in bleomycin-resistant HeLa cells. 247 71
H2O2, in concentrations achieved in the proximity of stimulated leukocytes, induces injury and lysis of target cells. This may be an important aspect of inflammatory injury of tissues. Cell lysis in two target cells, the murine macrophage-like tumor cell line P388D1 and human peripheral lymphocytes, was found to be associated with activation of poly(ADP-ribose) polymerase (EC 2.4.2.30), a nuclear enzyme. This enzyme is activated under various conditions of DNA damage. Poly(ADP-ribose) polymerase utilizes nicotinamide adenine dinucleotide (NAD) as substrate and has been previously shown to consume NAD during exposure of cells to oxidants that was associated with inhibition of glycolysis, a decrease in cellular ATP, and cell death. In the current studies, inhibition of poly(ADP-ribose) polymerase by 3-aminobenzamide, nicotinamide , or theophylline in cells exposed to lethal concentrations of H2O2 prevented the sequence of events that eventually led to cell lysis--i.e., the decrease in NAD, followed by depletion of ATP, influx of extracellular Ca2+, actin polymerization and, finally, cell death. DNA damage, the initial stimulus for poly(ADP-ribose) polymerase activation, occurred despite the inhibition of this enzyme. Cells exposed to oxidant in the presence of the poly(ADP-ribose) polymerase inhibitor 3-aminobenzamide failed to demonstrate repair of DNA strand breaks.
...
PMID:Hydrogen peroxide-induced injury of cells and its prevention by inhibitors of poly(ADP-ribose) polymerase. 294 60
The chemical synthesis of adenosine(5') [alpha-thio]diphospho(5')ribofuranosyl- nicotinamide (NAD[S]) is described. The product occurs as a pair of diastereomers with different configuration at the sulfur-bearing phosphorus atom. The diastereomers were separated by high-performance liquid chromatography and their absolute configuration was determined after chemical degradation to the ADP[alpha S] diastereomers and chromatographic comparison with enzymically synthesized ADP[alpha S] diastereomers of known absolute configuration. Additional support for this assignment is based on different rates in the phosphodiesterase-catalyzed hydrolysis. Furthermore the synthesis of [14C]NAD[S] is described. The coenzyme activity of NAD[S] in the reaction with alcohol dehydrogenase from baker's yeast and lactate dehydrogenase from pig heart is very similar to that of beta-NAD. Also, NAD and NAD[S] serve equally well as substrates for NAD glycohydrolase from calf spleen. In contrast, no reaction was detected with NAD pyrophosphorylase, and hydrolysis of the separated NAD[S] diastereomers with snake venom phosphodiesterase showed a 26-fold and a 33-fold slower reaction rate than that of NAD. Nucleotide pyrophosphatase was less sensitive to the S substitution, hydrolyzing NAD[S] 14-times slower than NAD. Poly(ADP-ribose) polymerase from Ehrlich ascites tumor cell nuclei accepted NAD[S] as a substrate but the reaction was significantly slower and approached saturation at much lower values than with NAD. Alkaline hydrolysis of the products insoluble in trichloroacetic acid yielded AMP[S] as the main derivative. It is concluded that with NAD[S] as a substrate the nuclear acceptors were nearly exclusively mono(ADP-ribosyl) ated .
...
PMID:NAD[S], an NAD analogue with reduced susceptibility to phosphodiesterase. Chemical synthesis and enzymic properties. 614 44
Poly(ADP-ribose) polymerase was purified 2900-fold from lamb thymus with a recovery of 5%. Addition of exogenous DNA was essential for activity of the purified enzyme, and the reaction was stimulated by the addition of either a mixture of histones or purified histone H1. The enzyme is inhibited by sulfhydryl binding agents such as phenylmethanesulfonyl fluoride or N-ethylmaleimide. It does not require magnesium or other metal ion cofactors for activity. The enzyme migrated as a single polypeptide chain with an apparent molecular weight of 135 000 when gel electrophoresis was performed in the presence of sodium dodecyl sulfate. The apparent molecular weight was 175 000 when determined by gel filtration on Sepharose CL-6B-200. The isoelectric point was pH 9.6, and the pH optimum for activity was 8.6-8.8. The apparent Km for NAD+ was 160 microM at 37 degrees C. The activity of the purified polymerase was unaffected by the presence of ADP-ribose, 3',5'-cAMP, or NaF. Nicotinamide , 5-methyl- nicotinamide , theophylline, and thymidine markedly inhibited enzyme activity. Lamb thymus DNA, originally associated with the enzyme, was more effective than commercially obtained calf thymus DNA as an enzyme activator.
...
PMID:Purification and properties of poly(ADP-ribose) polymerase from lamb thymus. 627 86
Poly(ADP-ribose) polymerase has been purified 12 000-fold from human tonsils with an 83% recovery of enzymatic activity relative to that of the initial homogenate. The specific activity of the purified enzyme is 862 units/mg of protein. The isolated protein has a molecular weight of approximately 116 000 as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The apparent Km for NAD+ is estimated to be 185 microM at pH 8.0 and 37 degrees C. The purified enzyme has an absolute requirement for exogenous DNA for catalytic activity, and the reaction is enhanced by the addition of purified histone H1. The enzyme does not require magnesium or other divalent cations for activity. Enzyme activity is inhibited by p-(hydroxymercuri)benzoate and N-ethylmaleimide. Thymidine, theophylline, nicotinamide , and 5-methylnicotinamide markedly inhibit enzyme activity whereas ADP-ribose, 3',5'-cAMP, and sodium fluoride have a minimal effect on enzyme activity. Autoradiograms of labeled products of the reaction catalyzed by the purified enzyme at different concentrations of NAD+ and at different incubation times show that at low concentrations of NAD+ and after short incubations, poly(ADP-ribosyl)ation of the enzyme occurs preferentially over that of histone H1; at higher concentrations of NAD+ or after longer incubations, poly(ADP-ribosyl)ation of histone H1 is increased.
...
PMID:Purification and characterization of human lymphoid poly(adenosine diphosphate ribose) polymerase. 629 41
Inhibitors of poly(ADP-ribose) polymerase stimulated the level of DNA, RNA, and protein synthesis in DNA-damaged L1210 cells but had negligible effects in undamaged L1210 cells. The poly(ADP-ribose) polymerase inhibitors stimulated DNA repair synthesis after cells were exposed to high concentrations of N-methyl-N'-nitro-N-nitrosoguanidine (68 and 136 microM) but not after exposure to low concentrations (13.6 and 34 microM). When the L1210 cells were exposed to 136 microM N-methyl-N'-nitro-N-nitrosoguanidine, the activation of poly(ADP-ribose) polymerase resulted in the rapid depletion of oxidized nicotinamide adenine dinucleotide (NAD+) levels and subsequent depletion of adenosine 5'-triphosphate (ATP) pools. After low doses of N-methyl-N'-nitro-N-nitrosoguanidine (13.6 microM), there were only small decreases in NAD+ and ATP. Poly(ADP-ribose) polymerase inhibitors prevented the rapid fall in NAD+ and ATP pools. This preservation of the ATP pool has a permissive effect on energy-dependent functions and accounts for the apparent stimulation of DNA, RNA, and protein synthesis. Thus, the mechanism by which poly(ADP-ribose) polymerase inhibitors stimulate DNA, RNA, and protein synthesis in DNA-damaged cells appears to be mediated by their ability to prevent the drastic depletion of NAD+ pools that occurs in heavily damaged cells, thereby preserving the cells' ability to generate ATP and maintain energy-dependent processes.
...
PMID:Poly(ADP-ribose) Polymerase inhibitors preserve nicotinamide adenine dinucleotide and adenosine 5'-triphosphate pools in DNA-damaged cells: mechanism of stimulation of unscheduled DNA synthesis. 631 18
Poly(ADP-ribose) polymerase and poly(ADP-ribose) glycohydrolase have been detected in chromatin extracts from the dinoflagellate Crypthecodinium cohnii. Poly(ADP-ribose) glycohydrolase was detected by the liberation of ADP-ribose from poly(ADP-ribose). Poly(ADP-ribose) polymerase was proved by (a) demonstration of phosphoribosyl-AMP in the phosphodiesterase digest of the reaction product, (b) demonstration of ADP-ribose oligomers by fractionation of the reaction product on DEAE-Sephadex. The (ADP-ribose)-protein transfer is dependent on DNA; it is inhibited by nicotinamide , thymidine, theophylline and benzamide. The protein-(ADP-ribose bond is susceptible to 0.1 M NaOH (70%) and 0.4 M NH2OH (33%). Dinoflagellates, nucleated protists, are unique in that their chromatin lacks histones and shows a conformation like bacterial chromatin [Loeblich, A. R., III (1976) J. Protozool. 23, 13--28]; poly(ADP-ribose) polymerase, however, has been found only in eucaryotes. Thus our results suggest that histones were not relevant to the establishment of poly(ADP-ribose) during evolution.
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PMID:Presence of poly (ADP-ribose) polymerase and poly (ADP-ribose) glycohydrolase in the dinoflagellate Crypthecodinium cohnii. 632 Nov 75
Cell lines deficient in poly(ADP-ribose) synthesis due to enzyme deficiency (ADPRT54 and ADPRT351) or substrate deficiency (N2, N3, and N4) are resistant to topoisomerase II-directed agents, including etoposide (VP-16), N-[4-(9-acridinylamino)-3-methoxyphenyl]methanesulfonamide, and Adriamycin, relative to the effect of these agents on parental V79 Chinese hamster cells. Resistance is stable in the ADPRT54 and ADPRT351 cell lines, whereas resistance in the N2, N3, and N4 cell lines occurs when the cells are grown in nicotinamide -deficient medium to produce a state of NAD deficiency. However, sensitivity to VP-16 reverts to normal when cellular NAD levels return to control levels during growth in nicotinamide -containing complete medium. Poly(ADP-ribose) polymerase -deficient cell lines show constitutively increased levels of a protein at M(r) 78,000 on Coomassie blue-stained, sodium dodecyl sulfate-polyacrylamide gels that was subsequently confirmed with monoclonal antibodies to be M(r) 78,000 glucose-regulated stress protein (GRP78). Similarly, N2, N3, and N4 cells show induction of GRP78 under nicotinamide -deficient conditions. Induction of GRP78 is associated with elevated levels of GRP78 mRNA and appears to be regulated at the transcriptional level. When N3 cells with deficiency of poly(ADP-ribose) synthesis due to NAD deficiency are shifted to complete, nicotinamide -containing medium, they restore their NAD content, undergo a decrease in GRP78 levels, and regain sensitivity to VP-16. When V79 cells are shifted to nicotinamide -deficient medium they undergo a reduction in NAD content, followed by a progressive elevation in GRP78 levels, and they subsequently become increasingly resistant to VP-16. These studies demonstrate a clear association between deficiency of the NAD-poly(ADP-ribose) synthesis system, induction of GRP78 synthesis, and resistance to VP-16.
...
PMID:Induction of M(r) 78,000 glucose-regulated stress protein in poly(adenosine diphosphate-ribose) polymerase- and nicotinamide adenine dinucleotide-deficient V79 cell lines and its relation to resistance to the topoisomerase II inhibitor etoposide. 804 89
| http://www.nactem.ac.uk/facta/cgi-bin/facta3.cgi?query=UNIPROT%3AQ96P95%7C111111%7C0%7C0%7C366222%7C0%7C10 |
Cassette tape: Music for Children's Theater, approximately 1970 | Kenneth Spencer Research Library Archival Collections
File — Box: 6, Folder: 19
Citation
University of Kansas. Kenneth Spencer Research Library
American Dance Symposia records (RH MS 959)
Papers
Cassette tape: Music for Children's Theater, approximately 1970
Dates
approximately 1970
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Box: 6, Folder: 19 (Mixed Materials)
Repository Details
Repository Details
Part of the University of Kansas. Kenneth Spencer Research Library Repository
http://spencer.lib.ku.edu/
Contact:
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American Dance Symposia records
Papers Papers
1969 Kansas Dance Council, Inc. American Dance Symposium 1969 Kansas Dance Council, Inc. American Dance Symposium
Wichita Dance Association clippings Wichita Dance Association clippings, undated
Funding (Kansas Dance Council) Funding (Kansas Dance Council)
Old endnotes (1-108) Old endnotes (1-108)
Laser printer - Kosmos Laser printer - Kosmos
Loose scraps - check for omissions Loose scraps - check for omissions
Outlines Outlines
Wichita Public Library Wichita Public Library
Other symposiums Other symposiums, undated
Intro notes Intro notes
Editing help - Sherbon, Alex Editing help - Sherbon, Alex
Survey of related research Survey of related research
Bauman Collection - articles and reviews on dance in general, and other arts in Kansas (especially Wichita) Bauman Collection - articles and reviews on dance in general, and other arts in Kansas (especially Wichita), undated
Cartoons and clippings Cartoons and clippings, undated
Elizabeth's suggestions/ideas Elizabeth's suggestions/ideas
[blank form] [blank form]
[Miscellaneous American Dance Symposium papers] [Miscellaneous American Dance Symposium papers], approximately 1970
Miscellaneous Miscellaneous
Orals presentation [re:American Dance Symposium] Orals presentation [re:American Dance Symposium], approximately 1970
Miscellaneous Miscellaneous
1973 Lawsuit - 1972 Debt for Dorm 1973 Lawsuit - 1972 Debt for Dorm
Miscellaneous (correspondence, clippings, etc.) Miscellaneous (correspondence, clippings, etc.), undated
Miscellaneous notes and questionnaire Miscellaneous notes and questionnaire
1972 Contracts 1972 Contracts
Ideas - Alice Bauman Ideas - Alice Bauman
Sherbon [clippings] Sherbon [clippings], undated
Found in Wichita newspapers [clippings re: American Dance Symposium] Found in Wichita newspapers [clippings re: American Dance Symposium], circa 1970
[Kansas Dance Council papers] [Kansas Dance Council papers]
Missal [empty folder] Missal [empty folder]
Mann [empty folder] Mann [empty folder]
Stevan Bauman Photographer [empty folder] Stevan Bauman Photographer [empty folder]
46 [empty folder] 46 [empty folder]
44 [empty folder] 44 [empty folder]
43 [empty folder] 43 [empty folder]
American Dance Symposium American Dance Symposium, approximately 1972
American Dance Symposium American Dance Symposium
Audio reel: drum solo by Cimber Audio reel: drum solo by Cimber, undated
American Dance Symposium American Dance Symposium
Posters Posters
The History of the American Dance Symposia by Arvella Ruth Frazier The History of the American Dance Symposia by Arvella Ruth Frazier, 1986
American Dance Symposia miscellaneous American Dance Symposia miscellaneous
American Dance Symposium pictures American Dance Symposium pictures, approximately 1968
American Dance Symposium miscellaneous American Dance Symposium miscellaneous
Paul Taylor Dance Company playbill Paul Taylor Dance Company playbill
American Dance Symposium miscellaneous American Dance Symposium miscellaneous
1969 Symposium, Kansas Dance Council 1969 Symposium, Kansas Dance Council
American Dance Symposium American Dance Symposium
Kansas State Historical Society Archives Kansas State Historical Society Archives
Symposium contracts Symposium contracts, 1969
Symposium 1970 Symposium 1970
Contracts for Symposium 1970 Contracts for Symposium 1970
Kansas Dance Councils, Inc Kansas Dance Councils, Inc
American Dance Symposium American Dance Symposium
Dance in Kansas clippings Dance in Kansas clippings
National Association of Regional Ballet National Association of Regional Ballet
Programs - concerts Programs - concerts
Bauman Collection - clippings about symposium Bauman Collection - clippings about symposium, approximately 1970
1969 Kansas Dance Council, Inc. American Dance Symposium 1969 Kansas Dance Council, Inc. American Dance Symposium
Mid-America Dance Network Mid-America Dance Network
Symposium 1968 Contacts Symposium 1968 Contacts
Miscellaneous dance materials (magazines, programs, etc.) Miscellaneous dance materials (magazines, programs, etc.)
Nagrin [empty folder] Nagrin [empty folder]
Percival Borde Percival Borde
Alphonse Cimber Alphonse Cimber
1969 American Dance Symposium 1969 American Dance Symposium
1970 American Dance Symposium [ad mockup] 1970 American Dance Symposium [ad mockup]
Clipping re: Russian Ballet Clipping re: Russian Ballet
Dance pamphlets Dance pamphlets
American Dance Symposium fliers American Dance Symposium fliers
"Horizons Unlimited" "Horizons Unlimited", Fall 1989
American Dance Symposium American Dance Symposium
1969 American Dance Symposium 1969 American Dance Symposium
Artists who participated in one or more of the 4 Symposia Artists who participated in one or more of the 4 Symposia
American Dance Symposium and Sherbon Vita American Dance Symposium and Sherbon Vita
Program and Artists listed by year of participation Program and Artists listed by year of participation
Letters from Artists about Symposium Series Letters from Artists about Symposium Series
Miscellaneous Miscellaneous
1970 American Dance Symposium 1970 American Dance Symposium
Playbill: Winter Garden Playbill: Winter Garden, undated
[Kansas Cultural Arts Commission programs and clippings] [Kansas Cultural Arts Commission programs and clippings]
Dance Symposium of Kansas Colleges; Wichita Children's Theater Dance Symposium of Kansas Colleges; Wichita Children's Theater, 1938 & 1956
Formation of the Kansas Cultural Arts Commission Formation of the Kansas Cultural Arts Commission, undated
"In Process: An Informal Evening of Solo Dancing Works by Mary L. Halverstadt" program "In Process: An Informal Evening of Solo Dancing Works by Mary L. Halverstadt" program, October 9, 1983
Miscellaneous Miscellaneous
"American Caucus" and L&H vitamins "Health Newsline," "American Caucus" and L&H vitamins "Health Newsline,", undated
Kansas Dance Council (Symposium) Kansas Dance Council (Symposium), 1973-1974
[Creation of Kansas Cultural Arts Commission] [Creation of Kansas Cultural Arts Commission]
[Kansas Cultural Arts Commission clippings] [Kansas Cultural Arts Commission clippings]
Fowler [empty folder] Fowler [empty folder]
Hering [empty folder] Hering [empty folder]
Frazier, Bernard and Beverly [empty folder] Frazier, Bernard and Beverly [empty folder]
Evans [empty folder] Evans [empty folder]
35 [empty folder] 35 [empty folder]
Miscellaneous Miscellaneous
Laban [empty folder] Laban [empty folder]
Paul Taylor Dance Co. posters Paul Taylor Dance Co. posters, 1969
Miscellaneous: dance pamphlets Miscellaneous: dance pamphlets
Audio reels: rehearsals, etc Audio reels: rehearsals, etc, approximately 1970
Cassette tape: Music for Children's Theater Cassette tape: Music for Children's Theater, approximately 1970
"Modern Dance: Building and Teaching Lessons" by Aileene Lockhart, Second Edition "Modern Dance: Building and Teaching Lessons" by Aileene Lockhart, Second Edition, 1957
"Modern Dance: Building and Teaching Lessons" by Aileene Lockhart and Esther E. Pease, Fourth Edition "Modern Dance: Building and Teaching Lessons" by Aileene Lockhart and Esther E. Pease, Fourth Edition, 1973
Miscellaneous: music, magazines, etc Miscellaneous: music, magazines, etc
Miscellaneous: clippings Miscellaneous: clippings
Miscellaneous: magazines and clippings Miscellaneous: magazines and clippings
Miscellaneous: clippings and sheet music Miscellaneous: clippings and sheet music
Miscellaneous: clippings and reports Miscellaneous: clippings and reports
Sheet music Sheet music
Kansas Arts Commission Annual Budget Kansas Arts Commission Annual Budget, 1980
Miscellaneous magazines and clippings Miscellaneous magazines and clippings
Photos: identified people Photos: identified people, approximately 1970
Photos: identified people Photos: identified people, approximately 1940
Photos: unidentified people Photos: unidentified people, mid-20th century
Studio Rental Address Book Studio Rental Address Book
Journal of Alice Sherbon Bauman Journal of Alice Sherbon Bauman, 1939-1943
Art postcards sent to Alice and Elizabeth Art postcards sent to Alice and Elizabeth, undated
American Dance Therapy Association: Proceedings of Fourth Annual Conference American Dance Therapy Association: Proceedings of Fourth Annual Conference, October 31, 1969
Miscellaneous: pamphlets. programs, magazines, clippings and letters Miscellaneous: pamphlets. programs, magazines, clippings and letters
Pre-Classic (unbound) Danceforms by Louis Horst; Miscellaneous magazines, programs, etc Pre-Classic (unbound) Danceforms by Louis Horst; Miscellaneous magazines, programs, etc
Dance programs and miscellaneous correspondence Dance programs and miscellaneous correspondence, approximately 1934-1979
Miscellaneous: clippings, programs, etc Miscellaneous: clippings, programs, etc
Miscellaneous dance materials Miscellaneous dance materials
Photos: Studio in Wichita Photos: Studio in Wichita, 1958
Miscellaneous: magazines, newsletters, clippings and pamphlets Miscellaneous: magazines, newsletters, clippings and pamphlets
Dance Symposium miscellaneous Dance Symposium miscellaneous
Dance Center Committee Dance Center Committee
Dance Symposium Dance Symposium, 1968
1969 Dance Symposium 1969 Dance Symposium
American Dance Symposium and Kansas Dance History American Dance Symposium and Kansas Dance History
Wichita Dance Association Wichita Dance Association
American Dance Symposium American Dance Symposium
Sheet music Sheet music
Photographs Photographs
Oversize materials Oversize materials
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Cassette tape: Music for Children's Theater, approximately 1970, Box: 6, Folder: 19. American Dance Symposia records, RH MS 959. University of Kansas. Kenneth Spencer Research Library. Copy to clipboard Cite Finding Aid
Cassette tape: Music for Children's Theater, approximately 1970, Box: 6, Folder: 19. American Dance Symposia records, RH MS 959. University of Kansas. Kenneth Spencer Research Library. https://archives.lib.ku.edu/repositories/3/archival_objects/37912 Accessed July 03, 2023. Copy to clipboard Close
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Drug localization in different lung cancer phenotypes by MALDI mass spectrometry imaging | Request PDF
Request PDF | Drug localization in different lung cancer phenotypes by MALDI mass spectrometry imaging | Lung cancer is a common cause of cancer mortality in the world, largely due to the risk factor of tobacco smoking. The drug therapy at the... | Find, read and cite all the research you need on ResearchGate
March 2011 Journal of Proteomics 74(7):982-92
DOI: 10.1016/j.jprot.2011.03.019
Source PubMed
Authors:
György Marko-Varga
Lund University
Thomas Fehniger
Lund University
Melinda Rezeli
Lund University
Balázs Döme
Balázs Döme
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References (48)
Abstract
Lung cancer is a common cause of cancer mortality in the world, largely due to the risk factor of tobacco smoking. The drug therapy at the molecular level includes targeting the epidermal growth factor receptor (EGFR) tyrosine kinase activity by using inhibitors, such as erlotinib (Tarceva) and gefitinib (Iressa). The heterogeneity of disease phenotypes and the somatic mutations presented in patient populations have a great impact on the efficacy of treatments using targeted personalized medicine. In this study, we report on basic physical and chemical properties of erlotinib and gefitinib in three different lung cancer tumor phenotypes, using MALDI instrumentation in imaging mode, providing spatial localization of drugs without chemical labeling. Erlotinib and gefitinib were analyzed in i) planocellular lung carcinoma, ii) adenocarcinoma and iii) large cell lung carcinoma following their deposition on the tissue surfaces by piezo-dispensing, using a controlled procedure. The importance of high-resolution sampling was crucial in order to accurately localize the EGFR tyrosine kinase inhibitors deposited in heterogeneous cancer tissue compartments. This is the first report on personalized drug characterization with localizations at a lateral resolution of 30μm, which allowed us to map these compounds at attomolar concentrations within the lung tumor tissue microenvironments.
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Citations (105) References (48)
... The potential of early detection, screening and therapeutics have made their identification a worthy job . A brief review about lung cancer and principles for monitoring a number of reactions and MALDI-TOF imaging mass spectrometry has been presented by
Végvári and Döme (2011)
, which would be hopefully helpful in the histopathological diagnosis of lung cancers (nonsmall cell lung cancers). In lung cancer cells number of phospholipids especially phosphatidylcholines (PCs) were found to be over-expressed . ...
... In lung cancer cells number of phospholipids especially phosphatidylcholines (PCs) were found to be over-expressed . Furthermore, pharmacological parameters were used to determine the concentration of these chemicals at molar concentrations in the microenvironment of cancerous lung tissues (Marko- Varga et al., 2011)
, as well as its comparison with spatial segmentation of the same tissues section with histological labeling (Alexandrov, Becker, Guntinas-Lichius, Ernst and von Eggeling, 2013). MALD-TOF identifying biomarkers, which are involved in different types of lung cancer and different stages of lung cancer as well. ...
Proteomic approaches in the study of cancers
Chapter
Mar 2023
Khair Ul Nisa Najeebul Tarfeen
Humaira Bhat Adil Farooq Wali
View
... The potential of early detection, screening and therapeutics have made their identification a worthy job . A brief review about lung cancer and principles for monitoring a number of reactions and MALDI-TOF imaging mass spectrometry has been presented by
Végvári and Döme (2011)
, which would be hopefully helpful in the histopathological diagnosis of lung cancers (nonsmall cell lung cancers). In lung cancer cells number of phospholipids especially phosphatidylcholines (PCs) were found to be over-expressed . ...
... In lung cancer cells number of phospholipids especially phosphatidylcholines (PCs) were found to be over-expressed . Furthermore, pharmacological parameters were used to determine the concentration of these chemicals at molar concentrations in the microenvironment of cancerous lung tissues (Marko- Varga et al., 2011)
, as well as its comparison with spatial segmentation of the same tissues section with histological labeling (Alexandrov, Becker, Guntinas-Lichius, Ernst and von Eggeling, 2013). MALD-TOF identifying biomarkers, which are involved in different types of lung cancer and different stages of lung cancer as well. ...
Proteomics approaches in the identification of cancer biomarkers and drug discovery Chapter Full-text available
Feb 2023
Nasir Nisar Suhail Ahmad Mir
Ozaifa Kareem Faheem Pottoo
Proteomics is the study which involves analyzing proteins from both a basic science and a clinical perspective. Proteins can be assessed for abundance, diversity of proteoforms owing to posttranslational modifications, and protein–protein interactions. Proteomics is useful in molecular sciences since it offers information on protein identification, expression levels, and alteration in various disorders including cancer. Proteomic characterization of cancer plays a crucial role in gaining a complete grasp of major molecular aberrations. The discovery of specific diagnostic and prognostic cancer biomarkers by proteomic techniques has transformed the prevailing practices in oncology. The continued research and evaluation is important for amending early diagnosis, risk evaluation, prognosis, and monitoring patient response to therapy. Proteomics has a dual purpose: It may be used to find novel compounds that can be used as therapeutic targets, as well as to do high-throughput drug profiling. Proteomic technologies like 2-D gel electrophoresis, mass spectrometry, and laser capture microdissection have emerged as important techniques for the detection of molecular markers of cancer and protein patterns. In this chapter, we have discussed proteomics and its role in cancer research. The current techniques and advancements in proteomics with present challenges in the field have also been discussed in detail.
View Show abstract
... propranolol, and reserpine in rodents (Hamm et al., 2012, Shahidi-Latham et al., 2012, Takai et al., 2013, ipratropium in the human lung
(Marko-Varga et al., 2011)
, and cocaine in a postmortem human nucleus accumbens (Pirman et al., 2012). One approach to quantify biomolecules of interest using MALDI-IMS is to spot calibration standards on or beneath the tissue (Pirman et al., 2012). ...
... While MALDI-IMS is now widely used as a qualitative tool to image the distribution of biomolecules of interest, its use in absolute quantification has been mostly limited to pharmaceuticals
(Marko-Varga et al., 2011
, Hamm et al., 2012, Pirman et al., 2012, Shahidi-Latham et al., 2012, Takai et al., 2013. Recently, however, a study by Jadoul et al. (2015) demonstrated the use of MALDI-IMS to quantify PC species in the rat brain, using lipid-spiked porcine brain tissue homogenates. ...
Distribution of Lipids in the Human Brain and their Differential Expression in Alzheimer's Disease: A Matrix-Assisted Laser Desorption/Ionisation-Imaging Mass Spectrometry (MALDI-IMS) Study Thesis Full-text available
Nov 2016
Lakshini H. S. Mendis
Alzheimer’s disease (AD), the leading cause of dementia, is pathologically characterised by β-amyloid plaques and tau tangles. However, there is also evidence of lipid-dyshomeostasis-mediated AD pathology. Given the structural diversity of lipids, mass spectrometry (MS) is a useful tool for studying lipid changes in AD. The use of matrix-assisted laser desorption/ionization (MALDI)-imaging mass spectrometry (IMS) circumvents the limitation of traditional MS, allowing users to visualise the distribution of lipids. Thus, I optimised MALDI-IMS to image the distribution of lipids in the postmortem human middle temporal gyrus (MTG) and hippocampus, and analyse its differential expression in AD. In order to study a large number of cases, compared to previously published MALDI-IMS papers, I developed an analysis workflow to efficiently evaluate large, heterogeneous datasets and accurately detect lipids that were differentially expressed in AD. I hypothesised that the MTG would show similar lipid differences to those previously reported in other cortical regions. Further, given that each hippocampal anatomical sub-field has its own function, I postulated that there would be lipid differences unique to each sub-field. Both positively- and negatively-charged lipid ion species were abundantly detected in the control and AD cohorts. Grey matter and white matter had unique lipid profiles. However, there were variations in the distribution of lipids even within the same region, especially in the grey matter in the MTG and the CA1 region in the hippocampus. In AD, while the distribution patterns of lipids were comparable to the control cohort, some lipids were expressed at different levels. For example, the expression of some phosphatidylethanolamine (PE) lipids was decreased in the MTG. The majority of lipids that were differentially expressed in the hippocampus were found in the CA1 region. Further, there were differences in eight lipids that were specific to the dentate gyrus (DG) region. High-resolution MALDI IMS revealed that these lipids showed a heterogeneous distribution amongst the three DG layers. Finally, I quantified PE lipids with MALDI-IMS, using a lipid-spiked tissue homogenate approach. This is the first time that this approach has been successfully used to quantify lipids the human MTG and the DG. The concentration of PE did not change in the DG in AD; however, the concentrations of four PE species, namely PE 38:4, PE 39:5, and PE 40:6, were reduced in the grey matter in the MTG. Thus, the MALDI-IMS technique, the analysis workflow, and the lipid quantification approach, provided a novel method to investigate specific lipid differences in the postmortem human brain in AD. This work extends the understanding of the lipid composition of the human brain and how it differs in AD. Future work will focus on elucidating if these lipid differences are a driver, or consequence, of AD pathogenesis.
View Show abstract
... In accordance with previous observations [25, 27]
, in several instances, lower signal intensities of tamoxifen were observed in tumor cell dense regions as annotated in yellow lines by a trained pathologist (see Fig. 2a). However, the complex patterns of tumor cells, especially in the ER-positive tissue sections, limited the visual comparison of drug signal distributions. ...
... It was found that the drug signal distributed heterogeneously over the tissue sections showing characteristically higher intensities from stroma compared to tumor cell dense areas typically in ER-negative sections, whereas ER-positive tissue sections displayed an opposite distribution of tamoxifen signals ( Table 1). The results of ER-negative tissues agreed well with previous findings when a drug solution was spotted on heterogeneous tumor surface un equal amount at each position [27]
. It was hypothesized that tumor cells might had different surface properties regulated by their altered molecular composition as compared with normal (stromal) cells. ...
Localization of tamoxifen in human breast cancer tumors by MALDI mass spectrometry imaging Article Full-text available
Dec 2016
Alexander Sergeyevich Shavkunov
Thomas Fehniger György Marko-Varga
Akos Végvári
Background:
Tamoxifen is used in endocrine treatment of breast cancer to inhibit estrogen signaling. A set of stratified ER-positive and ER-negative tumor sections was subjected to manual deposition of tamoxifen solution in order to investigate its spatial distribution upon exposure to interaction within thin tissue sections.
Methods:
The localization of tamoxifen in tumor sections was assessed by matrix assisted laser deposition/ionization mass spectrometry imaging. The images of extracted ion maps were analyzed for comparison of signal intensity distributions.
Results:
The precursor ion of tamoxifen (m/z 372.233) displayed heterogeneous signal intensity distributions in histological compartments of tumor tissue sections. The levels of tamoxifen in tumor cells compared with stroma were higher in ER-positive tissues, whereas ER-negative tissue sections showed lower signal intensities in tumor cells.
Conclusions:
The experimental model was successfully applied on frozen tumor samples allowing for differentiation between ER groups based on distribution of tamoxifen.
View Show abstract
... Given the known pathological heterogeneity of human diseases, it is extremely important to understand the pathological cellular origins of these observed metabolites and their distributions among disease pathologies at the cellular levels that can be probed by MSI. Recently, of note, MSI studies on human tissue specimens, as well as samples generated from human cancerous cells, have been reported for prostate, (Banerjee et al., 2017;Kurreck et al., 2018;Wang et al., 2017;Morse et al., 2019;Mutuku et al., 2019;Randall et al., 2019), and lung cancers,
(Marko-Varga et al., 2011;
Végvári et al., 2013;Li et al., 2015;Tsubata et al., 2017;Bensussan et al., 2020), respectively. ...
Multiplatform Metabolomics Studies of Human Cancers With NMR and Mass Spectrometry Imaging Article Full-text available
Apr 2022
Anya B. Zhong Isabella H. Muti Stephen J Eyles Leo L. Cheng
The status of metabolomics as a scientific branch has evolved from proof-of-concept to applications in science, particularly in medical research. To comprehensively evaluate disease metabolomics, multiplatform approaches of NMR combining with mass spectrometry (MS) have been investigated and reported. This mixed-methods approach allows for the exploitation of each individual technique’s unique advantages to maximize results. In this article, we present our findings from combined NMR and MS imaging (MSI) analysis of human lung and prostate cancers. We further provide critical discussions of the current status of NMR and MS combined human prostate and lung cancer metabolomics studies to emphasize the enhanced metabolomics ability of the multiplatform approach.
View Show abstract
... By using MALDI imaging to evaluate the localization of anticancer agents in different cancer models with distinct morphology and drug sensitivity, heterogeneous drug penetration in the tumor tissue microenvironments can be characterized. This information is important for understanding drug action mechanisms and efficacy [109]
[110][111]. A MALDI imaging study on the spatial penetration of perifosine in a 3D spheroid of colorectal carcinoma revealed heterogeneous drug distribution that could be linked to drug resistance and disease relapse [112]. ...
Molecular tissue profiling by MALDI imaging: recent progress and applications in cancer research Article Full-text available
Jul 2021
Pey Yee Lee Yeelon Yeoh Nursyazwani Omar Teck Yew Low
Matrix-assisted laser desorption/ionization (MALDI) imaging is an emergent technology that has been increasingly adopted in cancer research. MALDI imaging is capable of providing global molecular mapping of the abundance and spatial information of biomolecules directly in the tissues without labeling. It enables the characterization of a wide spectrum of analytes, including proteins, peptides, glycans, lipids, drugs, and metabolites and is well suited for both discovery and targeted analysis. An advantage of MALDI imaging is that it maintains tissue integrity, which allows correlation with histological features. It has proven to be a valuable tool for probing tumor heterogeneity and has been increasingly applied to interrogate molecular events associated with cancer. It provides unique insights into both the molecular content and spatial details that are not accessible by other techniques, and it has allowed considerable progress in the field of cancer research. In this review, we first provide an overview of the MALDI imaging workflow and approach. We then highlight some useful applications in various niches of cancer research, followed by a discussion of the challenges, recent developments and future prospect of this technique in the field.
View Show abstract
... This platform can be utilized to either detect all ion masses within a tissue microenvironment or to perform selected-ion monitoring (SIM) of a single, specific ion mass. Furthermore, with the automated computational procedures [18, 19]
, the data generated by MALDI-MSI can exhibit the spatial localization of all the detected natural products as a single integrated image. Accordingly, MALDI-MSI is a powerful tool for validating the interactions between a natural product and its protein targets ex vivo without any labeling probes or chemical immobilization [20,21]. ...
Identification and Validation of VEGFR2 Kinase as a Target of Voacangine by a Systematic Combination of DARTS and MSI Article Full-text available
Mar 2020
Yonghyo Kim Yutaka Sugihara
Taeyoung Kim Ho Jeong Kwon
Although natural products are an important source of drugs and drug leads, identification and validation of their target proteins have proven difficult. Here, we report the development of a systematic strategy for target identification and validation employing drug affinity responsive target stability (DARTS) and mass spectrometry imaging (MSI) without modifying or labeling natural compounds. Through a validation step using curcumin, which targets aminopeptidase N (APN), we successfully standardized the systematic strategy. Using label-free voacangine, an antiangiogenic alkaloid molecule as the model natural compound, DARTS analysis revealed vascular endothelial growth factor receptor 2 (VEGFR2) as a target protein. Voacangine inhibits VEGFR2 kinase activity and its downstream signaling by binding to the kinase domain of VEGFR2, as was revealed by docking simulation. Through cell culture assays, voacangine was found to inhibit the growth of glioblastoma cells expressing high levels of VEGFR2. Specific localization of voacangine to tumor compartments in a glioblastoma xenograft mouse was revealed by MSI analysis. The overlap of histological images with the MSI signals for voacangine was intense in the tumor regions and showed colocalization of voacangine and VEGFR2 in the tumor tissues by immunofluorescence analysis of VEGFR2. The strategy employing DARTS and MSI to identify and validate the targets of a natural compound as demonstrated for voacangine in this study is expected to streamline the general approach of drug discovery and validation using other biomolecules including natural products.
View Show abstract
... This platform can be utilized to either detect all ion masses within a tissue microenvironment, or to perform selected-ion monitoring (SIM) of a single, specific ion mass. Furthermore, with the automated computational procedures [17, 18]
, the data generated by MALDI-MSI can exhibit the spatial localization of all the detected natural products as a single integrated image. Accordingly, MALDI-MSI is a powerful tool for validating the interactions between a natural product and its protein targets ex vivo without any labeling probes or chemical immobilization [19,20]. ...
Identification and Validation of VEGFR2 Kinase as a Target of Voacangine by a Systematic Combination of DARTS and MSI Preprint
Feb 2020
Yonghyo Kim Taeyoung Kim Ho Jeong Kwon Yutaka Sugihara
Although natural products are an important source of drugs and drug leads, identification and validation of their target proteins have proven difficult. Here, we report the development of a systematic strategy for target identification and validation employing drug affinity responsive target stability (DARTS) and mass spectrometry imaging (MSI) without modifying or labeling natural compounds. Through a validation step using curcumin, which targets aminopeptidase N (APN), we successfully standardized the systematic strategy. Using label-free voacangine, an antiangiogenic alkaloid molecule as the model natural compound, DARTS analysis revealed vascular endothelial growth factor receptor 2 (VEGFR2) as a target protein. Voacangine inhibits VEGFR2 kinase activity and its downstream signaling by binding to the kinase domain of VEGFR2, as was revealed by docking simulation. Through cell culture assays, voacangine was found to inhibit the growth of glioblastoma cells expressing high levels of VEGFR2. Specific localization of voacangine to tumor compartments in a glioblastoma xenograft mouse was revealed by MSI analysis. The overlap of histological images with the MSI signals for voacangine was intense in the tumor regions and showed colocalization of voacangine and VEGFR2 in the tumor tissues by immunofluorescence analysis of VEGFR2. The strategy employing DARTS and MSI to identify and validate the targets of a natural compound as demonstrated for voacangine in this study is expected to streamline the general approach of drug discovery and validation using other biomolecules including natural products.
View Show abstract
... In this research, the C trough of gefitinib was significantly different between patients with CYP3A4 rs2242480 and ABCG2 rs2231142, implying that the blood C trough of gefitinib might be influenced by the polymorphisms of metabolic enzymes in the liver and transporters in the kidney. Second, both preclinical and clinical researches revealed that the concentration of gefitinib in tumor and skin was much higher than its plasma concentration in xenograft mice and patients (24)
(25)(26). Using positron emission tomography, 11 C and 14 C gefitinib was accumulated in tumor tissues and normal tissues such as skin and intestine rather than evenly distributed in blood, both in rat and human (25,27,28). ...
The analysis of pharmacokinetic and pharmacogenomic impact on gefitinib efficacy in advanced non-small cell lung cancer patients: results from a prospective cohort study Article
Dec 2019
Yuxiang Ma Lin Qingguang Shuang Xin Xueding Wang
Background:
The current study is aimed to examine the impact of pharmacokinetics and gene polymorphisms of enzymes involving in absorption, distribution, metabolism and excretion (ADME) on the efficacy of gefitinib in non-small cell lung cancer (NSCLC) patients.
Methods:
Eligible patients with indication of gefitinib treatment were prospectively enrolled in this study. Two peripheral blood samples at baseline and before cycle 2 day 1 were collected for the detection of single nucleotide polymorphisms (SNPs) of drug ADME enzymes and trough drug concentration (Ctrough) at steady state. Thirteen SNPs were genotyped using the Sequenom Massarray system. Ctrough was determined by validated high-performance liquid chromatographic method with tandem mass spectrometric (LC-MS/MS).
Results:
Fifty-eight NSCLC patients were enrolled in this study. The median of Ctrough was 175ng/mL (range from 47.8 to 470 ng/mL). The trough concentration was not associated with either objective response or progression free survival (PFS). Ctrough was significantly lower in CYP3A4 rs2242480 CC + CT genotype than in TT genotype (P=0.019) and in ABCG2 rs2231142 AA genotype than in AC + CC genotype (P=0.031). ABCB1 rs2032582 dominant model was significantly correlated with overall response rate (ORR) and patients with GG phenotype respond better than patients with GT + TT phenotypes (84.6% vs. 51.2%, P=0.032). ABCB1 rs10256836 recessive model was significantly correlated with PFS and patients with GG phenotype achieved longer PFS than patients with GC + CC phenotypes (17.40 vs. 10.33 months, P=0.040).
Conclusions:
The Ctrough of gefitinib was significantly different between CYP3A4 and ABCG2 genotypes, but not with the efficacy of gefitinib treatment. ABCB1 rs2032582 and rs10256836 polymorphisms were correlated treatment outcome. Polymorphisms analysis of ABCB1 could be a predictive biomarker for gefitinib treatment.
View Show abstract
... With regard to non-SIMS imaging applications, applied MCR-ALS to a nanostructure-initiator mass spectrometry (NIMS) microbial dataset by Louie et al. (2013), results of which are shown in Figure 6. They also applied MCR-ALS to a mouse lung MALDI Orbitrap IMS dataset by
Marko-Varga et al. (2011)
, available from the openMSI platform (Rübel et al., 2013). The data were baseline corrected and TIC-normalized. ...
Unsupervised machine learning for exploratory data analysis in imaging mass spectrometry Article Full-text available
May 2020 MASS SPECTROM REV
Nico Verbeeck Richard M. Caprioli
Raf Van de Plas
Imaging mass spectrometry (IMS) is a rapidly advancing molecular imaging modality that can map the spatial distribution of molecules with high chemical specificity. IMS does not require prior tagging of molecular targets and is able to measure a large number of ions concurrently in a single experiment. While this makes it particularly suited for exploratory analysis, the large amount and high‐dimensional nature of data generated by IMS techniques make automated computational analysis indispensable. Research into computational methods for IMS data has touched upon different aspects, including spectral preprocessing, data formats, dimensionality reduction, spatial registration, sample classification, differential analysis between IMS experiments, and data‐driven fusion methods to extract patterns corroborated by both IMS and other imaging modalities. In this work, we review unsupervised machine learning methods for exploratory analysis of IMS data, with particular focus on (a) factorization, (b) clustering, and (c) manifold learning. To provide a view across the various IMS modalities, we have attempted to include examples from a range of approaches including matrix assisted laser desorption/ionization, desorption electrospray ionization, and secondary ion mass spectrometry‐based IMS. This review aims to be an entry point for both (i) analytical chemists and mass spectrometry experts who want to explore computational techniques; and (ii) computer scientists and data mining specialists who want to enter the IMS field. © 2019 The Authors. Mass Spectrometry Reviews published by Wiley Periodicals, Inc. Mass SpecRev 00:1–47, 2019.
View Show abstract
... deuterated molecule) of the substance of interest are sprayed to allow for relative quantitation 165 . The use of internal standards is one way to overcome ion suppression that is varying in different tissue regions and is also varying between different tissue types/organs 166, 167
...
Investigation of Cancerous Tissues by MALDI Mass Spectrometry Imaging - Imaging of proteolytic activity in frozen tissue and standardised on-tissue digestion Thesis
Jan 2019
Katrin Erich
Multiple alterations of a normal cell can lead to a localised tumour that potentially develops the ability to become invasive and metastasize. Proteolysis of the surrounding tissue environment is driven by proteases, as they are involved in degradation of e.g. extracellular matrix. Proteases are a class of tightly regulated enzymes that hydrolyse peptide bonds. To investigate the spatial distribution of enzyme activity, typically fluorescence-based substrate reporters are developed for in vivo and in vitro applica¬tions. The design of such chemical probes is complex and requires knowledge about the target enzymes’ specificity. The topical application of fluorescent probes to frozen tissue has rarely been done but enables the visualization of specific proteolytic activity. Matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) is an analytical tool with increasing acceptance for tissue analysis in pre-clinical applications. The technique offers the spatially resolved analysis of hundreds of molecules at a time by their mass-to-charge ratio (m/z). Enabling the visualization of protease activity by MALDI MSI, without the necessity of extensive probe design, would have a major impact on the investigation of proteases in cancerous tissue. An absolute requirement for all newly developed methods, but especially if they should be transferred to clinical applications, is repeatability and reproducibility. However, MALDI MSI studies currently still lack a rational, score-based evaluation of repeatability. Thus, this thesis had the following aims: 1. Develop a method for monitoring of tissue protease activity by using MALDI MSI on different porcine tissues. 2. Validate the developed method by their time-dependence, concentration-dependence of chemical inhibition, as well as by the identification of specific protein degradation products. Furthermore, use a gastric tumour mouse model to evaluate differences in protease activity for tumorous tissue compared to non-tumourous tissue. 3. Demonstrate the transferability of the developed MALDI MSI method to relevant clinical samples, by analysing proteolytic activity in human tissue biopsies from gastroscopy. 4. Develop scores for the analysis of repeatability by using clinical material and compare published on-tissue digestion workflows for MALDI MSI in order to identify the best method. The main results of this dissertation are: 1. Development of a method for visualizing the degradation of a universal protease substrate (substance P) on porcine tissues. An optimization system using water-sensitive paper and the dye rhodamine B was developed to ensure homogeneous substrate application and minimised delocalization effects. 2. Time- and protease inhibitor-concentration-dependent substance P degradation was shown in time-course experiments based on the proteolytic activity of different porcine tissues. Transiently occurring C-terminally cleaved peptides from substance P were identified by mass spectrometry. In addition, their spatial distribution could be imaged. With these lines of evidence, the decrease of the substance P signal could be correlated to a proteolytic digestion process. Pancreatic tissue showed the fastest degradation, whereas muscle tissue showed no degradation of substance P. The different proteolytic activities of porcine tissues were confirmed by adapting a photometric method using protein extracts and therewith quantifying protease activity. Furthermore, the method was applied to a gastric mouse tumour model which showed higher protease activities for tumorous compared to non-tumorous tissue. 3. The method was shown to be transferable to human gastric tumour biopsies. In order to get significant biological results, clinical studies with large and more defined patient cohorts are required. 4. Scores for evaluating the homogeneity of the application system as well as repeatability of on-tissue digestion protocol for MALDI MSI were developed. With the scores, one out of several published methods was identified to be superior to the others. The main difference was a prolonged incubation time that might be responsible for good repeatability. In summary, the developed MALDI MSI method for visualising proteolytic activity in frozen tissue sections holds a high potential to become an important tool in pre-clinical studies.
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... The lung has been previously studied by MSI showing xenobiotic distribution in lung (19)(20) (21)
or differences induced by inhalation and intratracheal administration. (22) Recently, we reported the use of MSI to evaluate the distribution and retention of salmeterol in lung tissue and the dependence of distribution on administration route (inhalation vs. IV). ...
Revealing the Regional Localization and Differential Lung Retention of Inhaled Compounds by Mass Spectrometry Imaging Article
Jul 2019
Mikael Brülls Gregory Hamm Erica Bäckström Richard J. A. Goodwin
Background:
For the treatment of respiratory disease, inhaled drug delivery aims to provide direct access to pharmacological target sites while minimizing systemic exposure. Despite this long-held tenet of inhaled therapeutic advantage, there are limited data of regional drug localization in the lungs after inhalation. The aim of this study was to investigate the distribution and retention of different chemotypes typifying available inhaled drugs [slowly dissolving neutral fluticasone propionate (FP) and soluble bases salmeterol and salbutamol] using mass spectrometry imaging (MSI).
Methods:
Salmeterol, salbutamol, and FP were simultaneously delivered by inhaled nebulization to rats. In the same animals, salmeterol-d3, salbutamol-d3, and FP-d3 were delivered by intravenous (IV) injection. Samples of lung tissue were obtained at 2- and 30-minute postdosing, and high-resolution MSI was used to study drug distribution and retention.
Results:
IV delivery resulted in homogeneous lung distribution for all molecules. In comparison, while inhalation also gave rise to drug presence in the entire lung, there were regional chemotype-dependent areas of higher abundance. At the 30-minute time point, inhaled salmeterol and salbutamol were preferentially retained in bronchiolar tissue, whereas FP was retained in all regions of the lungs.
Conclusion:
This study clearly demonstrates that inhaled small molecule chemotypes are differentially distributed in lung tissue after inhalation, and that high-resolution MSI can be applied to study these retention patterns.
View Show abstract
... In the oncology field, publications have highlighted applications of MALDI IMS in lung cancer, breast cancer, brain tumours, gastrointestinal tract cancer, urogenital cancer, and head and neck cancer, among others. [34][35] [36]
[37] This technique has been experimentally applied for the detection of malignant tumour margins, tumour typing, grading 37 and determination of cancer heterogeneity. 21 Most papers are in the research phase, though some include potential applications in diagnostic decision-making, for example, for determination of primary carcinoma type in peritoneal or pleural fluid washes. ...
Next-generation protein analysis in the pathology department
Article
Jul 2019
Melek Ahmed Glenn Broeckx
Geert Baggerman Amelie Dendooven
Traditionally, immunohistochemistry (IHC) is used by pathologists to localise specific proteins or peptides in tissue slides. In the era of personalised medicine, however, molecular tissue analysis becomes indispensable for correct diagnosis, prognosis and therapeutic decision, not only on the DNA or mRNA level but also on the protein level. Combining molecular information with imaging presents many advantages. Therefore, matrix-assisted laser desorption/ionisation imaging mass spectrometry (MALDI IMS) is a promising technique to be added to the armamentarium of the pathologist. Here, we focus on the workflow, advantages and drawbacks of both MALDI IMS and IHC. We also briefly discuss a few other protein imaging modalities and give examples of applications.
View Show abstract
... Drug signal intensity was higher in stroma than in tumour tissue for each of the tumour sub-types. The EGFR mutation status of the tumours was not reported so it is unclear whether the absence of such mutations contributed to the lower intratumoural drug concentrations
(Marko-varga et al., 2011)
. Interestingly, in breast cancers exposed to tamoxifen drug signal (again identified using a MALDI LTQ Orbitrap XL mass spectrometer) was higher in tumour than in stroma in oestrogen receptor (ER) positive tumours; the opposite was found in ER negative tumours (Végvári et al., 2016). ...
Precision pharmacology: Mass spectrometry imaging and pharmacokinetic drug resistance Article
Jul 2019 CRIT REV ONCOL HEMAT
Maria Jove Jade Spencer Chris Twelves
Malcolm R Clench
Failure of systemic cancer treatment can be, at least in part, due to the drug not being delivered to the tumour at sufficiently high concentration and/or sufficiently homogeneous distribution; this is termed as “pharmacokinetic drug resistance”. To understand whether a drug is being adequately delivered to the tumour, “precision pharmacology” techniques are needed. Mass spectrometry imaging (MSI) is a relatively new and complex technique that allows imaging of drug distribution within tissues. In this review we address the applicability of MSI to the study of cancer drug distribution from the bench to the bedside. We address: (i) the role of MSI in pre-clinical studies to characterize anti-cancer drug distribution within the body and the tumour, (ii) the application of MSI in pre-clinical studies to define optimal drug dose or schedule, combinations or new drug delivery systems, and finally (iii) the emerging role of MSI in clinical research.
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... For a proper highly selective method to be applied on liquid chromatography/mass spectrometry systems is necessary to accurately optimize the detection selectivity parameters (options related to the MS equipment); concurrently with separation selectivity components (mobile phase; stationary phase; temperature; flow; etc.). It is the combination of these two techniques; liquid chromatography for separation of compounds based on physico-chemical properties and mass spectrometry for differentiation based on mass-to-charge ratio; that generates an extremely powerful analytical tool
[69]
. ...
The Relevance of Mass Spectrometry Analysis for Personalized Medicine through Its Successful Application in Cancer “Omics” Article Full-text available
May 2019 INT J MOL SCI
Ciocan-Cartita Ancuta Jurj Mihail Buse Ioana Berindan - Neagoe
Mass spectrometry (MS) is an essential analytical technology on which the emerging omics domains; such as genomics; transcriptomics; proteomics and metabolomics; are based. This quantifiable technique allows for the identification of thousands of proteins from cell culture; bodily fluids or tissue using either global or targeted strategies; or detection of biologically active metabolites in ultra amounts. The routine performance of MS technology in the oncological field provides a better understanding of human diseases in terms of pathophysiology; prevention; diagnosis and treatment; as well as development of new biomarkers; drugs targets and therapies. In this review; we argue that the recent; successful advances in MS technologies towards cancer omics studies provides a strong rationale for its implementation in biomedicine as a whole.
View Show abstract
... 32,33 Therefore, this in situ technology is a powerful tool to acquire spatial molecular information in tissues and has been increasingly adopted in drug discovery and development research to investigate distributions of drugs in relation to tissue morphology and histopathology. 31,[34][35] [36]
The principles of MALDI imaging and varieties of applications have been reviewed in a number of articles 31,37-39 and will not be discussed in detail. Briefly, four sequential steps are involved in the MALDI imaging analysis. ...
Beyond tissue concentrations: Antifungal penetration at the site of infection Article
Mar 2019 MED MYCOL
Shane R Baistrocchi
Despite advances in antifungal therapy, invasive fungal infections remain a significant cause of morbidity and mortality worldwide. One important factor contributing to the relative ineffectiveness of existing antifungal drugs is insufficient drug exposure at the site of infection. Despite the importance of this aspect of antifungal therapy, we generally lack a full appreciation of how antifungal drugs distribute, penetrate, and interact with their target organisms in different tissue subcompartments. A better understanding of drug distribution will be critical to guide appropriate use of currently available antifungal drugs, as well as to aid development of new agents. Herein we briefly review current perspectives of antifungal drug exposure at the site of infection and describe a new technique, matrix-assisted laser desorption ionization (MALDI) mass spectrometry imaging, which has the potential to greatly expand our understanding of drug penetration.
View Show abstract
... A large number of studies utilized MSI techniques in lung biology, to investigate the distribution and quantify drugs in different types of lung cancers
40
, in tissues treated with several anti-tuberculosis drugs 41,42 and to molecularly characterize various lung cancers based on their proteomic profiles 43 . MSI has been applied to visualize the major surfactant lipid dipalmitoylphosphatidylcholine [DPPC, (PC32:0)] in human lung 44 and in xenografts from human lung cancer cells 45 . ...
High-resolution atmospheric-pressure MALDI mass spectrometry imaging workflow for lipidomic analysis of late fetal mouse lungs Article Full-text available
Feb 2019
Vannuruswamy Garikapati Srikanth Karnati Dhaka Ram Bhandari Bernhard Spengler
Mass spectrometry imaging (MSI) provides label-free, non-targeted molecular and spatial information of the biomolecules within tissue. Lipids play important roles in lung biology, e.g. as surfactant, preventing alveolar collapse during normal and forced respiration. Lipidomic characterization of late fetal mouse lungs at day 19 of gestation (E19) has not been performed yet. In this study we employed high-resolution atmospheric pressure scanning microprobe matrix-assisted laser desorption/ionization MSI for the lipidomic analysis of E19 mouse lungs. Molecular species of different lipid classes were imaged in E19 lung sections at high spatial and mass resolution in positive- and negative-ion mode. Lipid species were characterized based on accurate mass and on-tissue tandem mass spectrometry. In addition, a dedicated sample preparation protocol, homogenous deposition of matrices on tissue surfaces and data processing parameters were optimized for the comparison of signal intensities of lipids between different tissue sections of E19 lungs of wild type and Pex11β-knockout mice. Our study provides lipid information of E19 mouse lungs, optimized experimental and data processing strategies for the direct comparison of signal intensities of metabolites (lipids) among the tissue sections from MSI experiments. To best of our knowledge, this is the first MSI and lipidomic study of E19 mouse lungs.
View Show abstract
... The matrix absorbs the energy from the laser, which is transferred to the analyte via a process referred to as Bsoft^ionization. MALDI-MSI is widely used to characterize drug distribution in various tissue types (Buck et al. 2015;Fehniger et al. 2011;
Marko-Varga et al. 2011;
Sun and Walch 2013;Torok et al. 2017;Torok et al. 2015). The method is also used to investigate various endogenous molecules, such as lipids, carbohydrates, peptides, and proteins (reviewed in (Cillero-Pastor and Heeren 2014; Gode and Volmer 2013;Harvey 2006)). ...
Challenging the heterogeneity of disease presentation in malignant melanoma—impact on patient treatment Article Full-text available
Feb 2019 CELL BIOL TOXICOL
Attila Marcell Szász Melinda Rezeli
Johan Malm György Marko-Varga
There is an increasing global interest to support research areas that can assist in understanding disease and improving patient care. The National Cancer Institute (NIH) has identified precision medicine-based approaches as key research strategies to expedite advances in cancer research. The Cancer Moonshot program (https://www.cancer.gov/research/key-initiatives/moonshot-cancer-initiative) is the largest cancer program of all time, and has been launched to accelerate cancer research that aims to increase the availability of therapies to more patients and, ultimately, to eradicate cancer. Mass spectrometry-based proteomics has been extensively used to study the molecular mechanisms of cancer, to define molecular subtypes of tumors, to map cancer-associated protein interaction networks and post-translational modifications, and to aid in the development of new therapeutics and new diagnostic and prognostic tests. To establish the basis for our melanoma studies, we have established the Southern Sweden Malignant Melanoma Biobank. Tissues collected over many years have been accurately characterized with respect to the tumor and patient information. The extreme variability displayed in the protein profiles and the detection of missense mutations has confirmed the complexity and heterogeneity of the disease. It is envisaged that the combined analysis of clinical, histological, and proteomic data will provide patients with a more personalized medical treatment. With respect to disease presentation, targeted treatment and medical mass spectrometry analysis and imaging, this overview report will outline and summarize the current achievements and status within malignant melanoma. We present data generated by our cancer research center in Lund, Sweden, where we have built extensive capabilities in biobanking, proteogenomics, and patient treatments over an extensive time period.
View Show abstract
... 32,33 To assess the spatial distribution of unlabeled small molecules (and their metabolites) in clinical tissue samples, matrixassisted laser desorption ionization-mass spectrometry imaging (MALDI-MSI) can be applied 34,35 to a section of a fresh frozen biopsies. 35, 36
By multiplexing (multiple stains per section), other histological assays can be applied to detect other factors in the tumor microenvironment influencing drug penetration (e.g., CD31 immunohistochemistry (IHC) staining for blood vessels). ...
Tumor Drug Penetration Measurements Could Be the Neglected Piece of the Personalized Cancer Treatment Puzzle Article Full-text available
Aug 2018 CLIN PHARMACOL THER
Imke H Bartelink Ella F Jones
Sheerin Shahidi-Latham Geraldine Gebhart
Precision medicine aims to use patient genomic, epigenomic, specific drug dose and other data to define disease patterns that may potentially lead to an improved treatment outcome. Personalized dosing regimens based on tumor drug penetration can play a critical role in this approach. State-of-the-art techniques to measure tumor drug penetration focus on systemic exposure, tissue penetration, cellular or molecular engagement and expression of pharmacological activity. Using In silico methods, this information can be integrated to bridge the gap between the therapeutic regimen and the pharmacological link with clinical outcome. These methodologies are described, and challenges ahead are discussed. Supported by many examples, this review shows how the combination of these techniques provides enhanced patient-specific information on drug accessibility at the tumor tissue level, target binding and downstream pharmacology. Our vision of how to apply tumor drug penetration measurements offers a roadmap for the clinical implementation of precision dosing. This article is protected by copyright. All rights reserved.
View Show abstract
... Using MALDI ionisation, mass spectrometry was first demonstrated as a tool capable of providing molecular images of proteins by Caprioli et al. [3][4][5]. Other types of instruments such as the secondary ion mass spectrometer (SIMS) [6]
and the desorption electrospray ionisation (DESI) mass spectrometer [7] can be used for MS imaging (MSI). Nevertheless, today MALDI-MSI is the preferred and most frequently used approach for the localisation of biomolecules and drugs over a wide molecular mass range. ...
Endogenous expression mapping of malignant melanoma by mass spectrometry imaging Article Full-text available
Dec 2018
Daniel Rivas Johan Malm Yutaka Sugihara György Marko-Varga
Background:
Currently, only a limited number of molecular biomarkers for malignant melanoma exist. This is the case for both diagnosing the disease, staging, and efficiently measuring the response to therapy by tracing the progression of disease development and drug impact. There is a great need to identify novel landmarks of disease progression and alterations.
Methods:
Matrix-assisted laser desorption ionisation mass spectrometry imaging (MALDI-MSI) has been developed within our group to study drug localisation within micro-environmental tissue compartments. Here, we expand further on this technology development and introduce for the first time melanoma tumour tissues to map metabolite localisation utilising high resolution mass spectrometry. MALDI-MSI can measure and localise the distribution pattern of a number of small molecule metabolites within tissue compartments of tumours isolated from melanoma patients. Data on direct measurements of metabolite identities attained at the local sites in tissue compartments has not been readily available as a measure of a clinical index for most cancer diseases. The current development on the mapping of endogenous molecular expression melanoma tumours by mass spectrometry imaging focuses on the establishment of a cancer tissue preparation process whereby a matrix crystal formation is homogenously built on the tissue surface, providing uniform molecular mapping. We apply this micro-preparation technology to disease presentation by mapping the molecular signatures from patient tumour sections.
Results:
We have automated the process with a micro-technological dispensing platform. This provides the basis for thin film generation of the cancer patient tissues prior to imaging screening. Compartmentalisation of the tumour regions are displayed within the image analysis interfaced with histopathological grading and characterisation.
Conclusions:
This enables site localisation within the tumour with image mapping to disease target areas such as melanoma cells, macrophages, and lymphocytes.
View Show abstract
... During cancer development, neoplastic cells produce different proteins and metabolites than normal cells in the surrounding microenvironment [97,98]. Proteomic and metabolomic profiling of gastric [99][100][101][102], lung [103, 104]
, prostate [105][106][107], and some other cancers [94,97,108] has been characterized. Recently thyroid cancer subtypes have been classified according to the different spatial distribution of proteins analyzed by MALDI-TOF IMS [109]. ...
Applications of MALDI-TOF mass spectrometry in clinical proteomics
Article
Jul 2018
Viviana Greco Cristian Piras Luisa Pieroni Andrea Urbani
Introduction: The development of precision medicine requires advanced technologies to address the multifactorial disease stratification and to support personalized treatments. Among omics techniques, proteomics based on Mass Spectrometry (MS) is becoming increasingly relevant in clinical practice allowing a phenotypic characterization of the dynamic functional status of the organism. From this perspective, Matrix Assisted Laser Desorption Ionization Time of Flight (MALDI-TOF) MS is a suitable platform for providing a high-throughput support to clinics.
Areas covered: This review aims to provide an updated overview of MALDI-TOF MS applications in clinical proteomics. The most relevant features of this analysis have been discussed, highlighting both pre analytical and analytical factors that are crucial in proteomics studies. Particular emphasis is placed on biofluids proteomics for biomarkers discovery and on recent progresses in clinical microbiology, drug monitoring and minimal residual disease (MRD).
Expert commentary: Despite some analytical limitations, the latest technological advances together with the easiness of use, the low time and low cost consuming and the high throughput are making MALDI-TOF MS instruments very attractive for the clinical practice. These features offer a significant potential for the routine of the clinical laboratory and ultimately for personalized medicine.
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... This enables mapping of the local distribution of multiplexed, label-free, molecular species in tissue sections at micro-meter scale (>5 mm). MSI has been previously applied to study the distribution of compounds in lungs but with limited spatial resolution (Nilsson et al., 2010;
Marko-Varga et al., 2011;
Prideaux et al., 2011;Sun et al., 2016;Matsumoto et al., 2017;Zecchi et al., 2013). MSI can also describe the morphology of lung based on the molecular profile of tissue sub-regions as alveoli, airways or blood vessels (Berry et al., 2011;Zemski Berry et al., 2017). ...
Uncovering the regional localization of inhaled salmeterol retention in the lung
Article Full-text available
Mar 2018
Erica Bäckström Anna Nilsson Markus Fridén Gregory Hamm
Treatment of respiratory disease with a drug delivered via inhalation is generally held as being beneficial as it provides direct access to the lung target site with a minimum systemic exposure. There is however only limited information of the regional localization of drug retention following inhalation. The aim of this study was to investigate the regional and histological localization of salmeterol retention in the lungs after inhalation and to compare it to systemic administration. Lung distribution of salmeterol delivered to rats via nebulization or intravenous (IV) injection was analyzed with high-resolution mass spectrometry imaging (MSI). Salmeterol was widely distributed in the entire section at 5 min after inhalation, by 15 min it was preferentially retained in bronchial tissue. Via a novel dual-isotope study, where salmeterol was delivered via inhalation and d3-salmeterol via IV to the same rat, could the effective gain in drug concentration associated with inhaled delivery relative to IV, expressed as a site-specific lung targeting factor, was 5-, 31-, and 45-fold for the alveolar region, bronchial sub-epithelium and epithelium, respectively. We anticipate that this MSI-based framework for quantifying regional and histological lung targeting by inhalation will accelerate discovery and development of local and more precise treatments of respiratory disease.
View Show abstract
... As a consequence, MALDI was best suited to the aims of our study. Several other studies have also used MALDI MSI for erlotinib imaging [39] [40]
[41][42] . A major advantage of MSI is that it can separate drugs and their metabolites, which is not able to be achieved by imaging techniques like autoradiography that involve labelling drugs. ...
MALDI mass spectrometry imaging of erlotinib administered in combination with bevacizumab in xenograft mice bearing B901L, EGFR-mutated NSCLC cells Article Full-text available
Dec 2017
Masanobu Nishidate Kaname Yamamoto
Chinami Masuda Akinobu Hamada
Combination therapy of erlotinib plus bevacizumab improves progression-free survival of patients with epidermal growth factor receptor–mutated (EGFR-mutated) advanced non–small-cell lung cancer (NSCLC) compared with erlotinib alone. Although improved delivery and distribution of erlotinib to tumours as a result of the normalization of microvessels by bevacizumab is thought to be one of the underlying mechanisms, there is insufficient supporting evidence. B901L cells derived from EGFR-mutated NSCLC were subcutaneously implanted into mice, and mice were treated with bevacizumab or human IgG followed by treatment with erlotinib. The distribution of erlotinib in their tumours at different times after erlotinib administration was analysed by matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI). We also analysed the distribution of erlotinib metabolites and the distribution of erlotinib in tumours refractory to erlotinib, which were established by long-term treatment with erlotinib. We found that erlotinib was broadly diffused in the tumours from B901L-implanted xenograft mice, independently of bevacizumab treatment. We also found that erlotinib metabolites were co-localized with erlotinib and that erlotinib in erlotinib-refractory tumours was broadly distributed throughout the tumour tissue. Multivariate imaging approaches using MALDI MSI as applied in this study are of great value for pharmacokinetic studies in drug development.
View Show abstract
... Lung cancer has its origin in lung tissues, typically in the cells lining air passages, and was responsible for 13% of all cancer cases and 18% (1.4 million) of all deaths caused by cancer in 2008 worldwide [108]
. More recently, Huh et al. [109] developed a biomimetic microsystem that reconstitutes the critical functional alveolar-capillary interface of the human lung by seeding human alveolar epithelial cells and microvascular endothelial cells in the microchannels which then attached to opposite surfaces of the ECM coated membrane. ...
Anti-Cancer Drug Validation: the Contribution of Tissue Engineered Models Article Full-text available
Jun 2017 STEM CELL REV
Mariana Carvalho Daniela Lima Rui L. Reis Vitor M Correlo
Drug toxicity frequently goes concealed until clinical trials stage, which is the most challenging, dangerous and expensive stage of drug development. Both the cultures of cancer cells in traditional 2D assays and animal studies have limitations that cannot ever be unraveled by improvements in drug-testing protocols. A new generation of bioengineered tumors is now emerging in response to these limitations, with potential to transform drug screening by providing predictive models of tumors within their tissue context, for studies of drug safety and efficacy. Considering the NCI60, a panel of 60 cancer cell lines representative of 9 different cancer types: leukemia, lung, colorectal, central nervous system (CNS), melanoma, ovarian, renal, prostate and breast, we propose to review current “state of art” on the 9 cancer types specifically addressing the 3D tissue models that have been developed and used in drug discovery processes as an alternative to complement their study.
View Show abstract
... Pharmacoproteomics studies using imaging MS have had a tremendous impact because it allows both localizing the distribution of the drug and determining the deposition of its metabolites in lung tissues, opening a new opportunity for personalized pharmaceutical applications. By applying this technology, Marko-Varga et al. were able to localize the EGFR-TKIs erlotinib and gefitinib to different tissue compartments in three different LC phenotypes
(Marko-Varga et al., 2011)
. The goal of personalized medicine is not only to individualize treatment to increase clinical benefits of therapy but also to reduce possible adverse reactions in patients. ...
Personalized Medicine in Respiratory Disease
Chapter
Dec 2016
Priyadharshini V.S. Luis M Teran
Respiratory diseases affect humanity globally, with chronic lung diseases (e.g., asthma, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, among others) and lung cancer causing extensive morbidity and mortality. These conditions are highly heterogeneous and require an early diagnosis. However, initial symptoms are nonspecific, and the clinical diagnosis is made late frequently. Over the last few years, personalized medicine has emerged as a medical care approach that uses novel technology aiming to personalize treatments according to the particular patient's medical needs. This review highlights the contributions of proteomics toward the understanding of personalized medicine in respiratory disease and its potential applications in the clinic.
View Show abstract
... In subsequent work, Marko-Varga et al. used MALDI-IMS to study drug distribution in three different lung tumors [54]
(Fig. 3). Interestingly, the localization of erlotinib and gefitinib-small-molecule drugs used in EGFR-targeted therapy [55,56]-varied among the tumor types. ...
Clinical Applications of MALDI Imaging Technologies in Cancer and Neurodegenerative Diseases Article
Jan 2017 BBA-PROTEINS PROTEOM
Yasemin Ucal Zeynep Aslıhan Durer
Hakan Atak Aysel Ozpinar
Matrix-assisted laser desorption/ionization (MALDI) time-of-flight (TOF) imaging mass spectrometry (IMS) enables localization of analytes of interest along with histology. More specifically, MALDI-IMS identifies the distributions of proteins, peptides, small molecules, lipids, and drugs and their metabolites in tissues, with high spatial resolution. This unique capacity to directly analyze tissue samples without the need for lengthy sample preparation reduces technical variability and renders MALDI-IMS ideal for the identification of potential diagnostic and prognostic biomarkers and disease gradation. MALDI-IMS has evolved rapidly over the last decade and has been successfully used in both medical and basic research by scientists worldwide. In this review, we explore the clinical applications of MALDI-IMS, focusing on the major cancer types and neurodegenerative diseases. In particular, we re-emphasize the diagnostic potential of IMS and the challenges that must be confronted when conducting MALDI-IMS in clinical settings. This article is part of a Special Issue entitled: MALDI Imaging, edited by Dr. Corinna Henkel and Prof. Peter Hoffmann.
View Show abstract
... Matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI MSI) has been widely used for in situ analysis of endogenous small molecular metabolites and exogenous drugs in tissue sections [1][2] [3]
[4] . The most promising advantage of MALDI MSI is the reality of label-free detection, and to perform compound analysis avoiding extraction and/or separation steps and preserve the morphological integrity of analyzed tissues. ...
Electrospray deposition device used to precisely control the matrix crystal to improve the performance of MALDI MSI Article Full-text available
Nov 2016
Shilei Li Yangyang Zhang Jian’an Liu
Zhenwen Zhao
MALDI MSI has been recently applied as an innovative tool for detection of molecular distribution within a specific tissue. MALDI MSI requires deposition of an organic compound, known as matrix, on the tissue of interest to assist analyte desorption and ionization, in which the matrix crystal homogeneity and size greatly influence the imaging reproducibility and spatial resolution in MALDI MSI. In this work, a homemade electrospray deposition device was developed for deposition of matrix in MALDI MSI. The device could be used to achieve 1 μm homogeneous matrix crystals in MALDI MSI analysis. Moreover, it was found, for the first time, that the electrospray deposition device could be used to precisely control the matrix crystal size, and the imaging spatial resolution was increased greatly as the matrix crystals size becoming smaller. In addition, the easily-built electrospray deposition device was durable for acid, base or organic solvent, and even could be used for deposition of nanoparticles matrix, which made it unparalleled for MALDI MSI analysis. The feasibility of the electrospray deposition device was investigated by combination with MALDI FTICR MSI to analyze the distributions of lipids in mouse brain and liver cancer tissue section.
View Show abstract
... In contrast, MALDI MSI provides non-targeted molecular information of any tissue. Previous studies in several different cancers have shown that MALDI MSI can acquire a more comprehensive proteomic picture than immunohistochemistry [16][17] [18]
, and as such, MALDI MSI is slowly being introduced into commercial pathology laboratories around the world. The images generated by the technique allow new insights into tumour tissues as MALDI MSI allows for the detection and characterisation of tumour cells and their environment in a spatial context. ...
Annexin A2 and alpha actinin 4 expression correlates with metastatic potential of primary endometrial cancer Article
Oct 2016 BBA-PROTEINS PROTEOM
Parul Mittal Manuela Klingler-Hoffmann Martin K Oehler Georgia Arentz
The prediction of lymph node metastasis using clinic-pathological data and molecular information from endometrial cancers lacks accuracy and is therefore currently not routinely used in patient management. Consequently, although only a small percentage of patients with endometrial cancers suffer from metastasis, the majority undergo radical surgery including removal of pelvic lymph nodes. Upon analysis of publically available data and published research, we compiled a list of 60 proteins having the potential to display differential abundance between primary endometrial cancers with versus those without lymph node metastasis. Using data dependent acquisition LC-ESI-MS/MS we were able to detect 23 of these proteins in endometrial cancers, and using data independent LC-ESI-MS/MS the differential abundance of five of those proteins was observed. The localization of the differentially expressed proteins, was visualized using peptide MALDI MSI in whole tissue sections as well as tissue microarrays of 43 patients. The proteins identified were further validated by immunohistochemistry. Our data indicate that annexin A2 protein level is upregulated, whereas annexin A1 and α actinin 4 expression are downregulated in tumours with lymph node metastasis compared to those without lymphatic spread. Moreover, our analysis confirmed the potential of these markers, to be included in a statistical model for prediction of lymph node metastasis. The predictive model using highly ranked m/z values identified by MALDI MSI showed significantly higher predictive accuracy than the model using immunohistochemistry data. In summary, using publicly available data and complementary proteomics approaches, we were able to improve the prediction model for lymph node metastasis in EC.
View Show abstract
... MALDI-MSI can identify peptides and other molecules from samples whilst retaining the important spatial information of the tissue. Previous studies in the gastrointestinal tract, lung, brain and other gynaecological cancers have shown that MALDI-MSI can acquire a more comprehensive proteomic picture than immunohistochemical testing [14][15]
[16]
[17]. ...
MALDI Mass Spectrometry Imaging Reveals Decreased CK5 Levels in Vulvar Squamous Cell Carcinomas Compared to the Precursor Lesion Differentiated Vulvar Intraepithelial Neoplasia Article Full-text available
Jul 2016 INT J MOL SCI
Chao Zhang Georgia Arentz Lyron Juan Winderbaum Peter Hoffmann
Vulvar cancer is the fourth most common gynecological cancer worldwide. However, limited studies have been completed on the molecular characterization of vulvar squamous cell carcinoma resulting in a poor understanding of the disease initiation and progression. Analysis and early detection of the precursor lesion of HPV-independent vulvar squamous cell carcinoma (VSCC), differentiated vulvar intraepithelial neoplasia (dVIN), is of great importance given dVIN lesions have a high level of malignant potential. Here we present an examination of adjacent normal vulvar epithelium, dVIN, and VSCC from six patients by peptide Matrix-assisted laser desorption/ionization Mass Spectrometry Imaging (MALDI-MSI). The results reveal the differential expression of multiple peptides from the protein cytokeratin 5 (CK5) across the three vulvar tissue types. The difference observed in the relative abundance of CK5 by MALDI-MSI between the healthy epithelium, dVIN, and VSCC was further analyzed by immunohistochemistry (IHC) in tissue from eight VSCC patients. A decrease in CK5 immunostaining was observed in the VSCC compared to the healthy epithelium and dVIN. These results provide an insight into the molecular fingerprint of the vulvar intraepithelial neoplasia that appears to be more closely related to the healthy epithelium than the VSCC.
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... The distribution of the multiple-receptor tyrosine kinase inhibitor AEE788 in rodent prostate cancer models was analyzed by MALDI-MSI (35). The tyrosine kinase inhibitors erlotinib and gefitinib have been analyzed, after depositing single droplets of drugs on tissue slices of planocellular lung carcinoma, adeno-carcinoma and large cell lung carcinoma (36)
(37)(38). Yasunaga et al. (39) showed that paclitaxel-incorporating micelles deliver more paclitaxel to the tumor and less paclitaxel to normal tissue, as compared with treatment with paclitaxel alone. A simple and reproducible protocol for MALDI-MSI was described to visualize the different distribution of paclitaxel in tumor and normal tissues, related to the dosage schedules and pathological features of the tumors (40). ...
Imaging Techniques for Evaluation of Drug Distribution in Solid Tumor
Article
Jan 2016
Jianfen Gu Ningfang Jiang Huanrong Lan
Ketao Jin
Imaging drug distribution inside a tumor is an important tool to support strategies to improve penetration of anticancer drugs and consequently the outcome of chemotherapy. Methods for mapping the distribution of pharmaceutical compounds and their metabolites in situ are of great interest to researchers and to the pharmaceutical industry. There is a particular interest in the distribution of anti-cancer agents within solid tumors. Direct assessment of the distribution of drugs in tumor tissue is technically challenging, and requires the quantification of drug exposure to cells at specific locations relative to blood vessels. The quantification of drugs in plasma, as well as in tissue homogenates, has relied extensively on well-established analytical methods of high-performance liquid chromatography (HPLC) and liquid chromatography-tandem mass spectrometry (LC-MS-MS). In the last 20 years, imaging techniques such as positron emission tomography (PET), magnetic resonance spectroscopy (MRS), mass spectrometry imaging (MSI), fluorescence microscopy (FM), and autoradiography have evolved as powerful tools for the noninvasive study of drug distribution in vivo as well as for studying drug effects at their target sites. In this article, we review the current state of knowledge of the available imaging techniques to measure intratumor drug distribution.
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... An ion suppression effect is often observed in MALDI-MSI experiments as a result of the difficulties in producing a homogeneous matrix layer on the tissue surface. However, the heterogeneous surface properties of tissue sections (e.g., salt and pH gradients or phospholipid background) are also likely to be responsible for differential spectral response, as often observed in tumor tissues [60]
. As a consequence, the observed intensities of a given m/z signal may not reveal the actual local concentrations in the tissue. ...
Novel insights in drug metabolism by MS imaging
Article
Feb 2016
Yutaka Sugihara Ken-Ichi Watanabe
Akos Végvári
During the last decade, lateral and temporal localization of drug compounds and their metabolites have been demonstrated and dynamically developed using MS imaging. The pharmaceutical industry has recognized the potential of the technology that provides simultaneous distribution and quantitative data. In this review, we present the latest technological achievements and summarize applications of drug imaging focusing on studies about metabolites by MALDI-MS imaging. We also introduce potential areas with pharmaceutical applications that are currently under exploration, including pharmacological, toxicological characterizations and metabolic enzyme localization in comparison with drug and metabolite distribution.
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... Its distribution in healthy rat liver, spleen, and muscle resembled autoradiographic results. In 2011, differences in distribution of erlotinib in three different lung cancer tumor phenotypes were reported (20)
, and in 2013, drug distribution of erlotinib and other molecules in the microenvironmental tissue compart-ments of lung cancer that were either submerged or spotted with the compounds was investigated (21). ...
Modeling Therapy Response and Spatial Tissue Distribution of Erlotinib in Pancreatic Cancer Article
Jan 2016
B. M. Gruner Isabel Winkelmann Annette Feuchtinger Jens T Siveke
Pancreatic ductal adenocarcinoma (PDAC) is likely the most aggressive and therapy-resistant of all cancers. Aim of this study was to investigate the emerging technology of matrix assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) as a powerful tool to study drug delivery and spatial tissue distribution in PDAC. We utilized an established genetically engineered mouse model of spontaneous PDAC to examine the distribution of the small molecule inhibitor erlotinib in healthy pancreas and PDAC. MALDI IMS was utilized on sections of single-dose or long-term-treated mice to measure drug tissue distribution. Histological and statistical analyses were performed to correlate morphology, drug distribution and survival. We found that erlotinib levels were significantly lower in PDAC compared to healthy tissue (p = 0.0078). Survival of long-term-treated mice did not correlate with overall levels of erlotinib or with overall histological tumor grade but both with the percentage of atypical glands in the cancer (p = 0.021, rs = 0.59) and the level of erlotinib in those atypical glands (p = 0.019, rs = 0.60). The results of this pilot study present MALDI IMS as a reliable technology to study drug delivery and spatial distribution compounds in a preclinical setting and supports drug imaging-based translational approaches.
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... In this latter case the drug will not exhibit (adequate) efficacy as many cells will not be touched by itand this lack of efficacy is a chief cause of drug failures (Cook et al., 2014) -while those areas with more concentrated drug may have levels that are toxic (the other main cause of attrition). Where chemical imaging of drugs is used in various tissues or organs it turns out that drug distribution is indeed highly heterogeneous (e.g., Khatib-Shahidi et al., 2006;Nilsson et al., 2010;Römpp et al., 2010Römpp et al., , 2011Castellino et al., 2011;
Marko-Varga et al., 2011;
Ait-Belkacem et al., 2012;Marko-Varga et al., 2012;El-Mashtoly et al., 2014), just as is the distribution of all known proteins, as may be observed in the human proteome atlas (http://proteinatlas.org/) (Persson et al., 2006;Pontén et al., 2008). Indeed there is considerable variance in protein expression even between cells of the same type grown in axenic culture (Newman et al., 2006). ...
The transporter-mediated cellular uptake of pharmaceutical drugs is based on their metabolite-likeness and not on their bulk biophysical properties: Towards a systems pharmacology Article Full-text available
Oct 2015
Douglas Kell
Several recent developments are brought together: (i) the new availability of a consensus, curated human metabolic network reconstruction (Recon2), approximately a third of whose steps are represented by transporters, (ii) the recognition that most successful (marketed) drugs, as well as natural products, bear significant similarities to the metabolites in Recon2, (iii) the recognition that to get into and out of cells such drugs hitchhike on the transporters that are part of normal intermediary metabolism, and the consequent recognition that for intact biomembrane Phospholipid Bilayer diffusion Is Negligible (PBIN), and (iv) the consequent recognition that we need to exploit this and to use more phenotypic assays to understand how drugs affect cells and organisms. I show in particular that lipophilicity is a very poor predictor of drug permeability, and that we need to (and can) bring together our knowledge of both pharmacology and systems biology modelling into a new systems pharmacology.
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... In our research, the BSA and trough concentration were not significantly correlated. Further, both preclinical and clinical research revealed that the concentrations of gefitinib in tumor and skin were much higher than plasma concentrations in xenograft mice and patients, indicating potential tissue concentration of gefitinib [9][10] [11]
. In this research, the trough concentration ranged from 34.0 ng/ mL to 503.0 ng/mL. ...
The Dissociation of Gefitinib Trough Concentration and Clinical Outcome in NSCLC Patients with EGFR Sensitive Mutations Article Full-text available
Aug 2015
Shuang Xin YUANYUAN ZHAO
Xueding Wang Li Zhang
Gefitinib is an essential drug for NSCLC patients harboring EGFR sensitive mutations. The approved dose 250mg/day is based on limited clinical trials, this research aims to explore the relationship between drug exposure and gefitinib response. Ctrough of 87 NSCLC patients harboring EGFR sensitive mutations were determined by LC-MS/MS. The median of Ctrough was 173.9 ng/ml (P25-P75, 130.5-231.2 ng/ml), and cutoff value 200 ng/ml was determined by X-Tile. The PFS between Ctrough < 200 ng/ml and Ctrough ≥ 200 ng/ml groups were not significantly different (17.3 VS 14.8 months; p = 0.258). Ctrough was not significantly associated with rash, diarrhea and hepatotoxicity. Non-smokers enjoyed longer PFS than smokers (18.7 VS 9.3 months; p = 0.025). The results showed that, for NSCLC patients with EGFR sensitive mutations, the PFS in lower trough concentration group were not inferior to that in higher trough concentration group and dose reduction is a rational suggestion for adjustment of dose regimen for aforementioned patients. More clinical trials are warranted to explore the precision dose schedule of gefitinib.
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Role of proteomics in surgical oncology
Chapter
Jan 2023
Toyeeba Hassan Parveena Firdous
Kamran Nissar Zuha Imtiyaz
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Detection and characterization of simvastatin and its metabolites in rat tissues and biological fluids using MALDI high resolution mass spectrometry approach Article Full-text available
Mar 2022
Yin Wencui Reem I. Al-wabli
Mohamed W Attwa Adnan A Kadi
Simvastatin (SV) is a hypolipidemic agent, and it is the 2nd most widely prescribed lipid-lowering drug. Here, the detection and characterization of SV and its metabolites was studied in selected organs/tissues (lung, liver, brain, heart and kidney) and biological samples (blood, urine and feces) of rats. MALDI Orbitrap MS was used as a high-resolution mass analyzer. 2,5-Dihydroxybenzoic acid (DHB) and 1,5-diaminonaphthalene (DAN) were used as matrices. Several sample loading methods onto the MALDI plate were attempted and dried droplet method was found to be superior. Two different cell disruption methods, pulverization and homogenization, were also evaluated for the optimum sensitivity in MALDI. Pulverization allowed the detection of more metabolites in all organs except the liver, where homogenization led to the detection of more metabolites. Altogether, 13 metabolites were detected, and one metabolite tentatively identified as a reduced product is being reported for the first time. SV and its metabolites were distributed to all the tissues studied except the brain. Overall, the results implied that the pulverized samples were more uniform and larger in surface area, resulting in their more efficient and complete extraction during sample preparation. As shown in the present study, MALDI Orbitrap MS is a useful tool to study drug and metabolite detection and characterization.
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IoT-Based Reconfigurable Micropump for Drug Delivery Applications
Conference Paper
Oct 2021
Youssef Kotb Mariam Hegazy Kareem Mohamed Abdelrahman Mohamed Serry
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Quantitative DESI mass spectrometry imaging of lung distribution of inhaled drug Article
Aug 2021 J DRUG DELIV SCI TEC
Huimin Beng Junhua Hu Rui Zhang
Wen Tan
Clinically, the particle size and size distribution of inhaled drug play an extremely important role in airway drug deposition and therapeutic outcome. It is necessary to fully understand the spatial distribution of inhaled drugs, which will contribute to the drug development. However, all spatial information is lost in the sample processing of conventional pharmacokinetic study. Mass spectrometry imaging (MSI) is a powerful tool for visualization of spatial localization of biological molecules or metabolites in tissue section without the procedure of any tagging or labeling chemistry. In this study, we have established a quantitative DESI imaging to detect the drug concentration in lung and the results of two administration methods (inhalation and oral) were compared. In addition, the spatial localization of inhaled drug was also visualized, and the in vitro in vivo correlations (IVIVCs) of lung distribution of inhaled drug were explored. Our results indicated that the spatial localization of drug aerosol delivered by the Pari nebulizer at the lung parenchyma has a tendency to be higher than the results obtained by Omron nebulizer. The signal intensity in the primary bronchi by Omron nebulizer was significantly higher than that result of Pari nebulizer. In vitro particle characterization, the ratio of small particles produced by the Pari nebulizer is higher than the results of Omron nebulizer. The in vivo and in vitro results show a consistency. The quantitative DESI-MSI is a potential tool for analysis and quantify the drug concentration in lung tissue.
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Spatial transcriptomics and proteomics technologies for deconvoluting the tumor microenvironment Article
Jun 2021
Nan Wang Xia Li Rongshui Wang Zhiyong Ding
The tumor microenvironment (TME) harbors heterogeneous contents and plays critical roles in tumorigenesis, metastasis, and drug resistance. Therefore, the deconvolution of the TME becomes increasingly essential to every aspect of cancer research and treatment. Novel spatially-resolved high-plex molecular profiling technologies have been emerging rapidly as powerful tools to obtain in-depth understanding from TME perspectives due to their capacity to allow high-plex protein and RNA profiling while keeping valuable spatial information. Based on our practical experience, we review a variety of available spatial proteogenomic technologies, including 10X Visium, GeoMx Digital Spatial Profiler (DSP), cyclic immunofluorescence-based CODEX and Multi-Omyx, mass spectrometry (MS)-based imaging mass spectrometry (IMS) and multiplex ion-beam imaging (MIBI). We also discuss FISSEQ, MERFISH, Slide-seq, and HDST, some of which may become commercially available in the near future. In particular, with our experience, we elaborate on DSP for spatial proteogenomic profiling and discuss its unique features designed for immuno-oncology and propose anticipation towards its future direction. The emerging spatially technologies are rapidly reshaping the magnitude of our understanding of the TME.
This article is protected by copyright. All rights reserved
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Efficacy of pH-Sensitive Nanomedicines in Tumors with Different c-MYC Expression Depends on the Intratumoral Activation Profile Article
Feb 2021
Hitoshi Shibasaki Hiroaki Kinoh
Horacio Cabral Kazunori Kataoka
Effective inhibition of the protein derived from cellular myelocytomatosis oncogene (c-Myc) is one of the most sought-after goals in cancer therapy. While several c-Myc inhibitors have demonstrated therapeutic potential, inhibiting c-Myc has proven challenging, since c-Myc is essential for normal tissues and tumors may present heterogeneous c-Myc levels demanding contrasting therapeutic strategies. Herein, we developed tumor-targeted nanomedicines capable of treating both tumors with high and low c-Myc levels by adjusting their ability to spatiotemporally control drug action. These nanomedicines loaded homologues of the bromodomain and extraterminal (BET) motif inhibitor JQ1 as epigenetic c-Myc inhibitors through pH-cleavable bonds engineered for fast or slow drug release at intratumoral pH. In tumors with high c-Myc expression, the fast-releasing (FR) nanomedicines suppressed tumor growth more effectively than the slow-releasing (SR) ones, whereas, in the low c-Myc tumors, the efficacy of the nanomedicines was the opposite. By studying the tumor distribution and intratumoral activation of the nanomedicines, we found that, despite SR nanomedicines achieved higher accumulation than the FR counterparts in both c-Myc high and low tumors, the antitumor activity profiles corresponded with the availability of activated drugs inside the tumors. These results indicate the potential of engineered nanomedicines for c-Myc inhibition and spur the idea of precision pH-sensitive nanomedicine based on cancer biomarker levels.
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Drug distribution in lung tissue
Chapter
Jan 2021
Erica Bäckström Markus Fridén
The conceptof drug distribution in tissue relates to defining the state of the drug (free/bound) as well as the spatial location in lung tissue at several levels. The chapter begins by theoretically introducing general pharmacokinetic concepts that determine drug distribution in tissue, that are also relevant for the lung and the inhaled drug. This is followed by the main section describing current state of knowledge of the actual mechanisms involved in inhaled drug distribution in conjunction with the applied experimental techniques. This is followed by a discussion on how to obtain data on the spatial distribution of compounds in the heterogenous lung tissue. Finally, some suggestions are put forth for improving the understanding of lung tissue distribution and its pharmacological consequences.
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Mass Spectrometry Imaging of Neurotransmitters
Chapter Full-text available
Oct 2020
Katherine A. Stumpo
Mass spectrometry imaging (MSI) is a powerful analytical method for the simultaneous analysis of hundreds of compounds within a biological sample. Despite the broad applicability of this technique, there is a critical need for advancements in methods for small molecule detection. Some molecular classes of small molecules are more difficult than others to ionize, e.g., neurotransmitters (NTs). The chemical structure of NTs (i.e., primary, secondary, and tertiary amines) affects ionization and has been a noted difficulty in the literature. In order to achieve detection of NTs using MSI, strategies must focus on either changing the chemistry of target molecules to aid in detection or focus on new methods of ionization. Additionally, even with new strategies, the issues of delocalization, chemical background noise, and ability to achieve high throughput (HTP) must be considered. This chapter will explore previous and up-and-coming techniques for maximizing the detection of NTs.
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Cellular resolution in clinical MALDI mass spectrometry imaging: The latest advancements and current challenges Article
Oct 2019
Klára Ščupáková Benjamin Balluff
Caitlin M. Tressler Gökhan Ertaylan
Mass spectrometry (MS) is the workhorse of metabolomics, proteomics and lipidomics. Mass spectrometry imaging (MSI), its extension to spatially resolved analysis of tissues, is a powerful tool for visualizing molecular information within the histological context of tissue. This review summarizes recent developments in MSI and highlights current challenges that remain to achieve molecular imaging at the cellular level of clinical specimens. We focus on matrix-assisted laser desorption/ionization (MALDI)-MSI. We discuss the current status of each of the analysis steps and remaining challenges to reach the desired level of cellular imaging. Currently, analyte delocalization and degradation, matrix crystal size, laser focus restrictions and detector sensitivity are factors that are limiting spatial resolution. New sample preparation devices and laser optic systems are being developed to push the boundaries of these limitations. Furthermore, we review the processing of cellular MSI data and images, and the systematic integration of these data in the light of available algorithms and databases. We discuss roadblocks in the data analysis pipeline and show how technology from other fields can be used to overcome these. Finally, we conclude with curative and community efforts that are needed to enable contextualization of the information obtained.
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Optimized Bexarotene Aerosol Formulation Inhibits Major Subtypes of Lung Cancer in Mice Article
Mar 2019
Qi Zhang Sang Beom Lee Xu Chen
Ming You
Bexarotene has exhibited inhibitory effects in preclinical models of lung, mammary gland tumorigenesis and in phase I/II trials of non-small cell lung cancer. The major side effects of bexarotene when administered orally were hypertriglyceridemia and hypercholesterolemia. In our previous study we demonstrated that aerosolized bexarotene through nasal inhalation exhibited potent chemopreventive activity in a lung adenoma preclinical model without the hypertriglyceridemia. To facilitate its future clinical translation, we modified the formula of the aerosolized bexarotene with a clinically relevant solvent system. This optimized aerosolized bexarotene formulation was tested in lung squamous cell carcinoma and lung adenocarcinoma. Aerosolized delivery showed significant chemopreventive effect in these models. The new formula did not show visible signs of toxicity and did not increase plasma levels of triglyceride and cholesterol. The distribution of aerosolized bexarotene in mouse lung, which tested by matrix assisted laser desoprtion/ionization imaging mass spectrometry, demonstrated that aerosolized bexarotene was evenly distributed to the mouse lung parenchyma. Bexarotene modulated the microenvironment in vivo by increasing the tumor infiltrating T cell population. RNA sequencing of the lung cancer cell lines suggested multiple pathways that appear to be altered by bexarotene. For the first time, our studies demonstrate a new, clinically relevant aerosolized bexarotene formulation that exhibits preventive efficacy in major subtypes of lung cancer. This approach would be a major advance in preventing lung cancer incidence in persons at high risk of lung cancer e.g., former or present smokers.
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High resolution mapping of fluoroquinolones in TB rabbit lesions reveals specific distribution in immune cell types Article Full-text available
Nov 2018 eLife
Landry Blanc Isaac Daudelin Brendan Podell Véronique A. Dartois
Understanding the distribution patterns of antibiotics at the site of infection is paramount to selecting adequate drug regimens and developing new antibiotics. Tuberculosis (TB) lung lesions are made of various immune cell types, some of which harbor persistent forms of the pathogen, Mycobacterium tuberculosis. By combining high resolution MALDI MSI with histology staining and quantitative image analysis in rabbits with active TB, we have mapped the distribution of a fluoroquinolone at high resolution, and identified the immune-pathological factors driving its heterogeneous penetration within TB lesions, in relation to where bacteria reside. We find that macrophage content, distance from lesion border and extent of necrosis drive the uneven fluoroquinolone penetration. Preferential uptake in macrophages and foamy macrophages, where persistent bacilli reside, compared to other immune cells present in TB granulomas, was recapitulated in vitro using primary human cells. A nonlinear modeling approach was developed to help predict the observed drug behavior in TB lesions. This work constitutes a methodological advance for the co-localization of drugs and infectious agents at high spatial resolution in diseased tissues, which can be applied to other diseases with complex immunopathology.
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Mass spectrometry imaging and its application in pharmaceutical research and development: A concise review Article
Mar 2018 INT J MASS SPECTROM
John G Swales Gregory Hamm
Malcolm R Clench Richard J. A. Goodwin
Understanding the biodistribution, metabolism and accumulation of drugs in the body is a fundamental of pharmaceutical research and development. Mass Spectrometry imaging (MSI) has been proven to be a powerful tool to image the unlabelled spatial distribution of exogenous drugs and endogenous metabolites from the surface of tissue sections or small clinical biopsies, aiding the delivery of safe and effective medicines to the market and ultimately benefiting patients. Here we review the current advancements in MSI sample preparation, qualitative and quantitative MSI methodology and drug discovery and development applications. MSI is shown to be supporting R&D from early target identification through to the clinic. In conclusion, we discuss future directions of the technology and the hurdles that need addressing to strengthen its status in multimodal imaging.
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Derivatization Strategies for the Detection of Triamcinolone Acetonide in Cartilage by Using Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry Imaging Article Full-text available
Nov 2016
Florian Barré Bryn Flinders João Pedro Garcia Berta Cillero Pastor
Osteoarthritis (OA), characterized by degeneration of the cartilaginous tissue in articular joints, severely impairs mobility in many people worldwide. The degeneration is thought to be mediated by inflammatory processes occurring in the tissue of the joint, including the cartilage. Intra-articular administered Triamcinolone acetonide (TAA) is one of the drug treatments employed to ameliorate the inflammation and pain that characterizes OA. However, the penetration and distribution of TAA into the avascular cartilage is not well understood. We employed matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI), which has been previously used to directly monitor the distribution of drugs in biological tissues, to evaluate the distribution of TAA in human cartilage after in vitro incubation. Unfortunately, TAA is not easily ionized by regular electrospray ionization (ESI) or MALDI. To overcome this problem, we developed an on-tissue derivatization method with Girard’s reagent T (GirT) in human incubated cartilage being able to study its distribution and quantify the drug abundance (up to 3.3 ng/µl). Our results demonstrate the depth of penetration of a corticosteroid drug in human OA cartilage using MALDI-MSI.
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Preparation and characterization of newly developed matrix using functional γ -Fe 2 O 3 nanoparticles for mass spectrometry in small molecules: Functional γ -Fe 2 O 3 nanoparticles for mass spectrometry Article
Jul 2016 SURF INTERFACE ANAL
S. Morimoto Tomoya Ishikawa K. Hyodo
Yuko Ichiyanagi
Iron oxide magnetic nanoparticles were prepared by our original chemical wet method. These particles were functionalized by modification of amino groups and other molecules for biomedical application. The obtained particles were characterized by X-ray diffraction, fourier transform infrared spectroscopy (FT-IR), and magnetization measurements, and then local structures were analyzed using X-ray absorption near edge structure (XANES). Functional nanoparticles were further developed as new matrices for mass spectrometry by modification of α-cyano-4-hydroxycinnamic acid (CHCA) so that small molecular weight could be detected, which was hard to observe the spectra so far. We have detected small molecular analytes such as colchicin (MW = 399.4 Da) and aspirin (MW = 180.1 Da) using our developed functional nanoparticles. We have successfully developed new matrices for analytes in the low mass range without impurities. Finally, we aimed to detect 2-octynate methyl (2-OAm, MW = 154.2 Da), which is one of the important candidates for the triggering of primary biliary cirrhosis (PBC), a liver disease almost exclusively found in women. Our functional magnetic nanoparitlces are expected to contribute to the biomedical field. Copyright
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Mass spectrometry imaging and its application in pharmaceutical sciences
Article
Feb 2014
X. Li H. Wu C. Wang F. Feng
Mass spectrometry imaging(MSI) is a new analytical technique to study the composition and distribution of molecules or ions at tissue, cellular or subcellular level. It can detect analytes qualitatively and quantitatively on sample surface in situ without complex pre-treatment, mapping their spatial distribution. MSI technique is now emerging with its advantages in pharmaceutical science. Principle, sample preparation and ionization techniques concerning MSI are introduced in this review. Its application in drug metabolism study, pharmacodynamic and toxicological evaluation, pharmacoproteomics exploration, targeted drug screening and solid preparations investigation are also reviewed.
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Theoretical and Vibrational Study of N-(3-chloro-4-fluoro-phenyl)-7-methoxy-6-(3-morpholin-4-ylpropoxy)-quinazolin-4-amine (gefitinib) Article
Jul 2015 J MOL STRUCT
Özlem Mıhçıokur Talat Ozpozan
N-(3-chloro-4fluoro-phenyl)-7-methoxy-6-(3-morpholin-4ylpropoxy)-quinazolin-4-amine (GEF), a quinalizoline derivative used as new anti-cancer agent, designed to target activity of epidermal growth factor receptor (EGFR) promoting the growth, division and spread of cancer cells, was examined from the vibrational and theoretical point of view. All calculations have been carried out both in gaseous and aqueous phases. In the calculations of both phases, the molecule has been optimized through conformer analysis beginning with the x-ray data. The conformer analyses have been carried out in each phases and the geometrical differences between the most stable structures in gaseous and in aqueous phases have been discussed. The solvent effect for GEF in aqueous solution was simulated by using self-consistent reaction field (SCRF) calculations employing the integral equation formalism variant (IEFPCM) model. NBO analysis has been performed to indicate the presence of intramolecular charge transfer. The complete assignments of the vibrational spectra (IR&Raman) were made with the aid of calculated spectra both in gaseous and aqueous phases. The observed spectral data of the title compound were compared with the calculated spectra obtained by DFT/B3LYP and DFT/B3PW91 methods using 6-31G(d,p) basis set. The theoretical results were found to be in good agreement with the measured experimental data especially for the interpretation of intra molecular interactions.
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Fine Mapping the Spatial Distribution and Concentration of Unlabeled Drugs within Tissue Micro-Compartments Using Imaging Mass Spectrometry Article Full-text available Jul 2010 PLOS ONE Anna Nilsson Per E Andrén Thomas Fehniger Lena Gustavsson Readouts that define the physiological distributions of drugs in tissues are an unmet challenge and at best imprecise, but are needed in order to understand both the pharmacokinetic and pharmacodynamic properties associated with efficacy. Here we demonstrate that it is feasible to follow the in vivo transport of unlabeled drugs within specific organ and tissue compartments on a platform that applies MALDI imaging mass spectrometry to tissue sections characterized with high definition histology. We have tracked and quantified the distribution of an inhaled reference compound, tiotropium, within the lungs of dosed rats, using systematic point by point MS and MS/MS sampling at 200 microm intervals. By comparing drug ion distribution patterns in adjacent tissue sections, we observed that within 15 min following exposure, tiotropium parent MS ions (mass-to-charge; m/z 392.1) and fragmented daughter MS/MS ions (m/z 170.1 and 152.1) were dispersed in a concentration gradient (80 fmol-5 pmol) away from the central airways into the lung parenchyma and pleura. These drug levels agreed well with amounts detected in lung compartments by chemical extraction. Moreover, the simultaneous global definition of molecular ion signatures localized within 2-D tissue space provides accurate assignment of ion identities within histological landmarks, providing context to dynamic biological processes occurring at sites of drug presence. Our results highlight an important emerging technology allowing specific high resolution identification of unlabeled drugs at sites of in vivo uptake and retention. View Show abstract Erratum to: Autoradiography, MALDI-MS, and SIMS-MS Imaging in Pharmaceutical Discovery and Development Article Full-text available Dec 2009 AAPS J Eric Solon Alain Schweitzer Markus Stoeckli Brendan Prideaux This article was published with incorrect reference citations in the permission notes in the legends for Figures 8 and 9. The permission note for Figure 8 should read: (Adapted with permission from Ref. 84). The permission note for Figure 9 should read: (Adapted with permission from Ref. 85). View Show abstract Autoradiography, MALDI-MS, and SIMS-MS imaging in pharmaceutical discovery and development Article Full-text available Nov 2009 AAPS J Eric Solon Alain Schweitzer Brendan Prideaux Markus Stoeckli Whole-body autoradiography ((WBA) or quantitative WBA (QWBA)), microautoradiography (MARG), matrix-assisted laser desorption/ionization mass spectrometric imaging (MALDI-MSI), and secondary ion mass spectrometric imaging (SIMS-MSI) are high-resolution, molecular imaging techniques used to study the tissue distribution of radiolabeled and nonlabeled compounds in ex vivo, in situ biological samples. WBA, which is the imaging of the whole-body of lab animals, and/or their organ systems; and MARG, which provides information on the localization of radioactivity in histological preparations and at the cellular level, are used to support drug discovery and development efforts. These studies enable the conduct of human radiolabeled metabolite studies and have provided pharmaceutical scientists with a high resolution and quantitative method of accessing tissue distribution. MALDI-MSI is a mass spectrometric imaging technique capable of label-free and simultaneous determination of the identity and distribution of xenobiotics and their metabolites as well as endogenous substances in biological samples. This makes it an interesting extension to WBA and MARG, eliminating the need for radiochemistry and providing molecular specific information. SIMS-MSI offers a complementary method to MALDI-MSI for the acquisition of images with higher spatial resolution directly from biological specimens. Although traditionally used for the analysis of surface films and polymers, SIMS has been used successfully for the study of biological tissues and cell types, thus enabling the acquisition of images at submicrometer resolution with a minimum of samples preparation. View Show abstract Imaging of Lipids in Spinal Cord Using Intermediate Pressure Matrix-Assisted Laser Desorption-Linear Ion Trap/Orbitrap MS Article Full-text available Sep 2009 ANAL CHEM Rachelle R Landgraf Maria C Prieto Conaway Timothy J Garrett Richard A Yost A hybrid linear ion trap/Orbitrap mass spectrometer was used to perform tandem mass spectrometry (MS/MS) experiments and high-resolution mass analysis of lipids desorbed from nerve tissue. A dramatic improvement in mass spectral resolution and a decrease in background are observed in the spectra collected from the Orbitrap mass analyzer, which allows generation of more accurate mass spectrometric images of the distribution of lipids within nerve tissue. Employment of both mass analyzers provides a rapid and reliable means of compound identification based on MS/MS fragmentation and high-resolution mass spectrometry (HRMS) accurate mass. View Show abstract Gefitinib or CarboplatinΓÇôPaclitaxel in Pulmonary Adenocarcinoma Article Full-text available Aug 2009 NEW ENGL J MED Tony S K Mok Yi-Long Wu Sumitra Thongprasert Masahiro Fukuoka Previous, uncontrolled studies have suggested that first-line treatment with gefitinib would be efficacious in selected patients with non-small-cell lung cancer.
In this phase 3, open-label study, we randomly assigned previously untreated patients in East Asia who had advanced pulmonary adenocarcinoma and who were nonsmokers or former light smokers to receive gefitinib (250 mg per day) (609 patients) or carboplatin (at a dose calculated to produce an area under the curve of 5 or 6 mg per milliliter per minute) plus paclitaxel (200 mg per square meter of body-surface area) (608 patients). The primary end point was progression-free survival.
The 12-month rates of progression-free survival were 24.9% with gefitinib and 6.7% with carboplatin-paclitaxel. The study met its primary objective of showing the noninferiority of gefitinib and also showed its superiority, as compared with carboplatin-paclitaxel, with respect to progression-free survival in the intention-to-treat population (hazard ratio for progression or death, 0.74; 95% confidence interval [CI], 0.65 to 0.85; P<0.001). In the subgroup of 261 patients who were positive for the epidermal growth factor receptor gene (EGFR) mutation, progression-free survival was significantly longer among those who received gefitinib than among those who received carboplatin-paclitaxel (hazard ratio for progression or death, 0.48; 95% CI, 0.36 to 0.64; P<0.001), whereas in the subgroup of 176 patients who were negative for the mutation, progression-free survival was significantly longer among those who received carboplatin-paclitaxel (hazard ratio for progression or death with gefitinib, 2.85; 95% CI, 2.05 to 3.98; P<0.001). The most common adverse events were rash or acne (in 66.2% of patients) and diarrhea (46.6%) in the gefitinib group and neurotoxic effects (69.9%), neutropenia (67.1%), and alopecia (58.4%) in the carboplatin-paclitaxel group.
Gefitinib is superior to carboplatin-paclitaxel as an initial treatment for pulmonary adenocarcinoma among nonsmokers or former light smokers in East Asia. The presence in the tumor of a mutation of the EGFR gene is a strong predictor of a better outcome with gefitinib. (ClinicalTrials.gov number, NCT00322452.) View Show abstract Breathnach OS, Freidlin B, Conley B, Green MR, Johnson DH, Gandara DR, O'Connell M, Shepherd FA, Johnson BETwenty-two years of phase III trials for patients with advanced non-small-cell lung cancer: sobering results. J Clin Oncol 19: 1734-1742 Article Full-text available Apr 2001 O S Breathnach Boris Freidlin Barbara Conley Bruce E. Johnson To determine the changes in clinical trials and outcomes of patients with advanced-stage non-small-cell lung cancer (NSCLC) treated on phase III randomized trials initiated in North America from 1973 to 1994.
Phase III trials for patients with advanced-stage NSCLC were identified through a search of the National Cancer Institute's Cancer Therapy Evaluation Program database from 1973 to 1994, contact with Cooperative Groups, and by literature search of MEDLINE. Patients with advanced NSCLC treated during a similar time interval were also examined in the SEER database. Trends were tested in the number of trials, in the number and sex of patients entered on the trials, and in survival over time.
Thirty-three phase III trials were initiated between 1973 and 1994. Twenty-four trials (73%) were initiated within the first half of this period (1973 to 1983) and accounted for 5,359 (64%) of the 8,434 eligible patients. The median number of patients treated per arm of the trials rose from 77 (1973 to 1983) to 121 (1984 to 1994) (P <.001). Five trials (15%) showed a statistically significant difference in survival between treatment arms, with a median prolongation of the median survival of 2 months (range, 0.7 to 2.7 months).
Analysis of past trials in North America shows that the prolongation in median survival between two arms of a randomized study was rarely in excess of 2 months. Techniques for improved use of patient resources and appropriate trial design for phase III randomized therapeutic trials with patients with advanced NSCLC need to be developed. View Show abstract EGFR Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy Article Full-text available Jul 2004 SCIENCE J Guillermo Paez Pasi A Jänne Jeffrey ChangBing Lee Matthew Meyerson Receptor tyrosine kinase genes were sequenced in non–small cell lung cancer (NSCLC) and matched normal tissue. Somatic mutations
of the epidermal growth factor receptor gene EGFR were found in 15of 58 unselected tumors from Japan and 1 of 61 from the United States. Treatment with the EGFR kinase inhibitor
gefitinib (Iressa) causes tumor regression in some patients with NSCLC, more frequently in Japan. EGFR mutations were found in additional lung cancer samples from U.S. patients who responded to gefitinib therapy and in a lung
adenocarcinoma cell line that was hypersensitive to growth inhibition by gefitinib, but not in gefitinib-insensitive tumors
or cell lines. These results suggest that EGFR mutations may predict sensitivity to gefitinib. View Show abstract Mass Spectrometry Sampling Under Ambient Conditions with Desorption Electrospray Ionization Article Full-text available Nov 2004 SCIENCE Zoltan Takats Justin Wiseman Bogdan Gologan R. Graham Cooks A new method of desorption ionization is described and applied to the ionization of various compounds, including peptides and proteins present on metal, polymer, and mineral surfaces. Desorption electrospray ionization (DESI) is carried out by directing electrosprayed charged droplets and ions of solvent onto the surface to be analyzed. The impact of the charged particles on the surface produces gaseous ions of material originally present on the surface. The resulting mass spectra are similar to normal ESI mass spectra in that they show mainly singly or multiply charged molecular ions of the analytes. The DESI phenomenon was observed both in the case of conductive and insulator surfaces and for compounds ranging from nonpolar small molecules such as lycopene, the alkaloid coniceine, and small drugs, through polar compounds such as peptides and proteins. Changes in the solution that is sprayed can be used to selectively ionize particular compounds, including those in biological matrices. In vivo analysis is demonstrated. View Show abstract A Genomic Strategy to Refine Prognosis in Early-Stage Non–Small-Cell Lung Cancer Article Full-text available Sep 2006 NEW ENGL J MED Anil Potti Sayan Mukherjee Rebecca P Petersen Joseph R Nevins Clinical trials have indicated a benefit of adjuvant chemotherapy for patients with stage IB, II, or IIIA--but not stage IA--non-small-cell lung cancer (NSCLC). This classification scheme is probably an imprecise predictor of the prognosis of an individual patient. Indeed, approximately 25 percent of patients with stage IA disease have a recurrence after surgery, suggesting the need to identify patients in this subgroup for more effective therapy.
We identified gene-expression profiles that predicted the risk of recurrence in a cohort of 89 patients with early-stage NSCLC (the lung metagene model). We evaluated the predictor in two independent groups of 25 patients from the American College of Surgeons Oncology Group (ACOSOG) Z0030 study and 84 patients from the Cancer and Leukemia Group B (CALGB) 9761 study.
The lung metagene model predicted recurrence for individual patients significantly better than did clinical prognostic factors and was consistent across all early stages of NSCLC. Applied to the cohorts from the ACOSOG Z0030 trial and the CALGB 9761 trial, the lung metagene model had an overall predictive accuracy of 72 percent and 79 percent, respectively. The predictor also identified a subgroup of patients with stage IA disease who were at high risk for recurrence and who might be best treated by adjuvant chemotherapy.
The lung metagene model provides a potential mechanism to refine the estimation of a patient's risk of disease recurrence and, in principle, to alter decisions regarding the use of adjuvant chemotherapy in early-stage NSCLC. View Show abstract A Five-Gene Signature and Clinical Outcome in Non–Small-Cell Lung Cancer Article Full-text available Feb 2007 NEW ENGL J MED Hsuan-Yu Chen Sung-Liang Yu Chun-houh Chen Pan-Chyr Yang Current staging methods are inadequate for predicting the outcome of treatment of non-small-cell lung cancer (NSCLC). We developed a five-gene signature that is closely associated with survival of patients with NSCLC.
We used computer-generated random numbers to assign 185 frozen specimens for microarray analysis, real-time reverse-transcriptase polymerase chain reaction (RT-PCR) analysis, or both. We studied gene expression in frozen specimens of lung-cancer tissue from 125 randomly selected patients who had undergone surgical resection of NSCLC and evaluated the association between the level of expression and survival. We used risk scores and decision-tree analysis to develop a gene-expression model for the prediction of the outcome of treatment of NSCLC. For validation, we used randomly assigned specimens from 60 other patients.
Sixteen genes that correlated with survival among patients with NSCLC were identified by analyzing microarray data and risk scores. We selected five genes (DUSP6, MMD, STAT1, ERBB3, and LCK) for RT-PCR and decision-tree analysis. The five-gene signature was an independent predictor of relapse-free and overall survival. We validated the model with data from an independent cohort of 60 patients with NSCLC and with a set of published microarray data from 86 patients with NSCLC.
Our five-gene signature is closely associated with relapse-free and overall survival among patients with NSCLC. View Show abstract Proteomic Signature Corresponding to the Response to Gefitinib (Iressa, ZD1839), an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor in Lung Adenocarcinoma Article Full-text available Mar 2007 Tetsuya Okano Tadashi Kondo Kiyonaga Fujii Setsuo Hirohashi We aimed to identify candidate proteins for tumor markers to predict the response to gefitinib treatment.
We did two-dimensional difference gel electrophoresis to create the protein expression profile of lung adenocarcinoma tissues from patients who showed a different response to gefitinib treatment. We used a support vector machine algorithm to select the proteins that best distinguished 31 responders from 16 nonresponders. The prediction performance of the selected spots was validated by an external sample set, including six responders and eight nonresponders. The results were validated using specific antibodies.
We selected nine proteins that distinguish responders from nonresponders. The predictive performance of the nine proteins was validated examining an additional six responders and eight nonresponders, resulting in positive and negative predictive values of 100% (six of six) and 87.5% (seven of eight), respectively. The differential expression of one of the nine proteins, heart-type fatty acid-binding protein, was successfully validated by ELISA. We also identified 12 proteins as a signature to distinguish tumors based on their epidermal growth factor receptor gene mutation status.
Study of these proteins may contribute to the development of personalized therapy for lung cancer patients. View Show abstract Interstitial Lung Disease in Japanese Patients with Lung Cancer Article Full-text available Jul 2008 AM J RESP CRIT CARE Shoji Kudoh Harubumi Kato Yutaka Nishiwaki Fredrik Nyberg Interstitial lung disease (ILD) occurs in Japanese patients with non-small cell lung cancer (NSCLC) receiving gefitinib.
To elucidate risk factors for ILD in Japanese patients with NSCLC during treatment with gefitinib or chemotherapy.
In a prospective epidemiologic cohort, 3,166 Japanese patients with advanced/recurrent NSCLC were followed for 12 weeks on 250 mg gefitinib (n = 1,872 treatment periods) or chemotherapy (n = 2,551). Patients who developed acute ILD (n = 122) and randomly selected control subjects (n = 574) entered a case-control study. Adjusted incidence rate ratios were estimated from case-control data by odds ratios (ORs) with 95% confidence intervals (CIs) using logistic regression. Crude (observed) incidence rates and risks were calculated from cohort data.
The observed (unadjusted) incidence rate over 12 weeks was 2.8 (95% CI, 2.3-3.3) per 1,000 person-weeks, 4.5 (3.5-5.4) for gefitinib versus 1.7 (1.2-2.2) for chemotherapy; the corresponding observed naive cumulative incidence rates at the end of 12-week follow-up were 4.0% (3.0-5.1%) and 2.1% (1.5-2.9%), respectively. Adjusted for imbalances in risk factors between treatments, the overall OR for gefitinib versus chemotherapy was 3.2 (1.9-5.4), elevated chiefly during the first 4 weeks (3.8 [1.9-7.7]). Other ILD risk factors in both groups included the following: older age, poor World Health Organization performance status, smoking, recent NSCLC diagnosis, reduced normal lung on computed tomography scan, preexisting chronic ILD, concurrent cardiac disease. ILD-related deaths in patients with ILD were 31.6% (gefitinib) versus 27.9% (chemotherapy); adjusted OR, 1.05 (95% CI, 0.3-3.2).
ILD was relatively common in these Japanese patients with NSCLC during therapy with gefitinib or chemotherapy, being higher in the older, smoking patient with preexisting ILD or poor performance status. The risk of developing ILD was higher with gefitinib than chemotherapy, mainly in the first 4 weeks. View Show abstract Cancer statistics Article Jan 2008 A. Jemel R. Siegel Elizabeth Ward Michael J. Thun View EGFR Mutations in Lung Cancer : correlation with Clinical Response to Gefitinib Therapy Article Jan 2004 J.G. Paez P.A. Janne J.C. Lee View ToF-SIMS: Surface analysis by mass spectrometry Article Jan 2001 Barbara Garrison John C Vickerman D. Briggs View Molecular imaging of biological samples: localization of peptides and proteins using MALDI-TOF MS Article Jan 1997 T.B. Famer Richard M. Caprioli Jocelyn Gile View Improved Resolution and Very High Sensitivity in MALDI TOF of Matrix Surfaces Made by Fast Evaporation Article Oct 1994 Ole Vorm Peter Roepstorff Matthias Mann Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI TOF) is becoming a standard tool in mass spectrometry in general and protein analysis in particular. Its advantages include high sensitivity, tolerance to buffers, fast data acquisition, and simple and robust instrumentation. Disadvantages have been relatively low resolution and mass accuracy and have mainly been caused by factors related to sample preparation. Here we describe a simple new sample preparation procedure in which matrix and sample handling are completely decoupled. Fast evaporation of a matrix solution based on, e.g,, acetone produces a thin layer, presumably consisting of microcrystals. In a second step a drop of analyte solution is deposited on the layer. Some of the features of this new procedure are as follows: (i) there is an improvement in sensitivity; peptides can routinely be analyzed in the attomole range; (ii) salts and impurities are more easily washed off the prepared samples; (iii) sample surfaces become much more homogeneous, allowing very fast data acquisition; (iv) spectra show a more linear mass scale and higher resolution, especially when a reflector is used. In examples, a sensitivity of 5 amol and a resolution of up to 5700 (fwhm) could be achieved for peptides. View Show abstract Design and development of a silicon microfabricated flow-through dispenser for on-line picolitre sample handling Article Nov 1999 T. Laurell Lars Wallman Johan Nilsson The development of a piezoactuated flow-through microdispenser is described. The dispenser can be used for on-line sampling in a continuous-liquid-flow system. A major application area is rapid sample handling in chemical microsystems, e.g. automated high-throughput analysis or screening systems. The microdispenser is constructed of two joined silicon structures forming a flow-through channel. One channel wall couples the impulse movement of a piezoceramic element into the flow channel, generating a pressure pulse. Droplets (of typically 100 picolitres) are ejected from an orifice in the opposite channel wall. The sequential improvements of the dispenser over three generations are presented. The actuation voltage could be lowered from 150 V to approximately 50 V. The final version of the dispenser had an internal volume of 2.6 microlitres. The impact on droplet stability and directivity of introducing a protruding p-n etch-stop-defined nozzle and a means of matching surface properties to the dispensed liquid for improved performance are discussed. The maximum frequency for stable droplet formation was found to be approximately 500 Hz. View Show abstract Compound and Metabolite Distribution Measured by Maldi Mass Spectrometric Imaging in Whole-Body Tissue Sections Article Feb 2007 INT J MASS SPECTROM Markus Stoeckli Dieter Staab Alain Schweitzer The determination of the compound distribution in laboratory animal tissue in early development is a standard process in pharmaceutical research. While this information is traditionally obtained by means of whole-body autoradiography using radiolabeled compounds, this technology does not distinguish between metabolites and parent compound. The technique described in this article, termed matrix-assisted laser desorption/ionization (MALDI) mass spectrometric imaging, can fill this gap by simultaneously measuring compound and multiple metabolites distributed in whole-body tissue sections, using non-labeled compounds. View Show abstract Detection of Pharmaceutical compounds in tissue by matrix-assisted laser desorption/ionization (MALDI) and laser desorption/chemical ionization (LD/CI) MS/MS with a quadrupole Ion trap Article Dec 1999 Frederick Joseph Troendle Christopher D Reddick Richard A Yost A novel quadrupole ion trap mass spectrometer laser microprobe instrument with an external ionization source was constructed and used to investigate the matrix-assisted laser desorption/ionization (MALDI) detection of pharmaceutical compounds in intact tissue. In addition to MALDI, laser desorption coupled with chemical ionization (LD/CI) was investigated. MALDI, using 2,5-dihydroxybenezoic acid (DHB) as a matrix, was employed to detect the anticancer drug paclitaxel from a thin section of rat liver tissue which had been incubated in a solution of paclitaxel. The results of that experiment showed that the ability to perform tandem mass spectrometry (MS/MS) with the quadrupole ion trap was crucial in the identification of drug compounds at trace levels in the complex tissue matrix. MALDI MS/MS was then used to detect the presence of paclitaxel in a human ovarian tumor at a concentration of approximately 50 mg/kg. Finally, the drug spiperone was detected in incubated rat liver tissue at an approximate level of 25 mg/kg using LD/CI (no MALDI matrix). Again, the MS/MS capability of the quadrupole ion trap was crucial in the identification of the drug at trace levels in the complex tissue matrix. View Show abstract Matrix-Assisted Laser Desorption/Ionization Imaging Mass Spectrometry for Direct Measurement of Clozapine in Rat Brain Tissue Article Mar 2006 Roger Casale Elaine Fukuda Yunsheng Hsieh Walter Korfmacher Matrix-assisted laser desorption/ionization hyphenated with quadrupole time-of-flight (QTOF) mass spectrometry (MS) has been used to directly determine the distribution of pharmaceuticals in rat brain tissue slices which might unravel their disposition for new drug development. Clozapine, an antipsychotic drug, and norclozapine were used as model compounds to investigate fundamental parameters such as matrix and solvent effects and irradiance dependence on MALDI intensity but also to address the issues with direct tissue imaging MS technique such as (1) uniform coating by the matrix, (2) linearity of MALDI signals, and (3) redistribution of surface analytes. The tissue sections were coated with various matrices on MALDI plates by airspray deposition prior to MS detection. MALDI signals of analytes were detected by monitoring the dissociation of the individual protonated molecules to their predominant MS/MS product ions. The matrices were chosen for tissue applications based on their ability to form a homogeneous coating of dense crystals and to yield greater sensitivity. Images revealing the spatial localization in tissue sections using MALDI-QTOF following a direct infusion of (3)H-clozapine into rat brain were found to be in good correlation with those using a radioautographic approach. The density of clozapine and its major metabolites from whole brain homogenates was further confirmed using fast high-performance liquid chromatography/tandem mass spectrometry (HPLC-MS/MS) procedures. View Show abstract Direct Molecular Analysis of Whole-Body Animal Tissue Sections by MALDI Imaging Mass Spectrometry Article Jul 2010 Pierre Chaurand Peggi Angel Michelle Reyzer Richard M. Caprioli The determination of the localization of various compounds in a whole animal is valuable for many applications, including pharmaceutical absorption, distribution, metabolism, and excretion (ADME) studies and biomarker discovery. Imaging mass spectrometry is a powerful tool for localizing compounds of biological interest with molecular specificity and relatively high resolution. Utilizing imaging mass spectrometry for whole-body animal sections offers considerable analytical advantages compared to traditional methods, such as whole-body autoradiography, but the experiment is not straightforward. This chapter addresses the advantages and unique challenges that the application of imaging mass spectrometry to whole-body animal sections entails, including discussions of sample preparation, matrix application, signal normalization, and image generation. Lipid and protein images obtained from whole-body tissue sections of mouse pups are presented along with detailed protocols for the experiments. View Show abstract A solvent-free matrix application method for matrix-assisted laser desorption/ionization imaging of small molecules Article Jun 2010 RAPID COMMUN MASS SP Richard J. A. Goodwin Lynsey MacIntyre David G Watson Andrew Pitt Matrix application continues to be a critical step in sample preparation for matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI). Imaging of small molecules such as drugs and metabolites is particularly problematic because the commonly used washing steps to remove salts are usually omitted as they may also remove the analyte, and analyte spreading is more likely with conventional wet matrix application methods. We have developed a method which uses the application of matrix as a dry, finely divided powder, here referred to as dry matrix application, for the imaging of drug compounds. This appears to offer a complementary method to wet matrix application for the MALDI-MSI of small molecules, with the alternative matrix application techniques producing different ion profiles, and allows the visualization of compounds not observed using wet matrix application methods. We demonstrate its value in imaging clozapine from rat kidney and 4-bromophenyl-1,4-diazabicyclo(3.2.2)nonane-4-carboxylic acid from rat brain. In addition, exposure of the dry matrix coated sample to a saturated moist atmosphere appears to enhance the visualization of a different set of molecules. View Show abstract Essential tactics of tissue preparation and matrix nano-spotting for successful compound imaging mass spectrometry Article Feb 2010 Akos Végvári Thomas Fehniger Lena Gustavsson György Marko-Varga The ultimate goal of MALDI-Imaging Mass Spectrometry (MALDI-IMS) is to achieve spatial localization of analytes in tissue sections down to individual tissue compartments or even at the level of a few cells. With compound tissue imaging, it is possible to track the transportation of an unlabelled, inhaled reference compound within lung tissue, through the application of MALDI-IMS. The procedure for isolation and preparation of lung tissues is found to be crucial in order to preserve the anatomy and structure of the pulmonary compartments. To avoid delocalization of analytes within lung tissue compartments we have applied an in-house designed nano-spotter, based on a microdispenser mounted on an XY table, of which movement and spotting functionality were fully computer controlled. We demonstrate the usefulness of this platform in lung tissue sections isolated from rodent in vivo model, applied to compound tissue imaging as exemplified with the determination of the spatial distribution of (1alpha,2beta,4beta,7beta)-7-[(hydroxidi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.0(2,4)]nonane, also known as tiotropium. We provide details on tissue preparation protocols and sample spotting technology for successful identification of drug in mouse lung tissue by using MALDI-Orbitrap instrumentation. View Show abstract Matrix-assisted laser desorption/ionization imaging mass spectrometry of oxaliplatin derivatives in heated intraoperative chemotherapy (HIPEC)-like treated rat kidney Article Feb 2010 RAPID COMMUN MASS SP Amina Bouslimani Nicole Bec Matthias Glueckmann Christian Larroque Oxaliplatin [1,2-diaminocyclohexane (dach)-Pt complex] is a platinum anticancer drug which is mainly used in the treatment of advanced colorectal cancer, particularly in Heated Intraoperative Chemotherapy (HIPEC) for the treatment of colorectal peritoneal carcinomatosis. In order to better understand the penetration of oxaliplatin in treated tissues we performed a direct imaging of tissue sections from HIPEC-like treated rat kidney using matrix-assisted laser desorption/ionization (MALDI) mass spectrometry. This procedure allowed the detection and localization of oxaliplatin and its metabolites, the monocysteine and monomethionine complexes, in kidney sections. Specifically, oxaliplatin and its metabolites were localized exclusively in the kidney cortex, suggesting that it did not penetrate deeply into the organ. Based on these results, an imaging analysis of human tumors collected after HIPEC is currently in progress to assess the distribution of oxaliplatin and/or metabolites with the aim of defining clinical conditions to improve drug penetration. View Show abstract Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J, Seto T, Satouchi M, Tada H, Hirashima T, Asami K, Katakami N, Takada M, Yoshioka H, Shibata K, Kudoh S, Shimizu E, Saito H, Toyooka S, Nakagawa K, Fukuoka M, West Japan Oncology GroupGefitinib versus cisplatin plus docetaxel in patients with non-small cell lung cancer harbouring mutations of epidermal growth factor receptor (WJTOG3405). Lancet Oncol 11(2): 121-128 Article Dec 2009 Tetsuya Mitsudomi Satoshi Morita Yasushi Yatabe Masahiro Fukuoka Patients with non-small-cell lung cancer harbouring mutations in the epidermal growth factor receptor (EGFR) gene respond well to the EGFR-specific tyrosine kinase inhibitor gefitinib. However, whether gefitinib is better than standard platinum doublet chemotherapy in patients selected by EGFR mutation is uncertain.
We did an open label, phase 3 study (WJTOG3405) with recruitment between March 31, 2006, and June 22, 2009, at 36 centres in Japan. 177 chemotherapy-naive patients aged 75 years or younger and diagnosed with stage IIIB/IV non-small-cell lung cancer or postoperative recurrence harbouring EGFR mutations (either the exon 19 deletion or L858R point mutation) were randomly assigned, using a minimisation technique, to receive either gefitinib (250 mg/day orally; n=88) or cisplatin (80 mg/m(2), intravenously) plus docetaxel (60 mg/m(2), intravenously; n=89), administered every 21 days for three to six cycles. The primary endpoint was progression-free survival. Survival analysis was done with the modified intention-to-treat population. This study is registered with UMIN (University Hospital Medical Information Network in Japan), number 000000539.
Five patients were excluded (two patients were found to have thyroid and colon cancer after randomisation, one patient had an exon 18 mutation, one patient had insufficient consent, and one patient showed acute allergic reaction to docetaxel). Thus, 172 patients (86 in each group) were included in the survival analyses. The gefitinib group had significantly longer progression-free survival compared with the cisplatin plus docetaxel goup, with a median progression-free survival time of 9.2 months (95% CI 8.0-13.9) versus 6.3 months (5.8-7.8; HR 0.489, 95% CI 0.336-0.710, log-rank p<0.0001). Myelosuppression, alopecia, and fatigue were more frequent in the cisplatin plus docetaxel group, but skin toxicity, liver dysfunction, and diarrhoea were more frequent in the gefitinib group. Two patients in the gefitinib group developed interstitial lung disease (incidence 2.3%), one of whom died.
Patients with lung cancer who are selected by EGFR mutations have longer progression-free survival if they are treated with gefitinib than if they are treated with cisplatin plus docetaxel.
West Japan Oncology Group (WJOG): a non-profit organisation supported by unrestricted donations from several pharmaceutical companies. View Show abstract In Situ Primary Metabolites Localization on a Rat Brain Section by Chemical Mass Spectrometry Imaging Article Jul 2009 ANAL CHEM Farida Benabdellah David Touboul Alain Brunelle Olivier Laprévote We describe here the detection and identification of 13 primary metabolites (AMP, ADP, ATP, UDP-GlcNAc, ...) directly from rat brain sections by chemical mass spectrometry imaging. Matrix-assisted laser desorption/ionization tandem mass spectrometry (MALDI-MS/MS) was combined with 9-aminoacridine as a powerful matrix. We also demonstrate that a new robotic sprayer allows us to homogeneously coat the surface with the matrix, enabling the acquisition of chemical images at a 50 microm resolution, leading us to precisely and simultaneously localize each metabolite over the tissue surface. These experiments open a new field of investigation for chemical mass spectrometry imaging and are of great interest for both chemists and biologists. View Show abstract Imaging Mass Spectrometry for Visualization of Drug and Endogenous Metabolite Distribution: Toward In Situ Pharmacometabolomes Article Jul 2009 J NEUROIMMUNE PHARM Yuki Sugiura Mitsutoshi Setou It is important to determine how a candidate drug is distributed and metabolized within the body in early phase of drug discovery. Recently, matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS; also referred to as mass spectrometry imaging) has attracted great interest for monitoring drug delivery and metabolism. Since this emerging technique enables simultaneous imaging of many types of metabolite molecules, MALDI-IMS can visualize and distinguish the parent drug and its metabolites. As another important advantage, changes in endogenous metabolites in response to drug administration can be mapped and evaluated in tissue sections. In this review, we discuss the capabilities of current IMS techniques for imaging metabolite molecules and summarize representative studies on imaging of both endogenous and exogenous metabolites. In addition, current limitations and problems with the technique are discussed, and reports of progress toward solving these problems are summarized. With this new tool, the pharmacological research community can begin to map the in situ pharmacometabolome. View Show abstract Cancer Statistics, 2009 Article Jul 2009 Ahmedin Jemal Rebecca Siegel Elizabeth Ward Michael J Thun Each year, the American Cancer Society estimates the number of new cancer cases and deaths expected in the United States in the current year and compiles the most recent data on cancer incidence, mortality, and survival based on incidence data from the National Cancer Institute, Centers for Disease Control and Prevention, and the North American Association of Central Cancer Registries and mortality data from the National Center for Health Statistics. Incidence and death rates are standardized by age to the 2000 United States standard million population. A total of 1,479,350 new cancer cases and 562,340 deaths from cancer are projected to occur in the United States in 2009. Overall cancer incidence rates decreased in the most recent time period in both men (1.8% per year from 2001 to 2005) and women (0.6% per year from 1998 to 2005), largely because of decreases in the three major cancer sites in men (lung, prostate, and colon and rectum [colorectum]) and in two major cancer sites in women (breast and colorectum). Overall cancer death rates decreased in men by 19.2% between 1990 and 2005, with decreases in lung (37%), prostate (24%), and colorectal (17%) cancer rates accounting for nearly 80% of the total decrease. Among women, overall cancer death rates between 1991 and 2005 decreased by 11.4%, with decreases in breast (37%) and colorectal (24%) cancer rates accounting for 60% of the total decrease. The reduction in the overall cancer death rates has resulted in the avoidance of about 650,000 deaths from cancer over the 15-year period. This report also examines cancer incidence, mortality, and survival by site, sex, race/ethnicity, education, geographic area, and calendar year. Although progress has been made in reducing incidence and mortality rates and improving survival, cancer still accounts for more deaths than heart disease in persons younger than 85 years of age. Further progress can be accelerated by applying existing cancer control knowledge across all segments of the population and by supporting new discoveries in cancer prevention, early detection, and treatment. View Show abstract Molecular Imaging of Biological Samples: Localization of Peptides and Proteins Using MALDI-TOF MS Article Jan 1998 Terry B. Farmer Jocelyn Gile Richard M. Caprioli Matrix-assisted laser desorption/ionization mass spectrometry (MALDI MS) has been used to generate ion images of samples in one or more mass-to-charge (m/z) values, providing the capability of mapping specific molecules to two-dimensional coordinates of the original sample. The high sensitivity of the technique (low-femtomole to attomole levels for proteins and peptides) allows the study of organized biochemical processes occurring in, for example, mammalian tissue sections. The mass spectrometer is used to determine the molecular weights of the molecular in the surface layers of the tissue. Molecules desorbed from the sample typically are singly protonated, giving an ion at (M + H)+, where M is the molecular mass. The procedure involves coating the tissue section, or a blotted imprint of the section, with a thin layer of energy-absorbing matrix and then analyzing the sample to produce an ordered array of mass spectra, each containing nominal m/z values typically covering a range of over 50,000 Da. Images can be displayed in individual m/z values as a selected ion image, which would localize individual compounds in the tissue, or as summed ion images. MALDI ion images of tissue sections can be obtained directly from tissue slices following preparative steps, and this is demonstrated for the mapping of insulin contained in an islet in a section of rat pancreas, hormone peptides in a small area of a section of rat pituitary, and a small protein bound to the membrane of human mucosa cells. Alternatively, imprints of the tissue can be analyzed by blotting the tissue sections on specially prepared targets containing an adsorbent material, e.g., C-18 coated resin beads. Peptides and small proteins bind to the C-18 and create a positive imprint of the tissue which can then be imaged by the mass spectrometer. This is demonstrated for the MALDI ion image analysis of regions of rat splenic pancreas and for an area of rat pituitary traversing the anterior, intermediate, and posterior regions where localized peptides were mapped. In a single spectrum from the anterior/intermediate lobe of a rat pituitary print, over 50 ions corresponding to the peptides present in this tissue were observed as well as precursors, isoforms, and metabolic fragments. View Show abstract Homogenous sample preparation for automated high throughput analysis with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry Article Mar 1999 Patrik Önnerfjord Simon Ekström Jonas Bergquist György Marko-Varga This work presents a simple method for obtaining homogeneous sample surfaces in matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOFMS) for the automated analysis of peptides and proteins. The sample preparation method is based on applying the sample/matrix mixture onto a pre-deposited highly diluted matrix spot. The pre-deposited crystals act as seeds for the new sample containing crystals which become much smaller in size and more evenly distributed than with conventional methods. This 'seed-layer' method was developed, optimised and compared with the dried-droplet method using peptides and proteins in the 1000-20,000 Da range. The seed-layer method increases the surface homogeneity, spot to spot reproducibility and sample washability as compared with the commonly used dried-droplet method. This methodology is applicable to alpha-cyanohydroxycinnamic acid, sinapinic acid and ferulic acid, which all form homogeneous crystal surfaces. Within-spot variation and between-spot variation was investigated using statistics at a 95% confidence level (n = 36). The statistical values were generated from more than 5000 data points collected from 500 spectra. More than 90% of the sample locations results in high intensity spectra with relatively low standard deviations (RSDs). Typically obtained data showed an RSD of 19-35% within a sample spot as well as in-between spots for proteins, and an RSD of < or = 50% for peptides. Linear calibration curves were obtained within one order of magnitude using internal calibration with a point-RSD of 3% (n = 10). The sample homogeneity allows mass spectra (average of 16 laser shots) to be obtained on each individual sample within 15 sec, whereby a 100 spot target plate can be run in 25 min. High density target plates using the seed-layer method were prepared by spotting approximately 100 picoliter droplets onto the target, resulting in sample spots < or = 500 microns in diameter using a flow-through piezo-electric micro-dispenser. By using this automated sample preparation step lower standard deviations are obtained in comparison to manually prepared samples. View Show abstract Erlotinib (Tarceva): An update on the clinical trial program Article Jul 2003 SEMIN ONCOL Roy S. Herbst Erlotinib HCI (Tarceva; Genentech, Inc, South San Francisco, CA) is an orally available, quinazoline-based agent that competes with adenosine triphosphate for binding with the intracellular catalytic domain of epidermal growth factor receptor (HER1/EGFR) tyrosine kinase, inhibiting phosphorylation. This action blocks downstream signal transduction and inhibits the tumorigenic effects associated with ligand-dependent and ligand-independent HER1/EGFR activation. In preclinical studies, erlotinib has substantial antitumor activity against various human tumor xenografts alone and in combination with chemotherapeutic drugs. Phase I data showed that erlotinib was well tolerated, with encouraging antitumor activity in patients with various types of solid tumors. Furthermore, phase II monotherapy trials in patients with advanced non-small cell lung cancer, ovarian cancer, and head and neck squamous cell cancer, respectively, show favorable activity compared with single-agent chemotherapy in similar patient populations. Phase III trials with erlotinib in non-small cell lung cancer and pancreatic cancer are in progress, as are a range of studies in various indications designed to optimize the use of erlotinib alone and in combination with chemotherapy, radiotherapy, and other targeted agents. View Show abstract Direct Analysis of Drug Candidates in Tissue by Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry Article Oct 2003 Michelle Reyzer Kwokei Ng Richard M. Caprioli Yunsheng Hsieh Matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) has been used to directly analyze and image pharmaceutical compounds in intact tissue. The anti-tumor drug SCH 226374 was unambiguously determined in mouse tumor tissue using MALDI-QqTOFMS (QSTAR) by monitoring the dissociation of the protonated drug at m/z 695.4 to its predominant fragment at m/z 228.1. A second drug, compound A, was detected in slices of rat brain tissue following oral administration with doses ranging from 1-25 mg/kg. Quantitation of compound A from whole brain homogenates using routine high-performance liquid chromatography/tandem mass spectrometry (HPLC/MS/MS) procedures revealed that concentrations of the drug in whole brain varied from a low of 24 ng/g to a high of 1790 ng/g. The drug candidate was successfully detected by MALDI-QqTOF in samples from each dose, covering a range of approximately two orders of magnitude. In addition, good correlation was observed between the MALDI-QqTOFMS intensities at each dose with the HPLC/MS/MS results. Thus the MALDI-MS response is proportional to the amount of drug in tissue. Custom software was developed to facilitate the imaging of small molecules in tissue using the MALDI-QqTOF mass spectrometer. Images revealing the spatial localization of SCH 226374 in tumor tissue and compound A in brain tissue were acquired. View Show abstract A Randomized Trial of Adjuvant Chemotherapy with Uracil-Tegafur for Adenocarcinoma of the Lung Article May 2004 NEW ENGL J MED Yukito Ichinose Morio Ohta Mitsuo Ohta Harubumi Kato In a previous phase 3 trial of adjuvant chemotherapy after resection of non-small-cell lung cancer, a combination of uracil and tegafur (often referred to as UFT) taken orally was shown to prolong survival. A subgroup analysis disclosed that most patients who benefited had pathological stage I adenocarcinoma.
We randomly assigned patients with completely resected pathological stage I adenocarcinoma of the lung to receive either oral uracil-tegafur (250 mg of tegafur per square meter of body-surface area per day) for two years or no treatment. Randomization was performed with stratification according to the pathological tumor category (T1 vs. T2), sex, and age. The primary end point was overall survival.
From January 1994 through March 1997, 999 patients were enrolled. Twenty patients were found to be ineligible and were excluded from the analysis after randomization; 491 patients were assigned to receive uracil-tegafur and 488 were assigned to observation. The median duration of follow-up for surviving patients was 73 months. The difference in overall survival between the two groups was statistically significant in favor of the uracil-tegafur group (P=0.04 by a stratified log-rank test). Grade 3 toxic effects occurred in 10 of the 482 patients (2 percent) who actually received uracil-tegafur.
Adjuvant chemotherapy with uracil-tegafur improves survival among patients with completely resected pathological stage I adenocarcinoma of the lung. View Show abstract Activating Mutations in the Epidermal Growth Factor Receptor Underlying Responsiveness of Non–Small-Cell Lung Cancer to Gefitinib Article Jun 2004 NEW ENGL J MED Thomas J Lynch Daphne W. Bell Raffaella Sordella Daniel A Haber Most patients with non-small-cell lung cancer have no response to the tyrosine kinase inhibitor gefitinib, which targets the epidermal growth factor receptor (EGFR). However, about 10 percent of patients have a rapid and often dramatic clinical response. The molecular mechanisms underlying sensitivity to gefitinib are unknown.
We searched for mutations in the EGFR gene in primary tumors from patients with non-small-cell lung cancer who had a response to gefitinib, those who did not have a response, and those who had not been exposed to gefitinib. The functional consequences of identified mutations were evaluated after the mutant proteins were expressed in cultured cells.
Somatic mutations were identified in the tyrosine kinase domain of the EGFR gene in eight of nine patients with gefitinib-responsive lung cancer, as compared with none of the seven patients with no response (P<0.001). Mutations were either small, in-frame deletions or amino acid substitutions clustered around the ATP-binding pocket of the tyrosine kinase domain. Similar mutations were detected in tumors from 2 of 25 patients with primary non-small-cell lung cancer who had not been exposed to gefitinib (8 percent). All mutations were heterozygous, and identical mutations were observed in multiple patients, suggesting an additive specific gain of function. In vitro, EGFR mutants demonstrated enhanced tyrosine kinase activity in response to epidermal growth factor and increased sensitivity to inhibition by gefitinib.
A subgroup of patients with non-small-cell lung cancer have specific mutations in the EGFR gene, which correlate with clinical responsiveness to the tyrosine kinase inhibitor gefitinib. These mutations lead to increased growth factor signaling and confer susceptibility to the inhibitor. Screening for such mutations in lung cancers may identify patients who will have a response to gefitinib. View Show abstract Determination of pharmaceutical compounds in skin by imaging matrix-assisted laser desorption/ionisation mass spectrometry Article Dec 2004 Josephine Bunch Malcolm R Clench Don Richards Matrix-assisted laser desorption/ionisation (MALDI) quadrupole time-of-flight mass spectrometry (Q-TOFMS) has been used to detect and image the distribution of a xenobiotic substance in skin. Porcine epidermal tissue was treated with 'Nizoral', a medicated shampoo containing ketoconazole (+/-)-1-acetyl-4-[p-[[(2R,4S)-2-(2,4-dichlorophenyl)-2-(imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazine) as active ingredient. Following incubation for 1 h at 37 degrees C all excess formulation was washed from the surface. A cross-section of the drug-treated tissue was then blotted onto a cellulose membrane, precoated in matrix (alpha-cyano-4-hydroxycinnamic acid (CHCA)), by airspray deposition. In separate experiments the tissue surface was treated with Nizoral within a triangular former, and subsequently blotted onto a matrix-coated membrane. Sample membranes were then mounted into the recess of specialised MALDI targets with adhesive tape. All samples were analysed by MALDI-TOFMS using an Applied Biosystem 'Q-star Pulsar i' hybrid Q-TOF mass spectrometer fitted with an orthagonal MALDI ion source and imaging software. Detection of the protonated molecule was readily achievable by this technique. Treatment of the tissue within a template gave rise to images depicting the expected distribution of the drug, demonstrating that this technique is capable of producing spatially useful data. Ion images demonstrating the permeation of the applied compound into the skin were achieved by imaging a cross-sectional imprint of treated tissue. A calibration graph for the determination of ketoconazole was prepared using the sodium adduct of the matrix ion as an internal standard. This enabled construction of a quantitative profile of drug in skin. Conventional haematoxylin and eosin staining and microscopy methods were employed to obtain a histological image of the porcine epidermal tissue. Superimposing the mass spectrometric and histological images appeared to indicate drug permeation into the dermal tissue layer. View Show abstract Maldi Mass Spectrometric Imaging of Biological Tissue Sections Article Feb 2005 MECH AGEING DEV Tatiana Rohner Dieter Staab Markus Stoeckli In biomedical research, the discovery of new biomarkers and new drugs demands analytical techniques with high sensitivity together with increased throughput. The possibility to localize or to follow changes in organisms at the molecular level by imaging component distributions of specific tissues, is of prime importance to unravel biochemical pathways and develop new treatments and drugs. Established molecular imaging techniques such as MRI and PET are already widely used, however their need for molecular probes to report the presence of the analytes of interest precludes the simultaneous exploration of different biomolecules. Matrix-assisted laser desorption/ionization mass spectrometric imaging (MALDI MSI) takes full advantage of the high sensitivity of mass spectrometry instrumentation but also of the ability of the latter to simultaneously detect a wide range of compounds, almost regardless from their nature and mass. To perform MALDI MSI, sections of biological tissues are introduced in an MALDI MS instrument, where the UV pulsed laser of the MALDI source is used to raster over a selected area while acquiring mass spectra of the ablated ions at every image point. From this array of spectra, hundreds of analyte-specific images can be generated based on the selected masses. MALDI MSI can be used to track biomarkers such as peptides or proteins but also to map drug/tissue interactions. In this paper, an overview of the possibilities of MSI will be given. As an example, MSI on brain tissue sections for the study of Alzheimer's disease (AD) will be shown. Mapping of amyloid peptides as a new approach for drug lead optimization will be presented. Target identification thanks to MSI will be introduced and the last part will be dedicated to the molecular scanner approach, which gives access to high-mass range by combining tissue blotting and digestion in a one-step process. View Show abstract Subcellular imaging mass spectrometry of brain tissue Article Feb 2005 Liam A. McDonnell Sander R Piersma A F MaartenAltelaar Ron M A Heeren Imaging mass spectrometry provides both chemical information and the spatial distribution of each analyte detected. Here it is demonstrated how imaging mass spectrometry of tissue at subcellular resolution can be achieved by combining the high spatial resolution of secondary ion mass spectrometry (SIMS) with the sample preparation protocols of matrix-assisted laser desorption/ionization (MALDI). Despite mechanistic differences and sampling 10(5) times less material, matrix-enhanced (ME)-SIMS of tissue samples yields similar results to MALDI (up to m/z 2500), in agreement with previous studies on standard compounds. In this regard ME-SIMS represents an attractive alternative to polyatomic primary ions for increasing the molecular ion yield. ME-SIMS of whole organs and thin sections of the cerebral ganglia of Lymnaea stagnalis demonstrate the advantages of ME-SIMS for chemical imaging mass spectrometry. Subcellular distributions of cellular analytes are clearly obtained, and the matrix provides an in situ height map of the tissue, allowing the user to identify rapidly regions prone to topographical artifacts and to deconvolute topographical losses in mass resolution and signal-to-noise ratio. View Show abstract Mapping pharmaceutical in tissues using MALDI imaging mass spectrometry Article Mar 2007 J Pharmacol Toxicol Meth Yunsheng Hsieh Jiwen Chen Walter Korfmacher During drug discovery and development stage, often the question is raised as to whether the drug can reach the site of action which helps researchers better assess the potential value of that compound as a pharmaceutical product and toxicological outcomes. High performance liquid chromatography coupled to a tandem mass spectrometer (HPLC-MS/MS) has totally replaced HPLC methods that use UV or other detectors for most drug analysis applications. However, HPLC-MS/MS approaches are not able to provide the answer to certain questions regarding the distribution of a drug in various organs or tissues from laboratory animal experiments. Whole body radioautography (WBA) normally provides a standard means to answer this question on the time course of the drug candidates. However, the major disadvantage in this radioautographic technique is to allow for visualization of total drug-related materials but to image the distribution of the administrated drugs and their metabolites in all tissues. In addition, the availability of radiolabeled compounds at drug discovery stage is another concern. To overcome these issues, matrix-assisted laser desorption/ionization-mass spectrometric method (MALDI-MS) has been developed to directly determine the distribution of pharmaceuticals in tissue sections which might unravel their disposition or biotransformation pathway for new drug development. View Show abstract Analysis of rosuvatatin by imaging mass spectrometry Article Nov 2006 Simone Cristoni Maura Brioschi Andrea Rizzi Cristina Banfi View Analysis of erlotinib and its metabolites in rat tissue sections by MALDI quadrupole time-of-flight mass spectrometry Article Jul 2007 Luca Signor Emmanuel Varesio Roland F Staack Gérard Hopfgartner A qualitative and quantitative analysis of erlotinib (RO0508231) and its metabolites was carried out on rat tissue sections from liver, spleen and muscle. Following oral administration at a dose of 5 mg/kg, samples were analyzed by matrix-assisted laser desorption ionization (MALDI) with mass spectrometry (MS) using an orthogonal quadrupole time-of-flight instrument. The parent compound was detected in all tissues analyzed. The metabolites following drug O-dealkylation could also be detected in liver sections. Sinapinic acid (SA) matrix combined with the dried-droplet method resulted in better conditions for our analysis on tissues. Drug quantitation was investigated by the standard addition method and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis on the tissue extracts. The presence of the parent compound and of its O-demethylated metabolites was confirmed in all tissue types and their absolute amounts calculated. In liver the intact drug was found to be 3.76 ng/mg tissue, while in spleen and muscle 6- and 30-fold lower values, respectively, were estimated. These results were compared with drug quantitation obtained by whole-body autoradiography, which was found to be similar. The potential for direct quantitation on tissue sections in the presence of an internal standard was also investigated using MALDI-MS. The use of alpha-cyano-4-hydroxycinnamic acid (CHCA) as the matrix resulted in better linearity for the calibration curves obtained with reference solutions of the drug when compared to SA, but on tissue samples no reliable quantitative analysis was possible owing to the large variability in the signal response. MS imaging experiments using MALDI in MS/MS mode allowed visualizing the distribution of the parent compound in liver and spleen tissues. By calculating the ratio between the total ion intensities of MS images for liver and spleen sections, a value of 6 : 1 was found, which is in good agreement with the quantitative data obtained by LC-MS/MS analysis. View Show abstract Personalized Medicine and Proteomics: Lessons from Non-Small Cell Lung Cancer Article Sep 2007 György Marko-Varga Atsushi Ogiwara Toshihide Nishimura Harubumi Kato Personalized medicine allows the selection of treatments best suited to an individual patient and disease phenotype. To implement personalized medicine, effective tests predictive of response to treatment or susceptibility to adverse events are needed, and to develop a personalized medicine test, both high quality samples and reliable data are required. We review key features of state-of-the-art proteomic profiling and introduce further analytic developments to build a proteomic toolkit for use in personalized medicine approaches. The combination of novel analytical approaches in proteomic data generation, alignment and comparison permit translation of identified biomarkers into practical assays. We further propose an expanded statistical analysis to understand the sources of variability between individuals in terms of both protein expression and clinical variables and utilize this understanding in a predictive test. View Show abstract
Keys to success for large-scale proteomics analysis [36] Improved resolution and very high-sensitivity in MALDI TOF of matrix surfaces made by fast evaporation 3281-7 A Ogiwara T Kawakami K Nagasaka Tanaka K Wada M Otsuji
Ogiwara A, Kawakami T, Nagasaka K, Tanaka N, Wada K, Otsuji M, et al. Keys to success for large-scale proteomics analysis [36] Vorm O, Roepstorff P, Mann M. Improved resolution and very high-sensitivity in MALDI TOF of matrix surfaces made by fast evaporation. Anal Chem 1994;66:3281–7. Jan 2009 225-274 A Jemal R Siegel E Ward Yp Hao Jq Xu Mj Thun
Jemal A, Siegel R, Ward E, Hao YP, Xu JQ, Thun MJ. Cancer
statistics, 2009. CA Cancer J Clin 2009;59:225–49.
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Breathnach OS, Freidlin B, Conley B, Green MR, Johnson DH,
Gandara DR, et al. Twenty-two years of phase III trials for
patients with advanced non-small-cell lung cancer: sobering
results. J Clin Oncol 2001;19:1734–42.
Subcellular imaging mass spectrometry of brain tissue Jan 2005 160-168 La Mcdonnell Sr Piersma Afm Altelaar Th Mize Sl Luxembourg P Verhaert
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2 Chronicles 25:15-25 - CJB Bible - As a result, the anger of ADONAI blazed up against...
2 Chronicles 25:15-25 As a result, the anger of ADONAI blazed up against Amatzyah, and he sent him a prophet, who said to him, " Why have you sought out the gods of those people, when they couldn't even rescue their own people from you?" But as [the prophet] was speaking t... Read verse in The Complete Jewish Bible
2 Chronicles 25:15-25
15 As a result, the anger of ADONAI blazed up against Amatzyah, and he sent him a prophet, who said to him, "Why have you sought out the gods of those people, when they couldn't even rescue their own people from you?"
16 But as [the prophet] was speaking to him, he interrupted him: "Were you made an adviser to the king? You had better stop before you get yourself killed!" So the prophet stopped, but he added, "I know that God is planning to destroy you for having done this and for refusing to listen to my advice."
17 Then, after taking counsel, Amatzyah king of Y'hudah sent a challenge to Yo'ash the son of Y'ho'achaz, the son of Yehu, king of Isra'el: "Come on, let's have it out face-to-face."
18 Yo'ash the king of Isra'el sent this reply to Amatzyah king of Y'hudah: "Once, in the L'vanon, the thistle sent a message to the cedar: 'Give your daughter to my son in marriage.' But a wild animal passed by the thistle and squashed it.
19 You say you defeated Edom, which is true; so you're excited and itching for more glory. But now, stay home! Why provoke calamity, to your own ruin, yours and Y'hudah's too?"
20 But Amatzyah wouldn't listen. And this was from God, so that he could hand them over [to their enemies], because they had sought the gods of Edom.
21 So Yo'ash king of Isra'el went up; and he and Amatzyah king of Y'hudah had it out face-to-face at Beit-Shemesh, which belongs to Y'hudah.
22 Y'hudah was defeated by Isra'el, and every man fled to his tent.
23 Yo'ash king of Isra'el took Amatzyah king of Y'hudah, the son of Yo'ash the son of Y'ho'achaz, prisoner at Beit-Shemesh. Then he brought him to Yerushalayim and demolished the wall of Yerushalayim between the Gate of Efrayim and the Corner Gate, a section 600 feet long.
24 [He took] all the gold and silver, all the articles he could find in the house of God, with 'Oved-Edom, and the treasures of the royal palace, together with hostages; then he returned to Shomron.
25 Amatzyahu the son of Yo'ash, king of Y'hudah, lived another fifteen years after the death of Yo'ash son of Y'ho'achaz king of Isra'el.
2 Chronicles 25:15-25 Meaning and Commentary
INTRODUCTION TO 2 CHRONICLES 25
This chapter begins with the reign of Amaziah, and some of the first acts of it, slaying those that killed his father, 2Ch 25:1-4, raising a large army in his own kingdom, to which he added 100,000 more he hired out of Israel, whom yet he sent home by the advice of a prophet, 2Ch 25:5-10, and with his own army marched against the Edomites, and obtained a victory over them, 2Ch 25:11,12, but the Israelites being displeased with him for dismissing them, fell on some of his cities, and slew many in them, 2Ch 25:13, and such was his stupidity, as to worship the gods of the Edomites he had conquered, for which he was reproved by a prophet, 2Ch 25:14-16and being elated with his victory, he sent a challenge to the king of Israel, who accepting of it, a battle ensued, in which Judah was worsted, their king taken, and treasuries spoiled, 2Ch 25:17-24, and the chapter is closed with the death and burial of Amaziah, 2Ch 25:25-28.
\\reign\\ Of these verses, \\See Gill on "2Ki 14:2"\\. \\See Gill on "2Ki 14:3"\\. \\See Gill on "2Ki 14:5"\\. \\See Gill on "2Ki 14:6"\\. 19664-950124-2127-2Ch25.2
2 Chronicles 25:15-25 In-Context
13 Meanwhile, the men in the army that Amatzyahu had sent back and hadn't allowed to join him in battle fell on the cities of Y'hudah, all the way from Shomron to Beit-Horon, killed 3,000 of them and took much spoil.
14 After Amatzyahu returned from the slaughter of the people from Edom, he brought the gods of the people of Se'ir and set them up as his own gods, prostrating himself before them and offering incense to them.
15 As a result, the anger of ADONAI blazed up against Amatzyah, and he sent him a prophet, who said to him, "Why have you sought out the gods of those people, when they couldn't even rescue their own people from you?"
16 But as [the prophet] was speaking to him, he interrupted him: "Were you made an adviser to the king? You had better stop before you get yourself killed!" So the prophet stopped, but he added, "I know that God is planning to destroy you for having done this and for refusing to listen to my advice."
17 Then, after taking counsel, Amatzyah king of Y'hudah sent a challenge to Yo'ash the son of Y'ho'achaz, the son of Yehu, king of Isra'el: "Come on, let's have it out face-to-face."
18 Yo'ash the king of Isra'el sent this reply to Amatzyah king of Y'hudah: "Once, in the L'vanon, the thistle sent a message to the cedar: 'Give your daughter to my son in marriage.' But a wild animal passed by the thistle and squashed it.
19 You say you defeated Edom, which is true; so you're excited and itching for more glory. But now, stay home! Why provoke calamity, to your own ruin, yours and Y'hudah's too?"
20 But Amatzyah wouldn't listen. And this was from God, so that he could hand them over [to their enemies], because they had sought the gods of Edom.
21 So Yo'ash king of Isra'el went up; and he and Amatzyah king of Y'hudah had it out face-to-face at Beit-Shemesh, which belongs to Y'hudah.
22 Y'hudah was defeated by Isra'el, and every man fled to his tent.
23 Yo'ash king of Isra'el took Amatzyah king of Y'hudah, the son of Yo'ash the son of Y'ho'achaz, prisoner at Beit-Shemesh. Then he brought him to Yerushalayim and demolished the wall of Yerushalayim between the Gate of Efrayim and the Corner Gate, a section 600 feet long.
24 [He took] all the gold and silver, all the articles he could find in the house of God, with 'Oved-Edom, and the treasures of the royal palace, together with hostages; then he returned to Shomron.
25 Amatzyahu the son of Yo'ash, king of Y'hudah, lived another fifteen years after the death of Yo'ash son of Y'ho'achaz king of Isra'el.
26 Other activities of Amatzyah, from beginning to end, are recorded in the Annals of the Kings of Y'hudah and Isra'el.
27 From the time that Amatzyahu turned away from following ADONAI, they formed a conspiracy against him in Yerushalayim. So he fled to Lakhish; but they followed him to Lakhish and killed him there.
| https://www.biblestudytools.com/cjb/2-chronicles/passage/?q=2+chronicles+25%3A15-25 |
Ezra 3 | NLT Bible | YouVersion
The Altar Is Rebuilt In early autumn,#:1 Hebrew In the seventh month. The year is not specified, so it may have been during Cyrus& #8217;s first year (538 b.c.) or second year (537 b.c.). The seventh
Ezra 3
The Altar Is Rebuilt
1 In early autumn, # 3:1 Hebrew In the seventh month. The year is not specified, so it may have been during Cyrus’s first year (538 b.c. ) or second year (537 b.c. ). The seventh month of the ancient Hebrew lunar calendar occurred within the months of September/October 538 b.c. and October/November 537 b.c. when the Israelites had settled in their towns, all the people assembled in Jerusalem with a unified purpose. 2 Then Jeshua son of Jehozadak # 3:2 Hebrew Jozadak, a variant spelling of Jehozadak; also in 3:8. joined his fellow priests and Zerubbabel son of Shealtiel with his family in rebuilding the altar of the God of Israel. They wanted to sacrifice burnt offerings on it, as instructed in the Law of Moses, the man of God. 3 Even though the people were afraid of the local residents, they rebuilt the altar at its old site. Then they began to sacrifice burnt offerings on the altar to the Lord each morning and evening.
4 They celebrated the Festival of Shelters as prescribed in the Law, sacrificing the number of burnt offerings specified for each day of the festival. 5 They also offered the regular burnt offerings and the offerings required for the new moon celebrations and the annual festivals as prescribed by the Lord . The people also gave voluntary offerings to the Lord . 6 Fifteen days before the Festival of Shelters began, # 3:6 Hebrew On the first day of the seventh month. This day in the ancient Hebrew lunar calendar occurred in September or October. The Festival of Shelters began on the fifteenth day of the seventh month. the priests had begun to sacrifice burnt offerings to the Lord . This was even before they had started to lay the foundation of the Lord ’s Temple.
The People Begin to Rebuild the Temple
7 Then the people hired masons and carpenters and bought cedar logs from the people of Tyre and Sidon, paying them with food, wine, and olive oil. The logs were brought down from the Lebanon mountains and floated along the coast of the Mediterranean Sea # 3:7 Hebrew the sea. to Joppa, for King Cyrus had given permission for this.
8 The construction of the Temple of God began in midspring, # 3:8 Hebrew in the second month. This month in the ancient Hebrew lunar calendar occurred within the months of April and May 536 b.c. during the second year after they arrived in Jerusalem. The work force was made up of everyone who had returned from exile, including Zerubbabel son of Shealtiel, Jeshua son of Jehozadak and his fellow priests, and all the Levites. The Levites who were twenty years old or older were put in charge of rebuilding the Lord ’s Temple. 9 The workers at the Temple of God were supervised by Jeshua with his sons and relatives, and Kadmiel and his sons, all descendants of Hodaviah. # 3:9 Hebrew sons of Judah (i.e., bene Yehudah ). Bene might also be read here as the proper name Binnui; Yehudah is probably another name for Hodaviah. Compare 2:40; Neh 7:43; 1 Esdras 5:58. They were helped in this task by the Levites of the family of Henadad.
10 When the builders completed the foundation of the Lord ’s Temple, the priests put on their robes and took their places to blow their trumpets. And the Levites, descendants of Asaph, clashed their cymbals to praise the Lord , just as King David had prescribed. 11 With praise and thanks, they sang this song to the Lord :
“He is so good!
His faithful love for Israel endures forever!”
Then all the people gave a great shout, praising the Lord because the foundation of the Lord ’s Temple had been laid.
| https://www.bible.com/en-GB/bible/116/EZR.3.NLT |
Evaluation of the effects of service core reduction on tall building structures
Evaluation of the effects of service core reduction on tall building structures
Date
2019
Author
Fakıoğlu, Beste
Metadata
Item Usage Stats
Optimum design of the service core where the vertical circulation systems, building services, HVAC elements etc. located, is one of the major tasks in tall building design process as it directly effects the net leasable area. Among others, the elevators are one of the most area consuming elements of service core, especially valid for supertall (+300m) office buildings. By making use of developing elevator technologies, decreasing the elevator footprint area and thereby decreasing the service core area is possible, indeed. However, the core of a tall building typically serves as an important member of lateral load resisting system, namely as a structural core. The aim of this study is to investigate the effects of service core reduction due to the elevator footprint decrease. Computer models of typical outriggered frame and framed-tube office buildings with 300m height (75 story) are generated. Then, the strength and stiffness constraints of reduced core buildings have been satisfied by making several modifications such as adding outriggers, using of belt trusses, increasing the section or the number or both of perimeter columns etc. This way, the modified reduced core models having similar structural performance with standard core models in terms of strength and stiffness have been obtained. Thereafter, fundamental architectural aspects such as net leasable area, the obstruction of panoramic exterior view, the amount of structural material etc. of standard core and modified reduced core buildings are compared to investigate the trade-offs of reducing the core.
Subject Keywords
Tall buildings.,Elevators, Automatic.,Structural engineering., High-rise apartment buildings.
URI
http://etd.lib.metu.edu.tr/upload/12623104/index.pdf https://hdl.handle.net/11511/28047
Collections
Graduate School of Natural and Applied Sciences, Thesis
OpenMETU
Core
Evaluation of The Effects of Service Core Reduction on Tall Building Structures Fakıoğlu, Beste; Ay, Bekir Özer (2019-04-20) One of the primary goals in tall building design is the optimum design of service core where the vertical transportation, building services, HVAC elements etc. are situated. Particularly for supertall (+300) office buildings, a significant portion of the core space is occupied by elevators when compared to the rest of the service core elements. Actually, with the utilization of recently developed elevator technologies, it is possible to decrease the elevator footprint area and thereby to decrease the servic...
Planning considerations of tall buildings : service core configuration and typologies Keskin, Zeynep; Günel, Mehmet Halis; Department of Building Science in Architecture (2012) In general, tall buildings, some of which are termed as “skyscrapers”, are among the typical and almost unavoidable features of the metropolitan cities. There is a competititive race of constructing higher and higher buildings since the birth of the infamous Home Insurance Building in Chicago which is still considered to be the pioneer of the modern tall buildings. Recently, an efficient service core design is strongly needed and inquired with the increase in height and capacity of tall buildings. Such need...
The Effects of Service Core Reduction on Tall Building Structures Fakıoğlu, Beste; Ay, Bekir Özer (2019-04-20) One of the primary goals in tall building design is the optimum design
of service core where the vertical transportation, building services,
HVAC elements etc. are situated. Particularly for supertall (+300)
office buildings, a significant portion of the core space is occupied by
elevators when compared to the rest of the service core elements.
Actually, with the utilization of recently developed elevator
technologies, it is possible to decrease the elevator footprint area and
thereby to decre...
EVALUATION OF DISPLACEMENT AMPLIFICATION FACTORS FOR STEEL BUCKLING RESTRAINED BRACED FRAMES Bozkurt, Mehmet Bakir; Ozkilic, Yasin Onuralp; Topkaya, Cem (2016-12-09) In the United States, design of buckling restrained braced frames (BRBFs) is conducted using the recommendations given in the Seismic Provisions for Structural Steel Buildings (AISC341-10) and Minimum Design Loads for Buildings and Other Structures (ASCE 7-10). In this study, deflection amplification factor given in ASCE7-10 for BRBFs was evaluated. Pursuant to this goal. three archetypes composed of single diagonal BRBFs were designed. The archetypes represent designs in high seismic regions which are defi...
An investigation of legal aspects of BIM in construction contracts Kaya, Fatih; Akçamete Güngör, Aslı; Birgönül, Mustafa Talat (null; 2019-04-17) Building Information Modeling (BIM) has been adopted worldwide in recent years as a novel way of working that enables efficiency in the construction industry. Lately, numerous countries made it compulsory to utilize BIM in public construction projects. Similarly, BIM became a contractual requirement in some public infrastructure and Build-Operate-Transfer (BOT) projects in Turkey. However, in order to benefit from the advantages of BIM, some legal concerns such as intellectual property, liability, legal val...
| https://open.metu.edu.tr/handle/11511/28047 |
Metabolites | Free Full-Text | Associated Effect of SLC40A1 and TMPRSS6 Polymorphisms on Iron Overload
Mutations in the ferroportin (FPN) gene SLC40A1 alter iron recycling and cause disturbances in iron homeostasis. The variants of TMPRSS6 contribute to the development of iron deficiencies. In this study, we determined the role of FPN and TMPRSS6 gene polymorphisms in the modulation of iron homeostasis based on biochemical parameters. PCR analysis and sequencing were performed to determine the single nucleotide polymorphisms (SNPs) SLC40A1 c.44–24G>C (rs1439816), SLC40A1 c.663T>C (rs2304704), and TMPRSS6 c.2207T>C (rs855791). Hemoglobin concentration and iron status were determined by standard procedures. We studied 79 iron-loaded individuals for SLC40A1 polymorphisms. Interestingly, 35/79 individuals with SLC40A1 SNPs also carried a TMPRSS6 c.2207T>C polymorphism. The biochemical values of the iron overloaded individuals were compared to those of the individuals carrying TMPRSS6 SNPs and the healthy individuals (wild-type group). The ferritin concentration, transferrin saturation % (TS%), and hemoglobin concentration were significantly higher in the participants with FPN SNPs than in the other three groups. The ferritin concentration and TS% were higher in participants with both SLC40A1 and TMPRSS6 SNPs than in the TMPRSS6 and wild-type groups, while hemoglobin concentration was significantly higher than that in the TMPRSS6 SNP group only. The participants with TMPRSS6 SNPs had significantly lower ferritin concentration, TS%, and hemoglobin concentration than all the other groups. SLC40A1 and TMPRSS6 SNPs might act in the opposite direction, preventing the development of severe iron overload, and the modulation of the iron status by TMPRSS6 SNPs might provide protection.
Associated Effect of SLC40A1 and TMPRSS6 Polymorphisms on Iron Overload
by Lorena Duca * , Francesca Granata , Elena Di Pierro , Valentina Brancaleoni , Giovanna Graziadei and Isabella Nava
Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, U.O.C. Medicina Generale, 20122 Milano, Italy
Author to whom correspondence should be addressed.
Metabolites 2022 , 12 (10), 919; https://doi.org/10.3390/metabo12100919
Received: 10 August 2022 / Revised: 15 September 2022 / Accepted: 27 September 2022 / Published: 29 September 2022
(This article belongs to the Special Issue Advances in Iron Metabolism and Anemia )
Abstract
:
Mutations in the ferroportin (FPN) gene
SLC40A1
alter iron recycling and cause disturbances in iron homeostasis. The variants of
TMPRSS6
contribute to the development of iron deficiencies. In this study, we determined the role of FPN and
TMPRSS6
gene polymorphisms in the modulation of iron homeostasis based on biochemical parameters. PCR analysis and sequencing were performed to determine the single nucleotide polymorphisms (SNPs)
SLC40A1
c.44–24G>C (rs1439816),
c.663T>C (rs2304704), and
TMPRSS6
c.2207T>C (rs855791). Hemoglobin concentration and iron status were determined by standard procedures. We studied 79 iron-loaded individuals for
SLC40A1
polymorphisms. Interestingly, 35/79 individuals with
SLC40A1
SNPs also carried a
TMPRSS6
c.2207T>C polymorphism. The biochemical values of the iron overloaded individuals were compared to those of the individuals carrying
TMPRSS6
SNPs and the healthy individuals (wild-type group). The ferritin concentration, transferrin saturation % (TS%), and hemoglobin concentration were significantly higher in the participants with FPN SNPs than in the other three groups. The ferritin concentration and TS% were higher in participants with both
SLC40A1
and
TMPRSS6
SNPs than in the
TMPRSS6
and wild-type groups, while hemoglobin concentration was significantly higher than that in the
TMPRSS6
SNP group only. The participants with
TMPRSS6
SNPs had significantly lower ferritin concentration, TS%, and hemoglobin concentration than all the other groups.
SLC40A1
and
TMPRSS6
SNPs might act in the opposite direction, preventing the development of severe iron overload, and the modulation of the iron status by
TMPRSS6
SNPs might provide protection.
Keywords:
SLC40A1
;
TMPRSS6
;
ferroportin
;
matriptase-2
;
iron
;
iron overload
;
iron deficiency
;
hemoglobin
;
ferritin
;
transferrin saturation
1. Introduction
Iron homeostasis is fundamental for maintaining biological functions in humans and involves the interplay between iron supply from duodenal absorption, macrophage recycling, and liver storage and iron requirements for oxygen transport, the immune system, and cognitive functions. Although iron is biologically essential, it can also be potentially toxic at high levels. Thus, it is tightly regulated at the cell and systemic levels to prevent both deficiency and overload [
1
]. The liver peptide hepcidin is the master regulator of systemic iron homeostasis. It controls serum iron by degrading ferroportin (FPN) in iron-absorptive enterocytes and iron-recycling macrophages [
2
]. Sub-optimal production of hepcidin or dysregulation of the hepcidin–FPN axis can lead to iron overload.
The active form of hepcidin functions by binding to its FPN receptor specifically expressed on the basolateral membrane of duodenal enterocytes, the membrane of splenic macrophages that recycle iron in red blood cells, and the membrane of hepatocytes. After FPN is bound by hepcidin, it is internalized and degraded; this inhibits the release of circulating iron. The expression of hepcidin is driven by changes in the levels of circulating and tissue iron.
Ferroportin is encoded by the SLC40A1 gene that localizes on chromosome 2 (2q32) [ 3 ]. The highly conserved protein FPN, also known as IREG1 or MTP1, which plays a key role in elemental iron acquisition and transfer, was simultaneously discovered by three separate groups [ 4 ]. The protein consists of 571 amino acid residues with 12 transmembrane domains and both cytosolic N- and C-termini [ 5 ].
Mutations in the FPN gene impair iron recycling and affect iron homeostasis. Ferroportin disease, also described as hereditary hemochromatosis Type IV, HFE 4 (Online Mendelian Inheritance in Man, OMIM number 606069), unlike classical hereditary hemochromatosis, is an autosomal dominant disorder characterized by iron accumulation in macrophages of the reticuloendothelial system [ 6 ], and FPN gene knockout in the duodenum impairs iron absorption [ 7 ].
Ferroportin disease is a clinically heterogeneous iron overload syndrome. The canonical form, presenting as hepatic and spleen iron overload, is characterized by hyperferritinemia, normal to low transferrin saturation, and Kupffer cell iron storage [ 8 ]. Additionally, increased transferrin saturation, hepatocellular iron overload, hyperferritinemia, and macrophage iron loading are considered to be typical features of the non-classical phenotype [ 8 ].
Most patients presenting classical hemochromatosis are homozygous for the missense mutation c.845G>A (C282Y) in the HFE gene, but due to incomplete penetrance of this genotype and other environmental or genetic factors, a wide spectrum of phenotypic expression occurs for the c.845G>A homozygous condition. Diet, alcohol, gender, and viral hepatitis influence the clinical presentation of hemochromatosis [ 3 ]. Several studies were conducted to determine the role of putative genetic modifiers in iron overload and found that the ferroportin gene polymorphic variants play a key role.
Altès et al. [ 9 ] studied hemochromatosis patients with the classical HFE homozygous mutation and the c.44–24G>C SLC40A1 polymorphism (rs1439816) and associated this FPN gene polymorphism with the amount of iron overload, the presence of liver disease, and, consequently, clinical aggressiveness. In another study, the presence of at least one C allele of the c.44–24G>C SLC40A1 polymorphism was found to modulate the biochemical phenotype, specifically serum iron and transferrin saturation, in classical hemochromatosis patients [ 10 ].
Another study on patients from the South African population identified significant associations between c.44–24G>C and c.663T>C SLC40A1 polymorphisms and iron overload [ 11 ]. The c.44–24G>C SNP, located in the 5′ untranslated region within 24 nucleotides upstream of the start of exon 2, affects the splicing machinery, as shown by the in silico analysis conducted using Mutation Taster ( https://www.mutationtaster.org (accessed on 9 August 2022)). The c.663T>C polymorphism classified as rs2304704 (also known as V221V) does not change the amino acid sequence in the protein but alters the splice site, as determined by prediction tools ( https://www.mutationtaster.org (accessed on 9 August 2022)).
Interestingly, the allelic frequencies of the c.44–24G>C and c.663T>C SLC40A1 SNPs were found to be significantly higher in Italian blood donors with mild-to-moderate iron overload compared to the control group. This supported the idea that polymorphisms in the ferroportin gene are important contributors to iron storage and load in apparently healthy subjects [ 12 ].
Several studies on disorders of iron metabolism indicated the existence of a genetic contribution to the development of iron deficiency [ 13 ]. Specifically, the Trans-Membrane Protease Serine 6 ( TMPRSS6 , gene locus c. 22q12.3) that encodes matriptase-2 expressed by the liver influences iron metabolism in humans and other animals.
TMPRSS6
is an essential regulator of iron homeostasis, as it represents a physiological suppressor of hepcidin.
TMPRSS6
mutations cause iron refractory iron deficiency anemia (IRIDA) (OMIM number 206200) due to an increase in the concentrations of hepcidin, which degrades intestinal ferroportin and prevents normal iron absorption [
14
]. Familial and sporadic cases of IRIDA have been described in individuals of different ages with different types of
TMPRSS6
mutations and different clinical presentations. These may range from severe anemia with a parenteral iron requirement in infancy to isolated microcytosis and low transferrin saturation with unremarkable anemia in adulthood [
15
,
16
].
The expression of matriptase-2 can be modulated by the iron status [ 17 ]. In rats under acute iron deprivation, hepatic matriptase-2 protein levels are upregulated to repress hepcidin production [ 18 ]. Some studies have also found that the expression of the TMPRSS6 mRNA is suppressed by inflammation [ 19 ] and upregulated by hypoxia [ 20 , 21 ] and erythropoietin [ 22 ].
TMPRSS6 polymorphisms are associated with the risk of developing iron deficiency anemia (IDA) in individuals of European and Asian ancestry [ 23 ]. One of the principal TMPRSS6 polymorphisms analyzed was c.2207T>C (rs855791) in exon 17. This polymorphism is responsible for a missense variant that substitutes the amino acid 736 valine with alanine (V736A), and it was first reported by Chambers et al. [ 24 ]. Its allelic frequency varies between 34% and 63%, depending on the studied population [ 25 ]. The c.2207T>C polymorphism was shown to be associated with lower hemoglobin levels, mean corpuscular volume (MCV), and serum iron in genome-wide association studies on general adult populations [ 26 , 27 ]. Additionally, in other concomitant pathologies, such as thalassemia, this polymorphism negatively influences the capability of iron store repletion, the degree of anemia, and the response to oral iron supplementation. Finally, the polymorphism was hypothesized to be a potential risk factor in conditions of iron malabsorption (i.e., celiac disease) [ 28 ] or iron loss in fertile women [ 29 ].
The aim of this study was to elucidate the role of polymorphisms in genes that encode FPN and matriptase-2 in the modulation of iron balance in the body by observing biochemical parameters in individuals with mild-to-severe iron overload, not due to genetic hemochromatosis, metabolic diseases, transfusion-dependent pathologies, or xenobiotic factors.
2. Materials and Methods
2.1. Study Population
Peripheral blood samples were collected from 161 individuals (mean age 44 ± 16 years). The study was conducted following the Word Medical Association’s Declaration of Helsinki for Medical Research. All participants signed a form providing informed consent for the diagnosis and research approved by the ethics committee of Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico of Milan (Italy). The identity of the participants was not revealed.
2.2. Collection of DNA Samples
Genomic DNA was extracted from the lymphomonocytes of peripheral blood samples using the Maxwell ® 16 SEV Blood DNA Purification Kit (Catalog No. AS1010 Promega, Madison, WI, USA) following the manufacturer’s instructions. The DNA samples were stored at −20 °C until use.
2.3. Genotyping for Common Polymorphisms in Ferroportin and Matriptase-2 Genes
Classical PCR and sequencing techniques were used to analyze the entire coding regions of SLC40A1 and TMPRSS6 . The primers used for conducting PCR and cycle sequencing of the exons containing the studied SNPs are listed in Table 1 . Direct sequencing was performed using the BigDye Terminator Cycle Sequencing Ready Reaction Kit v3.1 for AbiPrism 310 Genetic Analyzer (Applied Biosystems, Life Technologies Corporation, Carlsbad, CA, USA). The tested polymorphisms included SLC40A1 c.44–24G>C (rs1439816), SLC40A1 c.663T>C (rs2304704), and TMPRSS6 c.2207T>C (rs855791).
2.4. Biochemical Analyses
Full blood panel, hemoglobin levels, and iron status (serum iron, transferrin, TS%, and ferritin) were analyzed following the standard diagnostic laboratory procedures of Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico.
2.5. Statistical Analysis
To determine the differences between the groups, a one-way ANOVA test was performed. The differences were considered to be statistically significant at p < 0.05. All analyses were conducted using GraphPad Prism.
Fisher’s exact test was conducted to verify the association between the simultaneous presence of SLC40A1 and TMPRSS6 SNPs and the serum ferritin concentration below 200 μg/L in this iron overload cohort.
A sample size of 12 was calculated to provide 95% power to the study (α error of 0.01).
3. Results
3.1. Patients
The patients (48 ± 17 years, n = 79) who were diagnosed with iron overload were examined for SLC40A1 c.44–24G>C (rs1439816) and c.663T>C (rs2304704) polymorphisms after they were excluded as carriers of genetic hemochromatosis, metabolic diseases, transfusion-dependent pathologies, other possible causes of secondary iron overload, liver disease, and inflammation. None of them had unusual dietary habits or consumed abnormal levels of ethanol that could explain their iron overload. As some individuals showed borderline values for ferritin or TS% even though they were not subdued to phlebotomy or chelation therapy, we investigated all subjects for the TMPRSS6 c.2207T>C SNP (rs855791), which is associated with the risk for the development of IDA [ 23 ].
3.2. Genetic Analysis
Of the 79 patients presenting iron overload, 44 had SLC40A1 polymorphisms only, 19 showed one of the two polymorphisms in homozygosis or heterozygosis, and 25 showed both polymorphisms. Additionally, 35 individuals with SLC40A1 polymorphisms also carried the TMPRSS6 c.2207T>C SNP ( Table 2 and Table 3 ).
For every SNP studied, the allelic frequencies were analyzed, and the obtained data were compared to the allelic frequencies obtained from the most important projects on common human genetic variations ( Table 4 ). The allelic frequencies of SLC40A1 SNPs in our study were similar to those of the 1000 Genomes, ALFA, and TOPMED projects. The allelic frequency of TMPRSS6 c. 2207T>C in our study was lower than that reported in the resources on human genetic variation, as expected in a selected population for iron overload.
3.3. Biochemical Analysis
The biochemical parameters of all 79 participants were evaluated, and the results were as follows: ferritin 443 ± 47 μg/L, TS% 34.0 ± 2.0%, and hemoglobin 13.2 ± 0.2 g/dL (values are expressed as the mean ± standard error).
These participants were then divided into two groups based on their genotypes. The first group only consisted of
SLC40A1
SNP carriers, while the second group consisted of individuals with both
SLC40A1
and
TMPRSS6
polymorphisms.
The obtained data were compared to the biochemical parameters of a previously studied group of 47 patients who lacked variants in the
SLC40A1
gene and carried the
TMPRSS6
c.2207T>C SNP, 22 of whom exhibited homozygosis, and 25 exhibited heterozygosis. These patients were referred to the Rare Disease Centre of Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico of Milan (Italy) for persistent IDA without celiac disease, gastrointestinal bleeding, or
Helicobacter pylori
infection.
Additionally, 35 healthy participants with wild-type genotypes for the two investigated genes were selected, and they were matched for sex and age and included in the control group for total blood count and iron parameters.
The ferritin concentration, TS%, and hemoglobin concentrations were significantly higher in the participants carrying only FPN gene polymorphisms than in the other three groups. The ferritin concentration and TS% were significantly higher in the participants with both
SLC40A1
and
TMPRSS6
SNPs than in the participants with
TMPRSS6
SNPs and the healthy participants (wild-type); furthermore, the hemoglobin concentration was significantly higher than that in the participants with the
TMPRSS6
polymorphism only. The ferritin concentration, TS%, and hemoglobin concentration were significantly lower in the participants with
TMPRSS6
SNPs only than in the participants of all other groups (all
p
-values are reported in
Table 5
and its caption).
The results of Fisher’s exact test showed that the simultaneous presence of
SLC40A1
and
TMPRSS6
SNPs was strongly associated with serum ferritin concentration below 200 μg/L in this iron overload cohort (
p
< 0.00001; α error of 0.01).
4. Discussion
The regulation of ferroportin expression is complex, with strictly controlled mechanisms at the transcriptional, post-transcriptional, and post-translational levels. This indicates that the control of systemic iron flux under different conditions is flexible [ 30 ]. In this study, the high variability of the FPN gene was observed in a group of 79 patients without HFE mutations or secondary causes of iron overload but presenting alterations in TS% and serum ferritin levels. Specifically, among 44 carriers of SLC40A1 SNPs only, 19 individuals showed SLC40A1 c.44–24G>C or c.663T>C SPNs in homozygosis or heterozygosis, and 25 showed both polymorphisms. Their iron overload parameters were significantly higher than those in the control group of healthy individuals (wild-type) for the studied genes. These observations were consistent with the findings of previous studies, where it was shown that the polymorphic variants of SLC40A1 c.44–24G>C (rs1439816) and c.663T>C (rs2304704) had a significant effect on iron metabolism and could explain the considerable unrelated HFE phenotypic variability that might exist in iron overload [ 9 , 12 ]. Moreover, 35 of the 79 individuals carried SLC40A1 SNPs and the TMPRSS6 c.2207T>C polymorphism together. Ferritin concentrations and TS% were significantly lower in these individuals than in the carriers of SLC40A1 SNPs only and higher than in the individuals carrying the TMPRSS6 SNP only and the healthy individuals (wild-type). Additionally, the iron and hemoglobin parameters were significantly lower in participants carrying the TMPRSS6 SNPs only than in the individuals carrying the SLC40A1 SNPs, the SLC40A1 and TMPRSS6 SNPs, and the healthy participants (wild-type). These results were similar to those of genome-wide association studies, where it was shown that the TMPRSS6 c.2207T>C polymorphism is associated with lower transferrin saturation, hemoglobin concentration, and MCV levels in the general adult population [ 26 , 31 ]. Based on the findings in this study, we detected an intermediate iron status phenotype in individuals carrying both SLC40A1 polymorphisms and TMPRSS6 c.2207T>C SNP relative to the participants carrying either SLC40A1 or TMPRSS6 SNP only. TMPRSS6 , which codes for matriptase-2, and SLC40A1 , which codes for ferroportin, are upstream and downstream of hepcidin production, respectively. Hence, alterations in the function of matriptase-2 might lead to insufficient downregulation of hepcidin expression and increased internalization of ferroportin. On the other hand, modifications of the ferroportin protein prevent its internalization and destruction by hepcidin, causing iron overload. Therefore, based on the mechanism of action and regulation of hepcidin and the presence of an intermediate iron status phenotype in individuals carrying both SLC40A1 and TMPRSS6 SNPs, our results support the hypothesis that SLC40A1 and TMPRSS6 SNPs modulate iron homeostasis by acting in the opposite direction and preventing a severe iron overload. Moreover, the TMPRSS6 c.2207T>C SNPs might protect individuals carrying variants in genes responsible for iron overload by modulating iron homeostasis.
Author Contributions
L.D. designed the study, performed statistical analysis, and wrote the manuscript. I.N. performed the genotyping, prepared the tables, and wrote the manuscript. F.G. and E.D.P. supervised the manuscript. V.B. was involved in the visualization of the manuscript. G.G. was involved in the management of studied subjects. All authors have read and agreed to the published version of the manuscript.
Funding
This study was supported by the Italian ministry of health with the RC2022 grant.
Institutional Review Board Statement
The study was conducted following the guidelines of the Declaration of Helsinki (Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milano P.704.500.G of 21-03-2019).
Informed Consent Statement
Informed written consent for the diagnosis and research, approved by the ethics committee of the institution, was signed by all participants.
Data Availability Statement
Conflicts of Interest
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Table 1. The list of primer sequences and annealing temperatures for PCR and sequencing used for detecting the studied polymorphisms.
Table 1. The list of primer sequences and annealing temperatures for PCR and sequencing used for detecting the studied polymorphisms.
Gene Polymorphism Primer Sequences (Forward and Reverse) Amplicon Length (bp) Annealing Temperature (°C) SLC40A1 c.44–24G>C (rs1439816) 5′-GTGGGCAGAGCAGGAGAGAAG-3′ 5′-GATGTGAGCAAAGGGCCAGAC-3′ 371 61 SLC40A1 c.663T>C (rs2304704) 5′-AACGAAATACATCGGTTCATAGG-3′ 5′-ATTAAAGCATGTGTACTTGGATG-3′ 495 58 TMPRSS6 c.2207T>C (rs855791) 5′-GGAATCTATACTCTTGGTTTACAG-3′ 5′-CTTGCCTCGTCTACCAAAGCG-3′ 337 61
Table 2. The number and genotype percentage of participants carrying SLC40A01 only. The genotype percentage is given in brackets.
Table 2. The number and genotype percentage of participants carrying SLC40A01 only. The genotype percentage is given in brackets.
Genotype of Subjects Carrying Only SLC40A1 Polymorphism: 44 (100) c.[44–24G>C];[44–24G>C] 3 (6.8) c.[44–24G>C];[=] 2 (4.5) c.[663T>C];[663T>C] 7 (16) c.[663T>C];[=] 7 (16) c.[44–24G>C];[44–24G>C] c.[663T>C];[663T>C] 9 (20.4) c.[44–24G>C];[44–24G>C] c.[663T>C];[=] 14 (32) c.[44–24G>C];[=] c.[663T>C];[663T>C] 0 (0) c.[44–24G>C];[=] c.[663T>C];[=] 2 (4.5)
Table 3. The number and genotype percentage of participants carrying both SLC40A01 and TMPRSS6 SNPs. The genotype percentage is given in brackets.
Table 3. The number and genotype percentage of participants carrying both SLC40A01 and TMPRSS6 SNPs. The genotype percentage is given in brackets.
Genotype of Subjects Carrying Both SLC40A1 and TMPRSS6 Polymorphisms: 35 (100) TMPRSS6 c.[2207T>C];[2207T>C] c.[2207T>C];[=] SLC40A1 c.[44–24G>C];[44–24G>C] 1 (2.9) 2 (5.7) c.[44–24G>C];[=] 0 (0) 1 (2.9) c.[663T>C];[663T>C] 0 (0) 1 (2.9) c.[663T>C];[=] 0 (0) 0 (0) c.[44–24G>C];[44–24G>C] c.[663T>C];[663T>C] 4 (11.2) 5 (14.3) c.[44–24G>C];[44–24G>C] c.[663T>C];[=] 7 (20.0) 9 (25.7) c.[44–24G>C];[=] c.[663T>C];[663T>C] 0 (0) 1 (2.9) c.[44–24G>C];[=] c.[663T>C];[=] 3 (8.6) 1 (2.9)
Table 4. The allelic frequencies of the analyzed SNPs in the studied population compared to those in the 1000 Genomes, ALFA, and TOPMED projects.
Table 4. The allelic frequencies of the analyzed SNPs in the studied population compared to those in the 1000 Genomes, ALFA, and TOPMED projects.
Polymorphisms Study Population 1000 Genomes Study Global Population ALFA Project Total Population TOPMED Program SLC40A1 c.44–24G>C rs1439816 G 0.74683 G = 0.6595 G = 0.78005 G = 0.682670 C 0.25317 C = 0.3405 C = 0.21995 C = 0.317330 SLC40A1 c.663T>C rs2304704 T 0.38608 T = 0.4499 T = 0.392810 T = 0.477706 C 0.61392 C = 0.5501 C = 0.607190 C = 0.522294 TMPRSS6 c.2207T>C rs855791 T 0.6835 T = 0.3954 T = 0.439967 T = 0.361479 C 0.3165 C = 0.6046 C = 0.560033 C = 0.638521
Table 5. Biochemical parameters of the individuals carrying SLC40A1 (44–24G>C and/or 663T>C) polymorphisms only, indicated as SLC40A1 , both SLC40A1 and TMPRSS6 c.2207T>C SNPs ( SLC40A1 and TMPRSS6 ), and only TMPRSS6 c.2207T>C polymorphism ( TMPRSS6 ), compared to the wild-type healthy group of participants (Wild-type).
Table 5. Biochemical parameters of the individuals carrying SLC40A1 (44–24G>C and/or 663T>C) polymorphisms only, indicated as SLC40A1 , both SLC40A1 and TMPRSS6 c.2207T>C SNPs ( SLC40A1 and TMPRSS6 ), and only TMPRSS6 c.2207T>C polymorphism ( TMPRSS6 ), compared to the wild-type healthy group of participants (Wild-type).
Polymorphisms Number of Subjects Serum Ferritin (μg/L) Transferrin Saturation % Hemoglobin (g/dL) SLC40A1 44 702 ± 57 * 40.2 ± 2.2 ^ 13.5 ± 0.2 •#° SLC40A1 and TMPRSS6 35 108 ± 23 °# 25.7 ± 2.9 °# 12.8 ± 0.4 ° TMPRSS6 47 8 ± 1 √ 7.1 ± 0.7 √ 10.5 ± 0.3 ∞ Wild-type 35 49 ± 7 19.6 ± 1.4 12.5 ± 0.2
| https://www.mdpi.com/2218-1989/12/10/919/xml |
Citalopram and Dexetimide and Escitalopram 10mg in Depression - Clinical Trials Registry - ICH GCP
Evaluate the therapeutic effects of Escitalopram versus an association of Escitalopram + Trichilia catigua Dry Extract (LABCAT TCJUSS) in the average alteration...
Study to Evaluate the Efficacy of LABCAT TCJUSS in Patients With Depressive Episode (LABCATTCJUSS)
Evaluate the therapeutic effects of Escitalopram versus an association of Escitalopram + Trichilia catigua Dry Extract (LABCAT TCJUSS) in the average alteration on depression score measured by the Hamilton Scale (HAM-D).
Study Overview
Status
Terminated
Conditions
Depression
Intervention / Treatment
Drug: Escitalopram 10mg
Drug: LABCAT TCJUSS
Drug: LABCAT TCJUSS Placebo
Drug: Escitalopram Placebo
Detailed Description
Evaluate the therapeutic effects of Escitalopram versus an association of Escitalopram + LABCAT TCJUSS in the following aspects:
Alteration on the average score of anhedonia symptoms through the Shaps-C Scale;
Alteration of average scores of Global Clinical Impression carried out by the investigator (CGI-S e CGI-I);
Average scores of the Patient Global Evaluation
Study Type
Interventional
Enrollment (Actual)
111
Phase
Phase 3
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Locations
Brazil
Ceará
Fortaleza, Ceará, Brazil, 60430-275
Unidade de Farmacologia Clínica (UNIFAC - Universidade Federal do Ceará)
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
18 years to 65 years (Adult, Older Adult)
Accepts Healthy Volunteers
No
Genders Eligible for Study
All
Description
Inclusion Criteria:
Subjects from both sexes aged between 18 and 65 years;
Patient diagnosed with mild depression episode confirmed by psychiatric and psychometric evaluation, presenting basal scores above 08 and below 24 measured by the Hamilton Rating Scale (HAM-D);
Capable of understanding the nature and objective of the study, including risks and adverse effects and intended to cooperate with the researcher and act in accordance with the requirements of the entire protocol, which comes to be confirmed by signing the informed consent.
Exclusion Criteria:
Have a known hypersensitivity to Trichilia catigua or history of serious adverse reactions;
Shows risk of suicide, assault, murder or moral exposure;
Clinical history of bleeding disorders;
Drug addiction, including alcohol;
Known or suspected neoplasia;
Knowledge positive test result for the human immunodeficiency virus;
Patient not willing to adhere to the procedures of the Protocol;
For women, can not be pregnant or nursing and must be in use of a contraception method during the participation in the study;
Patients using other drugs with sedative or antidepressant action, which can not be suspended for 15 days (wash out);
Diabetics;
Hyperthyroidism;
Participation in any experimental study or use of any experimental drug three months before the start of this study;
Has any condition which the investigator deems relevant to the non-participation of the study.
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 : Triple
3
Arms and Interventions
Participant Group / Arm Intervention / Treatment Experimental: Escitalopram + LABCAT TCJUSS Escitalopram 10mg + LABCAT TCJUSS 1000 mg daily (two 250mg capsules in the morning + 2 capsules of 250 mg at night); Drug: Escitalopram 10mg Escitalopram 10mg (1 pill once a day) Drug: LABCAT TCJUSS LABCAT TCJUSS 1000mg daily (two 250mg capsules in the morning + 2 capsules of 250 mg at night) Placebo Comparator: Escitalopram + LABCAT TCJUSS placebo Escitalopram 10mg + LABCAT TCJUSS placebo daily (2 capsules in the morning + 2 capsules at night); Drug: Escitalopram 10mg Escitalopram 10mg (1 pill once a day) Drug: LABCAT TCJUSS Placebo LABCAT TCJUSS placebo daily (2 capsules in the morning + 2 capsules at night); Experimental: Escitalopram Placebo + LABCAT TCJUSS Escitalopram Placebo + LABCAT TCJUSS 1000 mg daily (2 capsules in the morning + 2 capsules at night). Drug: LABCAT TCJUSS LABCAT TCJUSS 1000mg daily (two 250mg capsules in the morning + 2 capsules of 250 mg at night) Drug: Escitalopram Placebo Escitalopram Placebo (1 pill once a day)
What is the study measuring?
Primary Outcome Measures
Outcome Measure Measure Description Time Frame HAM-D SCORE REDUCTION Time Frame: WEEKS 2 (Visit 2), 4 (Visit 3), 8 (Visit 4) and 10 (Visit 5) A comparison will be performed between groups in mean reduction in the HAM-D score between baseline (V1-D1) and at weeks 2 (V2), 4 (V3), 8 (V4) and 10 (V5) treatment, following the primary and secondary described outcomes. WEEKS 2 (Visit 2), 4 (Visit 3), 8 (Visit 4) and 10 (Visit 5)
Secondary Outcome Measures
Outcome Measure Time Frame Evaluation of symptoms of anhedonia by the change in mean score of Shaps-C scale of pleasure Time Frame: WEEKS 2 (Visit 2), 4 (Visit 3), 8 (Visit 4) and 10 (Visit 5) WEEKS 2 (Visit 2), 4 (Visit 3), 8 (Visit 4) and 10 (Visit 5) Change in mean scores of Clinical Global Impression performed by the investigator (CGI-I - Improvement) Time Frame: WEEKS 2 (Visit 2), 4 (Visit 3), 8 (Visit 4) and 10 (Visit 5) WEEKS 2 (Visit 2), 4 (Visit 3), 8 (Visit 4) and 10 (Visit 5) Change in mean scores of Clinical Global Impression performed by the investigator (CGI-S - Severity) Time Frame: WEEKS 2 (Visit 2), 4 (Visit 3), 8 (Visit 4) and 10 (Visit 5) WEEKS 2 (Visit 2), 4 (Visit 3), 8 (Visit 4) and 10 (Visit 5) Change in mean scores of Global Patient Evaluation scale Time Frame: WEEKS 2 (Visit 2), 4 (Visit 3), 8 (Visit 4) and 10 (Visit 5) WEEKS 2 (Visit 2), 4 (Visit 3), 8 (Visit 4) and 10 (Visit 5) Change in mean scores of the of Arizona Sexual Experiences scale (ASEX) Time Frame: WEEKS 2 (Visit 2), 4 (Visit 3), 8 (Visit 4) and 10 (Visit 5) WEEKS 2 (Visit 2), 4 (Visit 3), 8 (Visit 4) and 10 (Visit 5)
Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Sponsor
Laboratório Catarinense SA
Collaborators
Financiadora de Estudos e Projetos
Universidade Federal do Ceara
Investigators
Principal Investigator: Maria Elisabete Moraes, Universidade Federal do Ceara (UFC)
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 (Actual)
July 2, 2018
Primary Completion (Actual)
June 1, 2022
Study Completion (Actual)
June 1, 2022
Study Registration Dates
First Submitted
August 23, 2015
First Submitted That Met QC Criteria
August 25, 2015
First Posted (Estimate)
August 26, 2015
Study Record Updates
Last Update Posted (Actual)
June 16, 2022
Last Update Submitted That Met QC Criteria
June 13, 2022
Last Verified
June 1, 2022
Parasympatholytics
Autonomic Agents
Peripheral Nervous System Agents
Muscarinic Antagonists
Cholinergic Antagonists
Cholinergic Agents
Psychotropic Drugs
Serotonin Uptake Inhibitors
Neurotransmitter Uptake Inhibitors
Membrane Transport Modulators
Serotonin Agents
Antidepressive Agents
Antidepressive Agents, Second-Generation
Antiparkinson Agents
Anti-Dyskinesia Agents
Citalopram
Dexetimide
Other Study ID Numbers
Laboratório Catarinense Ltda
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
No
Studies a U.S. FDA-regulated device product
No
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Epilepsy
Anxiety
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| https://ichgcp.net/clinical-trials-registry/NCT02532660 |
Examples of archaeological human tooth and bone samples and their... | Download Scientific Diagram
Download scientific diagram | Examples of archaeological human tooth and bone samples and their suitability for aDNA research. a-d: fresh-looking, intact samples with smooth surfaces have a good potential for aDNA research; in the case of bones (c, d), the periosteum should be dense and compact. e-h: evidence of mineral alteration and/or microbial attack (low density, dull surface, crumbly broken ends) usually indicates a poor preservation of aDNA. from publication: From the field to the laboratory: Controlling DNA contamination in human ancient DNA research in the high-throughput sequencing era | High-Throughput DNA Sequencing (HTS) technologies have changed the way in which we detect and assess DNA contamination in ancient DNA studies. Researchers use computational methods to mine the large quantity of sequencing data to detect characteristic patterns of DNA damage,... | DNA Contamination, Ancient DNA and High Throughput Sequencing | ResearchGate, the professional network for scientists.
Examples of archaeological human tooth and bone samples and their suitability for aDNA research. a-d: fresh-looking, intact samples with smooth surfaces have a good potential for aDNA research; in the case of bones (c, d), the periosteum should be dense and compact. e-h: evidence of mineral alteration and/or microbial attack (low density, dull surface, crumbly broken ends) usually indicates a poor preservation of aDNA.
From the field to the laboratory: Controlling DNA contamination in human ancient DNA research in the high-throughput sequencing era
High-Throughput DNA Sequencing (HTS) technologies have changed the way in which we detect and assess DNA contamination in ancient DNA studies. Researchers use computational methods to mine the large quantity of sequencing data to detect characteristic patterns of DNA damage, and to evaluate the authenticity of the results. We argue that unless comp...
Contexts in source publication
Context 1
... visual factors can indicate good macroscopic preservation, and high chances of endogenous DNA survival. For example, fresh-looking compact bones or bone fragments with smooth and intact surfaces are indicators for good macroscopic preservation (
Figure 2
). The weight of the skeletal element may also indicate good preservation, but requires (c, d), the periosteum should be dense and compact. ...
Context 2
... to bone sampling, smooth and intact sur- faces are indicators for good macroscopic preservation (
Figure 2
). Tooth extractions should be preferably per- formed with gloved fingers, by repeated gentle side- to-side movements. ...
Present‐Day DNA Contamination in Ancient DNA Datasets
Present‐day contamination can lead to false conclusions in ancient DNA studies. A number of methods are available to estimate contamination, which use a variety of signals and are appropriate for different types of data. Here an overview of currently available methods highlighting their strengths and weaknesses is provided, and a classification bas...
Citations
... Unfortunately, ancient DNA (aDNA) extracted from bone remains is scarce, highly degraded, and highly susceptible to exogenous contamination which can affect the reliability of aDNA studies [4,5]. Contamination of the aDNA can be avoided both by following the minimum guidelines during the excavation and collection of the samples and during the subsequent manipulation; aDNA should be manipulated in specialized structures and with rigorous protocols [6,
7]
. Studies aimed at identifying the degree of DNA degradation involve numerous research fields: cytotoxicity, cancer, forensic analysis, and aDNA studies. ...
... The excavation and recovery of the archaeological remains were carried out following a protocol to prevent possible contamination of the bone remains with modern DNA [33]. The samples selected for DNA extraction were treated as in previous works
[7,
34]. The bone remains come from three intact graves (S.46, S.48, and S.50) and from two reworked but well-preserved graves (S.44 and S.45). ...
... The extraction of aDNA was carried out following the guidelines for the analysis of human skeletal remains to prevent environmental contamination. The experiments were conducted in two separate laboratories, one pre-PCR and one post-PCR, equipped with dedicated equipment [6,
7]
. The bone powder samples have been prepared in the pre-PCR laboratory by milling a small area of bone findings [34]. ...
Estimation of DNA Degradation in Archaeological Human Remains
... The total number of false nucleotides present in a reconstructed genome depends on the amount of sequencing data obtained and postmortem DNA damage and whether or not DNA was pre-treated with a mixture of uracil-DNA glycosylase (UDG) and endonuclease VIII (the mixture makes it possible to remove uracil with the formation of a single-nucleotide gap) during the preparation of genomic libraries
[10]
... Capillary electrophoresis (CE) analysis of PCR (polymerase chain reaction) products is the gold standard approach in forensics [3,5], whereas MPS (massive parallel sequencing) is an emerging promising technology in the typing of low-template degraded samples [10][11][12]. Although high-throughput shotgun sequencing and the analysis of genome-wide data have largely replaced current PCR-based methods in ancient DNA (aDNA) analysis [1,2,13], there are many aspects that aDNA analysis and forensic DNA analysis have in common; for instance, the use of limited amounts of degraded DNA, the precautions adopted to prevent contamination, and the use of authenticity criteria [14][15][16][17]
[18]
[19][20]. In addition, both disciplines have developed strategies to select the skeletal element which provides, a priori, the highest probabilities of positive outcomes [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37]. ...
[18]
[19]47]. For the elimination database, buccal swabs were obtained after informed consent from all personnel involved in these operations, as well in the molecular analyses. ...
The Baron Pasquale Revoltella’s Will in the Forensic Genetics Era
Carlo Previderè
Serena Bonin
Solange Sorçaburu Ciglieri
Irena Zupanič Pajnič
In this article, we describe multiple analytical strategies that were first developed for forensic purposes, on a set of three bone samples collected in 2011. We analyzed a single bone sample (patella) collected from the artificially mummified body of the Baron Pasquale Revoltella (1795–1869), as well two femurs which allegedly belonged to the Baron’s mother (Domenica Privato Revoltella, 1775–1830). Likely due to the artificial mummification procedures, the inner part of the Baron’s patella allowed the extraction of high-quality DNA yields, which were successfully used for PCR-CE and PCR-MPS typing of autosomal, Y-specific, and mitochondrial markers. The samples extracted from the trabecular inner part of the two femurs yielded no typing results by using the SNP identity panel, whereas the samples extracted from the compact cortical part of the same bone samples allowed genetic typing, even by the employment of PCR-CE technology. Altogether, 10/15 STR markers, 80/90 identity SNP markers, and HVR1, HVR2, and HVR3 regions of the mtDNA were successfully typed from the Baron’s mother’s remains by the combined use of PCR-CE and PCR-MPS technologies. The kinship analysis showed a likelihood ratio of at least 9.1 × 106 (corresponding to a probability of maternity of 99.9999999%), and thus confirmed the identity of the skeletal remains as those of the Baron’s mother. This casework represented a challenging trial for testing forensic protocols on aged bones samples. It highlighted the importance of accurately sampling from the long bones, and that DNA degradation is not blocked by freezing at −80 °C.
... This review will predominantly, but not exclusively, focus on evidence for infectious diseases in the Pleistocene that has been gained from high-throughput and metagenomic sequencing efforts of pathogen and host. While approaches such as polymerase chain reaction (PCR), quantitative PCR (qPCR) and short-fragment sequencing have been used to great effect in many studies of ancient infectious diseases, they typically do not have the same agreed criteria for ancient DNA authentication, which have been reviewed in detail elsewhere (Key et al., 2017;
Llamas et al., 2017;
Salter et al., 2014;Warinner et al., 2017). PCR and short-fragment sequencing also convey different information to high-throughput sequencing and metagenomics. ...
Infectious disease in the Pleistocene: Old friends or old foes?
Simon Underdown
View
... In addition, PCR products from other lab facilities should never be transferred to the aDNA lab. Refer to Fulton (2012) for more details on how to set up an aDNA lab, and to Gilbert et al. (2005),
Llamas et al. (2017)
, and Orlando et al. (2021) for more detailed guidelines on aDNA research rigour. Sufficient amounts of authentic endogenous DNA are difficult to retrieve, first because there exists an amplification bias for undamaged modern DNA during PCR, even when aDNA might be found in higher concentrations (Shapiro and Cooper 2003), and second because oxidation and hydrolytic processes cause DNA degradation, leading to depurination (Pruvost et al. 2007;Rizzi et al. 2012). ...
Cryopreservation
Laura Forrest
María Paz Martín
... A similar difficulty may be encountered when analysing samples taken from museum specimens as they may be contaminated with exogenous DNA from other similarly aged exhibits. In this case, exogenous DNA can show the same characteristic damage patterns as ancient endogenous DNA, invalidating one of the commonly used authentication criteria
[60]
. ...
Methodological Changes in the Field of Paleogenetics
Joanna Żuraszek
Aleksandra Zielińska
Karl-Heinz Herzig
Karolina Wielgus
Paleogenetics has significantly changed since its inception almost forty years ago. Initially, molecular techniques available to the researchers offered minimal possibilities for ancient DNA analysis. The subsequent expansion of the scientific tool cabinet allowed for more remarkable achievements, combined has with the newfound popularity of this budding field of science. Finally, a breakthrough was made with the development of next-generation sequencing (NGS) technologies and the update of DNA isolation protocols, through which even very fragmented aDNA samples could be used to sequence whole genomes. In this paper, we review the achievements made thus far and compare the methodologies utilized in this field of science, discussing their benefits and challenges.
... The sampling of the material necessary for DNA extraction was performed in a room of the Doderlein Museum, following strict criteria for decontamination
[31]
. As ancient DNA analysis is a destructive technique, the sampling was carried out to maximize the yield of DNA, but at the same time to minimize the visual impact of the sampled area. ...
... The sample was processed in the Ancient DNA (aDNA) laboratory at the Department of Cultural Heritage (University of Bologna), following appropriate and strict criteria
[31,
34,35], to avoid contamination and to authenticate the data obtained. The tooth was first photographed, then decontaminated and drilled in a designated room. ...
Museomics Provides Insights into Conservation and Education: The Instance of an African Lion Specimen from the Museum of Zoology “Pietro Doderlein”
Diversity
Elisabetta Cilli
Francesco Fontani
Marta Maria Ciucani
Marcella Pizzuto
Sabrina Lo Brutto
Innovative technological approaches are crucial to enhance naturalistic museum collections and develop information repositories of relevant interest to science, such as threatened animal taxa. In this context, museomics is an emerging discipline that provides a novel approach to the enhancement and exploitation of these collections. In the present study, the discovery of a neglected lion skeleton in the Museum of Zoology “Pietro Doderlein” of the University of Palermo (Italy) offered the opportunity to undertake a multidisciplinary project. The aims of the study consisted of the following: (i) adding useful information for museographic strategies, (ii) obtaining a new genetic data repository from a vulnerable species, (iii) strengthening public awareness of wildlife conservation, and (iv) sharing new learning material. The remains of the lion were examined with a preliminary osteological survey, then they were restored by means of 3D printing of missing skeletal fragments. Phylogenetic analyses based on cytochrome b sequence clearly indicate that the specimen belongs to the Central Africa mitochondrial clade. At the end of the study, the complete and restored skeleton was exhibited, along with all of the information and data available from this project. This study shows a useful approach for the restoration and enhancement of a museum specimen, with important opportunities for preserving biodiversity and driving specific conservation policies, but also for providing Life Science learning material.
... Each bone was photographed and initially weighed on a scale with precision of 0.01 g. All ancient DNA lab work was conducted in the designated ancient DNA clean lab at the University of Oslo following established protocols for minimizing contamination (Gilbert et al., 2005;
Llamas et al., 2017)
. ...
Ancient DNA sequence quality is independent of fish bone weight
Bastiaan Star
The field of ancient DNA (aDNA) typically uses between 50 and 200 mg of minimum input weight of bone material for the extraction of DNA from archaeological remains. While laboratory and analysis techniques have focused on improved efficiency of extracting useable sequence data from older and poorer quality remains, bone material input requirements have rarely been critically evaluated. Here, we present the aDNA analysis of 121 size-constrained Atlantic herring remains – weighing between <10 and 70 mg – that were individually sequenced to explore the capacity of successful aDNA retrieval from small archaeological remains. We statistically evaluate the relationship between bone weight and several response variables, including library success, endogenous DNA content, and library complexity, i.e., the number of unique molecules that are obtained. Remarkably, we find no relationship between bone weight and library success, levels of endogenous DNA, or library complexity. Our results imply that – at least in the case of fish bone – even minute bones can yield positive results and that the presumed minimum sample size required should be re-evaluated. Archaeological site, instead of bone size, is the primary driver of DNA sequence quality. Our work expands the number of specimens considered suitable for aDNA analyses, and therefore facilitates efforts to minimize the destructive impact of aDNA research and mediate some of the ethical concerns surrounding destructive analysis.
... A sufficient amount of calculus for aDNA analysis was available only for nine human samples (Supplementary Table 1). The first steps of the investigation (e.g., aDNA extraction) were conducted in dedicated facilities of the Departmental Centre for Ancient DNA Studies (Villa Mondragone, Rome, Italy), specifically designed to eliminate potential contaminations, and in the Laboratories of Archaeobotany of the University of Rome Tor Vergata DAPHNE (Diet, Ancient DNA, Plant-Human Nexus, and Environment), following standard precautions and recommendations 16,[143][144][145]
[146]
. Amplicon sequencing and bioinformatics analyses, instead, were carried out by Bio-Fab research S.r.l (Rome, Italy). ...
Neolithic dental calculi provide evidence for environmental proxies and consumption of wild edible fruits and herbs in central Apennines
Alessia D’Agostino
Gabriele Di Marco
Looking for a biological fingerprint relative to new aspects of the relationship between humans and natural environment during prehistoric times is challenging. Although many issues still need to be addressed in terms of authentication and identification, microparticles hidden in ancient dental calculus can provide interesting information for bridging this gap of knowledge. Here, we show evidence about the role of edible plants for the early Neolithic individuals in the central Apennines of the Italian peninsula and relative cultural landscape. Dental calculi from human and animal specimens exhumed at Grotta Mora Cavorso (Lazio), one of the largest prehistoric burial deposits, have returned an archaeobotanical record made up of several types of palaeoecological proxies. The organic fraction of this matrix was investigated by a multidisciplinary approach, whose novelty consisted in the application of next generation sequencing to ancient plant DNA fragments, specifically codifying for maturase K barcode gene. Panicoideae and Triticeae starches, together with genetic indicators of Rosaceae fruits, figs, and Lamiaceae herbs, suggested subsistence practices most likely still based on wild plant resources. On the other hand, pollen, and non-pollen palynomorphs allowed us to outline a general vegetational framework dominated by woodland patches alternated with meadows, where semi-permanent settlements could have been established.
... Target DNA is embedded within a complex mixture of background (non-target) DNA, including bacteria present in the sample at the time of excavation, as well as modern bacterial contaminants. Non-target DNA can obfuscate the identification of endogenous pathogens, especially those pathogens that have close genetic relatives existing in the environment, as well as in common laboratory reagents Eisenhofer et al., 2019;
Llamas et al., 2017;
Vågene et al., 2022;Warinner et al., 2017) (Fig. 1). ...
Examining pathogen DNA recovery across the remains of a 14th century Italian friar (Blessed Sante) infected with Brucella melitensis
Objective
To investigate variation in ancient DNA recovery of Brucella melitensis, the causative agent of brucellosis, from multiple tissues belonging to one individual
Materials
14 samples were analyzed from the mummified remains of the Blessed Sante, a 14 th century Franciscan friar from central Italy, with macroscopic diagnosis of probable brucellosis.
Methods
Shotgun sequencing data from was examined to determine the presence of Brucella DNA.
Results
Three of the 14 samples contained authentic ancient DNA, identified as belonging to B. melitensis. A genome (23.81X depth coverage, 0.98 breadth coverage) was recovered from a kidney stone. Nine of the samples contained reads classified as B. melitensis (7−169), but for many the data quality was insufficient to withstand our identification and authentication criteria.
Conclusions
We identified significant variation in the preservation and abundance of B. melitensis DNA present across multiple tissues, with calcified nodules yielding the highest number of authenticated reads. This shows how greatly sample selection can impact pathogen identification.
Significance
Our results demonstrate variation in the preservation and recovery of pathogen DNA across tissues. This study highlights the importance of sample selection in the reconstruction of infectious disease burden and highlights the importance of a holistic approach to identifying disease.
Limitations
Study focuses on pathogen recovery in a single individual.
Suggestions for further research
Further analysis of how sampling impacts aDNA recovery will improve pathogen aDNA recovery and advance our understanding of disease in past peoples
| https://www.researchgate.net/figure/Examples-of-archaeological-human-tooth-and-bone-samples-and-their-suitability-for-aDNA_fig2_311238115 |
Full text of Federal Open Market Committee Meeting Minutes, Transcripts, and Other Documents : Meeting, March 6-7, 1939 : March 6, 1939 Historical Minutes | FRASER | St. Louis Fed
Full text of Federal Open Market Committee Meeting Minutes, Transcripts, and Other Documents :
Meeting, March 6-7, 1939
: March 6, 1939 Historical Minutes
A meeting of the Federal Open Market Committee was held
in
the offices of the Board of Governors of the Federal Reserve System
in Washington on Monday, March 6, 1939, at 10:00 a.m.
PRESENT:
Mr.
Mr.
Mr.
Mr.
Mr.
Mr.
Mr.
Mr.
Mr.
Mr.
Mr.
Eccles, Chairman
Harrison, Vice Chairman
Szymczak
McKee
Ransom
Davis
Draper
Fleming
Leach
Martin
Hamilton
Mr.
Mr.
Mr.
Mr.
Mr.
Mr.
Carpenter, Assistant Secretary
Wyatt, General Counsel
Goldenweiser, Economist
Williams, Associate Economist
Dreibelbis, Assistant General Counsel
Sproul, Manager of the System Open
Market Account
Mr. Thurston, Special Assistant to the
Chairman of the Board of Governors
The Assistant Secretary reported that records of the eleo
tions for the period of one year commencing March 1, 1939, of members
and alternate members of the Federal Open Market Committee repre
senting the Federal Reserve banks had been received in the office of
the Secretary of the Committee, that each newly elected member and
alternate had executed the required oath of office, and that it
was
the opinion of the Committee's counsel on the basis of these docu
ments that the following members and alternate members were legally
qualified to serve in those capacities:
George L. Harrison, President of the Federal
Reserve Bank of New York, with Roy A. Young, President
3/6/39
of the Federal Reserve Bank of Boston, as alternate
member;
M. J. Fleming, President of the Federal Reserve
Bank of Cleveland, with John S. Sinclair, President
of the Federal Reserve Bank of Philadelphia, as alter
nate member;
Hugh Leach, President of the Federal Reserve Bank
of Richmond, with Oscar Newton, President of the Fed
eral Reserve Bank of Atlanta, as alternate member
(Mr. Newton died on February 13, 1939);
Wm. McC. Martin, President of the Federal Reserve
Bank of St. Louis, with George J. Schaller, President
of the Federal Reserve Bank of Chicago, as alternate
member;
George H. Hamilton, President of the Federal Re
serve Bank of Kansas City, with William A. Day, Presi
dent of the Federal Reserve Bank of San Francisco, as
alternate member
Upon motion duly made and seconded, the
following officers of the Federal Open Mar
ket Committee were reelected by unanimous
votes to serve until the election of their
successors at the first
meeting of the Com
mittee after March 1, 1940:
Marriner S. Eccles, Chairman
George L. Harrison, Vice Chairman
S. R. Carpenter, Assistant Secretary
E. A. Goldenweiser, Economist
John H. Williams, Associate Economist
Walter Wyatt, General Counsel
J. P. Dreibelbis, Assistant General Counsel
Upon motion duly made and seconded, and
by unanimous vote, the Committee selected the
Federal Reserve Bank of New York to execute
transactions for the System open market account
until the adjournment of the first
meeting of
the Committee after March 1, 1940.
Mr. Harrison stated that it
was his intention to recommend
to the board of directors of the Federal Reserve Bank of New York
the selection of Allan Sproul as Manager of the System Open Market
Account.
-3-
3/6/39
Upon motion duly made and seconded, and
by unanimous vote, the Committee approved the
selection of Mr. Sproul as Manager of the Sys
tem Open Market Account in the event of his
reappointment by the board of directors of the
Federal Reserve Bank of New York to act in
that capacity.
Upon motion duly made and seconded, and
by unanimous vote, the following were selected
to serve with the Chairman of the Federal Open
Market Committee, who under the provisions of
the by-laws is also chairman of the executive
committee, as members and alternate members of
the executive committee until the first meeting
of the Federal Open Market Committee after
March 1, 1940:
Members
John K. McKee
Ernest G. Draper
George L. Harrison
Hugh Leach
Alternate Members
Ronald Ransom (to serve as
alternate only in the ab
sence or disability of
the Chairman)
M. S. Szymczak
Chester C. Davis
(to serve in the order
named as alternates for
Messrs. McKee and Draper
and also for Chairman
Eccles in the absence of
both the Chairman and
Mr. Ransom)
M. J. Fleming
Wm. McC. Martin
(to serve in the order
named as alternates for
Messrs. Harrison and Leach)
Upon motion duly made and seconded, and
by unanimous vote, the minutes of the meeting
of the Federal Open Market Committee held on
December 30, 1938, were approved.
Upon motion duly made and seconded, and
by unanimous vote, the actions of the executive
-4
3/6/39
committee of the Federal Open Market Com
mittee as set forth in the minutes of the
meeting of the executive committee on Decem
ber 30, 1938, were approved, ratified, and
confirmed.
Mr. McKee raised the question whether the Federal Open Market
Committee was under a responsibility of any kind with respect to
periodic or other audits of the System open market account.
Upon motion duly made and seconded, and
by unanimous vote, Messrs. Draper, Leach and
Martin were appointed a special committee to
examine this question for the purpose of de
termining whether there is any responsibility
on the part of the Committee to audit, or other
wise to verify the transactions in, the System
account, and to submit a report and recommenda
tion as to what action, if any, should be taken
by the Committee.
Mr. Sproul distributed copies of a report prepared at the
Federal Reserve Bank of New York of operations in the System open
market account since the last meeting of the Federal Open Market
Committee on December 30, 1938, and commented briefly on the trans
actions covered by the report.
Upon motion duly made and seconded, and
by unanimous vote, the transactions in the
System open market account for the period
from December 30, 1938, to March 4, 1939, in
clusive, were approved, ratified and confirmed.
Mr. McKee presented for discussion the question whether the
Federal Reserve banks should treat profits from sales of securities
held in the System open market account as additions to current earn
ings for the year as is
being done at the present time or whether
3/6/39
-5-
they should be used to reduce the book value of the account or to es
tablish reserves for depreciation in the account.
Mr. Sproul stated
that that question had been considered on various occasions in the
past and it
had been concluded that no substantial difference in the
position of a Federal Reserve bank would result from either procedure.
In this connection it
was pointed out that the rate of dividend that
may be paid by the Federal Reserve banks to stockholding member banks
was fixed by law, that the ability of the Federal Reserve banks to
meet a substantial depreciation in the System account would not be
any greater if profits derived from sales of securities in the account
were placed in
a special reserve or added to the banks'
surplus accounts,
and that the Federal Reserve banks differed from commercial banks in
that the latter were under no legal limitation as to the amount of divi
dends that might be paid and if
reserves for depreciation were not es
tablished and profits were added to surplus there would be a greater
temptation on the part of commercial banks to pay larger dividends.
At this point Messrs. Young,
Sinclair, Parker, Schaller, Peyton
and Day, Presidents of the Federal Reserve Banks of Boston, Philadelphia,
Atlanta, Chicago, Minneapolis and San Francisco; Mr. Giltert, First
Vice President of the Federal Reserve Bank of Dallas, Mr. Kimball,
Assistant Vice President of the Federal Reserve Bank of New York, and
Mr. Bethea, Assistant Secretary of the Board of Governors of the Fed
eral Reserve System, joined the meeting for the purpose of hearing the
-6
3/6/39
comments of Messrs. Goldenweiser and Williams with respect to the cur
rent business and credit situation.
Mr. Goldenweiser stated that he had prepared under date of
March 2, 1939,
a memorandum on recent business and credit developments,
copies of which would be distributed.
He then commented on the impor
tant points covered by the memorandum following which copies of the
memorandum were handed to those present.
Mr. Williams made a statement in which he commented on various
factors in the existing situation and the prospects for the continua
tion of the current recovery trend.
A summary of Mr. Williams'
state
ment has been placed in the files of the Federal Open Market Committee.
These statements were followed by a discussion of questions
which were asked of Messrs. Goldenweiser and Williams, particularly
with respect to the relation of prices to business conditions and the
present and future prospects of the construction and housing industry.
The meeting recessed at 1:00 p.m. and reconvened at 2:15 p.m.
with the same attendance as at the opening of the morning session ex
cept that Messrs. Thurston and Dreibelbis were not present.
Mr. Harrison moved that the following
resolutions, which are in the same form as
resolutions adopted at the meeting of the
Federal Open Market Committee at its meet
ing on December 30, 1938, be adopted for
substantially the same reasons given at
the time of their adoption in December.
That the executive committee be directed until other
wise directed by the Federal Open Market Committee, (1) to
arrange for the replacement of maturing Treasury bills in
3/6/39
the System open market account with other Treasury bills
or Treasury notes, or, from time to time, to allow such
bills to mature without replacement or pending subsequent
replacement (a) when market conditions are such as to make
it impossible to procure other bills or notes without pay
ing a premium over a no-yield basis, or (b) when such notes
are not obtainable without undue disturbance to the market;
(2) to arrange for the replacement of maturing Treasury
notes and bonds in the System open market account with
other Government securities; and (3) to arrange for such
shifts in maturities in the System open market account as
may be necessary in the proper administration of the ac
count; provided, (a) that the amount of securities in the
account maturing within two years be maintained at not
less than $1,000,000,000; (b) that the amount of bonds in
the account having maturities in excess of five years be
maintained at not less than $500,000,000 nor more than
900,000,000; and (c) that, if Treasury bills in the ac
count are allowed to mature without replacement, the total
amount of securities in the account be not decreased by
more than $200,000,000.
That, in addition to such authority as may be con
tained in other resolutions of the Federal Open Market Com
mittee and until otherwise directed by the Committee, the
executive committee be authorized, upon written, tele
phonic or telegraphic approval of a majority of the members
of the Federal Open Market Committee, to arrange for the
purchase or sale (which would include authority to allow
maturities to run off without replacement) of Government
securities in the open market from time to time for System
open market account to such extent as the executive commit
tee shall find to be necessary for the purpose of exercis
ing an influence toward maintaining orderly market condi
tions, provided (1) that the total amount of securities in
the account be not increased by more than $200,000,000 nor
decreased by more than $200,000,000 including such decreases
as may result from allowing Treasury bills in the account
to mature without replacement, and (2)
that the amount of
bonds in the account having maturities over five years be
maintained at not less than $500,000,000 nor more than
$900,000,000.
Mr. Harrison's motion was duly seconded.
Reference was made to the circumstances under which action was
-8
3/6/39
taken by the Federal Open Market Committee at its
meeting on December
30, 1938, and question was raised whether Messrs. Fleming, Martin and
Hamilton, who had not attended that meeting, had read the minutes of
the meeting.
The Assistant Secretary stated that under the procedure
in effect the three members mentioned had not been furnished with
copies of the minutes although a copy had been sent to Mr. Leach who
had attended the meeting as an alternate member.
Mr. Fleming stated
he had received the minutes of the meetings of the Committee for the
past year from Mr. Sinclair but had not had an opportunity to read them.
In response to a suggestion by Mr. Davis
it was understood that Chairman Eccles would
appoint a committee of three members of the
Federal Open Market Committee to consider the
question whether copies of the minutes of the
Federal Open Market Committee and its executive
committee should be sent to the alternate mem
bers of the Committee, and to make a recommenda
tion to the Committee with respect thereto and
with regard to the procedure to be followed in
furnishing minutes of the meetings of the Fed
eral Open Market Committee and its executive
committee to new regular members of the Commit
tee elected to take office as of March 1 each
year.
Mr. McKee suggested that for the purpose of acquainting the
new members of the Federal Open Market Committee with the basis for
the action at the meeting on December 30, 1938, the minutes of that
meeting be read.
Mr. Harrison stated that if
the members were to have a more
complete background of the circumstances which led up to the action
on December 30 it
would be necessary that they read all of the minutes
-9
3/6/39
of the full Committee beginning with the meeting of April 21-22, 1938.
It
was agreed that Messrs. Leach, Martin and Hamilton would be furnished
with copies of the minutes referred to by Mr. Harrison, that they and
Mr. Fleming would read the minutes during the evening, and that the Com
mittee would reconvene tomorrow morning for further consideration of the
open market policy to be adopted by the Committee.
Thereupon the meeting recessed with the understanding that it
would reconvene tomorrow, Tuesday, March 7, 1939,
at 10:00 a.m.
Assistant Secretary.
Approved:
Chairman.
| https://fraser.stlouisfed.org/title/federal-open-market-committee-meeting-minutes-transcripts-documents-677/meeting-march-6-7-1939-22670/content/fulltext/19390306Minutesv |
The Tunisia effect: where next? | libcom.org
The Tunisia effect: where next?
Submitted byMark.on January 29, 2011
On twitter
Syrians inspired by both tunisia and Egypt are planning a collective protest against their corrupt Government on #Feb5
Calls for anti-regime protests in #Algeria on 12 February http://bit.ly/fUx1SZ (in Arabic)
The Syrian and Sudanese have set their revolution dates already?! Four down, eighteen more to go! #ArabRevolutions
Spanish TV TVE just reported troops in #Morocco were mobilised from Sahara to #Rabat & #Casablanca.
The first of these protests will be in theSudan
KHARTOUM, SUDAN —
A group of young Sudanese activists proclaim January 30, 2011 to be the beginning of peaceful demonstrations to bring down the military regime in Sudan. This campaign is calling on all sectors of Sudanese to get out January 30th and demonstrate in the streets of Sudan's most populated cities. The largest assembly and demonstration will take place on Palace Street, which is located a few meters from the presidential palace of Sudanese President Omar Hassan Ahmad al-Bashir. The invitation for the demonstration excludes the leaders of the traditional opposition parties who are not willing to confront the Islamic military regime, which has been ruling Sudan since 1989.
The call for this action came one day after the leader of the Umma Party, Mr. Alsadiq Al-mahdi, announced that he would continue peaceful dialogue with the current government. His speech is widely regarded by most young Sudanese, including members of the Umma party, as disappointing and lacking insight into the systematic destruction of the country by Al-Bashir`s government. His political views show that he continues to disengage himself from the issues vital to Sudanese activists. This call for demonstrations coincides with the 116th anniversary of the liberation of Khartoum by Imam Mohammed Ahmed al-Mahdi on January 26, 1885, great grandfather of Mr. Alsadiq Al-Mahdi. Their intent is to peacefully express anger at the decades of corruption, violence, and human right violations, which led to the separation of the South and which could lead to the potential separation of the West.
It is no secret that the young people who have called for the demonstration have seen what has happened in Tunisia and Egypt, where young generations have loudly spoken against unemployment and political marginalization.
We would like to be clear that this is a call for removal of this government.
In a statement, on its Facebook page, the Liberal Democratic Party, represented by Mr. Adel Abd Atti and Ms. Noor Tour, invite all members to participate in the demonstration, planned for January 30th.
It is time to change the face of Sudan and to end decades of injustice, marginalization, and corruption.
Yesterday there was a demo inMauritaniain support of the uprising in Egypt.
Plusieurs centaines de Mauritaniens ont manifesté vendredi soir à Nouakchott pour exprimer leur soutien aux manifestants égyptiens, a constaté un correspondant de Xinhua.
Deux marches piétonne et motorisée ont parcouru l’avenue Nasser, principal artère de la capitale mauritanienne, scandant des slogans hostiles au président égyptien Hosni Moubarak.
Les manifestants ont également appelé le président Moubarak à "quitter le pouvoir et à laisser au peuple égyptien la liberté de choisir ses dirigeants". Les marcheurs qui se sont rassemblés devant l’ambassade d’Egypte à Nouakchott ont condamné la répression policière, dont ont été victimes les manifestants égyptiens avec lesquels ils ont exprimé toute leur solidarité.
Ces marches, qui se sont déroulées dans la discipline, étaient suivies par les forces de l’ordre.
rooieravotr
12 years 4 months ago
In reply toWelcomebylibcom.org
Submitted byrooieravotron January 30, 2011
From Raw Story, based on
From Raw Story, based on AFP:
More than 10,000 protesters marched against authorities in Algeria's northeastern city of Bejaia on Saturday, organisers said, in the country's latest rally inspired by neighbouring Tunisia.
Demonstrators marched peacefully in the city in Algeria's Berber-speaking Kabylie region, shouting Tunisia-inspired slogans such as: "For a radical change of the regime!," a lawmaker with the opposition Rally for Culture and Democracy (RCD), Mohamed Ikhervane, told AFP.
"The protest gathered more than 10,000 people," said RCD leader Said Sadi, whose group organised the rally.
Police were out in force around the city but protesters dispersed calmly, Ikhervane said.
Separately, pro-democracy group the Algerian League for the Defence of Human Rights (LADDH) said it plans a new march in Algiers on February 12.
Mark.
12 years 4 months ago
In reply toWelcomebylibcom.org
Submitted byMark.on January 30, 2011
Report on the EA
Report on theEA liveblog
0900 GMT: Reports coming in of an anti-Government demonstration in Sudan. A participant, who says there were up to a 100 protesters, sends the message, "Riot police attacked us. Numbers started to build up. Protesters are spreading into smaller groups in internal streets."
http://twitter.com/simsimt
CNN: Sudanese police, students clash in the capital http://bit.ly/enpk3q #Sudan
Thousands? RT @ykhogaly: Thousands of demonstrators are still in the center of Khartoum regrouping after tens of arrests, tear gas & beating
Epic moment of demo: college girl shouting at employees watching from distant at bank's doorstep: Why don't you join us? Aren't you men?
http://sudan30january.blogspot.com/ (in Arabic)
Mark.
12 years 4 months ago
In reply toWelcomebylibcom.org
Submitted byMark.on January 30, 2011
Facebook for Syria protests
Facebook for Syria protests (in Arabic)
http://www.facebook.com/pages/ywm-alghdb-alswry/147151028676674?v=wall
Mark.
12 years 4 months ago
In reply toWelcomebylibcom.org
Submitted byMark.on January 30, 2011
Breaking news: The
Breaking news: The facebook-organized protests have begun in Khartoum. Stay tuned for continuous updates
Edited to add:
Whether this will actually blow up to the same level we’ve seen in Tunisia and Egypt is something that remains to be seen. After all these recent events, nothing seems far fetched anymore.
There’s real anger, and rising prices and economic hardships are starting to sting people including those who are usually politically apathetic. Plus, with the results of the referendum, the South going bye bye, and weak opposition parties remaining, Northerners realize they’re going to be left all alone to deal with the government.
We’ve done it before twice, toppling two military dictatorships in 1964 and 1985, and it may just happen again if the people rise up.
…
UPDATE: Here’s a recently uploaded video of students from Khartoum University’s Faculty of Medicine protesting.
[youtube]Hj5-Z9EkgTo[/youtube]
Mark.
12 years 4 months ago
In reply toWelcomebylibcom.org
Submitted byMark.on January 30, 2011
Sudan police clash with
Sudan police clash with protesters (Al Jazeera)
Anti-government demonstrators in Khartoum faced riot police in protests inspired by those in Egypt and Tunisia.
Sudanese police have beaten and arrested students as protests broke out throughout Khartoum demanding the government resign, inspired by a popular uprising in neighbouring Egypt.
Hundreds of armed riot police on Sunday broke up groups of young Sudanese demonstrating in central Khartoum and surrounded the entrances of four universities in the capital, firing teargas and beating students at three of them.
Police beat students with batons as they chanted anti-government slogans such as "we are ready to die for Sudan" and "revolution, revolution until victory".
There were further protests in North Kordofan capital el-Obeid in Sudan's west, where around 500 protesters engulfed the market before police used tear gas to disperse them, three witnesses said.
"They were shouting against the government and demanding change," said witness Ahmed who declined to give his full name.
Sudan has a close affinity with Egypt - the two countries were united under British colonial rule. The unprecedented scenes there inspired calls for similar action in Sudan, where protests without permission, which is rarely given, are illegal.
Before Tunisia's popular revolt, Sudan was the last Arab country to overthrow a leader with popular protests, ousting Jaafar Nimeiri in 1985.
Groups have emerged on social networking sites calling themselves "Youth for Change" and "The Spark", since the uprisings in nearby Tunisia and close ally Egypt this month.
"Youth for Change" has attracted more than 15,000 members.
"The people of Sudan will not remain silent any more," itsFacebook pagesaid. "It is about time we demand our rights and take what's ours in a peaceful demonstration that will not involve any acts of sabotage."
The pro-democracy group Girifna ("We're fed up") said nine members were detained the night before the protest and opposition party officials listed almost 40 names of protesters arrested on Sunday. Five were injured, they added.
Opposition leader Mubarak al-Fadil told Reuters two of his sons were arrested on their way to the central protest.
Editor-in-chief of the al-Wan daily paper Hussein Khogali said his daughter had been detained by security forces since 0500 GMT accused of organising the Facebook-led protest.
Pro-government newspapers carried front page warnings against protests which they said would cause chaos and turmoil...
Mark.
12 years 4 months ago
In reply toWelcomebylibcom.org
Submitted byMark.on January 30, 2011
The Syrians are watching (Al
The Syrians are watching (Al Jazeera)
In the tea shops and internet cafes of Damascus, Syrians are asking what events in Egypt may mean for them.
In one of Old Damascus' new cafes, text messages buzzed between mobiles in quick succession, drawing woops of joy and thumbs up from astonished Syrians.
Suzan Mubarak, the wife of the Egyptian president, had flown into exile with her son - so the rumours went - driven out of the country by days of unprecedented protest against the 30-year rule of her husband.
The news from Cairo brought a flutter of excitement to this country, founded on principles so similar to Egypt that the two nations were once joined as one.
Like Egypt, Syria has been ruled for decades by a single party, with a security service that maintains an iron grip on its citizens. Both countries have been struggling to reform economies stifled for generations by central control in an effort to curb unemployment among a ballooning youth demographic.
Could the domino effect that spread from the streets of Tunis to Cairo soon hit Damascus? ...
Mike Harman
12 years 4 months ago
In reply toBreaking news: ThebyMark.
Submitted byMike Harmanon January 31, 2011
Mark. wrote: That chant
Mark.
[youtube]Hj5-Z9EkgTo[/youtube]
That chant sounds suspiciously like "No ifs, no buts, no education cuts". Someone with better (i.e. at all) video skills than me should make a compilation video.
Mark. did you change your username recently? If so would you pm me your old one?
Mark.
12 years 4 months ago
In reply toWelcomebylibcom.org
Submitted byMark.on February 1, 2011
Mike - I've sent you a pm.
Mike - I've sent you a pm.
Sudan student dies in clashes (Al Jazeera)
Protesters say he was beaten by police amid anti-government demonstrations in Khartoum and died of his wounds.
A student who was beaten by police during violent anti-government demonstrations in Khartoum, Sudan's capital, has died of his wounds in Omdurman hospital, protesters have said.
"Mohammed Abdulrahman, from Ahlia University, died last night in Omdurman hospital as a result of his ... wounds after he was beaten by police," said an activist who took part in Sunday's protests.
"This morning (Monday) both Ahlia University and the Islamic University of Omdurman have been closed by a government decision," said the activist, speaking on condition of anonymity.
Two other students said Abdulrahman had fallen during the clashes and was taken to the hospital, where medics informed them that he had died early on Monday.
"Medical sources confirmed to us that the student died yesterday from his injuries inflicted by security forces," said Yasir Arman, the top official in the north of south Sudan's main party, the Sudan People's Liberation Movement (SPLM).
Arman condemned the use of force and said the students were trying to hold peaceful demonstrations.
The Omdurman hospital morgue declined to comment on the death.
Witnesses said at least six universities in the capital and Sudan's regions were surrounded on Monday by hundreds of heavily armed police, preventing students from leaving the grounds.
University students in three towns in the north tried to escape to protest but were quickly arrested or beaten back by armed police, they said.
Sunday's demonstrations followed calls by the "30 January" Facebook group for Sudanese youth to take to the streets and stage peaceful anti-government rallies across Sudan.
The Facebook group, which has around 17,000 members, confirmed Abdulrahman had died, referring to him as a "martyr" who followed in the footsteps of another student killed in the October 1964 popular uprising that toppled the military regime then in power.
"Al-Gorashy was a martyr for us. And you are our martyr now, Mohammed Abdulrahman," it said in large red lettering.
Protesters on Sunday were confronted by a heavy police presence in different parts of Khartoum and Omdurman, and in El-Obeid, aabout 600km west of the capital.
The ensuing clashes resulted in at least 64 arrests and left many wounded.
...
The demonstrations came after nearly a week of turmoil in Egypt, and coincided with the first complete preliminary results from this month's vote on independence for south Sudan, which confirmed a landslide for secession.
In Omdurman, just across the Nile from Khartoum, around 1,000 demonstrators shouted slogans against Omar al-Bashir, the president, and hurled rocks at riot police, who retaliated with tear gas and batons.
At the medical faculty of Khartoum University, security officers tried to prevent about 300 student protesters from leaving the campus, but they eventually forced their way out onto the street, shouting: "Revolution against dictatorship!"
Police and security officers attacked them with batons, arresting several and forcing the students back inside the university compound, which was later surrounded by more than 20 police trucks.
On Monday, journalists said security forces prevented the opposition Ajras al-Huriya and the independent al-Sahafa newspapers from being distributed after they wrote about the protests.
"Security came to the printing press and stopped the paper going out," said Fayez al-Silaik, deputy editor of Ajras al- Huriya, adding his paper was targeted because it had a front page article on the protests.
Dozens of students including two sons of opposition politician Mubarak al-Fadil were arrested and many remain detained, activists and opposition officials said on Monday.
Widespread economic and political discontent has provoked sporadic street protests in north Sudan in recent weeks, with the security forces maintaining tight control in Khartoum.
Like Egypt, Sudan is also deep in economic crisis after a bloated import bill has eaten up foreign currency and forced an effective currency devaluation which sparked rising inflation.
This month the government cut subsidies on petroleum products and sugar, a key commodity in Sudan, sparking smaller protests throughout the north.
Mark.
12 years 4 months ago
In reply toWelcomebylibcom.org
Submitted byMark.on February 1, 2011
Thousands of Syrians vow a
Thousands of Syrians vow a protest against al-Assad
Thousands of Syrians have joined a Facebook group to call for a protest against their president on Friday, February 4, echoing Tunisia’s Jasmine Revolution and Egypt’s Day of Rage on January 25.
The group named “the Syria Revolution 2011,” is planning rallying young people in a march to protest against the Ba’thist regime led by Bashar al-Assad after Friday’s prayer.
The group described al-Assad’s rule as dictatorship and showed torture YouTube videos of political dissident in the country.
The group also called for civil disobedience, and encouraged “all of the brave Syrian youth, from all factions and social classes and from all provinces” to “not be silent about oppression.” ...
Mark.
12 years 4 months ago
In reply toWelcomebylibcom.org
Submitted byMark.on February 1, 2011
Algeria: confirmation of
Algeria: confirmation of march In Algiers, 12 February. Call out by "National Coordination for Change and Democracy, which groups theautonomous unions, opposition movements and civil society organisations".
La marcha del 12 de febrero en Argel, una apuesta por un cambio social en Argelia
Finalmente la marcha por el cambio ha sido fijada para el 12 de febrero en Argel por la Coordinación nacional para el cambio y la democracia, que agrupa al sindicalismo autónomo, a movimientos de oposición y organizaciones de la sociedad civil.
Esta coordinación, nacida el 21 de enero a raíz de las revueltas de principios de enero que provocaron cinco muertes y más de 800 heridos, había anunciado su intención de organizar una marcha en torno el 9 de febrero, fecha aniversario de la proclamación del estado de urgencia en Argelia.
El Presidente de honor de la Liga argelina para la defensa de los derechos humanos (LADDH), Ali Yahia Abdenour, anunció la fecha de la marcha para el sábado 12 de febrero, tras la reunión celebrada el viernes 28 de la coordinación, con participación de más de 200 personas en una reunión de aproximadamente 200 personas, viernes. El cambio de fecha se debe a que el sábado es día festivo por lo que la participación de l@s trabajador@s puede ser mucho mayor.
A partir de la reivindicación central, el levantamiento del estado de urgencia, instaurado hace 19 años, el planteamiento fundamental es “le départ du système", es decir, el cambio. Basándose en los ejemplos de Túnez y Egipto, se ha decidido adoptar el lema " sistema dégage" , haciendo hincapié en las reivindicaciones económicas y sociales, incluido el desempleo de los jóvenes (más del 20% de parad@s) y la escasez de vivienda, causas de la mayoría de las revueltas.
La marcha comenzará el sábado 12 de febrero a las 11 de la mañana en la plaza 1º de mayo para ir hasta la Plaza de los Mártires, al puie de la Casba y junto a Bad-el-oued, aunque el itinerario concreto se comunicará dios días antes, ya que se espera que la marcha sea prohibida, como lo fue la del RCD del día 22 de enero...
Mark.
12 years 4 months ago
In reply toWelcomebylibcom.org
Submitted byMark.on February 1, 2011
http://en.wikipedia.org/wiki/
http://en.wikipedia.org/wiki/2010–2011_Arab_world_protests
Mark.
12 years 4 months ago
In reply toWelcomebylibcom.org
Submitted byMark.on February 1, 2011
Oman protestors call for
Oman protestors call for fight against corruption
Around 200 Omanis took to the streets on Monday [17 January] to demonstrate against corruption and high food prices, it has been reported.
Despite protests and trade unions being largely prohibited in the Gulf, police did not intervene in the protest, said the newswire AFP.
Protesters chanted slogans calling for an end to corruption and carried banners saying “Rising prices have destroyed the dreams of ordinary citizens”.
The crowd, which gathered outside the housing ministry, were reported to have been calling for higher wages and fixed costs for basic food items, which have dramatically risen amid the global downturn.
The Omani demonstration comes days after a revolt in Tunisia which toppled the 23-year presidency of Zine Al Abidine Bin Ali.
Mark.
12 years 4 months ago
In reply toWelcomebylibcom.org
Submitted byMark.on February 1, 2011
Sudan follow-up: more
Sudan follow-up: more protests on Monday, big march called for Thursday
After Sunday's protests of hundreds throughout Sudan, with at least one student dying in clashes, some development on Monday....
Journalists said security forces prevented the opposition Ajras al-Huriya and the independent al-Sahafa newspapers from being distributed after they wrote about the protests.
A Facebook hub for the opposition posted messages of demonstrations such as "Launched demonstrations now in Kosti". Later postings spoke of a protest, starting from Jackson Square in Khartoum, honouring the funeral of Mohamed Abdelrahman, the demonstrator killed on Sunday. There were claims, via a Twitter activist and via Facebook, of beatings by police and more detentions in both Kosti and Khartoum.
The activists have now called formarches on Thursday, posting the following message:
We are young men and women of Sudan
We call on all to bring down the system, which has become an obstacle to the development of the country and we demand a pluralistic democratic system...for all states of Sudan, finding a just and comprehensive solution to the issue of Darfur and holding accountable perpetrators of crimes in this region.
We call on citizens to live with a decent resolution of economic hardship and for the alleviation of the suffering with an adjustment of prices and an end to unemployment.
We call on the junta to try to end corrupt and recover the people's money and to restore freedom and the dignity of our citizens.
The main image on the Facebook site mobilising protest has altered, featuring this message, "We won't let you die in vain --- Mohammad Abdel Rahman, martyr of the popular intifada. May God have mercy on his soul."
ocelot
12 years 4 months ago
In reply toWelcomebylibcom.org
Submitted byoceloton February 1, 2011
re Algeria le Parisien: Début
re Algeria
le Parisien: Début d'une série de grèves en Algérie
Even if the street seems quiet since the riots in early January, Algeria bubbles also. A series of strikes is scheduled to begin this Tuesday across the country. movements of paramedic and education staff claiming wage increases are announced while the opposition is calling for a march on February 12 in Algiers, to demand "the departure of the system."
The Union of Algerian Paramedics (SAP) wants to pressure the Ministry of Health in providing the minimum service in major hospitals. The staff of Education followed suit in calling for a rally outside the department. They particularly wanted a salary increase and a rise in perfromance bonus.
The unemployed are to provide their share on February 6 with a protest outside the headquarters of the Ministry of Labour in Algiers, where they intend to file a platform of demands.
These movements of discontent occur at a crucial moment for the country where the revolution in Tunisia and Egypt is being scrutinized by the government which fears a serious contamination. The all-new National Coordination for Change and Democracy, which includes opposition movements and civil society organizations, called for a big march in the capital on February 12.
Unauthorized demonstrations
This coordination, born January 21 in the wake of riots in early January that killed five people and injured over 1000, demands the lifting of emergency rule, established 19 years ago, but especially "the departure of the system .
The coordination, which includes the Rally for Culture and Democracy (RCD Opposition) expects government approval for the march to be refused. The Algerian Interior Minister Dahou Ould Kablia recalled Sunday that no contract shall be authorized by the authorities in Algiers, in an interview with French daily Liberté. The Minister explained that the ban on marches were justified by security reasons.
On 22 January, a demonstration of the opposition RCD, was severely repressed by the authorities. Clashes between protesters and security forces have made a fifty wounded including seven policemen.
Mark.
12 years 4 months ago
In reply toWelcomebylibcom.org
Submitted byMark.on February 1, 2011
Sudan update Quote: Sudanese
Sudan update
Sudanese students defied arrests and beatings on Tuesday, pressing ahead with anti-government protests inspired by demonstrations in neighboring Egypt.
Opposition activists blame the government for rising food prices and have been protesting since Sunday around the country. They plan more demonstrations on February 3.
On Tuesday, some 200 students demonstrated outside al-Nilein university in Khartoum before hundreds of police beat them back and surrounded the university buildings with 20 vehicles.
…
Late on Monday students in Gezira, Sudan's farming heartland, and young people in the busy Khartoum suburb of al-Kalakla gathered chanting slogans against rising prices and repression.
…
"These ongoing rights violations are a pattern to silence dissident voices and limit access to information," the African Center for Justice and Peace Studies said in a statement.
"The responses undertaken by police forces...exemplify the extent to which the (ruling party) are unwilling to tolerate any other voices on the road to democratic transformation."
It said police had detained more than 100 people on the first day and arrests were continuing with people also being taken from their homes and offices. Activists are struggling to keep track of how many of their members have been detained...
Mark.
12 years 4 months ago
In reply toWelcomebylibcom.org
Submitted byMark.on February 1, 2011
Syrian revolution on facebook
Syrian revolution on facebook
The Syrian Revolution 2011 الثورة السورية ضد بشار الاسد GO To Twitter Now and Share Our Page PLEASE!!! http://on.fb.me/Syrians Dont Forget the hash's #sharek #SyrianRevolution
Also please Send SMS Now To the Syrians By the country code 009639 Follow by any 8 Random numbers. Tell them we are going after the Friday Prayer for the Syrian Anger Dyay For Your FREEDOM infront of all Syrian Embassy's...DO IT NOW!! also in twitter...GO!
Mark.
12 years 4 months ago
In reply toWelcomebylibcom.org
Submitted byMark.on February 1, 2011
Senegal government seeks to
Senegal government seeks to avoid the Tunisian scenario
Friday, 14 January 2011
As Tunisians await the outcome of their rather rewarding protests, after weeks of demonstrations that ended the rule of their authoritarian leadership, the government of Senegal is searching for a suitable way of avoiding a similar situation.
President Abdoulaye Wade has reportedly tasked his government to figure out proposals to lower prices of basic commodities. This announcement was done Friday, as the Tunisian protest on similar grounds approached its climax.
Wade, according to a statement released by the cabinet, "expressed great concern about the high prices of essential commodities." The statement said he had therefore instructed his prime minister, Souleymane Ndene Ndiaye and the ministers of finance and commerce "to promptly submit possible proposals suitable to lower prices to relieve households."
Amid threats of action by the authorities, opposition politicians have since been nursing the idea of taking to the streets in protest of the rising prices of basic food stuffs in the country. The latest date for that protest has now been put at Tuesday.
Rise in prices of foodstuff and gas, which is mainly used for cooking, coupled with the country’s prevalent electricity problem, could be a perfect recipe for unrest in a country that is already engulfed in a messy political situation.
Mark.
12 years 4 months ago
In reply toWelcomebylibcom.org
Submitted byMark.on February 1, 2011
Mid-East contagion fears for
Mid-East contagion fears for Saudi oil fields
"Yemen, Sudan, Jordan and Syria all look vulnerable. However, the greatest risk in terms of both probability and severity is in Saudi Arabia," said a report by risk consultants Exclusive Analysis.
While markets have focused on possible disruption to the Suez Canal, conduit for 8pc of global shipping, it is unlikely that Egyptian leaders of any stripe would cut off an income stream worth $5bn (£3.1bn) a year to the Egyptian state.
"I don't think the Egyptians will ever dare to touch it," said Opec chief Abdalla El-Badri, adding that the separate Suez oil pipeline is "very well protected". The canal was blockaded after the Six Days War in 1967.
There has been less focus on the risk of instability spreading to Saudi Arabia's Eastern Province, headquarters of the Saudi oil giant Aramco. The region boasts the vast Safaniya, Shaybah and Ghawar oilfields. "This is potentially far more dangerous," said Faysal Itani, Mid-East strategist at Exclusive...
Mark.
12 years 4 months ago
In reply toWelcomebylibcom.org
Submitted byMark.on February 2, 2011
Libya: calls for protest on
Libya: calls for protest on 17 February
Sandwiched between Tunisia, as it surmounts the impossible, and Egypt, as it wakes the sleeping giant, Libya has been, for the last 41 years, seemingly acquiescent to Gaddafi’s regime, despite its remarkable, historical struggle for independence against Mussolini’s Italy. Since the earliest days of the Tunisian uprising, many people have speculated as to whether the Sidi Bouzid contagion would infect the Libyan masses. When news of unrest over a ‘housing situation’ leaked via YouTube, many scrambled to follow further developments.
And then it was silent.
Libyan citizens, activists and members of the media struggled to navigate the Libyan black hole, eager to confirm any information that trickled out. It became exceptionally difficult to discern whether or not a Libyan uprising was in the making and to distinguish rumor from reality. Even under ‘normal’ circumstances, sources inside of Libya are scarce. As the potential for mass protests mount and the regime continues to execute its counter strategy, those sources have become even harder to access. As Egypt absorbs the majority of the world’s attention, there are promising developments that could bring us good news—the real possibility of Libyans demanding what they have been denied for decades as more and more Libyans inside and outside the country call for nationwide protests on February the 17th.
...
And finally, there has been some activity on the internet and on-the-ground suggesting that Libyans are organizing a day of protest, similar to that seen in Egypt, for the 17th of February. Students in Benghazi, for example, have posted a press release calling on all Libyans to join them on the 17th.A Facebook pagehas recently been established in support of this day of solidarity. There are also reports of protest supporters in Tripoli. The large distances between Tripoli and Benghazi, both in regards to space and living conditions, have historically prevented uprisings that start in Benghazi to spread to Tripoli or even those that start in Libya’s south to spread northward. Support in Tripoli is, therefore, promising news.
Mark.
12 years 4 months ago
In reply toWelcomebylibcom.org
Submitted byMark.on February 2, 2011
Facebook page for revolution
Facebook page for revolution in Morocco
Enough torture, enough oppression, enough monarchy. We the people of Morocco want a revolution to overthrow King Mohammed VI. We want freedom and democracy. Just like our sisters and brothers in Egypt and Tunisia we will rise against the tyrant regime.
Mark.
12 years 4 months ago
In reply toWelcomebylibcom.org
Submitted byMark.on February 3, 2011
(No subject)
[youtube]ijG0CXxlSrk[/youtube]
Mark.
12 years 4 months ago
In reply toWelcomebylibcom.org
Submitted byMark.on February 3, 2011
The Syrian revolution يوم
The Syrian revolutionيوم الغضب السوري
xslavearcx
12 years 4 months ago
In reply toWelcomebylibcom.org
Submitted byxslavearcxon February 3, 2011
is there anything significant
is there anything significant happening in saudi??
Mark.
12 years 4 months ago
In reply toWelcomebylibcom.org
Submitted byMark.on February 3, 2011
Nothing I've heard of as yet
Nothing I've heard of as yet though I haven't really looked for information. There has been unrest from the Shia minority in the past and I've seen the suggestion somewhere that the Iranian government's position of support for the uprisings in Tunisia and Egypt is linked to an attempt to destabilise Saudi. I don't know enough to say whether there's any truth in this.
xslavearcx
12 years 4 months ago
In reply toWelcomebylibcom.org
Submitted byxslavearcxon February 3, 2011
thanks mark
thanks mark :)
Entdinglichung
12 years 4 months ago
In reply toWelcomebylibcom.org
Submitted byEntdinglichungon February 3, 2011
therer were some protests by
therer were some protests by unemployed teachers in early January:
http://blogs.ft.com/beyond-brics/2011/02/03/saudi-arabia-riddle-of-the-regime/ & http://af.reuters.com/article/worldNews/idAFTRE7081FW20110109
Boris Badenov
12 years 4 months ago
In reply toWelcomebylibcom.org
Submitted byBoris Badenovon February 3, 2011
Quote: 3 February - Algerians
3 February -Algerians are active planning for protests similar to those in Tunisia and Egypt.A great march is announced for 12 February. But the Algiers government threatens to react as harshly as Mubarak in Egypt.
Several opposition groups in Algeria have called for mass protests in the Algerian capital Algiers on Saturday 12 February. The call comes from the political opposition, human rights groups, trade unions, student organisations and an association of the unemployed.
The groups' main demand is the lifting of Algeria's 19-year-old state of emergency, which has allowed the regime to limit political activities and human rights. They further demand the widening of the right to establish political parties, improved social welfare and democracy.
Contrary to most of the earlier unrests in Algeria - which regularly are violently suppressed by the army - it is neither the Berber minority nor the large Islamist opposition standing behind the call for protests. It is the same population groups that organised the Tunisia and Egypt protests.
This was also made clear in choosing a Saturday for the announced Algiers protest marches, not a Friday, which easily could have mobilised Islamists after the Friday prayers. The new opposition seems mostly secular and Arab.
Potentials for a social upheaval in Algeria are seen as enormous. While labour conditions have rapidly improved over the last years, youth unemployment is still exceeding 20 percent, according to official statistics. Most observers believe it is much higher, although below youth unemployment rates in other North African countries.
Early in January - responding to the unrest in Tunisia and triggered by significant price increases of basic food items - spontaneous protests broke out in Algeria. "But the authorities were able to take rapid measures to reduce these prices with the temporary elimination of custom duties and the value-added tax on those items," according to Algiers IMF mission head Joël Toujas-Bernaté.
But not only these social polices paused the Algeria unrests. On 22 January, police were ordered to stop and disperse protesters in Algiers. Several were injured in the clashes as police troops made it clear they would not allow any dissent.
The 22 January manifestations had demanded wider democratic and human rights in the country, with slogans calling for the freedom of assembly and expression. Further slogans called for President Abdelaziz Bouteflika.
The announced slogans for the planned 12 February protests are less provocative, but still call for wider political and human rights.
But Algerian acting Prime Minister Nouredine Yazid Zerhouni yesterday made it clear that such protests would be treated heavy-handedly, emphasising they were illegal. Whoever called for the protests later must "take on responsibility if damage should occur or if things get out of control," he warned in front of journalists.
Mr Zerhouni added that it was necessary to maintain the age-old state of emergency in place, given the threat of Al Qaeda and other militant Islamist movements in Algeria. The state of emergency originally was put in place during an Islamist uprising, 19 years ago, which was brutally crushed by the army, leaving over 100,000 dead.
The Algerian army, mostly seen as very loyal to President Bouteflika, has a long history of crushing revolts and uprisings. Most significantly, it fought a brutal civil war against - even more brutal - Islamists in the 1990s. But it has also crushes several local riots, often organised by the mostly rural Berber people.
Many therefore fear that a popular uprising in Algeria could become especially bloody. Others however hold that Algerian army privates would react in the same way as in Egypt if ordered to shoot at people like themselves.
Algeria has one of North Africa's most liberal media policies, with critical media existing, good access to foreign broadcasters such as 'Al Jazeera' and uncensored internet and mobile phone net access. There are repeated attacks on critical journalists, but generally, Algerians are free to receive information. The unrest in Egypt is well known and watched with great interest in the country.
The brutal attacks on protesters in Cairo yesterday however could spread fears about the consequences of a popular uprising in Algeria. The Algerian population to a large degree is exhausted by decades of insecurity, although mostly fed up with the Bouteflika regime.
http://www.afrol.com/articles/37221
Valeriano Orob…
12 years 4 months ago
In reply toWelcomebylibcom.org
Submitted byValeriano Orob…on February 3, 2011
Quote: The groups' main
The groups' main demand is the lifting of Algeria's 19-year-old state of emergency, which has allowed the regime to limit political activities and human rights.
It has already been lifted according to al-arabiya breaking news i posted in the egypt thread and it has just been confirmed in al-jazeera live stream too.
Valeriano Orob…
12 years 4 months ago
In reply toWelcomebylibcom.org
Submitted byValeriano Orob…on February 3, 2011
It keeps being confirmed in
It keeps being confirmed in al-arabiya stream by all contributors
ocelot
12 years 4 months ago
In reply toWelcomebylibcom.org
Submitted byoceloton February 3, 2011
random opinion from Saudi The
random opinion from Saudi
The Arab Revolution’s effect on Saudis
With what’s going on right now in Yemen, Jordan, Syria, Tunis and Egypt, I get a lot of questions about how Saudis are taking it and what’s the reaction. The short answer is they are shocked and captivated but haven’t made up their minds about any of it.
[...]
They are watching, though. All over the country, all these Saudis who rarely watch or read the news and their only interests in doing so are for more local social openness or conservativeness (depending on their background), are now carefully observing what’s going on in neighboring countries. Saudis who didn’t know what the channel number for AlJazeera News was on their receivers now have it saved on their favorites list. University and high school students are now watching the news and social media feeds in their study breaks instead of an episode of Friends. It’s a new atmosphere. The thing lacking is analysis or a discussion on what it means for us.
Entdinglichung
12 years 4 months ago
In reply toWelcomebylibcom.org
Submitted byEntdinglichungon February 3, 2011
Morocco? http://www.spsrasd.i
Morocco?
http://www.spsrasd.info/en/detail.php?id=16315
Rabat (Morocco), February 2, 2011 (SPS) - Following the developments in Tunisia and Egypt, Moroccan youth groups have started organising the first protest marches in the country to demand political reform and greater human rights in Morocco, afrol News reported Tuesday.
The first mass protests have already been organised in Morocco. On Sunday, the group ATTAC Morocco staged a larger demonstration in the northern city of Tangiers, with protesters focusing on "the deterioration of social conditions and high basic food prices."
The Tangier protest however was brutally stopped by security forces, according to eyewitnesses. Batons and tear gas were used to disperse demonstrators who had gathered in the Square of Nations in central Tangier. Protesters had chanted slogans of solidarity with the people of Tunisia and Egypt, demanding a "right to employment, housing and a decent life."
But Moroccan protesters have not given up, despite the brutal response by security forces. Today, there are reports from the capital, Rabat, about demonstrations in front of the Egyptian Embassy, with hundreds of protesters chanting slogans in solidarity of their counterparts in Egypt.
Further protests are now being prepared by a magnitude of groups in Morocco.
A group of young Moroccans is currently spreading the protest call through the social network Facebook, calling for demonstrations on 27 February "in front of the prefectures and the wilayas in all regions and central authorities in cities and villages, to demand the freedom of political organisation, the alternation of power and human rights."
The so-called "Movement for Freedom and Democracy Now" in a statement specifies that this protest is "part of a spontaneous global transformation that aims at giving people their rightful place in society," further calling for democracy, freedom and the adherence to popular will.
According to the statement, there is a list of demands including "the abolition of the current constitution, dissolve parliament and government, parties who have contributed to the consolidation of political corruption and take immediate real action for a political transition."
The organisers further refer to "the terrible conditions of poverty, unemployment and human rights violations and restrictions on freedom of press" in Morocco. Morocco is known to be the poorest and least developed state in North Africa, facing enormous social problems.
Also other organisations are calling for protests. A grouping of the political opposition, trade unions, human rights organisations and an association of the unemployed has issued a statement calling for rallies and demonstrations to be held next Saturday, 5 February.
Also, the Labor Council of the Democratic Labour Confederation of Morocco has called for Sunday 6 February to be a day of protest. Marches are planned for in the south-eastern town of Ouarzazate "to protest the inhumane living conditions in Morocco."
As the calls for protests are widening in Morocco, the regime is increasingly insecure. King Mohammed VI has met with French government officials and his most trusted military leaders in his private chateau outside Paris to discuss the security situation.
Several unconfirmed reports from Morocco and occupied Western Sahara agree that security forces now are being pulled out from the occupied territory to be deployed in Morocco-proper in preparation of a possible popular revolt.
The reported regrouping of Moroccan troops may leave Western Sahara - a territory whose indigenous Saharawi population is always ready to revolt - open to rebellion. Security forces stationed in Western Sahara are famed for great brutality against civilians, which could bode unwell for protesters trying to organise marches in Morocco. (SPS)
baboon
12 years 4 months ago
In reply toWelcomebylibcom.org
Submitted bybaboonon February 3, 2011
According to the ICC's French
According to the ICC's French website a strike by hundreds of phosphate workers in Algeria started yesterday over pay and conditions. The day before saw strikes of paramedics and education workers followed by between 80 and 100% of the workers involved from the country to the cities.
Thousands of students have taken to the streets denouncing the "assassins" of the government and shouting slogans against corruption.
Mark.
12 years 4 months ago
In reply toWelcomebylibcom.org
Submitted byMark.on February 4, 2011
Djibouti protest
Djibouti protest
Mike Harman
12 years 4 months ago
In reply toWelcomebylibcom.org
Submitted byMike Harmanon February 4, 2011
Not sure if it was on here
Not sure if it was on here yet, but Senegal implemented price adjustment measures, didn't see any sign it was in response to protests in Senegal, looked more like a 'just in case' measure, but that's the first I've heard from sub-saharan Africa in terms of responses.
Light relief, nice animation but the voice over is lacking:
http://www.markfiore.com/political-cartoons/watch-egypt-middle-east-revolution-mubarak-yemen-saudi-arabia-animated-video-mark-fiore-animation
Mark.
12 years 4 months ago
In reply toWelcomebylibcom.org
Submitted byMark.on February 4, 2011
Sudan protest yesterday
Sudan protest yesterday
Mark.
12 years 4 months ago
In reply toWelcomebylibcom.org
Submitted byMark.on February 4, 2011
Quote: The Syrian Revolution
The Syrian Revolution 2011 الثورة السورية ضد بشار الاسدFor All Major European Cities, Canada & USA & Australia: We Are going to Protest Today on the 4th of Feb For the Syrians Freedom. Starts at 1pm In front of All the Syrian Embassies there. Go now and tell all your friends to be there EVEN if they are not from Syria. Thousands of confirmed Protesters are coming. SPREAD THE WORD! Today at 1PM..... GO!
squaler
12 years 4 months ago
In reply toWelcomebylibcom.org
Submitted bysqualeron February 4, 2011
http://globalvoicesonline.org
http://globalvoicesonline.org/2011/02/04/gabon-the-invisible-revolt/
ludd
12 years 4 months ago
In reply toWelcomebylibcom.org
Submitted byluddon February 4, 2011
Demonstrations in Iraq,
Demonstrations in Iraq, police opened fire, injured 3
Mark.
12 years 4 months ago
In reply toWelcomebylibcom.org
Submitted byMark.on February 4, 2011
Contagion effect: will
Contagion effect: will regional protests reach Bahrain?
It looks like the answer is yes, going offthis videoposted up today.
Khawaga
12 years 4 months ago
In reply toWelcomebylibcom.org
Submitted byKhawagaon February 4, 2011
I think the Angry Arab had
I think the Angry Arab had something on Bahrain as well. Can't find it now though... I should've posted it when I read it. Seems like the Bahraini govt. is trying to preempt protests by increasing food subsidies...
Mark.
12 years 4 months ago
In reply toWelcomebylibcom.org
Submitted byMark.on February 4, 2011
Angry Arab correspondent on
Angry Arab correspondent on Bahrain
Bahrain Online on facebook
February 14 statement
We, the Bahraini youth, from all different sects and backgrounds, call the people to unify their position and demand their rights. We call on Bahrainis to take to the streets on Monday 14 February in a peaceful and orderly manner. The time of waiting has ended, and the time of action is now. If we do not demand our rights by our own hands then no one will grant them to us. We have witnessed our brothers in Tunisia and Egypt carry the banner of freedom and justice. For what is the value of life without freedom? And how will we have our dignity without justice? Change will not come without sacrifice, so let us sacrifice for the sake of our future and the future of our people...
Mark.
12 years 4 months ago
In reply toWelcomebylibcom.org
Submitted byMark.on February 5, 2011
Day of rage in Syria Protests
Day of rage in Syria
Protests in Syria?
Demonstrations in Jordan but little in Syria on day of rage
Calls for weekend protests in Syria
Mark.
12 years 4 months ago
In reply toWelcomebylibcom.org
Submitted byMark.on February 5, 2011
Algeria opposition bent on
Algeria opposition bent on protest despite government move
Algerian opposition groups said on Friday they would probably go ahead with a planned protest march next week despite promises from the president to heed some of their demands and allow more political freedoms. President Abdelaziz Bouteflika, keen to stop uprisings in Egypt and Tunisia spreading to his energy-exporting state, said on Thursday he would give the opposition air time on television and soon lift a 19-year-old state of emergency.
"I believe we will march as Bouteflika's new measures did not convince us," said Rachid Malawi, head of the independent union of civil servants and one of the protest organizers.
"I don't think this government is serious about implementing democracy in Algeria," he told Reuters.
A coalition of civil society groups, small trade unions and some opposition parties had been planning to hold a protest march in the capital on Feb. 12 to demand a change of government and reforms including the lifting of emergency powers.
The protest is not backed by Algeria's main trade unions or the biggest opposition forces -- the FFS party and Islamist parties which were banned in the early 1990s but still retain some influence.
Officials have said they will not give permission for a march for reasons of public order, potentially setting the stage for clashes with riot police. The authorities have said the protesters can instead hold a protest in a designated venue.
"We will march because Bouteflika did not accept our demand to lift the state of emergency without conditions," said Mohsen Belabes, a spokesman for the opposition RCD party.
"Algiers is the safest city in Algeria but Bouteflika is against allowing marches in Algiers.
"
The state of emergency had been cited as the grounds for banning marches across Algeria, but Bouteflika said on Thursday that restriction would stay in force in the capital.
Several members of the opposition coalition told Reuters they would meet in the next few days to reach a final decision on the protest and what form it would take…
Mark.
12 years 4 months ago
In reply toWelcomebylibcom.org
Submitted byMark.on February 5, 2011
Palestine snapshot: will
Palestine snapshot: will Egypt and Tunisia examples bring change?
Hamas worried upheaval in Arab world will spill into Gaza
Hamas leaders in the Gaza Strip are concerned about the effects of the upheaval in the Arab world, as Facebook messages call on Gaza residents to demonstrate against Hamas rule on Friday [4 February].
Several thousand people have joined the Facebook group calling for a protest against Hamas rule in the Gaza Strip. Another Facebook group is calling for protests against the Palestinian Authority in the West Bank. Far fewer people have expressed interest in that page, but Palestinian leaders in the West Bank also recognize that the protests in Tunisia and Egypt could spill over into Palestinian territory.
...
In Gaza City, Hamas police used force earlier this week to disperse a small rally showing solidarity with Egyptian protesters. Police officers dressed in civilian clothing arrested six women and detained some 20 others, according to Human Rights Watch.
The women were taken to a police station, where policewomen insulted them and slapped one of them during an interrogation, according to the report. The protesters were told not to demonstrate again without Hamas police authorisation...
Mark.
12 years 4 months ago
In reply toWelcomebylibcom.org
Submitted byMark.on February 5, 2011
(No subject)
[youtube]5eqyOSWfZ0k[/youtube]
Mark.
12 years 4 months ago
In reply toWelcomebylibcom.org
Submitted byMark.on February 6, 2011
Police beat and tear gassed
Police beat and tear gassed students protesting in Sudan's Sennar state
Around 200 students, protesting against price rises and calling for change, tried to rally outside Sennar university on Thursday afternoon, before officers moved in with batons and then surrounded the compound, witnesses told Reuters.
Sudan has used armed riot police to disperse a series of demonstrations by young Sudanese across the north of the country in recent weeks.
Protests earlier last month focused on food prices and human rights abuses and broadened to include calls for political change after images of massed protests in Cairo, Tunis and other cities were broadcast across the world...
Mark.
12 years 4 months ago
In reply toWelcomebylibcom.org
Submitted byMark.on February 5, 2011
Saudi women demonstrate to
Saudi women demonstrate to demand release of longtime prisoners
About 40 women staged a rare demonstration in the Saudi capital Saturday, demanding the release of prisoners being held without trial as part of the kingdom's efforts to fight al-Qaeda insurgents, activists said.
The black-clad women gathered in front of the Interior Ministry in central Riyadh amid a heavy police presence. One held up a poster reading, "God, free our prisoners."
Activist Mohammed al-Qahtani said later that the women's focus was on those imprisoned in a campaign against terrorism in 2003-04. "Many people have been held for a long time without trial or have nothing to do with al-Qaeda," he said.
…
In another unusual sign of rising discontent in Saudi Arabia, a group of Saudi Web activists has launched an online campaign calling for political reform in the world's biggest oil exporter.
The campaign, launched Jan. 29 on Facebook, calls for a constitutional monarchy, an end to corruption, an even distribution of wealth and a serious solution for unemployment, among other demands.
"Before it is too late, I call the government, and the king, to reform the country and heed our requests ... if they wish to continue ruling this country," one group member, Safaa Jaber, posted on the group's Facebook wall Friday.
Activists in Egypt have used social media Web sites to rally supporters and coordinate protests.
Saudi Arabia does not allow public dissent. Last month, police detained dozens in the port city of Jiddah after they protested against poor infrastructure following deadly floods.
| https://libcom.org/comment/416439 |
District of Maryland | Three Alleged Members of the Violent Extremist Group “The Base” Facing Federal Firearms and Alien-Related Charges | United States Department of Justice
Press Release
Three Alleged Members of the Violent Extremist Group “The Base” Facing Federal Firearms and Alien-Related Charges
For Immediate Release
U.S. Attorney's Office, District of Maryland
Greenbelt,Maryland – A federal criminal complaint has been filed charging three alleged members of the racially motivated violent extremist group “The Base” with firearms and alien-related charges. The complaint charges Brian Mark Lemley, Jr., age 33, of Elkton, Maryland, and Newark, Delaware, and William Garfield Bilbrough IV, age 19, of Denton, Maryland, with transporting and harboring aliens and conspiring to do so. Lemley is also charged with transporting a machine gun and disposing of a firearm and ammunition to an alien unlawfully present in the United States. Further, the complaint charges Lemley and Canadian national Patrik Jordan Mathews, age 27, currently of Newark, Delaware, with transporting a firearm and ammunition with intent to commit a felony. The complaint also charges Mathews with being an alien in possession of a firearm and ammunition. The complaint was filed January 14, 2020, and was unsealed today upon their arrests by the FBI.
The defendants are expected to have initial appearances beginning at 2:45 p.m. today in U.S. District Court in Greenbelt, 6400 Cherrywood Lane, before U.S. Magistrate Judge Charles B. Day.
The criminal complaint was announced by United States Attorney for the District of Maryland Robert K. Hur; United States Attorney for the District of Delaware David C. Weiss; Special Agent in Charge Jennifer C. Boone of the Federal Bureau of Investigation, Baltimore Field Office; and Special Agent in Charge Rob Cekada of the Bureau of Alcohol, Tobacco, Firearms and Explosives (ATF) Baltimore Field Division.
The affidavit filed in support of the criminal complaint alleges that on August 19, 2019, Mathews unlawfully crossed from Canada into the United States near the Manitoba/Minnesota border. On August 30, 2019, Lemley and Bilbrough allegedly drove from Maryland to Michigan in order to pick up Mathews, and all three men returned to Maryland on August 31, 2019.
As detailed in the criminal complaint, on November 3, 2019, the three men drove from Virginia to the Eastern Shore of Maryland, where Bilbrough resided. Lemley and Mathews then continued to the area of Elkton, Maryland, where Lemley obtained a motel room for Mathews. The following day, Lemley drove Mathews to Delaware, where Lemley rented an apartment in which the two have resided since that time.
According to the affidavit, during December 2019, Lemley and Mathews used an upper receiver ordered by Lemley, as well as other firearms parts, to make a functioning assault rifle. Also in December, Lemley, Mathews, and Bilbrough allegedly attempted to manufacture a controlled substance, DMT, at Lemley and Mathews’s apartment. Furthermore, Lemley, Mathews, and Bilbrough discussed The Base’s activities and spoke about other members of the organization. Mathews also allegedly showed the assault rifle to Bilbrough, who examined the assault rifle and returned it to Mathews.
In January 2020, according to the affidavit, that Lemley and Mathews purchased approximately 1,650 rounds of 5.56mm and 6.5mm ammunition; traveled from Delaware to a gun range in Maryland, where they shot the assault rifle; and retrieved plate carriers (to support body armor) and at least some of the purchased ammunition from Lemley’s prior residence in Maryland.
If convicted, Lemley and Bilbrough each face a maximum sentence of five years for transporting and harboring certain aliens, and 10 years for conspiracy to do so. Lemley also faces a maximum of five years in prison for transporting a machine gun in interstate commerce, and a maximum of 10 years in federal prison for disposing of a firearm and ammunition to an illegal alien. Lemley and Mathews each face a maximum of 10 years in federal prison for transporting a firearm and ammunition in interstate commerce with intent to commit a felony offense. Finally, Mathews faces a maximum of 10 years in federal prison for being an alien in possession of a firearm and ammunition. Actual sentences for federal crimes are typically less than the maximum penalties. A federal district court judge will determine any sentence after taking into account the U.S. Sentencing Guidelines and other statutory factors.
A criminal complaint is not a finding of guilt. An individual charged by criminal complaint is presumed innocent unless and until proven guilty at some later criminal proceedings.
United States Attorneys Robert K. Hur and David C. Weiss commended the FBI Baltimore Joint Terrorism Task Force (JTTF) and ATF for their work in the investigation, and thanked U.S. Homeland Security Investigations, the Maryland Department of Natural Resources, the Maryland State Police, and the Delaware State Police for their assistance. Mr. Hur and Mr. Weiss thanked their offices’ national security prosecutors, who are handling the case.
# # #
Topics
Firearms Offenses
Immigration
National Security
Component
USAO - Maryland
Superseding Indictment Charges Maryland Man with Wire Fraud, Identity Theft, and Drug-Related Counts, in Addition to Original Charges for COVID-19 Cares Act Unemployment Benefits Fraud and Illegal Possession of a Firearm
Press Release
Prince George’s County Felon Sentenced to Seven Years in Federal Prison for Two Counts of Illegal Possession of a Firearm
| https://www.justice.gov/usao-md/pr/three-alleged-members-violent-extremist-group-base-facing-federal-firearms-and-alien?fbclid=IwAR04MbkJo0WLp7Gt9k4eAeRDDJgVul0GHwBJXbVcNLauduj3FjK3EQ2nfTU |
Adalah Legal Center for Arab Minority Rights in Israel v. Minister of Religious Affairs | Cardozo Israeli Supreme Court Project
HCJ 1113/99
Adalah Legal Center for Arab Minority Rights in Israel v. Minister of Religious Affairs
Decided:
April 18, 2000
Type:
Original
Topics:
Constitutional Law -- Basic Law: Human Dignity and Liberty , -- Equality Before the Law
ABSTRACT
Facts: The primary question raised in the petition: was whether the Ministry of Religious Affairs was violating the principle of equality in its allocation of funds for the maintenance of cemeteries. Among other claims, the petitioners claimed in their petition that the relative proportion of the Arab communities in the budget of the Ministry of Religious Affairs does not reflect their relative proportion in the population.
Held: The Court held that the Ministry of Religious Affairs is to operate in allocation of funds in the Ministry of Religious Affair’s budget for cemeteries on the basis of the principle of equality, as detailed in the judgment. The Court ordered the Ministry of Religious Affairs to allocate the money in its budget for the year 2000, for cemeteries of members of the various religions, in an equal manner. However, the court decided that under the circumstances of the present case there was not a justification to order that money be paid from the budget of the Ministry of Religious Affairs for the purpose of maintenance of Arab cemeteries for the year in which the petition was filed (1999). The Ministry of Religious Affairs was ordered to pay the petitioner court expenses in the amount of 20,000 NIS.
JUSTICES
Zamir, Itzchak Primary Author majority opinion Barak, Aharon majority opinion Beinisch, Dorit majority opinion
Justice I. Zamir
1. The petitioner is an association whose purpose is to advance the rights of the Arab minority. It claims that in the budget year 1999 the Arab minority is not receiving from the Ministry of Religious Affairs funds for cemetery maintenance, which it is entitled to receive, inter alia, based on the principle of equality. The following is the primary issue which arises from the petition: is the Ministry of Religious Affairs violating the principle of equality in the allocation of funds for the maintenance of cemeteries?
The Background to the Petition
"The relative proportion of the Arab communities in the budget of the Ministry of Religious Affairs does not reflect their relative proportion in the population, and in any case is not sufficient to fulfill their needs. This discrimination in allocation of resources... violates the right of the Arab minority to respect, to freedom of religion and conscience, and the necessary conclusion from this is that these budget sections and others are to be declared unconstitutional, while also declaring that the Arab communities are entitled to a budget appropriate to their proportion in the population."
In the judgment that was handed down in that petition the Court agreed that it would appear that the funds that were allocated in the budget of the Ministry of Religious Affairs for the religious purposes of the Arab population are not in proper proportion to the proportion of that population in the general population. Justice Cheshin said the following on this matter (at p. 178):
". . . The Arab communities constitute about 20% of the State's population, but the Ministry of Religions only allocates 2% of its budget for their religious needs. Regarding this disparity one is to say res ipsa loquitur."
At the conclusion of the decision Justice Cheshin added (at p. 192):
"Reading the petition raises genuine challenges which it is proper and appropriate to try and find a way to resolve... The program that the Ministry of Religions initiated at the time was titled ‘One Law.’ Let us remember from where the name of the program was taken: "there shall be one law for you, for the stranger as for the citizen it shall be, as I am the Lord your G-d" (Leviticus 24, 22). [30]
Despite this, the Court denied the petition. The reason for the denial was that the petition was not focused on a particular matter, with a proper basis on facts, in such a manner that the court could examine the factual foundation, determine if it proves discrimination, and decide accordingly what the proper remedy should be. In the words of Justice Cheshin (at 171):
"The petitioners preferred to spread out their arguments and their complaints from one end to the other -- from the east end to the west end -- and on the basis of these claims they have asked us to declare as void a law of the Knesset. This is not the way and this is not the Court’s way of doing justice."
What then is the proper path to be taken? As one can see from the decision, it was proper for the petitioners, in their struggle for equality in the allocation of funds for the Arab population, to focus on one issue, for which they would properly prepare a factual foundation, which the Court could then properly review.
The petitioner understood one thing from another and filed this petition, which focuses on the claim of breach of equality in allocation of funds for the maintenance of Arab cemeteries. On the basis of this claim it petitions for specific sections in the Budget Law for the year 1999, relating to the allocation of funds for the maintenance of cemeteries, to be declared void.
The petition raises additional claims in support of the petitioner’s position. It claims that those sections violate human dignity, as established in the Basic Law: Human Dignity and Liberty as well as other rights of Arabs, including freedom of religion and conscience. However, these arguments, in the manner put forth in the petition, are not forceful, and in any case, we have found that it is not necessary to consider them in this petition.
The first question, which must be answered in this petition, is whether the Ministry of Religious Affairs is obligated to allocate funds, from the Ministry’s budget, in an equal manner to all segments of the population, without distinction as to religion or nationality.
The Principle of Equality in the State Budget
3. In the Declaration of the Establishment of the State of Israel [28] it was stated that the state “will ensure complete equality of social and political rights to all its inhabitants irrespective of religion, race, or sex.” One of the expressions for the principle of equality is, as was stated in the Declaration, that the state “will safeguard the Holy Places of all religions.” In that vein, the Declaration calls “to the Arab inhabitants of the state of Israel to preserve peace and participate in the upbuilding of the State on the basis of full and equal citizenship.” Therefore, from the State of Israel’s first day, the declaration established the principle of equality as one of the basic values of the State. Over the years, the principle of equality was established and developed, via legislation and case law, and has also earned for itself, beyond the status of a basic value, the status of a basic right. (See I. Zamir, M. Sobel ‘Equality before the Law’ [24]).
The principle of equality binds every public entity in the State. First, it binds the State itself. The principle of equality applies to all the areas in which the State operates. It applies first and foremost to the allocation of the State’s funds. The resources of the State, whether in land or money, as well as other resources, belong to all citizens, and all citizens are entitled to benefit from them in accordance with the principle of equality, without discrimination on the basis of religion, race, gender or other illegitimate consideration.
The principle of equality must also guide the legislative authority, which too, like any other authority in the State, must act as a fiduciary to the public in accord with the basic values of the State of Israel as a Jewish and democratic state, which include equality. This is the case in each and every law, and this is also the case in the Budget Law.
However it is not sufficient that the laws of the State fulfill the principle of equality, rather, it is no less important than this that the implementation of the laws be consistent with this principle. This is the case for every law, so too the Budget Law. Indeed, since the laws of the State generally fulfill the principle of equality, the primary threat to this principle stems from the implementation of the law. The threat is particularly severe in implementation of the Budget Law. From a practical standpoint, in implementing the Budget Law the relatively easy possibility exists, occasionally to the point of temptation, of discrimination in allocation of funds by state authorities, on the grounds, inter alia, of religion or nationality. Such discrimination, particularly if it is methodical, may cause very severe damage, not only to a specific person or a specific entity, but also to the social fabric and the feeling of partnership which is a pre-condition for proper living in community. In any event, such discrimination is illegitimate at its core, from both a moral as well a legal perspective.
4. Recently the Court has clarified well the prohibition on discrimination on the grounds, among others, of religion or nationality, in the allocation of state funds. In HCJ 6698/95 Ka’adan v. Israel Land Administration [2], the claim was made of illegitimate discrimination against an Arab, because he was an Arab, in the allocation of state lands. In that instance the State allocated land to the Jewish Agency for Israel, and on that land, the Jewish Agency established a communal settlement, the settlement of Katzir, which would only enable land purchase and home construction in the settlement to Jews. In the judgment President Barak stated (in paragraphs 23, 24, 31, 34):
“The State’s obligation to act in accordance with the principle of equality applies to all of its actions. As such, it also applies to the allocation of state land . . . all agree that equality precludes different treatment on the grounds of religion or nationality. . . There is, therefore, no contradiction between the values of the State of Israel as a Jewish and democratic state and between the absolute equality of all of its citizens. Indeed, the opposite is true: the principle of equal rights for all people in Israel, irrespective of their religion or nationality, stems from the values of the State of Israel as a Jewish and democratic state. . . The State’s duty to respect equality in allocating rights in land is violated by the transfer of land to a third party that itself discriminates on the basis of nationality or religion. The State cannot escape its obligation to respect the principle of equality merely by going through a third party that acts according to a discriminatory policy. What the State cannot do directly, it cannot do indirectly.”
Therefore the Court declared that the State was prohibited from allocating the land to the Jewish Agency for the purpose of establishing the communal settlement on the basis of discrimination between Jews and those who are not Jews.
5. Discrimination on the basis of religion or nationality in allocation of state funds, which is even prohibited if it is done indirectly, certainly is a fortiori prohibited when it is done directly. A marked example is discrimination in allocation of funds from the state budget by a government office. In HCJ 59/88 Tzaban v. Minister of Finance (at p. 706) [3] Justice Barak stated:
"Budget funds are state funds. Government authorities authorized to use them do not have the right to do with them as they please. Government authorities are fiduciaries of the public, the expenditure and distribution of these funds must be done in a manner that is consistent with this trust... Support must be provided based on principles of reasonableness and equality."
Indeed, it is standard for budget funds not to be sufficient for all the needs and all the needy, and therefore it is necessary to allocate funds according to a list of priorities which create differences between one person and another and between one group and another. But the preferences and the differences must be based on relevant considerations which are consistent with the principle of equality, and not illegitimate considerations, such as, religion or nationality. Justice Mazza clarified this in HCJ 205/94 Nof v. Ministry of Defence [4] (at p. 463), and he stated as follows:
The duty incumbent on all authorities to allocate state funds in an equal manner is expressed in the Budget Principles Law, 5745 – 1985. Section 3a of this law coordinates provision of support by government offices from the state budget to public institutions operating for purposes of education, culture, religion, and more. It establishes that such support will be distributed exclusively "according to egalitarian criteria."
The principle of equality in allocation of funds from the state budget is not limited to the provision of support to public institutions, as established in section 3a of the Budget Principles Law, but it also applies, even without a law that establishes this explicitly, in allocation of funds from the state budget in another manner, and for other purposes. This was recently stated, for example, in HCJ 1703/92 C.A.L. Freight Airlines Ltd v. The Prime Minister [5] as to the provision of a subsidy for the funding of security expenses for airlines, and it was also so stated in HCJ 1/98 MK Eitan Cabel v. Prime Minister of Israel [6] (paragraph 28 of the decision of Justice Cheshin) as to provision of support for the building of rental apartments.
In HCJ 2422/98 Adalah Legal Center for Arab Minority Rights in Israel v. Minister of Labor and Social Affairs [7] the petitioners claimed that the Ministry of Labor and Social Affairs was acting in a discriminatory manner in the allocation of funds from the Ministry's budget for the support of the needy during the period leading up to the Passover holiday (in the framework of operation "Passover Flour"), and was not allocating funds for the Arab needy during their holiday times. The Ministry of Labor and Social Affairs acknowledged its duty to act in an equal manner in the provision of support for the needy of different religions. As a result, the parties reached an agreement according to which the Ministry of Labor and Social Affairs would amend the criteria relating to support of needy families on the occasion of the Passover holiday such that it would also apply to members of other religions. The Court granted the parties’ application and granted the agreement the status of a judgment.
6. From the general to the specific. It is clear that the Ministry of Religious Affairs must act in an egalitarian manner when it allocates funds from the Ministry’s budget to provide for the religious needs of members of the various religions. In fact, there are differences in the religious needs of members of the different religions: each religious community has holidays of its own, tradition of its own, institutions of its own and needs of its own. It is possible and appropriate to take these differences into consideration, in connection with the allocation of funds from the State budget, out of a desire to provide for the special religious needs of each and every community. (See for example HCJ 98/54 Lazarovitch v. Jerusalem Food Inspector [8] (at 55-56); HCJ 200/83 Wathad v. Minister of Finance [9]). Therefore, allocation of funds from the state budget for the satisfaction of religious needs does not need to be equal in the formal sense. It must be equal in the substantive sense. An unequal allocation of funds can still be equal in a substantive sense.
However, from a substantive perspective, the differences that exist between living individuals, members of different religions, are blurred for deceased individuals of those same religions. The dignity of deceased individuals, which is derived from the dignity of living individuals, requires that the cemetery where they are buried be well-kept and well-maintained, and this is one and the same whether Jews, Muslims, Christians, or Druze are buried there. Therefore, substantive equality, relating to allocation of funds from the State budget for the maintenance of cemeteries, approximates formal equality.
Indeed, counsel for the Minister of Religious Affairs wholeheartedly agreed that the equality imperative also applies to the Ministry of Religious Affairs in the allocation of funds for the maintenance of cemeteries.
The question is, and opinions differ on this, whether the Ministry of Religious Affairs breached the equality imperative in its allocation of funds for the maintenance of cemeteries. In order to answer this question, it must be ascertained first what the directives of the Budget Law are as they pertain to the support of the Ministry of Religious Affairs for the maintenance of cemeteries, and then, how the Ministry implemented the law’s directives.
The Law's Directives
7. The petitioner aims its arrows at two paragraphs in the budget of the Ministry of Religions (section no. 22) in the Budget Law of 1999: the first, which is found in Chapter (02) of Religious Services, is section 02-17 that deals with cemeteries; the second, which is found in Chapter (08) of Religious Sites, is section 08-20 which also deals with cemeteries. These sections are, according to the petitioner's claim, the root of the discrimination against Arabs as relates to cemeteries. To be precise, the petitioner does not claim discrimination against the Druze, who received in a separate budget in 1999 a relatively large sum (6 million NIS) for their cemeteries. The petitioner makes claims therefore, in the name of Muslim Arabs and Christian Arabs. These Arabs, according to its claim, receive from the Ministry of Religious Affairs only a small portion of the funds allocated for cemeteries, which does not reflect the relative proportion of Arabs in the general population.
The respondents claim, in turn, that the Budget Law itself, in the sections which relate to cemeteries, including sections that were not mentioned by the petitioner, does not discriminate between Jews and those who are not Jews, and that the implementation of the law by the Ministry of Religious Affairs also does not create such discrimination. In fact, they claim, the Arabs receive for their cemeteries the full proportional share they are entitled to of funds that are allocated for these purposes.
What, then, does the Budget Law establish as pertains to cemeteries?
8. The two sections in the budget of the Ministry of Religious Affairs, on which the petition relies, state (in the expenditure page) as follows:
02--17
Cemeteries
403 Thousand NIS
02--17—14
Contribution to the budget of cemetery councils
201 Thousand NIS
02--17—15
Evacuation, relief, burial
202 Thousand NIS
16,457 Thousand NIS
08--20—12
Development of cemeteries
8025 Thousand NIS
08--20—13
Development of cemeteries for alternative burial
868 Thousand NIS
08--20—15
Reserves for cemeteries
2508 Thousand NIS
08--20—17
Reserve for a master plan for multi-level burial
5056 Thousand NIS
9. The petitioner claims that these two sections allocate money for Jewish cemeteries only, and therefore it asks that the Court determine that they are unlawful. In my opinion, it is neither necessary nor appropriate to determine that these sections are unlawful and that, therefore, they are void.
First, the Budget Law is a law, and the Court, respectful of the dignity of every law, is not willing to declare a directive in the law void unless it contradicts a directive with constitutional status. Indeed, the Budget Law is a unique law, and has special status in relation to the Budget Principles Law, 5745 – 1985. Indeed, the question has come up whether or not the Court has the grounds to declare as void a directive in an annual budget law which contradicts a directive in the Budget Principles Law, 5745 – 1985. (See HCJ 1438/98 Conservative Movement v. Minister of Religious Affairs [10]). However, that is not the question in the case before us. In the case before us the question is more difficult. The question is, whether the Court has the grounds to declare as void a directive in an annual budget law, even when it does not contradict a directive in the Budget Principles Law, for the reason that it violates the principle of equality. As said, the Court is not willing to declare as void a directive in the law unless it contradicts a directive with constitutional status. Such are the directives of the basic laws. However, there is not a directive in the basic laws, which specifically establishes the principle of equality. Indeed, there is a view, which also includes the view of judges, that human dignity, which was established as a directive in the Basic Law: Human Dignity and Liberty, includes by deduction the principle of equality. But this view has not risen to the status of law. Therefore, it does not consist, in its status today, of enough to declare as void a directive in the Budget Law, even if that directive violates the principle of equality.
Second, even if one section or another in the Budget Law allocates money for the needs of Jews alone, such as for the cemeteries of Jews alone, this still is not sufficient to indicate that it violates the principle of equality. After all, it is possible that along with this section there will be another section that will allocate money for the needs of Muslim Arabs, or the needs of Christian Arabs, in a manner that will not violate the equality between members of different religions. For example, in the budget of the Ministry of Religious Affairs for 1999 there are to be found, in the framework of allocation for religious services (section 02), the following sections: Religious Services for Karaites (section 02 -- 31), the Druze Religious Council (section 02 -- 32), Religious Services for Muslims (section 02 -- 33), Religious services for Christians (section 02 -- 34), and more. Are there grounds to say that a section which allocates money for Karaites or for Muslims, for needs related to religion, violates the principle of equality and therefore is to be declared void? In order to determine if there has been a violation of the principle of equality the full picture must be seen, namely the full budget, and a partial picture is not sufficient, namely just one section of the budget. Accordingly, one must see whether a section in the Budget Law which explicitly allocates money to members of a specific religion, or to members of another group, is not balanced out by other sections in the Budget Law, in a manner that realizes equality. From now on it is to be said that even if it were established explicitly in section 02-17 and in section 08 – 20, that they allocate money only to Jewish cemeteries, this would still not be sufficient to indicate that they violate the principle of equality, as long as the Budget Law, in an overall manner, fulfills this principle.
This is all the more so, when these two sections, based on their wording, refer to cemeteries and not to cemeteries for members of a certain religion. It is known, that it is a broad rule that it is proper to interpret every law, where the language and context permit, in a manner that will be commensurate with the basic values of the legal system, including the principle of equality. Certainly it is proper to do so before declaring as void a directive in the law as a result of violation of such a value. Therefore, this is also the appropriate action to be taken as to section 02 -- 17 and section 08 -- 20 in the budget of the Ministry of Religious Affairs.
The conclusion is that it is neither appropriate nor necessary for the court to determine, as per the petitioner’s application, that these two sections are unlawful and therefore void.
If so, the question that needs to be clarified is whether the Ministry of Religious Affairs is implementing the Budget Law, in all that pertains to cemeteries, in a manner that fulfills the principle of equality.
Implementation of the Law
10. The Ministry of Religious Affairs claims that it distributes the funds that were allocated in the Budget Law for cemeteries in a manner that fulfills the principle of equality and does not discriminate between Jewish cemeteries and other cemeteries.
The rule is that any discrimination is illegitimate, even if it is denied. Camouflage will not salvage discrimination. The substance and not the form are determinative. As Justice Berinson has said in a different context, HCJ 98/54 Lazarovitch v. Jerusalem Food Inspector [8] at p. 47: "This Court examines, as usual, both the external form and the internal substance of the acts of the authorities, the peel and the insides together, and will not leave as is, acts which indeed are wrapped in kosher outer clothing but whose insides are not as their outsides." From here on in it is to be said that it is sufficient that a government office implements the Budget Law in a manner that creates prohibited discrimination, for example on the basis of religion or nationality, to invalidate the implementation, and the fact that intent to discriminate was not proven or that intent to discriminate was denied is not sufficient to validate the discrimination. Attractive words are not sufficient to validate bad acts. The illegitimacy in discrimination is embodied within the act of discrimination. (See HCJ 1/98 MK Eitan Cable v. Prime Minister of Israel [6] (paragraph 21 of the judgment of Justice Cheshin). See also HCJ 392/72 Berger v. District Committee for Building and Planning, Haifa Region [11] (at p. 770); HCJ 118/62 Landau v. Minister of Agriculture [12] (at p. 2544); HCJ 953/87 Poraz v. Mayor of Tel Aviv -- Jaffa [13] (at p. 334)).
11. The primary facts as to the implementation of the sections in the Budget law that pertain to cemeteries are not in dispute. And these are the facts:
A. Section 02 -- 17 -- 14 establishes an amount of 201,000 NIS as "participation in the budget of the cemetery councils." However, in practice, a cemetery council has only been established for Jews in Jerusalem. See the Council of Jewish Cemeteries in Jerusalem Regulations 5727-1967. Therefore the Ministry of Religious Affairs allocated the entire amount to participation in the budget of the Jewish Cemeteries in Jerusalem Council.
B. Section 02 -- 17 -- 15 allocates the amount of 202,000 NIS for removal of fatal casualties in times of emergency. It is clear that in this matter there is no difference between fatal casualties on the basis of religion or nationality. In practice, during calm times this section is used for the purchase of equipment for times of emergency. This is how it has been for the past few years. The result is that in practice this section does not serve the needs of cemeteries. However there are no grounds to say that use of this section is discriminatory.
C. Section 08 -- 20 – 12 allocates the amount of 8,025,000 NIS to the "development of cemeteries.” The Ministry of Religious Affairs has established criteria for distribution of sums according to this section, and has not limited them to Jewish cemeteries. This is so in theory. However, in practice, out of this sum, 2,000,000 NIS has been allocated by the Ministry of Religious Affairs to restore the ancient cemetery in T’zfat (which is a Jewish cemetery) and the cemetery in Mount Olives in Jerusalem (also a Jewish cemetery), the remainder of the sum is distributed among 120 religious and regional councils, all of them Jewish. In practice there is not a single Muslim or Christian religious or local council that received money on the basis of this section.
D. Section 08 -- 20 -- 13 establishes the amount of 868,000 NIS for "the development of cemeteries for alternative burial," in accordance with the Right to Alternative Civilian Burial Law, 5756-1996. This law was intended, as was stated in the explanatory note of the Bill, "to solve the problem of the burial of Jews, those who are not Jews or members of other recognized religious communities, who desire a burial that will take place according to their principles and worldview." (See Hatza'ot Chok--Official Gazette-Bills No. 2520, 5756-1996 at p. 600). However, the petitioner claims that in fact, Arabs do not need and will not request for themselves alternative civilian burial. Indeed, as can be seen from the response of the Ministry of Religious Affairs, to date there has not been a request on behalf of Arab entities, and it is not known of a request by Muslims or Christians, to use alternative burial services. It appears therefore that the section will not serve, and in any event will not serve in a significant manner, the burial needs of Arabs, at least in the near future.
E. Section 08--20 -- 15 allocates the amount of 2,508,000 NIS as "reserve for cemeteries." This section is designated for general development of Jewish cemeteries only.
F. Section 08--20 -- 17 was established as "reserve for a master plan for multi-level burial" and allocates the amount of 5,056,000 NIS for this purpose. To date, this section served to implement this program in Jewish cemeteries in the large cities (Jerusalem, Tel Aviv and Haifa). The Ministry of Religious Affairs notes that "in the future expanding the program to additional communities and additional religious communities will be considered"; and is of the opinion that half of the sum that was determined in this section is to be seen as a sum that is not designated specifically for members of a certain religion. However, in response to the petitioner's questions, the Ministry stated that it does not know of an Arab community in which there will be multi-level burial in the said budget year, and that no amount of money based on this section has ever been allocated to an Arab community, and that no request has been submitted on behalf of an Arab community to implement multi-level burial. It is clear, therefore, that in said budget year this section will not serve the burial needs of Arabs at all. Moreover, the likelihood that this section will serve the burial needs of Arabs in the near future is not great, among other reasons because the land shortage, which incentivizes multi-level burial, exists primarily in the large cities, and not in Arab communities.
In conclusion, of the budget of the Ministry of Religious Affairs designated for cemeteries in the year 1999, in section 02 -- 17 and in section 08 -- 20, only the amount of 202,000 NIS, which is designated for clearing of fatal casualties in times of emergency, and which appears not to be used to maintain cemeteries, may also serve a population that is not Jewish. The remainder of the amount, namely, the amount of 16,658,000 NIS serves Jewish cemeteries entirely (or almost entirely).
What is the reason that Arab, Muslim and Christian cemeteries, which serve more than one sixth of the total population in Israel, do not receive their portion of budget sections designated to serve cemeteries? We have not heard any reason from the Ministry of Religious Affairs that would explain why it has implemented these sections in a manner that seemingly violates equality.
12. The Ministry of Religious Affairs claims that this is only seemingly so but not so in practice, as, in the budget of the Ministry there is an additional section, section 08 -- 21, which is also utilized for Arab cemeteries. This section allocates the amount of 6,375,000 NIS for “religious structures of non-Jewish communities," and out of this amount 3,009,000 NIS for Muslim religious structures, 602,000 NIS for Bedouin religious structures, and 2,006,000 NIS for religious structures of Christian communities. What constitute religious structures for purposes of this section? The Ministry of Religious Affairs responds that it includes Mosques, Churches, Holy Places, and more, and this also includes cemeteries. What is the amount that is allocated, in the framework of this section, for cemeteries? The amount of 2,006,000 NIS, which is allocated for religious structures of Christian Communities, serves entirely for the development of religious tourist structures in anticipation of the year 2000, and is not used for cemeteries; although the Ministry of Religious Affairs notes the possibility that an additional budget will be allocated for the purpose of the Ministry’s preparedness for the year 2000, and if it is received, the amount of 300,000 NIS will be set aside for Christian cemeteries. Parenthetically, it is worth noting that from the Ministry of Religious Affairs’ response it appears that both in 1997 and in 1998 no funds were allocated for Christian cemeteries. And as for Muslim religious structures, the Ministry of Religious Affairs estimates that of the amount of 3,009,000 NIS allocated for these structures, the amount of approximately 1,000,000 NIS will be used for cemeteries. Similarly, the amount of 200,000 NIS will be directed to Bedouin cemeteries.
However, even so, this section does not substantively change the picture as to the allocation of funds for Muslim and Christian cemeteries. First, to the extent that this section is also used for Muslim and Christian cemeteries, it is a matter of a small sum relative to the proportion of the Muslims and Christians in the population, which is not sufficient for realizing the requisite equality.
Second, according to the criteria of the Ministry of Religious Affairs, funds from this section are not allocated to a local authority (with the exception of the local authority of Bedouins in the Negev) but rather to one type of religious structure each year. Accordingly, the local authority must choose whether to ask for funds from this section, for example, to renovate a mosque or renovate a cemetery, and cannot ask for funds for both. It appears that here too equality has been harmed, as this is not the case for Jewish religious structures. For them, separate budget sections exist: for example, section 02-15 in which the amount of 2,157,000 NIS is set for “synagogues”, and section 08-13 in which the amount of 38,119,000 NIS is set for the “development of synagogues and ritual baths”.
Third, in the framework of section 08-21 the Ministry of Religious Affairs does not participate in the ongoing maintenance costs of Arab cemeteries, as it does for Jewish cemeteries, but only in the costs of renovation and development of the cemeteries.
Fourth, if we turn to other sections that may be used for Arab cemeteries, such as section 08-21, it is proper to inquire whether there are also other sections which serve Jewish cemeteries. This is the petitioner’s claim. According to its claim, it is also necessary to take into account the budgeting for local religious councils in accordance with the Jewish Religious Services Law [Consolidated Version] 5731-1971. According to section 02-12 in the budget of the Ministry of Religious Affairs, Jewish religious councils receive the amount of 149,827,000 NIS for 1999. As can be seen from the Ministry’s response, about 10% of this amount is used for burial services. It appears that there is no equivalent or similar financing for burial services of Arabs. Therefore, if the budget of the Jewish religious councils is also taken into account, it appears that the inequality in the allocation of funds for Arab cemeteries is only exacerbated.
13. I would like to add a comment to all this. After I turned the Ministry of Religious Affairs’ budget over and over, as would an interpreter of dreams, for the purpose of answering the question what amount was allocated to Jewish cemeteries and what amount to other cemeteries, I felt as though I was getting lost in the midst of the sections and numbers. One can’t see the answer for the sections. Because of the structure and the dispersion of the sections it can be argued one way, as the petitioner does, or otherwise, as the Ministry does, and we don’t have a clear answer.
This is not how a government ministry’s budget should be constructed. The Ministry’s budget should be clear as is to the average person outside the Ministry, including a judge, and not just to those who are in the know in the Ministry of Religious Affairs, or Ministry of Finance. As, after all, the budget is the law of the State, and this is why it benefits from the status and immunity of a law, and this is the law that determines what will be done with the State’s assets, which are the assets of all the citizens. And so, is it not obvious that the law should be clear? The law, including the budget law, should be clear, not only so that any person can read and understand the law, as is the imperative of democracy, but also so that a path will not be opened before the employees of the Ministry, of any ministry, to make inappropriate manipulations of the budget.
Why for example, does section 08 -- 20 refer to "cemeteries" generally, and in its framework section 08 -- 20 -- 12 refers to "development of cemeteries" generally, and seemingly it relates to cemeteries for members of all religions, but the Ministry of Religious Affairs states that development of cemeteries for Muslims is included in section 08 -- 21, which refers to "religious structures for non-Jewish communities"? If section 08 -- 20 is intended to serve only Jewish cemeteries, as is in fact the case, it is appropriate to state this explicitly, and then it is appropriate to establish a separate section for other cemeteries; but the Ministry does not say this, rather it says in its response that section 08 -- 20 also partially serves cemeteries that are not Jewish; if that is the case, why is it necessary to hide Muslim cemeteries also in section 08 -- 21 which deals with religious structures?
It would be proper for the Ministry’s employees who prepare the budget proposal, and no less so for employees of the Ministry of Finance, to take diligent care that the budget law is clearer and more methodical.
14. In any event, there is no need to state specific amounts in order to conclude that the petitioner has shown that inequality exists in the allocation of funds from the budget of the Ministry of Religious Affairs for Jewish cemeteries on the one hand and Arab cemeteries (excluding Druze cemeteries) on the other. The petitioner has shown this with dual significance. First, it has shown this in numerical data from the Budget Law. Second, it has also shown this in descriptions and pictures that were attached to the petition, as to the difficult situation that prevails in Arab cemeteries. The Ministry of Religious Affairs claims in its response that the pictures and descriptions relate to deserted cemeteries, which the Ministry no longer deals with. However, the picture arises from the petition of severe neglect also of Arab cemeteries that are not deserted, if only some of them, and does not give respect neither to the dead nor to the living.
This picture is in line with the picture that arises from a letter of the Attorney General, dated 1.26.95, to the Prime Minister and the Minister of Religious Affairs in which he alerted that "the non-Jewish population [receives] a low proportion of the support budget [of the Ministry of Religious Affairs] without any proportion to its segment in the general population in Israel," and raised a proposal for "more balanced budgeting for the religious needs and the religious judicial services of the non-Jewish communities in the State." Similar things were also said in the Report of the State Comptroller, number 46 from the year 1995 [29], and the following was stated (at p. 287) in it: "in the opinion of the office of the State Comptroller, the Ministry of Religious Affairs is to operate to increase the equality among the various segments of the population, and to ensure that the portion the Muslims have in the budget of the Ministry will match their relative proportion in the population." This Court received a similar impression in the previous petition submitted by the petitioner: HCJ 240/98. See supra paragraph 2.
This being the case, and after the petitioner has shown that the Ministry of Religious Affairs did not fulfill its duty of equality in allocation of funds for cemeteries in the year 1999, the question arises what is the remedy that may and that should be awarded under the circumstances.
The Remedy
The problem does not lie with the principle but with the implementation. The question is, first of all, what is the implementation that is dictated by the principle. Therefore, it is appropriate for the court to explain, in order to remove any obstacles down the road, what the implementation is that is dictated by the principle of equality in the above matter.
Since the Ministry of Religious Affairs, like any public entity, is obligated by the principle of equality in all that it does, it must fulfill this principle already at the phase of the preparation of the proposed budget for the next year. At that phase, the employees of the Ministry, together with the employees of the Ministry of Finance, can act in one of two primary ways. In the first way, the Ministry of Religious Affairs can establish in the budget bill one sum for the cemeteries of all the religions, in order for this amount to be distributed later by the Ministry of Religious Affairs amongst the cemeteries of the various religions, of course in an equal manner. In the second way, the Ministry of Religious Affairs can allocate in the budget bill various amounts to cemeteries according to the various religions, for each religion a set sum.
16. According to the second way, the Ministry of Religious Affairs needs to fulfill the duty of equality already at the bill phase. This means that that the amounts that will be allocated to the cemeteries of the various religions, according to religious affiliation, will match the relative proportion of members of each religion within the population in Israel. And why? Because this proportionality is, in relation to cemeteries, the primary criterion, even if not the only criterion, on the path to equality.
It is appropriate to add, in order to avoid error, several comments as road markers. First, according to the proportionality criterion, the goal for distribution of the money among the cemeteries must be allocation according to the relative proportion of members of each religion in the population, and the result of the distribution of the money must match the said proportion closely. What does this mean? In distributing the money significant deviation from the relative proportion must be avoided; with that, it is doubtful whether it is possible to be exacting as in a mathematical formula, and whether it is necessary to be accurate to the hair's breath, in dividing the money. A slight deviation from the relative partiality does not necessarily mean discrimination.
Second, the criterion of proportionality is not necessarily the only criterion. It is possible to knowingly deviate from this criterion, inter alia, for purposes of affirmative action. Affirmative action of a specific public or specific group, that seemingly violates equality, in fact advances equality. See, for example, HCJ 453/94 Israel Women’s Network v. Government of Israel [14]. It is permitted, and may be appropriate, when it is directed at compensating a weak public or a weak group, which suffers from a situation of sub-equality, in particular if this situation stems from ongoing deprivation, knowing or unknowing, intentional or unintentional. This court so decided, for example, regarding government support for the establishment of permanent settlements for Bedouins: HCJ 528/88 Avitan v. Israel Land Administration [15]. The court determined that it is not illegitimate for such support to be given to Bedouins alone. And this is what Justice Or said (at page 299):
"The principle of equality comes to serve the purpose of achieving a just result. It is neither the ‘technical’ nor ‘the formal’ equality that is to be protected, but rather substantive equality. Meaning, equality among equals. People, or groups of people, differ in more ways than one in their conditions, characteristics, and needs, and at times it is necessary to discriminate between those that are not equal in order to protect the weak person or the needy person, to encourage him and advance him. Equality among those that are not equal is not, at times, anything other than mockery of the poor.”
We need not go far to attest to this. The Ministry of Religious Affairs adopted a five-year plan for advancing the Druze community, and in the framework of this program allocated in said budget year the amount of 6,000,000 NIS for Druze cemeteries. That is an amount that is relatively high compared to the amount allocated to Muslim and Christian cemeteries. It turns out that this is affirmative action that came to compensate the Druze community for lesser support in the past and to advance equality. Therefore, this is not prohibited, as long as such preference is not done at the expense of equality among the other communities. Meaning, affirmative action which benefits the Druze community is not meant to come at the expense, for example, of the Muslim community, in a manner that will create inequality or exacerbate inequality, for example, between Muslims and Jews. In other words, affirmative action toward the Druze does not justify inequality between Muslims and Jews.
Third, the proportionality criterion, in the context of cemeteries, is built primarily on religious affiliation, as burial in Israel is primarily religious burial. However there are exceptions to this. These exceptions have recently received legitimacy in the law: the Right to Alternative Civilian Burial Law, 5756-1996. According to this law every person has a right to be buried in a civilian cemetery in which the burial is done according to their worldview, and for this purpose the law determines that there will be cemeteries for alternative civilian burial in various regions of the country with reasonable distances between them. Therefore, at the time that money allocated for cemeteries is distributed, the need to allocate money in an appropriate measure for alternative civilian burial cemeteries is also to be taken into account, in accordance with the proportionality criterion.
Finally, even though the Ministry of Religious Affairs must fulfill the duty of equality already at the phase in which it prepares the bill, the question remains what is the possible appropriate remedy if the Ministry does not fulfill the duty of equality at that phase. It is known that there is a difference, as to every administrative authority, between the realm of the duty of the authority and the realm of the judicial remedy. The remedy the court sees fit to award is dependent on the circumstances of the case, including the substance of the administrative act. Accordingly, it is possible that an administrative authority will breach a duty, and despite this the court will not find it proper under the circumstances, to grant a remedy for the breach, for example, if the petition was delayed in its filing or the act is not justiciable. Inter alia, the court will not see fit to award a remedy in the case of a defect in the legislative process, from the stage of the bill proposal to the stage of the Knesset vote, with the exception perhaps of rare and unusual cases. (See MApp 166/84 Yeshivat Tomchei T’mimim Mercazit v State of Israel [16]; HCJ 761/86 Miari v. Knesset Speaker [17]). What will the appropriate remedy be, then, at the phase of preparation of an annual budget law which clearly violates the principle of equality? There is no need to answer this question in this petition. However, without connection to the question of the judicial remedy, it is to be hoped that employees of the Ministry preparing the bill, as well as employees of the Ministry of Finance and the legal advisors that guide them in legal questions, fulfill the duty of equality lawfully.
17. And what if the budget law takes the first path, and allocates one sum for all cemeteries, without distinction based on religious affiliation? In such a case, it is the duty of the Ministry of Religious Affairs to follow the appropriate path such that this sum will be distributed in an equal manner. The appropriate path is to determine egalitarian, clear and transparent criteria. Indeed section 3a of the Budget Principles Law, which requires the establishment of egalitarian criteria for the purpose of providing support from the state budget for public institutions, does not apply to support from the state budget for local authorities. But there are situations or matters in which distribution of the resources of the State or award of certain rights requires the establishment of egalitarian criteria. Such was decided regarding support of public institutions even before the Budget Principles Law required the establishment of egalitarian criteria. (See, for example HCJ 59/88 Tzaban v. Minister of Finance [17] (at p. 706)). This has also been decided in other contexts. (See HCJ 205/94 Nof v. Ministry of Defence [4] at p. 463; HCJ 1689/94 Harrari v. Minister of the Interior [18] at p. 19; HCJ 4146/95 Estate of the Deceased Lily Dankner v. Antiquities Authority [19] at pp. 790-791. See also I. Zamir Administrative Power (1996) [22] at pp. 780-782.) This is also appropriate in this context.
18. The petitioner who requested that egalitarian criteria be established for distribution of the amount that was allocated for cemeteries, does not suffice with this. It requests, in addition, that the Minister of Religious Affairs give a reason "as to why sums of money designated for the maintenance, expansion and renovation of cemeteries of the Arab communities in Israel are not to be allocated."
Indeed, as arises from this decision, the amount of money that was allocated to cemeteries in the budget of the Ministry of Religious Affairs for the year 1999 was not distributed in an equal manner, and from a substantive perspective it would have been appropriate to order the Ministry of Religious Affairs to change the distribution for that year in such a manner that the equality between cemeteries belonging to different religions would be fulfilled. However, as occurs more than once in petitions of this type, in particular when there is a need to discuss facts or make determinations as to a substantive question, the discussion goes past a given budget year. Indeed, even in such a case the court still can, if it is justified by the circumstances of the case, provide a remedy that will relate retroactively to a budget year that has already ended. But in every such case the difficulty involved in granting an order that will obligate a government ministry to allocate money from the current year's budget for purposes of a matter that was not included in this budget, such as, for purposes of support that should have been given from the budget of the last year, is not to be ignored.
In order to overcome a difficulty of this type the Court may, if in its opinion the circumstances of the case justify it, issue an interlocutory order that will secure a specific amount from the budget of the said year until the petition is decided, or take other steps in order not to frustrate the granting of an appropriate remedy. But in the circumstances of the present case, the Court did not find it appropriate to issue this or any other interlocutory order.
In my opinion in the circumstances of the present case there is no justification to order the payment of money from this year’s budget of the Ministry of Religious Affairs for the purpose of maintenance of Arab cemeteries for the year that has passed. The money is needed to a great extent for ongoing expenses, such as cleaning work, gardening, security and the like. It is proper to assume that the money for these and other expenses that was not available last year was not spent. If this is the case, what is the justification for paying money for expenses that were not spent? So too, it is not possible to pay money without detailed and well grounded requests as to last year, which we do not have. Who is to be paid and how much is to be paid? Indeed the local Arab authorities or other Arab entities, which maintain the cemeteries, are not even represented before the Court, and the court does not know what their needs and requests are. And finally, the primary purpose of the petition is not to be found in the receipt of money for the year in which the petition was filed, but rather, the purpose of the petition is primarily to change the situation from here on in, in a manner that will fulfill the principal of equality.
Therefore, in my opinion the balance of considerations which relate to the issue leads to the conclusion not to order the Ministry of Religious Affairs to pay the local authorities or other unknown entities unknown sums for the past year.
19. The situation is different as to the present budget year: the year 2000. In the present year it is still possible to distribute the money from the budget of the Ministry of Religious Affairs in a manner that realizes equality between the cemeteries of the different religions, and it is still possible to order and to receive requests for financial support on behalf of authorities and entities which maintain the cemeteries of members of the various religions.
The Ministry of Religious Affairs, that last year did not fulfill the duty of equality between cemeteries, can and must prepare to fulfill the duty this year, and from here on in, as is required by this judgment.
Indeed, it is possible that the Ministry of Religious Affairs has already decided how to allocate the amount that was determined in the budget of the Ministry for cemeteries this year; it is possible that it has already notified the entities that are to receive the money, and they have certainly made plans to operate this year in accordance with the notification; and it is also possible that it has already transferred part of this money to these entities. However, and despite a possible difficulty, the Ministry still can and needs to get ready, at this stage in the year, in a manner that will realize equality among the cemeteries, even if this entails administrative effort and even if it entails adding to the budget for cemeteries. If indeed there is a need for additional budget, the Ministry will need to operate (with the assistance of the Ministry of Finance, if the assistance is needed) in order to obtain the necessary additional budget by means of savings on the Ministry’s other budget sections, or from the Ministry’s reserve budget section, or by another way
20. In conclusion, the Ministry of Religious Affairs is to operate based on the principle of equality, as stated in this judgment, as relates to the allocation of money that was determined in the Ministry’s budget for cemeteries.
In accordance with this principle, we order the Ministry of Religious Affairs to allocate the money that was determined in the budget of the Ministry of Religious Affairs for the year 2000, for the purpose of the cemeteries of members of the various religions, in an equal manner.
The Ministry of Religious Affairs will pay the petitioner court expenses in the total amount of 20,000 NIS.
Justice D. Beinisch
President A. Barak
I agree with the judgment of my colleague, Justice Zamir. I wish only to add the following: my fundamental position is that equality constitutes a right possessing constitutional status (see A. Barak, Judicial Construction (Vol. 3, 1994) [23] at p. 423). It is contained within the right to dignity. Indeed, the principle of equality is derived from human dignity and is bound to it by an unseverable bond (see Y. Carp, ‘The Basic Law: Human Dignity and Liberty – A Biography of Power Struggles’ [25] at p. 352, and Henkin, ‘Human Dignity and Constitutional Rights’ [27] at p. 212).
H. Cohn expressed this well when he noted:
“The dignity which may not be violated and which is entitled to protection is not just a person's good name, but also his status as equal among equals. The damage to his dignity is not just in slander or insults and curses, but also in discrimination and deprivation, unequal treatment and treatment that is racist or degrading. The protection of human dignity is not just the prohibition of defamation, but also the assurance of equality of rights and chances, and the prevention of any discrimination for reasons of gender, religion, race, language, opinion, political or social association, family affiliation, ethnic origins, property or education" (H. H. Cohn, ‘The Values of a Jewish and Democratic State — Studies in the Basic Law: Human Dignity and Liberty’ [26] at 32).
Therefore, I am prepared -- if called upon -- to examine whether a regular law violates the principle of equality unlawfully (meaning, without fulfilling the directives of the limitations clause). In this framework it would be appropriate to examine whether the Budget Law has a problematic aspect that is unique to it. This examination is not necessary in the petition before us -- and my comments therefore are obiter dicta -- since my colleague's interpretation of the Budget Law -- an interpretation that is agreeable to me -- leads to the conclusion that the allocation of funds established in it must be undertaken in an egalitarian manner. Indeed, of two possible interpretations one must choose the interpretation that is consistent with the Basic Law (see HCJ 4562/92 Zandberg v. Broadcasting Authority [20] (at p. 810)). The accepted approach today is thereby expressed, according to which "the Court will not decide a constitutional problem... if there is another reason on the basis of which it is possible to determine the matter under consideration" (President Shamgar in CA 6821/93 United Mizrahi Bank Ltd v. Migdal Cooperative Village [21] (at p. 350)).
Therefore, it has been decided as per the judgment of Justice I. Zamir.
13 Nissan 5760
April 18, 2000
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Trenton Airport Zoning Regulations
Federal laws of Canada
Trenton Airport Zoning Regulations ( SOR /96-401)
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SCHEDULE (Sections 2, 3 and 6)
PART I Description of the Airport Zoning Reference Point
The airport zoning reference point, shown on Sheet 23 of Department of Public Works Trenton Airport Zoning Plan No. 12-011 84-33, dated May 5, 1988, is a point that may be located as follows:
Commencing at the intersection of the centre line and the threshold of runway 06, being the southwesterly end of runway 06-24;
thence northeasterly along the centre line of the said runway 1 290 m to a point;
thence southeasterly and perpendicular to the said runway centre line 80 m to the airport zoning reference point.
The elevation of the airport zoning reference point is 84 m above sea level.
PART II Description of the Strips
Each strip, shown on Department of Public Works Trenton Airport Zoning Plan No. 12-011 84-33, dated May 5, 1988 is described as follows:
(b)the strip associated with runway 13-31 is 150 m in width, 75 m being on each side of the centre line of the runway, and 1 052.3 m in length.
PART III Description of the Approach Surfaces
The approach surfaces, shown on Department of Public Works Trenton Airport Zoning Plan No. 12-011 84-33, dated May 5, 1988, are imaginary surfaces that abut each end of the strips associated with runways 06-24 and 13-31 and that are more particularly described as follows:
(a)a surface that abuts the end of the strip associated with runway 06 and consists of an inclined plane having a ratio of 1 m measured vertically to 60 m measured horizontally rising to an intersection with the outer surface; thence the approach surface slopes upward at a ratio of 1 m measured vertically to 50 m measured horizontally and rises to an imaginary horizontal line drawn at right angles to the projected centre line of the strip and at a distance of 15 000 m measured horizontally from the end of the strip; the outer ends of the imaginary horizontal line being 2 400 m from the projected centre line; the imaginary horizontal line being 291 m measured vertically above the assigned elevation at the end of the strip;
(b)a surface that abuts the end of the strip associated with runway 24 and consists of an inclined plane having a ratio of 1 m measured vertically to 60 m measured horizontally rising to an intersection with the outer surface; thence the approach surface slopes upward at a ratio of 1 m measured vertically to 50 m measured horizontally rising to an imaginary horizontal line drawn at right angles to the projected centre line of the strip and at a distance of 15 000 m measured horizontally from the end of the strip; the outer ends of the imaginary horizontal line being 2 400 m from the projected centre line; the imaginary horizontal line being 291.4 m measured vertically above the assigned elevation at the end of the strip;
(c)a surface that abuts the end of the strip associated with runway 13 and consists of an inclined plane having a ratio of 1 m measured vertically to 40 m measured horizontally rising to an imaginary horizontal line drawn at right angles to the projected centre line of the strip and at a distance of 1 800 m measured horizontally from the end of the strip; the outer ends of the imaginary horizontal line being 345 m from the projected centre line; the imaginary horizontal line being 45 m measured vertically above the assigned elevation at the end of the strip; and
(d)a surface that abuts the end of the strip associated with runway 31 and consists of an inclined plane having a ratio of 1 m measured vertically to 40 m measured horizontally rising to an imaginary horizontal line drawn at right angles to the projected centre line of the strip and at a distance of 1 880 m measured horizontally from the end of the strip; the outer ends of the imaginary horizontal line being 357 m from the projected centre line; the imaginary horizontal line being 47 m measured vertically above the assigned elevation at the end of the strip.
PART IV Description of the Transitional Surfaces
Each transitional surface, shown on Department of Public Works Trenton Airport Zoning Plan No. 12-011 84-33, dated May 5, 1988, is an inclined plane that rises at a ratio of 1 m measured vertically to 7 m measured horizontally at right angles to the centre line of a strip and that extends upward and outward from the lateral limits of the strip and its approach surfaces to an intersection with the outer surface or the transitional surface of an adjoining strip.
PART V Description of the Outer Surface
The outer surface, shown on Department of Public Works Trenton Airport Zoning Plan No. 12-011 84-33, dated May 5, 1988, is an imaginary surface that consists of a common plane established at a constant elevation of 45 m above the elevation of the airport zoning reference point, except that, where that common plane is less than 9 m above the surface of the ground, the imaginary surface is located at 9 m above the surface of the ground.
PART VI Description of the Outer Limits of the Outer Surface
ALL AND SINGULAR those certain parcels or tracts of land situate, lying and being in the City of Trenton and the Township of Sidney, both in the County of Hastings, and the Township of Murray in the County of Northumberland, and the Township of Ameliasburgh in the County of Prince Edward:
Commencing at the intersection of the northern boundary of Lot 4, Concession 1, formerly in the Township of Murray, County of Northumberland, now in the City of Trenton, County of Hastings, with the western limit of Water Street as shown on a plan of subdivision registered in the Land Registry Office for Hastings as Plan No. 230;
thence easterly along the northern boundary of Lot 4, Concession 1, to the intersection with the western bank of the Trent River;
thence in a straight line across the Trent River to the point of intersection of the water’s edge of the eastern bank with the southern limit of North Murray Street;
thence northerly along the said eastern bank of the Trent River to the intersection with the northern boundary of Lot 1, Concession 2, in the Township of Sidney, in the County of Hastings;
thence easterly along the northern boundary of Lots 1, 2, 3, 4, 5 and 6, Concession 2, to the northeastern corner of Lot 6;
thence easterly in a straight line across the road allowance between Lots 6 and 7, Concession 2, to the northwestern corner of Lot 7;
thence easterly along the northern boundary of Lots 7, 8, 9, 10, 11 and 12, Concession 2, to the northeastern corner of Lot 12;
thence easterly in a straight line across the road allowance between Lots 12 and 13, Concession 2, to the northwestern corner of Lot 13;
thence easterly along the northern boundary of Lots 13, 14, 15, 16, 17 and 18, Concession 2, to the northeastern corner of Lot 18;
thence easterly along the northern boundary of Lots 19, 20 and 21, Concession 2, to the northeastern corner of Lot 21;
thence southerly along the eastern boundary of Lot 21, to the intersection with the southern limit of County Road No. 22 through Concession 2;
thence easterly along the southern limit of County Road No. 22 to the intersection with the eastern boundary of Lot 24, Concession 2;
thence easterly in a straight line across the road allowance between Lots 24 and 25, Concession 2, to the intersection of the western boundary of Lot 25 with the southern limit of County Road No. 22;
thence easterly along the southern limit of County Road No. 22 to the intersection with the northwestern limit of the approach surface that abuts the end of the strip associated with runway 24;
thence south 43°54′29″ west along the northwestern limit of that approach surface to the intersection with a line drawn perpendicular to the centre line of runway 24 and at a distance of 3 700 m along the projection of the centre line from the northeasterly end of the strip associated with runway 24;
thence southerly along the perpendicular line to the intersection with the southeastern limit of that approach surface;
thence on a bearing of north 60°58′11″ east to the intersection with the eastern boundary of Lot 22, Concession 1, in the Township of Sidney;
thence southerly along the eastern boundary of Lot 22, Concession 1, and along the eastern boundary of Lot 22 in the Broken Front Concession, to the southeastern corner of Lot 22;
thence westerly along the southern boundary of Lot 22 to the southwestern corner of that Lot at the northern limit of the Bay of Quinte;
thence southerly in a straight line across the Bay of Quinte to the northeastern corner of Lot 79, Concession 1 Bayside, in the Township of Ameliasburgh and County of Prince Edward;
thence westerly in a straight line to a point located in Lot 91, Concession 1 Bayside, in the Township of Ameliasburgh, the co-ordinates of which are N 4 883 095.469 m and E 299 410.138 m;
thence westerly in a straight line to a point, the co-ordinates of which are N 4 883 173.825 m and E 295 110.329 m;
thence on a bearing of north 46°05′31″ west to the intersection with the southeastern limit of the approach surface that abuts the end of the strip associated with runway 06, the said intersection also being the intersection of the southeastern limit of that approach surface with a line drawn perpendicular to the centre line of runway 06 and at a distance of 3 700 m along the projection of the centre line from the southwesterly end of the strip associated with runway 06;
thence northerly along the perpendicular line to the intersection with the northwestern limit of that approach surface;
thence on a bearing of south 60°58′11″ west to the intersection with the western boundary of Lot 3, Concession A, formerly in the Township of Murray, now in the City of Trenton;
thence northerly along the western boundary of Lot 3 to the northwestern corner thereof;
thence northerly in a straight line across the road allowance between Concessions A and 1 to the southwestern corner of Lot 3, Concession 1;
thence northerly along the western boundary of Lot 3, Concession 1, to the intersection with the northwestern limit of Nicholas Street as shown on Registered Plan No. 230;
thence easterly along the said northwestern limit of Nicholas Street to the intersection with the northeastern limit of Front Street, formerly Wellington Street on Registered Plan No. 230;
thence westerly along the northeastern limit of Front Street to the intersection with the northwestern limit of Mill Street as shown on Registered Plan No. 230;
thence easterly along the northwestern limit of Mill Street as shown on Registered Plan No. 230 to its intersection with the western limit of Water Street;
The outer limits of the outer surface are shown on Department of Public Works Trenton Airport Zoning Plan No. 12-011 84-33, dated May 5, 1988.
All co-ordinates, distances and bearings in this description refer to Universal Transverse Mercator Grid Co-ordinates, Zone 18.
PART VII Description of the Outer Limits of the Lands in Respect of Which These Regulations Apply
ALL AND SINGULAR those certain parcels or tracts of land situate, lying and being in the City of Belleville, the City of Trenton, the Township of Sidney, and the Township of Thurlow, all in the County of Hastings, and the Township of Murray and the Township of Brighton, both in the County of Northumberland, and the Township of Ameliasburgh in the County of Prince Edward:
Commencing at the northwestern corner of Lot A, Concession 4, in the Township of Sidney;
thence easterly along the northern boundary of Lots A, 1 and 2, Concession 4, to the intersection of that boundary with the western limit of the Trent River;
thence easterly in a straight line across the Trent River to a point being the intersection of the northern limit of Lot 2, Concession 4, with the water’s edge of the eastern limit of the Trent River;
thence easterly along the northern limit of Lots 2, 3, 4, 5 and 6, Concession 4, to the northeastern corner of Lot 6;
thence easterly in a straight line across the road allowance between Lots 6 and 7, Concession 4, to the northwestern corner of Lot 7;
thence easterly along the northern boundary of Lots 7, 8, 9, 10, 11 and 12, Concession 4, to the northeastern corner of Lot 12;
thence easterly in a straight line across the road allowance between Lots 12 and 13, Concession 4, to the northwestern corner of Lot 13;
thence easterly along the northern boundary of Lots 13, 14, 15, 16, 17 and 18, Concession 4, to the northeastern corner of Lot 18;
thence easterly in a straight line across the road allowance between Lots 18 and 19, Concession 4, to the northwestern corner of Lot 19;
thence easterly along the northern boundary of Lot 19, Concession 4, to the northeastern corner thereof;
thence southerly along the easterly limit of Lot 19, Concession 4, to the southeastern corner thereof;
thence southerly in a straight line on the projection of the easterly limit of Lot 19, Concession 4, across the road allowance between Concessions 3 and 4 to the intersection with the southern boundary of that road allowance;
thence easterly along the southern boundary of that road allowance between Concessions 3 and 4 across part of Lot 20 and Lots 21, 22, 23 and 24, Concession 3, to the northeastern corner of Lot 24;
thence easterly in a straight line across the road allowance between Lots 24 and 25, Concession 3, to the northwestern corner of Lot 25;
thence easterly along the northern boundary of Lots 25 and 26, Concession 3, to the northeastern corner of Lot 26;
thence southerly along the limit between Lots 26 and 27, Concession 3, to the southeastern corner of Lot 26;
thence southerly in a straight line on the projection of the limit between Lots 26 and 27, Concession 3, across the road allowance between Concessions 2 and 3 to the intersection with the southern boundary of that road allowance;
thence easterly along the southern boundary of that road allowance across part of Lot 26 and Lots 27, 28, 29 and part of Lot 30, Concession 2, to the intersection with the northwestern limit of the approach surface that abuts the end of the strip associated with runway 24;
thence easterly along the northern limit of that approach surface on a bearing of north 43°54′29″ east to a point, the co-ordinates of which are N 4 899 961.450 m and E 309 321.284 m;
thence southerly along the northeastern limit of that approach surface on a bearing of south 37°33′40″ east to a point, the co-ordinates of which are N 4 896 156.123 m and E 312 247.676 m;
thence westerly along the southeastern limit of that approach surface on a bearing of south 60°58′11″ west to its intersection with the eastern limit of Lot 29, Concession 1, in the Township of Sidney;
thence southerly along the eastern boundary of Lot 29, Concession 1, and Lot 29 in the Broken Front Concession to the southeastern corner of Lot 29 in the Broken Front Concession, at the northern limit of the Bay of Quinte;
thence southerly in a straight line across the Bay of Quinte to the northeastern corner of Lot 71, Concession 1 Bayside, in the Township of Ameliasburgh, at the southern limit of the Bay of Quinte;
thence southerly along the eastern boundary of Lot 71, Concession 1 Bayside, to the southeastern corner of that Lot;
thence westerly along the southern boundary of Lots 71, 72, 73 and 74, Concession 1 Bayside, to the southwestern corner of Lot 74;
thence southerly in a straight line on the projection of the western boundary of that Lot, across the road allowance between Concessions 1 and 2 Bayside to the intersection with the southern boundary of that road allowance;
thence westerly along that southern boundary to the intersection with the eastern limit of County Road No. 23;
thence southerly along the eastern limit of County Road No. 23 to the intersection with the northern boundary of the road allowance between Concessions 2 and 3 Bayside;
thence westerly along the northern boundary of the road allowance between Concessions 2 and 3 Bayside across Lots 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100 and 101 to the southwestern corner of Lot 101, Concession 2 Bayside;
thence northerly along the western boundary of Lot 101 to the northwestern corner of that Lot;
thence westerly along the southern boundary of the road allowance between Concession 1 and 2 Bayside across Lots 102, 103, 104, 105 and 106 to the northwestern corner of Lot 106, Concession 2 Bayside;
thence westerly in a straight line on the projection of that southern boundary to the intersection with the western boundary of Highway 33 as established by the Ministry of Transportation and Communications Plan P-2050-3 deposited in the Registry Office for the Registry Division of Prince Edward as Highways Plan 38;
thence northerly along that western boundary of the said Highway, across Gore G and across the Concession East Side of Carrying Place to the point of intersection of that western boundary with the southeast limit of the road allowance between the Township of Ameliasburgh, in the County of Prince Edward, and the Township of Murray, in the County of Northumberland;
thence northerly in a straight line across that road allowance to the intersection of the northwesterly limit of that road allowance with the southwestern boundary of Highway 33 as established by the Ministry of Transportation and Communications Plan P-1968-1 deposited in the Registry Office for the Registry Division of Northumberland East as Plan Q;
thence northerly along that southwestern boundary through Lots 9, 10, 11 and 12, Carrying Place, Township of Murray, to its intersection with the southeastern boundary of the approach surface that abuts the end of the strip associated with runway 06;
thence westerly along the southeastern limit of that approach surface on a bearing of south 43°54′29″ west to a point, the co-ordinates of which are N 4 875 998.466 m and E 286 035.706 m;
thence northerly along the southwestern limit of that approach surface on a bearing of north 37°33′40″ west to a point, the co-ordinates of which are N 4 879 803.797 m and E 283 109.319 m;
thence easterly along the northwestern limit of that approach surface on a bearing of north 60°58′11″ east to the intersection with the eastern limit of Lot 11, Concession A, in the Township of Murray;
thence northerly along the eastern boundary of Lot 11, Concession A, to the northeastern corner of that Lot;
thence northerly in a straight line across the road allowance between Concessions A and 1 to the southeastern corner of Lot 11, Concession 1;
thence northerly along the eastern boundary of Lot 11, Concession 1, to the northeastern corner of that Lot;
thence westerly along the northern boundary of Lot 11, Concession 1, to the intersection with the southerly projection, across the road allowance between Concessions 1 and 2, of the western boundary of Lot 11, Concession 2;
thence northerly in a straight line across the road allowance between Concessions 1 and 2 to the southwestern corner of that Lot;
thence northerly along the western boundary of Lot 11, Concession 2, to the northwestern corner of that Lot;
thence easterly along the northern boundary of Lot 11, Concession 2, to the northeastern corner of that Lot;
thence easterly in a straight line across the road allowance between Lots 10 and 11, Concession 2, to the northwestern corner of Lot 10, Concession 2;
thence easterly along the northern boundary of Lots 10 and 9, Concession 2, to the intersection with the southerly projection, across the road allowance between Concessions 2 and 3, of the western boundary of Lot 9, Concession 3;
thence northerly in a straight line across that road allowance to the southwestern corner of Lot 9, Concession 3;
thence northerly along the western boundary of Lot 9, Concession 3, to the northwestern corner of that Lot;
thence easterly along the northern boundary of Lot 9, Concession 3, to the northeastern corner of that Lot;
thence easterly in a straight line across the road allowance between Lots 8 and 9, Concession 3, to the northwestern corner of Lot 8, Concession 3;
thence easterly along the northern boundary of Lots 8 and 7, Concession 3, to the northeastern corner of Lot 7, Concession 3;
thence northerly in a straight line across the road allowance between Concessions 3 and 4 to the southeastern corner of Lot 7, Concession 4;
thence northerly along the eastern boundary of Lot 7, Concession 4, to the northeastern corner of that Lot;
thence easterly in a straight line across the road allowance between Lots 6 and 7, Concession 4, to the northwestern corner of Lot 6, Concession 4;
thence easterly along the northern boundary of Lots 6 and 5, Concession 4, to the northeastern corner of Lot 5, Concession 4;
thence easterly in a straight line across the road allowance between Lots 4 and 5, Concession 4, to the northwestern corner of Lot 4, Concession 4;
thence easterly along the northern boundary of Lots 4 and 3, Concession 4, to the northeastern corner of Lot 3, Concession 4;
thence easterly in a straight line across the road allowance between Lots 2 and 3, Concession 4, to the northwestern corner of Lot 2, Concession 4;
thence easterly along the northern boundary of Lots 2 and 1, Concession 4, to the northeastern corner of Lot 1, Concession 4;
thence easterly on the projection of the northern boundary of Lot 1, Concession 4, across the road allowance between the Township of Murray in the County of Northumberland and the Township of Sidney in the County of Hastings to the intersection with the eastern boundary of the road allowance, which is also the western boundary of Lot A, Concession 4, in the Township of Sidney;
thence northerly along the western boundary of that Lot to the point of commencement.
The outer limits are shown on Department of Public Works Trenton Airport Zoning Plan No. 12-011 84-33, dated May 5, 1988.
All co-ordinates, distances and bearings in this description refer to Universal Transverse Mercator Grid Co-ordinates, Zone 18.
PART VIII Description of Lands Northeast of Runway 06-24
ALL AND SINGULAR that certain parcel or tract of land situate, lying and being in the Township of Sidney, in the County of Hastings, more particularly described as follows:
Commencing at the intersection of the runway centreline with the northeast end of the strip associated with runway 06-24, as shown on Department of Public Works Trenton Airport Zoning Plan No. 12-011 84-33, dated May 5, 1988;
thence northwesterly along the said northeast end of the strip north 37°33′40″ west for a distance of 150.000 m to the north corner of the strip;
thence on a bearing of north 43°54′29″ east for a distance of 2 022.375 m to a point, said point being 450.002 m measured perpendicular, in a northwesterly direction, from a point on the centreline of runway 06-24 produced, said point on the centreline being distant 2 000.000 m measured therealong from the point of commencement;
thence on a bearing of south 37°33′40″ east for a distance of 900.004 m to a point, said point being 450.002 m measured perpendicular, in a southeasterly direction, from a point on the centreline of runway 06-24 produced, said point on the centreline being distant 2 000.000 m measured therealong from the point of commencement;
thence on a bearing of south 60°58′11″ west for a distance of 2 022.375 m to the east corner of the strip; and
thence northwesterly along the said northeast end of the strip on a bearing of north 37°33′40″ west for a distance of 150.000 m to the point of commencement;
saving and excepting thereout and therefrom all that portion of the above described parcel or tract of land which lies within the ownership boundaries of the Department of National Defence facility known as Canadian Forces Base Trenton; and
containing an area of approximately 120.0 ha.
All coordinates, distances and bearings in this description refer to Universal Transverse Mercator Grid Coordinates, Zone 18.
PART IX Description of Lands Southwest of Runway 06-24
ALL AND SINGULAR that certain parcel or tract of land situate, lying and being in the City of Trenton and the Township of Sidney, in the County of Hastings, more particularly described as follows:
Commencing at the intersection of the runway centreline with the southwest end of the strip associated with runway 06-24, as shown on Department of Public Works Trenton Airport Zoning Plan No. 12-011 84-33, dated May 5, 1988;
thence southeasterly along the said southwest end of the strip on a bearing of south 37°33′40″ east for a distance of 150.000 m to the south corner of the strip;
thence on a bearing of south 43°54′29″ west for a distance of 2 022.375 m to a point, said point being 450.002 m measured perpendicular, in a southeasterly direction, from a point on the centreline of runway 06-24 produced, said point on the centreline being distant 2 000.000 m measured therealong from the point of commencement;
thence on a bearing of north 37°33′40″ west for a distance of 900.004 m to a point being 450.002 m measured perpendicular, in a northwesterly direction, from a point on the centreline of runway 06-24 produced, said point on the centreline being distant 2 000.000 m measured therealong from the point of commencement;
thence on a bearing of north 60°58′11″ east for a distance of 2 022.375 m to the west corner of the strip;
thence southeasterly along the said southwest end of the strip on a bearing of south 37°33′40″ east for a distance of 150.000 m to the point of commencement;
saving and excepting thereout and therefrom all that portion of the above described parcel of tract of land which lies within the ownership boundaries of the Department of National Defence facility known as Canadian Forces Base Trenton; and
containing an area of approximately 120.0 ha.
All coordinates, distances and bearings in this description refer to Universal Transverse Mercator Grid Coordinates, Zone 18.
| https://laws-lois.justice.gc.ca/eng/regulations/SOR-96-401/section-sched985975.html?txthl=allowance&wbdisable=true |
Evolution of a Late Oxfordian: early Kimmeridgian carbonate platform, French Jura Mountains | Swiss Journal of Geosciences | Full Text
A detailed facies analysis and interpretation of the evolution of depositional environments along a north–south transect of the Late Oxfordian—Early Kimmeridgian French Jura carbonate platform highlights hierarchically stacked depositional sequences. The identified small- and medium-scale depositional sequences are matched with the precise cyclostratigraphic framework initially established for the Swiss Jura platform. The superimposition of a long-term (2nd order) sea-level rise with long (400& nbsp;kyr) eccentricity cycles explains most of the French Jura platform architecture. During the Bimammatum and Planula zones, the climate became progressively warmer and more arid, allowing enhanced carbonate production. This resulted in a strong progradation of the French Jura platform that progressively evolved from a ramp to an oolitic rimmed shelf. A brief interval characterized by a more humid climate during the upper Bimammatum Zone caused an increase in siliciclastic and nutrient input, leading to a reduction in carbonate production and strong retrogradation of the platform. During the Platynota and lower Hypselocyclum zones, the shallow inner shelf carbonate production once more exceeded the accommodation, leading to a general aggradation of the platform. From the upper Hypselocyclum Zone, with a more humid climate, the carbonate production did not outweigh the accommodation creation and the platform evolved to a flat-topped shelf. Thus, sea-level changes and climatic conditions (temperature and humidity) are the key factors controlling the nature of the sedimentation and the depositional profile of the French Jura platform during the Late Oxfordian—Early Kimmeridgian.
Evolution of a Late Oxfordian: early Kimmeridgian carbonate platform, French Jura Mountains
Nicolas Olivier 1 ,
Elsa Cariou 2 &
Pierre Hantzpergue 3
Swiss Journal of Geosciences volume 108, pages273–288 ( 2015)Cite this article
Abstract
A detailed facies analysis and interpretation of the evolution of depositional environments along a north–south transect of the Late Oxfordian—Early Kimmeridgian French Jura carbonate platform highlights hierarchically stacked depositional sequences. The identified small- and medium-scale depositional sequences are matched with the precise cyclostratigraphic framework initially established for the Swiss Jura platform. The superimposition of a long-term (2nd order) sea-level rise with long (400 kyr) eccentricity cycles explains most of the French Jura platform architecture. During the Bimammatum and Planula zones, the climate became progressively warmer and more arid, allowing enhanced carbonate production. This resulted in a strong progradation of the French Jura platform that progressively evolved from a ramp to an oolitic rimmed shelf. A brief interval characterized by a more humid climate during the upper Bimammatum Zone caused an increase in siliciclastic and nutrient input, leading to a reduction in carbonate production and strong retrogradation of the platform. During the Platynota and lower Hypselocyclum zones, the shallow inner shelf carbonate production once more exceeded the accommodation, leading to a general aggradation of the platform. From the upper Hypselocyclum Zone, with a more humid climate, the carbonate production did not outweigh the accommodation creation and the platform evolved to a flat-topped shelf. Thus, sea-level changes and climatic conditions (temperature and humidity) are the key factors controlling the nature of the sedimentation and the depositional profile of the French Jura platform during the Late Oxfordian—Early Kimmeridgian.
1 Introduction
The Late Jurassic was a prolific Epoch for carbonate production and widespread carbonate platform construction (Kiessling et al.2003; Leinfelder et al.2002). Between the Paris Basin to the northwest and the Ligurian segment of the Mesozoic Tethys to the southeast, extensive shallow carbonate areas constituted the Jura, Lorraine and Swabian platforms (Reinhold1998; Colombié and Strasser2005; Carpentier et al.2010). The growth and demise of these carbonate platforms occurred in various climatic, eustatic and tectonic contexts (Pittet and Strasser1998; Pittet et al.2000; Jank et al.2006a; Carpentier et al.2006,2007). Indeed, these ‘carbonate factories’ were controlled by numerous environmental parameters such as water depth, light, nutrient supply, temperature, salinity, hydrodynamic processes, and oxygenation (Lees1975; Wright and Burchette1996; Halfar et al.2006). Late Jurassic carbonates recorded orbital (Milankovitch) cycles that were responsible for low-amplitude sea-level changes (Strasser2007; Strasser et al.1999,2012). Other factors, apart from sea-level variations, that can affect carbonate production are siliciclastic and nutrient input (Mutti and Hallock2003; Carpentier et al.2010). The Late Jurassic generally is thought to have had an equable global climate and warm temperatures (Frakes et al.1992; Hallam et al.1993). Nevertheless, several recent studies indicate Late Jurassic climate variations in shallow platform carbonates with short-term sea surface temperature changes in the northwestern Tethys (Dromart et al.2003a,b; Carpentier et al.2006; Brigaud et al.2008; Donnadieu et al.2011; Dera et al.2011).
The Late Jurassic Swiss Jura platform has been intensively studied, and a precise sequential and cyclostratigraphic framework has been established (Gygi and Persoz1986; Gygi1986; Strasser1994; Pittet1996; Strasser et al.1999,2000; Colombié2002; Hug2003; Jank et al.2006b). However, these works did not reconstruct a detailed depositional architecture of the Late Jurassic Swiss Jura platform, which is commonly represented by general lithostratigraphic profiles (Gygi et al.1998; Gygi2000). In comparison, there are several lithostratigraphic studies for the Late Jurassic French Jura platform available (Enay1966; Gaillard1983; Bernier1984; Enay et al.1988; Enay2000), but only one sequential study (Cochet et al.1994). Thus, the sequential framework of the French Jura platform needs to be improved, especially as correlation with the Swiss Jura is still fragmentary. Moreover, the depositional architecture and the nature of the controlling factors (i.e. tectonic or eustatic) for the French Jura platform are still debated (Cochet et al.1994). The work presented here gives a detailed sedimentological analysis of 10 sections along a north–south transect of the French Jura platform during the Late Oxfordian—Early Kimmeridgian interval. The aims of this paper are (1) to propose a new scheme of the French Jura platform architecture; (2) to illustrate a common sequential stratigraphic framework between the French and Swiss Jura Mountains; and (3) to decipher the main stages and mechanisms that governed the evolution of the French Jura platform.
2 Geographical and palaeogeographical settings
The study area is located in the Jura chain, which is an arcuate fold belt located in front of the western Alpine arc. The 10 studied sections are aligned along a general north–south 151 km long transect between Besançon and Oyonnax in eastern France (Fig.1a). Up to the Late Oxfordian—Early Kimmeridgian, the French Jura platform can be subdivided into northern (from Besançon to Champagnole), central (from Champagnole to Saint-Claude) and southern (from Saint-Claude to Belley) palaeogeographical sectors (Enay et al.1988; Cochet1995; Cariou2013). Two sections (Consolation and La Main) are located in the Northern Jura, five in the Central Jura (Mont-Rivel, La Châtelaine, Loulle, Balerne, and Morillon), and three in the Southern Jura (Chancia, Molinges, and Champfromier). During the Late Jurassic, the platform was part of a large shallow epicontinental sea, at the northern margin of the oceanic Ligurian Tethys, between the Paris Basin to the northwest and the Delphino-helvetic Basin to the south (Thierry et al.2000; Fig.1b). The Jura platform was at a palaeolatitude of around 26–27°N, with a climate that was subtropical, semi-arid to arid (Frakes et al.1992; Dercourt et al.1993). The platform was at the transition between the Tethyan and boreal realms (Cecca et al.2005). The sediments deposited on the Jura platform mainly correspond to shallow-water carbonates and marls (Gaillard1983; Bernier1984; Cochet1995; Pittet1996; Colombié2002; Hug2003).
Fig. 1
aGeographical and bpaleogeographical context at the Bimammatum/Planula boundary (Late Oxfordian), compiled after Cecca et al. (2005), Hug (2003), Jank et al. (2006a), and Cariou et al. (2014)
3 Lithostratigraphy and biostratigraphy
There have been several attempts to construct a Late Jurassic lithostratigraphic framework for the French Jura Mountains (Bernier1984; Enay et al.1988; Chevallier1989; Cochet et al.1994). The rarity of ammonites along the French Jura platform explains why the dating of some lithostratigraphic units is still subject to debate (Enay2000,2002; Bernier2002). Along the studied transect, only the Champfromier section—located in the southernmost part of the Southern Jura—displays a detailed biostratigraphic framework from the base of the Planula Zone to the top of the Divisum Zone (Hantzpergue1975; Cochet1995). The stratigraphic position of the Molinges section is given in Olivier et al. (2011). For the Central Jura, the stratigraphic position of the Loulle section refers to Cariou et al. (2014). The litho- and biostratigraphic frameworks presented in Table1, and used for the correlation of studied sections, largely follow the work of Cariou (2013). Only the main lithostratigraphic modifications, with the more recent attempts of Cochet et al. (1994) and Enay (2000), are specified below. Major changes concern the Central Jura sector, where the Couches du Morillon Formation is attributed to the Bimammatum Zone rather than the Planula Zone. This formation groups the Oolithe du Mont Rivel, the Calcaires blancs du Mont Rivel, the Calcaires marneux récifaux de Loulle, and the Calcaires de Loulle members (Cariou2013). As a consequence, the Central Jura lateral equivalent of the Southern Jura Oolithe de Ramasse (Oolithe de Corveissiat of Bernier1984; see Enay2000) Formation is therefore the Oncolithe de Pillemoine Member. Thus, contrary to the work of Cochet et al. (1994), the Central Jura was not emerged during the Platynota and lower Hypselocyclum zones, but recorded the Calcaires d’Aranc Formation and the lower part of the Calcaires et Marnes à ptérocères Formation (Cariou2013).
4 Materials and methods
The 10 studied sections illustrate a 200 m thick Upper Oxfordian—Lower Kimmeridgian succession. These sections were logged at bed scale and documented by field observations and by more than 950 polished slabs and 450 thin sections (Cariou2013). For the beds that were not sampled, facies were analysed in the field with a hand lens. The sedimentary structures were also described in the field. The classification of Dunham (1962) was used to determine textures. The main sedimentary grains and fossil abundances were established using a semi-quantitative estimation (see Cariou2013). All these sedimentological data were used to interpret the depositional environments. The high-resolution sequence stratigraphic analysis follows the concepts of Strasser et al. (1999). Facies changes and discontinuity surfaces allow different orders of hierarchically stacked depositional sequences to be identified.
5 Facies and depositional settings
Based on Cariou (2013), facies are grouped into five facies associations (FA1–FA5), typical of depositional environments ranging from outer shelf to tidal flats (Table2). Facies association FA1 includes mudstones with marly intercalations (F1.1) and mudstones with thin bioclastic horizons (F1.2). These two facies are observed in the Calcaires pseudolithographiques and Couches du Burlandier formations in the southernmost Jura and in the Calcaires à térébratules Member in the northernmost Jura (Figs.2,3). Their mud-supported texture and the presence of ammonites are consistent with deposition in a marine offshore setting (Enay1966,2000; Hantzpergue1975; Gaillard1983; Bernier1984; Olivier et al.2011; Görög and Wernli2013). Laminated bioclastic horizons of facies F1.2 reflect the influence of distal tempestites at the transition between the lower and upper offshore.
Table 2 Facies description and depositional setting interpretation
Fig. 2
Legend for Figs.3,4and5
Fig. 3
Correlation of sections and depositional sequences. The numbered medium-scale sequences (SI–SVII) are interpreted to correspond to the 100-kyr eccentricity cycle. Sequence boundaries Ox6′ to Kim 3 according to Hardenbol et al. (1998). Geographical coordinates of sections are in Fig.2
Facies association FA2 encompasses oncoid packstone (F2.1), coral-microbialite patch reefs and biostromes (F2.2), oncoid marls (F2.3), and bioclastic wackestone (F2.4). Facies F2.1–3 are characteristic of several lithostratigraphic members (troisième niveau à concretions, Calcaires marneux récifaux de Loulle, Oncolithe de Pillemoine, and Calcaires à térébratules) and of the Calcaires d’Aranc Formation in the southernmost Jura (Fig.3). Facies F2.4 is observed in the Calcaires et Marnes à ptérocères Formation. It did not coexist with other facies that constitute FA2. Oncoid packstone (F2.1) and coral-microbialite patch reefs (F2.2) are close to the inner- to mid-ramp transition, whereas coral-microbialite biostromes (F2.2) and oncoid marls (F2.3) were deposited in the central to distal parts of the mid ramp (Olivier et al.2011). Mud-supported texture of Facies F2.4 is consistent with deposition below the fair-weather wave base (upper offshore).
Facies association (FA3) corresponds to ooid grainstone (F3.1), ooid-bioclastic grainstone (F3.2), peloid-intraclastic packstone (F3.3), and coral patch reefs (F3.4). These facies are observed in the Oolithe du Mont Rivel and the Oolithe blanche de Balerne members, and in the Oolithe de Ramasse Formation (Fig.3). Facies F3.1, with grainstone texture, some micritic intraclasts, and local mud drapes, is interpreted as being part of a tidally-influenced shoal complex (Table2). Facies F3.2, with more abundant bioclasts (i.e. crinoid and bivalve fragments) associated with ooids, may have been deposited on the seaward side of the tide-dominated shoal complex (Halley et al.1983). Facies F3.3, with abundant intraclasts, coral fragments, oncoids and some gastropods, was deposited in channels that cut across the shoal. Facies F3.4 corresponds to meter-scale coral patch reefs surrounded by ooid grainstones. These bioconstructions are part of the shoal complex.
Facies association FA4 comprises peloid-oncoid packstone (F4.1) and peloid-oncoid packstone with stromatoporoids (F4.2), peloid grainstones (F4.3), bioturbated mudstones (F4.4) and bioclastic packstones (F4.5). Facies F4.1 and F4.3 are observed in the Calcaires blancs du Mont Rivel and Calcaires de Loulle members (Fig.3). Facies F4.2 and F4.3 are characteristic of the Calcaire à Cardium Member and the Calcaire d’Aranc Formation. Facies 4.5 is observed in the Calcaires et Marnes à ptérocères Formation. It did not coexist with other facies that constitute FA4. Facies F4.1 and F4.2 are both characterized by large oncoids with cortices made of Lithocodiumand Bacinella(oncoid types 3 and 4 of Védrine et al.2007). Facies F4.2 is characterized by abundant stromatoporoids of the genus Cladocoropsis, which are classically observed in shallow lagoon and inner ramp settings (Leinfelder et al.2005). Facies F4.1 and F4.2 are here interpreted as deposits of back shoal settings. Facies F4.3, with grain-supported texture and abundant peloids, represents small back shoal bars. Facies F4.4, with mud-supported texture and abundant infaunal activity, reflects low-energy internal platform deposition. Facies F4.5, with fauna observed in life position and packstone (locally grainstone) texture, is interpreted as deposits of a low-energy shoreface setting (Table2).
Facies association FA5 contains three facies (F5.1–F5.3) characteristic of tidal flats (Cariou2013). Facies F5.1 is observed in the Calcaires de Loulle Member. Facies F5.2 and F5.3 are observed in the Calcaires d’Aranc Formation (Fig.3). Facies F5.1 corresponds to biolaminites that record dinosaur tracks (Cariou et al.2014). Facies F5.2 corresponds to a finely laminated mudstone with intense infaunal activity and some desiccation cracks. Facies F5.3 corresponds to a black pebble limestone, suggesting phases of emersion (Strasser1984; Bernier1984).
6 Depositional sequences, facies models and sequential interpretation
Previous studies carried out on French Late Jurassic sedimentary successions show distinct hierarchical stacking patterns and facies evolution that allow large-, medium-, small-, very-small scale, and elementary depositional sequences to be identified (Olivier et al.2011; Cariou2013; Cariou et al.2014). The inhomogeneous outcrop quality of studied sections coupled to the influence of autocyclic processes that are common in shallow-marine settings make it difficult to correlate the elementary and very small-sequences (Cariou2013). Figure3shows an attempt to correlate studied sections based on small- and medium-scale depositional sequences. Examples of a detailed description of small-scale sequences can be found in Olivier et al. (2011) for the Molinges section and Cariou et al. (2014) for the Loulle section. The following description only considers medium-scale sequences (SI–SVII).
The first medium-scale sequence (SI) is observed in both the Central Jura and in the northernmost part of the Southern Jura. In the Central Jura, the sharp installation of ooid grainstones (F3.1) above inner shelf marly limestones of the Marnes de Besançon Formation marks the increasing accommodation trend of SI. The progressive progradation of peloid-oncoid packstone (F4.1) documents the decreasing accommodation trend of SI. In the Southern Jura, the increasing accommodation trend of SI is recorded by the deposition of oncoid marls (F2.3). The decreasing accommodation trend of SI corresponds to the deposition of oncoid packstone (F2.1) and coral-microbialite bioconstructions (F2.2; Olivier et al.2011). The second medium-scale sequence (SII) is still clearly visible in the Central Jura where the retrogradation of coral-microbialite bioconstructions (F2.2) over ooid-bioclastic grainstone (F3.2) marks the increasing accommodation trend of SII. The progradation of peloid-oncoid packstone (F4.1) and the incursion of dinosaurs in the Central Jura highlights the decreasing accommodation trend of SII. In the Southern Jura, the increasing accommodation trend of SII corresponds to coral-microbialite bioconstructions (F2.2) and oncoid packstone (F2.1). The decreasing accommodation trend is marked by the progradation of ooid grainstone (F3.1). The facies observed in the first two depositional sequences (SI and SII) are part of a first depositional model (Fig.4a). In this model, shoreface deposits correspond to (1) an ooid shoal (F3.1) with small coral patch reefs (F3.4); (2) a back shoal area with peloid-oncoid packstone (F4.1) and peloid bars (F4.3); and (3) a tidal flat with dinosaur tracks (F5.1). Upper offshore deposits correspond to oncoid packstone (F2.1), coral-microbialite bioconstructions (F2.2) and oncoid marls (F2.3). Lower offshore deposits correspond to limestones with marly intercalations (FA1) of the Calcaires lités Formation (Olivier et al.2011).
Facies models. Not to scale
The third medium-scale sequence (SIII) can be followed from the Northern to the Southern Jura. Thick ooidal deposits (Oolithe de Ramasse Formation) observed in the northernmost part of the Southern Jura (Chancia and Molinges sections) display an aggradational pattern that is consistent with the increasing accommodation trend of SIII. The decreasing accommodation trend of SIII is emphasized by the progradation of peloid-oncoid packstone (F4.2). Tidal flat deposits (F5.2) recorded in the northernmost part of the Southern Jura mark the top of SIII. The fourth and fifth medium-scale sequences (SIV and SV) are characterized by a general aggradational pattern. In the Northern and Central Jura, SIV and SV are represented by interior platform mudstones (F4.4) that display a progradational pattern towards the south, emphasizing decreasing accommodation trends of these sequences. Facies observed in the medium-scale sequences SIII to SV are part of a second depositional model (Fig.4b). This model is still characterized by an important tidal dominated shoal complex with the deposition of ooid grainstone (F3.1). Seaward of this shoal complex, mid-shelf deposits are characterized by oncoidal and bioclastic deposits (F2.1). Back shoal deposits correspond to oncoid packstone with stromatoporoids (F4.2), peloid bars (F2.3), and shallow interior platform mudstones (F4.4). Emergent areas are restricted to local islands probably generated by the growth of microbial mats (F5.2) on the interior of the platform.
The sixth medium-scale depositional sequence (SVI) marks a general accommodation gain over the entire Jura platform with the deposition of bioclastic wackestone (F2.4). With a general aggradational pattern, the increasing accommodation trend of SVI corresponds to the evolution from grain-supported to mud-supported texture. A thin interval of bioclastic packstone (F4.5), only recorded in the Central Jura, marks the decreasing accommodation trend of SVI. The seventh medium-scale depositional sequence (SVII) is incompletely recorded along the studied area. Nevertheless, the increasing accommodation trend is also marked by the general evolution from bioclastic packstone (F4.5) to bioclastic wackestone (F2.4) with some incursions of mudstone (FA1) from the Southern Jura to the Central Jura. The decreasing accommodation trend of SVII is beyond the scope of the present study but corresponds to the deposition of grain-supported limestones of the Calcaires des Gorges de Nouailles Formation in Northern and Central Jura, and the Calcaires à stromatoporidés de Matafelon Formation in the Southern Jura. Facies observed in SVI and in the lower part of SVII are part of a third depositional model (Fig.4c). In this model, the Jura platform corresponds to a large epeiric system, in which the distribution of the facies belts is consistent with a non-rimmed shelf. The large extension of shallow settings could have significantly damped the hydraulic energy of waves, explaining the deposition of mud in a mainly grain-supported fabric (F4.5) even in zones where wave friction would generally impact the sea floor. Below the fair-weather wave base, sediments correspond to bioclastic wackestone (F2.4), whereas lower offshore deposits are represented by mudstone with ammonites (FA1).
Numerous studies have been carried out on the Late Jurassic deposits of the Swiss Jura Mountains leading to a precise sequential and biostratigraphic framework (Pittet1996; Gygi2000; Hug2003; Jank et al.2006a,b; Colombié and Rameil2007; Strasser2007). Lithostratigraphic and biostratigraphic frameworks obtained for the French Jura Mountains allow a comparison to be made with the Swiss Jura and the sequence-chronostratigraphic chart of Hardenbol et al. (1998) (Table1; Fig.3). Thus, the lower boundary of medium-scale depositional sequences SII, SIII, SIV, and SVI can be tentatively correlated with sequence boundaries Ox7, Ox8, Kim1, and Kim2, respectively. The lower boundary of SI can be correlated with Ox6′ (Hug2003; Védrine et al.2007) and the upper boundary of SVII corresponds to Kim3. The cyclostratigraphic interpretation given by Strasser (2007) suggests that the durations of the Swiss depositional sequences correspond to orbital frequencies. Applied to the studied French Jura sections, this sequence-chronostratigraphic framework leads us to consider that the small- and medium-scale sequences SI–SVII were formed by the 100- and 400-kyr orbital cycles of eccentricity, respectively.
7 French Jura platform evolution and controlling factors
The evolution of the French Jura platform during the Late Oxfordian—Early Kimmeridgian can be subdivided into 6 main stages (Fig.5). The first stage corresponds to the first medium-scale depositional sequence, SI, during the Bimammatum Zone (Stage 1, Fig.5). According to Strasser et al. (2012), the climate evolution of the Jura platform during this time-interval was marked by a cooling trend. In the French Central Jura, the sharp installation of ooid deposits and coral reefs (Oolithe du Mont Rivel Member) does not point to cool seawater temperatures. Indeed, both corals and ooids are very rare or absent at temperatures below 20 °C, and the optimal conditions for coral development occur between 24 and 28 °C (Lees1975; Tucker and Wright1990). Rather than a putative control by temperature, the initiation of the carbonate production in the French Central Jura could be explained by a change in terrigenous input. Humidity changes in the hinterland influence the terrigenous influx, which modifies the water’s trophic level (Mutti and Hallock2003). For the Swiss Jura platform, the climate is considered to have become less humid above Ox6′ (Pittet1996; Hug2003; Védrine2007; Strasser et al.2012). Such a climate change may have favoured the formation of ooids and coral reefs on the inner shelf marly limestone of the Marnes de Besançon Formation. The installation of these shallow, high-energy deposits could also have been favoured by a position above a hypothetical NE–SW oriented axial swell (Enay et al.1988; Cochet et al.1994). Moreover, the first stage of development of the French Jura platform occurred during a sea-level rise both at the second order (Hardenbol et al.1998) and medium-scale cycle Ox6′ (Hug2003; Védrine et al.2007; Olivier et al.2011). In the Central Jura, this sea-level rise generated sufficient accommodation gain to accumulate the thick ooid interval, the Oolithe du Mont Rivel Member, on a carbonate platform that probably displayed a ramp profile (Cochet et al.1994). A sea-level fall at the scale of the medium-scale sequence SI controlled the progradation of back shoal deposits of the Calcaires blancs du Mont Rivel Member. Deposits observed in the Central Jura notably correspond to inner ramp ooids, corals, and oncoids with a cortex made of Lithocodium, which reflect well-oxygenated, well-agitated, oligotrophic conditions (Schmid and Leinfelder1996; Dupraz and Strasser1999; Shiraishi and Kano2004; Lefort et al.2011; Olivier et al.2012). In the Southern Jura, the presence of oncoids devoid of photo- and oligotrophic encrusters associated with mixed photo-heterotrophic coral assemblages indicates more nutrient-rich conditions in a mid ramp setting (Olivier et al.2011).
Fig. 5
French Jura platform evolution. Not to scale
The second stage of the French Jura platform growth occurred during the increasing accommodation trend of medium-scale sequence SII (Stage 2, Fig.5). This stage is characterized by a large extension of mid-ramp deposits over the northernmost part of the Southern and Central Jura. These deposits notably correspond to small-size bioconstructions composed of mixed photo-heterotrophic coral assemblages and abundant microbialites, which emphasize mesotrophic conditions (Olivier et al.2011; Cariou2013; Cariou et al.2014). The last record of siliciclastic inputs onto the Jura platform is known to have occurred sporadically in the upper part of the Bimammatum Zone (Gygi1986; Pittet1996; Pittet and Strasser1998; Hug2003). The presence of marly limestones in the Central Jura is consistent with a climate that became temporarily more humid during SII (Pittet1996; Hug2003; Strasser et al.2012). Even if an inner ramp shoal complex might have migrated towards the north (Fig.3), the carbonate production seems to have been reduced during this second stage. Indeed, nutrients linked to terrigenous inputs can limit coral growth and the formation of ooids (Hallock and Schlager1986; Leinfelder1993; Pittet1996). As the upper Bimammatum Zone is still characterized by a seawater temperature increase (Brigaud et al.2008; Martin-Garin et al.2010), more nutrient-rich waters coupled to the sea-level rise of SII led to an important retrogradation of the French Jura platform, which still displayed a ramp profile.
The third stage of the French Jura platform growth occurred during the decreasing accommodation trend of medium-scale sequence SII (Stage 3, Fig.5). The upper Bimammatum Zone is characterized by the installation of a warm, arid climate (Strasser et al.2012). The Burgundy platform recorded the temperature maximum during the Bimammatum Zone, although inputs of freshwater, characterized by low δ 18O values, may have led to a decrease in carbonate δ 18O values as well and thus to an overestimation of the calculated isotopic temperatures (Carpentier et al.2006; Martin-Garin et al.2010). Under a relatively warm climate, and with a reduced amount of terrigenous flux, this third stage reflects favourable conditions for enhanced carbonate production. The French Central Jura records the establishment of a new ooid shoal. In a back shoal position, some of the oncoids still display a thick cortex made of Lithocodium, signifying shallow, well-agitated waters and good light conditions. The return to oligotrophic conditions related to the sea-level fall of SII allowed carbonate production to exceed the available space. This explains the strong progradation of ooid deposits towards the Southern Jura (Fig.3). It also permitted the progradation of back shoal and tidal flat deposits with their abundant dinosaur tracks into the Central Jura. The presence of these tracks in the uppermost part of the Bimammatum Zone is the earliest record of a dinosaur incursion on the Jura platform during the Late Jurassic (Cariou et al.2014).
The fourth stage of the French Jura platform growth occurred during the medium-scale sequence SIII (Stage 4, Fig.5). This sequence is assigned to the Planula Zone, which is characterized by a warm, dry climate (Pittet et al.2000; Strasser et al.2012). Such climate conditions allowed intense carbonate production and the progradation of an ooid shoal-rimmed shelf that dipped gently both northwards and southwards. The retrogradation of the oncoid packstone of the Oncolithe de Pillemoine Member in the northern part of the Central Jura suggests an accommodation creation that was partially triggered by tectonics. On the other hand, the platform progradation towards the south can be explained by a carbonate production that exceeded the available space. This fourth stage of platform growth is characterized by a large extension of shallow inner shelf carbonates over the entire Central Jura and the northernmost part of the Southern Jura (Fig.3). Inner shelf deposits correspond to oncoid packstone rich in Cladocoropsis. While some stromatoporoid taxa might have tolerated slightly higher salinities (Leinfelder et al.2005), the presence of some corals and common oncoids with Lithocodiumand Bacinellaindicates prevailing oligotrophic marine conditions. In the Central and Northern Jura, mid-shelf deposits are still characterized by oncoids that display a cortex made of Lithocodiumand Bacinellaand by some corals. This suggests the presence of nutrient-depleted waters up to a mid-shelf position. The presence of marly intercalations and rare quartz observed in an outer shelf setting suggests more nutrient-rich waters in a distal part, below the storm wave base. During the sea-level fall of SIII, available space was completely filled by inner shelf deposits, leading to the record of tidal flat settings in the upper part of the Planula Zone. After the dinosaur incursion at the end of the Bimammatum Zone, this is the second occurrence of emersive deposits along the French Jura platform that had strongly prograded towards the south.
The fifth stage of the French Jura platform growth occurred during the medium-scale sequences SIV and SV (Stage 5, Fig.5). At the base of the Platynota Zone, Lefort (2011) observed a small decrease in calculated isotopic temperatures in the Lorraine-Champagne platform. Brigaud et al. (2008) also indicated a small decrease in calculated isotopic temperatures in the Lorraine platform between the Platynota and Hypselocyclum zones. From Kim1, Colombié (2002) indicates a semi-arid climate with relatively well-developed humid seasons for the Swiss Jura platform. In the Northern French Jura platform, an increase in quartz content is observed in deposits of the Calcaires à pétrocères inférieurs Member (Cariou2013). This confirms a greater terrigenous influx from the hinterland and thus a climate with a rainy season during the fifth stage. More nutrient-rich conditions might explain sparser occurrences of ooid limestones along the French Jura platform during the Platynota and lower Hypselocyclum zones (Fig.3). Combined with the installation of a more humid climate, the Early Kimmeridgian in the Central Swiss Jura is also characterized by a general loss of accommodation (Colombié2002; Colombié and Strasser2005). These authors suggest that a slowing down of the 2nd order sea-level rise coupled with an adequate carbonate production allowed sedimentation to keep up with sea-level rise. During the Platynota and lower Hypselocyclum zones, the French Jura platform reached maximum extent with mid-shelf oncoid limestones in the southernmost Jura (Fig.3). From the northern part of the Southern Jura up to the Northern Jura, shallow inner platform sediments built up close to sea level, locally filling available space as indicated by tidal flat deposits. This general aggradational pattern emphasizes a change in the platform profile that evolved into a flat-topped shelf.
The sixth stage of the French Jura platform growth occurred during the medium-scale sequences SVI and SVII pro parte(Stage 5, Fig.5). This stage is characterized by the retrogradation of mid-shelf deposits over the French Jura platform during the upper Hypselocyclum Zone. This pattern may reflect a long-term maximum flooding that occurred during the Hypselocyclum and Divisum zones (Contini and Hantzpergue1973,1975; Hantzpergue1975; Cochet et al.1994). Such retrogradation was also favoured by the flat-topped shelf topography established during the Panula Zone. Indeed, flat-topped carbonate platforms are highly sensitive to low-amplitude relative sea-level fluctuations, leading to the deposition of widespread and nearly synchronous beds similar in lithology and stacking pattern (Strasser et al.1999; Jank et al.2006c). Phases of retrogradation that occurred during the Hypselocyclum and Divisum zones emphasize a carbonate production that could not keep pace with the generated accommodation. A decrease in carbonate production could be explained by an increase in terrigenous input, which is consistent with a semi-arid climate with humid seasons up to the Divisum Zone observed for the Swiss Jura platform (Colombié2002). More nutrient-rich conditions are documented by the heterotrophic fauna observed in deposits of the Calcaires et Marnes à ptérocères Formation (Table2). The large extension of a flat inner shelf could have significantly reduced storm-induced waves and currents, accounting for the lack of high-energy deposits.
Thickness variations in Upper Jurassic sedimentary successions in the Swiss Jura Mountains are related to the synsedimentary reactivation of Permo-Carboniferous basement structures (Pittet1996; Allenbach2002; Wetzel et al.2003; Jank et al.2006a). The influence of a hypothetical NE-SW oriented axial swell has also been invoked as a facies control for the French Jura platform development (Enay et al.1988; Cochet et al.1994). However, the present does not support a major structural influence. Instead, it supports a control by variations in the carbonate production in tune with sea-level and climatic changes. Indeed, the Upper Jurassic sedimentary succession of the French Jura Mountains has revealed that the hierarchical stacking pattern of depositional sequences can be explained by the superposition of different orders of sea-level fluctuations (Olivier et al.2011; Cariou et al.2014). During the Late Oxfordian—Early Kimmeridgian interval, the different sedimentary bodies observed on the French Jura platform appear to have been formed in tune with a long-term (2nd order) sea-level rise coupled to eccentricity (400 kyr) cycles. Cariou et al. (2014) suggest that a 2.4 Myr cycle may have played a preponderant role in the subsequent incursions of dinosaurs onto the Jura platform. The regressive trend of the 2.4 Myr cycle, which includes the dinosaur track site of Loulle, ends around Kim1. In this scenario the general flat top morphology and successive emergent surfaces observed at the end of SIII could be characteristic of a highstand system within the 2.4 Myr cycle.
The successive stages of the French Jura platform growth also highlight the major role played by climatic conditions. The studied time-interval is effectively marked by a general and long-term climate-warming trend from the Early Oxfordian to the Kimmeridgian (Riboulleau et al.1998; Abbink et al.2001). Along with it, the climate became progressively less humid (Védrine2007; Strasser et al.2012), leading to warm, oligotrophic waters on the Jura platform. Such environmental conditions allowed intense carbonate production, as illustrated by the development of large ooid shoal complexes in the Central Jura during the Bimammatum Zone or in the Southern Jura during the Planula Zone. Such intense carbonate production was able to change the shelf morphology, which progressively evolved from a ramp to a shoal-rimmed shelf. Periods characterized by a notably more humid climate also had an impact on the nature of the sedimentation and on the platform growth. Thus a more humid climate led to the increase in the amount of terrigenous and nutrient input from the hinterland. Under more nutrient-rich conditions, the carbonate production decreased and when the platform was subjected to a rise in sea-level, it caused major phases of retrogradation (cf. Stages 2 and 6, Fig.5).
8 Conclusions
This study provides a detailed sedimentological analysis of an Upper Oxfordian—Lower Kimmeridgian succession along the French Jura platform. Facies evolution and the correlation of ten studied sections emphasize hierarchically stacked depositional sequences. The resulting sequential framework reveals small- and medium-scale depositional sequences that formed in tune with orbital cycles of short (100 kyr) and long (400 kyr) eccentricity, as had been previously established for the Swiss Jura platform.
The detailed analysis of sedimentary deposits permitted the identification of 5 main facies associations characteristic of depositional environments ranging from outer platform to tidal flat settings. Spatio-temporal evolution of facies along the platform has led to the reconstruction of three successive facies models, and to the subdivision of the platform development into six main stages. Throughout these stages, the profile of the platform progressively evolved from a ramp during the Bimammatum Zone, to an ooid shoal-rimmed shelf during the Planula and lower Hypselocyclum zones, and finally to a flat-topped shelf up to the lower Divisum Zone.
The French Jura platform evolution was directly controlled by the superimposition of different orders of sea-level fluctuations. Most of the sedimentary body geometries were triggered by the 400-kyr long eccentricity cycle superimposed onto a long-term (2nd order) sea-level rise. On two occasions the carbonate accumulation largely exceeded sea-level rise, leading to the subaerial exposure of part of the platform. At the end of the Bimammatum Zone, tidal flat deposits with dinosaur tracks were recorded in the French Central Jura. This is the first Late Jurassic dinosaur incursion onto the Jura platform. During the Platynota and lower Hypselocyclum zones, tidal flat deposits were recorded on the northern part of the Southern Jura, highlighting the strong progradation of the French Jura platform.
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Acknowledgments
This project was funded by the Franche-Comté regional council, the Jura departmental council, the municipality of Loulle, and the UMR CNRS 5276 LGL. We are grateful to Cédric Carpentier for his pertinent remarks on a previous version of this manuscript. We gratefully acknowledge Claude Colombié, Raymond Énay and Bernard Pittet for numerous discussions on French and Swiss Jura platforms. We thank Fran van Wyk de Vries for reviewing the English of this manuscript. Thanks to Beatriz Bádenas and Oliver Kempf for their reviews of the manuscript.
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Laboratoire Magmas et Volcans, Université Blaise Pascal, CNRS, IRD, OPGC, 5 rue Kessler, 63038, Clermont-Ferrand, France
Nicolas Olivier
Laboratoire de Planétologie et Géodynamique de Nantes, Université de Nantes, CNRS UMR 6112, 2, rue de la Houssinière, BP 92208, 44322, Nantes Cedex 3, France
Elsa Cariou
Laboratoire de Géologie de Lyon: Terre, Planètes, Environnement, Université de Lyon, CNRS UMR 5276, Université Claude Bernard LYON 1, Campus de la DOUA, Bâtiment Géode, 69622, Villeurbanne Cedex, France
Pierre Hantzpergue
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Nicolas Olivier
Elsa Cariou
Pierre Hantzpergue
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Editorial handling: W. Winkler.
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Olivier, N., Cariou, E. & Hantzpergue, P. Evolution of a Late Oxfordian: early Kimmeridgian carbonate platform, French Jura Mountains. Swiss J Geosci 108, 273–288 (2015). https://doi.org/10.1007/s00015-015-0189-9
DOI : https://doi.org/10.1007/s00015-015-0189-9
Keywords
Carbonate platform
Climate
French Jura Moutains
Late Jurassic
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